Yuichiro Suzuki

Redox (oxidation-reduction) reactions regulate signal transduction. Oxidants such as superoxide, hydrogen peroxide, hydroxyl radicals, and lipid hydroperoxides (i.e., reactive oxygen species) are now realized as signaling molecules under subtoxic conditions. Nitric oxide is also an example of a redox mediator. Reactive oxygen species induce various biological processes such as gene expression by stimulating signal transduction components such as Ca2+-signaling and protein phosphorylation. Various oxidants increase cytosolic Ca2+; however, the exact origin of Ca2+ is controversial. Ca2+ may be released from the endoplasmic reticulum, extracellular space, or mitochondria in response to oxidant-influence on Ca2+ pumps, channels, and transporters. Alternatively, oxidants may release Ca2+ from Ca2+ binding proteins. Various oxidants stimulate tyrosine as well as serine/threonine phosphorylation, and direct stimulation of protein kinases and inhibition of protein phosphatases by oxidants have been proposed as mechanisms. The oxidant-stimulation of the effector molecules such as phospholipase A2 as well as the activation of oxidative stress-responsive transcription factors may also depend on the oxidant-mediated activation of Ca2+-signaling and/or protein phosphorylation. In addition to the stimulation of signal transduction by oxidants, the observations that ligand–receptor interactions produce reactive oxygen species and that antioxidants block receptor-mediated signal transduction led to a proposal that reactive oxygen species may be second messengers for transcription factor activation, apoptosis, bone resorption, cell growth, and chemotaxis. Physiological significance of the role of biological oxidants in the regulation of signal transduction as well as the mechanisms of the oxidant-stimulation of signal transduction are discussed. Copyright © 1996 Elsevier Science Inc.

HomeCirculationVol. 114, No. 17Right Ventricular Function and Failure Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBRight Ventricular Function and FailureReport of a National Heart, Lung, and Blood Institute Working Group on Cellular and Molecular Mechanisms of Right Heart Failure Norbert F. Voelkel, MD, Robert A. Quaife, MD, Leslie A. Leinwand, PhD, Robyn J. Barst, MD, Michael D. McGoon, MD, Daniel R. Meldrum, MD, Jocelyn Dupuis, MD, PhD, Carlin S. Long, MD, Lewis J. Rubin, MD, Frank W. Smart, MD, Yuichiro J. Suzuki, PhD, Mark Gladwin, MD, Elizabeth M. Denholm, PhD and Dorothy B. Gail, PhD Norbert F. VoelkelNorbert F. Voelkel From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author , Robert A. QuaifeRobert A. Quaife From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author , Leslie A. LeinwandLeslie A. Leinwand From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author , Robyn J. BarstRobyn J. Barst From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author , Michael D. McGoonMichael D. McGoon From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author , Daniel R. MeldrumDaniel R. Meldrum From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author , Jocelyn DupuisJocelyn Dupuis From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author , Carlin S. LongCarlin S. Long From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author , Lewis J. RubinLewis J. Rubin From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author , Frank W. SmartFrank W. Smart From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author , Yuichiro J. SuzukiYuichiro J. Suzuki From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author , Mark GladwinMark Gladwin From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author , Elizabeth M. DenholmElizabeth M. Denholm From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author and Dorothy B. GailDorothy B. Gail From the Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver (N.F.V.); Department of Nuclear Medicine and Radiology, University of Colorado Hospital, Denver (R.A.Q.); CVI Institute, Department of Cardiology, Colorado University (L.A.L.); Columbia-Presbyterian Medical Center Babies Hospital, New York, NY (R.J.B.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (M.D.M.); Pulmonary Hypertension Association (M.D.M.); Department of Surgery, Indiana University School of Medicine (D.R.M.); Research Center, Montreal Heart Institute, Montreal, Quebec, Canada (J.D.); Department of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver (C.S.L.); Pulmonary Hypertension Center, University of California at San Diego (L.J.R.); Baylor College of Medicine, St Luke’s Episcopal Hospital/Texas Heart Institute, Houston (F.W.S.); Georgetown University Medical Center, Washington, DC (Y.J.S.); and National Heart, Lung, and Blood Institute, Bethesda, Md (M.G., E.M.D., D.B.G.). Search for more papers by this author Originally published24 Oct 2006https://doi.org/10.1161/CIRCULATIONAHA.106.632208Circulation. 2006;114:1883–1891Knowledge about the role of the right ventricle in health and disease historically has lagged behind that of the left ventricle. Less muscular, restricted in its role to pumping blood through a single organ, and less frequently or obviously involved than the left ventricle in diseases of epidemic proportions such as myocardial ischemia, cardiomyopathy, or valvulopathy, the right ventricle has generally been considered a mere bystander, a victim of pathological processes affecting the cardiovascular system. Consequently, comparatively little attention has been devoted to how right ventricular dysfunction may be best detected and measured, what specific molecular and cellular mechanisms contribute to maintenance or failure of normal right ventricular function, how right ventricular dysfunction evolves structurally and functionally, or what interventions might best preserve right ventricular function. Nevertheless, even the proportionately limited information related to right ventricular function, its impairment in various disease states, and its impact on the outcome of those diseases suggests that the right ventricle is an important contributor and that further understanding of these issues is of pivotal importance.For this reason, the National Heart, Lung, and Blood Institute convened a working group charged with delineating in broad terms the current base of scientific and medical understanding about the right ventricle and identifying avenues of investigation likely to meaningfully advance knowledge in a clinically useful direction. The following summary represents the presentations and discussions of this working group.The right ventricle is affected by and contributes to a number of disease processes, including perhaps most notably pulmonary hypertension caused by a variety of lung or pulmonary vascular diseases (cor pulmonale). Other diseases affect the right ventricle in different ways, including global, left ventricular–, or right ventricular–specific cardiomyopathy; right ventricular ischemia or infarction; pulmonary or tricuspid valvular heart disease; and left-to-right shunts.The Normal Right VentricleThe right ventricle pumps the same stroke volume as the left ventricle but with ≈25% of the stroke work because of the low resistance of the pulmonary vasculature. Therefore, by virtue of the Laplace relationship, the right ventricle is more thin walled and compliant (Figure 1). The geometry of the chamber is complex, consisting of an inlet (sinus) portion and an outlet (conus) section separated by the crista supraventricularis. Longitudinal shortening is a greater contributor to right ventricular stroke volume than short-axis (circumferential) shortening.1 It is linked to the left ventricle in several ways: by a shared wall (the septum), by mutually encircling epicardial fibers, by attachment of the right ventricular free wall to the anterior and posterior septum, and by sharing the pericardial space. The septum and free wall contribute approximately equally to right ventricular function. The right ventricular free wall blood supply is predominantly from the right coronary artery and receives about equal flow during systole and diastole. The left anterior descending coronary artery supplies the anterior two thirds of the septum, and the posterior descending artery supplies the inferoposterior one third. Download figureDownload PowerPointFigure 1. In idiopathic pulmonary arterial hypertension (IPAH), the right ventricle (RV) is characterized by increased end-diastolic volume, change of the normal ventricular conformation tetrahedron to a crescentic trapezoid, and varying degrees of right ventricular hypertrophy (B). The right ventricle in severe idiopathic pulmonary arterial hypertension assumes a spherical shape with a greater cross-sectional area than the left ventricle (LV), which is normally larger (A). The more spherical-shaped right ventricle results in abnormal septal function that also impairs left ventricle performance. C, MR angiogram of the right ventricle and pulmonary arteries. Note the prominence of the right atrium and the right ventricle. There is heavy trabeculation of the right ventricle defining marked hypertrophy in the pulmonary hypertensive ventricle. The degrees of dilation, hypertrophy, and sphericity of the right ventricle are variable in patients with right ventricular dysfunction, but these factors are all present in idiopathic pulmonary arterial hypertension.The Right Ventricle in Pulmonary HypertensionThe right ventricle is exposed to pressure overload by pulmonary valve stenosis or by chronic pulmonary hypertension from any cause (Table 1). An initial adaptive response of myocardial hypertrophy2 is followed by progressive contractile dysfunction. Chamber dilatation ensues to allow compensatory preload and maintain stroke volume despite reduced fractional shortening. As contractile weakening progresses, clinical evidence of decompensated right ventricular failure occurs, characterized by rising filling pressures, diastolic dysfunction,3 and diminishing cardiac output, which is compounded by tricuspid regurgitation due to annular dilatation and poor leaflet coaptation. The increased size and pressure overload of the right ventricle also produce diastolic dysfunction of the left ventricle.4,5 Thus, the function and size of the right ventricle are not only indicators of the severity and chronicity of pulmonary hypertension but impose an additional cause of symptoms and reduced longevity. Right ventricular function is the most important determinant of longevity in patients with pulmonary arterial hypertension.6–9TABLE 1. Classification of Pulmonary Hypertension761. Pulmonary arterial hypertension 1.1. Idiopathic (IPAH) 1.2. Familial (FPAH) 1.3. Associated with (APAH): 1.3.1. Collagen vascular disease 1.3.2. Congenital systemic-to-pulmonary shunts 1.3.3. Portal hypertension 1.3.4. HIV infection 1.3.5. Drugs and toxins 1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, chronic myeloproliferative disorders, splenectomy) 1.4. Associated with significant venous or capillary involvement 1.4.1. Pulmonary veno-occlusive disease (PVOD) 1.4.2. Pulmonary capillary hemangiomatosis (PCH) 1.5. Persistent pulmonary hypertension of the newborn2. Pulmonary hypertension with left heart disease 2.1. Left-sided atrial or ventricular heart disease 2.2. Left-sided valvular heart disease3. Pulmonary hypertension associated with lung diseases and/or hypoxemia 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Sleep-disordered breathing 3.4. Alveolar hypoventilation disorders 3.5. Chronic exposure to high altitude 3.6. Developmental abnormalities4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease 4.1. Thromboembolic obstruction of proximal pulmonary arteries 4.2. Thromboembolic obstruction of distal pulmonary arteries 4.3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign material)5. Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)The specific mechanisms underlying the development of right ventricular failure secondary to pulmonary hypertension are unclear. For example, it is uncertain whether some patients develop right ventricular myocardial ischemia, whether there is microvascular endothelial cell dysfunction, and whether or not myocytes undergo apoptosis. In severe, end-stage pulmonary hypertension, the shape of the right ventricle is changed from the normal conformation,10,11 and right ventricular wall stress and right ventricular free wall thickness appear to be inversely related12 (Figure 2). The mechanism by which a severely dilated “end-stage” right ventricle repairs itself after lung transplantation is also uncertain.13,14Download figureDownload PowerPointFigure 2. Inverse relationship between a calculated measure of end-systolic circumferential right ventricular wall stress (RVWS) and right ventricular systolic function as measured by ejection fraction (RVEF). Right ventricular wall stress summarizes the major factors that contribute to wall stress on the right ventricle including pressure, dilation or radius, and wall thickness. Note that the right ventricular wall stress is low in normally functioning ventricles, and the right ventricular wall stress is high in those with severe systolic dysfunction.Plasma levels of brain natriuretic peptide15–19 and troponin T20 correlate with pulmonary arterial pressure and pulmonary vascular resistance in patients with pulmonary arterial hypertension. Increases in brain natriuretic peptide plasma levels during serial follow-up visits are associated with increased mortality in idiopathic pulmonary arterial hypertension patients. Paradoxically, however, atrial natriuretic peptides may promote cardiomyocyte survival.21The Right Ventricle in Left-Sided Heart FailureThe hypothesis that enlargement of the left ventricle could affect function of the right ventricle was advanced in 1910.22 However, the role of the right ventricle in congestive heart failure has been relatively overlooked until recently,23 in part because of the perception that it is somewhat of a passive conduit.24 This impression has been reinforced on the one hand by observations of successful outcomes in Glenn and Fontan procedures and has been refuted on the other by recognition of the sequelae of right ventricular myocardial infarction. It is now recognized that the most common cause of pulmonary hypertension is that associated with left ventricle failure. Reeves and Groves25 reported that 44% of patients with coronary artery disease at the time of coronary arteriography and right heart catheterization have pulmonary hypertension.Right ventricular dysfunction may develop in association with left ventricular dysfunction via multiple mechanisms: (1) left ventricular failure increases afterload by increasing pulmonary venous and ultimately pulmonary arterial pressure, partly as a protective mechanism against pulmonary edema26; (2) the same cardiomyopathic process may simultaneously affect the right ventricle; (3) myocardial ischemia may involve both ventricles; (4) left ventricular dysfunction may lead to decreased systolic driving pressure of right ventricular coronary perfusion, which may be a substantial determinant of right ventricular function27; (5) ventricular interdependence due to septal dysfunction may occur; and (6) left ventricular dilation in a limited pericardial compartment may restrict right ventricular diastolic function. Conversely, right ventricular pressure overload, as may occur with pulmonary hypertensive states, may compromise left ventricular function and lead to coincident evidence of left ventricular failure, such as pulmonary edema or effusion. Furthermore, when the right ventricle fails in the setting of left ventricular failure, it may be unable to maintain the flow volume required to maintain adequate left ventricular preload. Because of the multiple influences affecting right ventricular function due to left ventricular failure, right ventricular status may constitute a “common final pathway” in the progression of congestive heart failure and therefore may be a sensitive indicator of impending decompensation or poor prognosis.Despite variations in study populations, severity and substrates of disease, and methodologies of assessment, studies demonstrate substantial agreement that evidence of right ventricular dysfunction portends an inferior outcome. Patients with ischemic cardiomyopathy and left ventricular ejection fractions of 18±8% who die during the next 2 years have a worse right ventricular ejection fraction (24±10% by radionuclide ventriculography) than survivors (42±23%).28 Among patients with an acute myocardial infarction, the presence of a low radionuclide right ventricular ejection fraction (<0.38) plus low left ventricular ejection fraction (<0.30) results in 3 times the 1-year mortality of patients with poor left ventricular function alone.29Patients with myocarditis and poor right ventricular function, defined as a low right ventricular descent (difference between the diastolic and systolic distance from the right ventricle apical endocardium to a perpendicular line through the tricuspid annulus; normal=2±0.2 cm), have a higher likelihood of death or transplantation than those with normal right ventricular function. Indeed, right ventricular dysfunction is the strongest predictor of a negative outcome.30The right ventricular ejection fraction (measured by thermodilution techniques) of patients with idiopathic dilated cardiomyopathy correlates linearly with echocardiographic left ventricular ejection fraction, and, by multivariate analysis of a large number of parameters, only right ventricular ejection fraction and left ventricular ejection fraction are predictors of survival.31 Survival is also predicted for patients with idiopathic dilated cardiom

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStructural and dynamic membrane properties of .alpha.-tocopherol and .alpha.-tocotrienol: Implication to the molecular mechanism of their antioxidant potencyYuichiro J. Suzuki, Masahiko Tsuchiya, Stephen R. Wassall, Yuen M. Choo, Girjesh Govil, Valerian E. Kagan, and Lester PackerCite this: Biochemistry 1993, 32, 40, 10692–10699Publication Date (Print):October 12, 1993Publication History Published online1 May 2002Published inissue 12 October 1993https://doi.org/10.1021/bi00091a020Request reuse permissionsArticle Views954Altmetric-Citations276LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (873 KB) Get e-Alertsclose Get e-Alerts

Antioxidants & Redox SignalingVol. 12, No. 3 Forum EditorialProtein CarbonylationYuichiro J. Suzuki, Marina Carini, and D. Allan ButterfieldYuichiro J. SuzukiDepartment of Pharmacology, Georgetown University Medical Center, Washington, District of Columbia.Search for more papers by this author, Marina CariniDipartimento di Scienze Farmaceutiche “Pietro Pratesi”, Università degli Studi di Milano, Milan, Italy.Search for more papers by this author, and D. Allan ButterfieldDepartment of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky.Search for more papers by this authorPublished Online:8 Jan 2010https://doi.org/10.1089/ars.2009.2887AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byAnnona crassiflora Mart. 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2Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging Supports a Warburg Neuroprotective Cascade against Alzheimer’s Disease25 January 2023 | Cells, Vol. 12, No. 3Radioresistance and radiosensitivity: a biophysical approach on bacterial cells robustness3 December 2022 | Theory in Biosciences, Vol. 142, No. 1Oxygen toxicity: cellular mechanisms in normobaric hyperoxia16 September 2022 | Cell Biology and Toxicology, Vol. 39, No. 1Murburn posttranslational modifications of proteins: Cellular redox processes and murzyme‐mediated metabolo‐proteomics30 January 2023 | Journal of Cellular Physiology, Vol. 292Oxidative Stress Triggered Damage to Cellular Biomolecules10 March 2023Correlative study on heavy metal-induced oxidative stress and hypertension among the rural population of Malwa Region of Punjab, India26 July 2022 | Environmental Science and Pollution Research, Vol. 29, No. 60OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: The impact of oxidative stress on reproduction: a focus on gametogenesis and fertilizationReproduction, Vol. 164, No. 6Favipiravir induces oxidative stress and genotoxicity in cardiac and skin cellsToxicology Letters, Vol. 371Targeted biomarkers of progression in chronic kidney diseaseClinica Chimica Acta, Vol. 536Does parental exposure to nanoplastics modulate the response of Hediste diversicolor to other contaminants: A case study with arsenicEnvironmental Research, Vol. 214Lipid–Protein Oxidation and In Vitro Digestibility of Fermented Turkey Sausages as Affected by Lipid Formulation7 September 2022 | European Journal of Lipid Science and Technology, Vol. 124, No. 10Protein Carbonylation as a Reliable Read-Out of Urban Pollution Damage/Protection of Hair Fibers26 September 2022 | Cosmetics, Vol. 9, No. 5Infrared spectrochemical findings on intermittent fasting-associated gross molecular modifications in rat myocardiumBiophysical Chemistry, Vol. 289Chitosan conjugated-ordered mesoporous silica: a biocompatible dissolution enhancer for promoting the antidiabetic effect of a poorly water-soluble drug of repaglinide20 September 2022 | Journal of Nanostructure in Chemistry, Vol. 15COPD and the modulation of CFTR by acute exposure to cigarette smoke19 September 2022 | American Journal of Physiology-Cell PhysiologyPotential of Hibiscus sabdariffa L. and Hibiscus Acid to Reverse Skin Aging17 September 2022 | Molecules, Vol. 27, No. 18Possibilities of using the continuous type of UV light on the surface of lor (whey) cheese: impacts on mould growth, oxidative stability, sensory and colour attributes during storage19 August 2022 | Journal of Dairy Research, Vol. 89, No. 3The protective effect of a novel sunscreen against blue light1 August 2022 | International Journal of Cosmetic Science, Vol. 44, No. 4The Prognostic Value of Derivatives-Reactive Oxygen Metabolites (d-ROMs) for Cardiovascular Disease Events and Mortality: A Review9 August 2022 | Antioxidants, Vol. 11, No. 8Non-Invasive Nasal Discharge Fluid and Other Body Fluid Biomarkers in Alzheimer’s Disease22 July 2022 | Pharmaceutics, Vol. 14, No. 8Evaluation of the Therapeutic Effect of the Traditional Herbal Medicine Atrifil and Oshagh Gum on Testosterone-Induced Benign Prostatic Hyperplasia in Wistar RatsAdvances in Urology, Vol. 2022Do magnetic fields related to submarine power cables affect the functioning of a common bivalve?Marine Environmental Research, Vol. 179Role of Oxidative Stress in the Pathogenesis of Atherothrombotic Diseases20 July 2022 | Antioxidants, Vol. 11, No. 7Post-Translationally Regulated Protein Arginine-to-Proline Conversion in Alzheimer’s Brains28 June 2022 | Life, Vol. 12, No. 7Maternal Exercise-Induced SOD3 Reverses the Deleterious Effects of Maternal High-Fat Diet on Offspring Metabolism Through Stabilization of H3K4me3 and Protection Against WDR82 Carbonylation15 March 2022 | Diabetes, Vol. 71, No. 6Cruciferous vegetables as functional foods: effects of selenium biofortification2 August 2021 | International Journal of Vegetable Science, Vol. 28, No. 3Therapeutic effects of CoenzymeQ10, Biochanin A and Phloretin against arsenic and chromium induced oxidative stress in mouse (Mus musculus) brain21 April 2022 | 3 Biotech, Vol. 12, No. 5Gram-Negative Bacterial Envelope Homeostasis under Oxidative and Nitrosative Stress28 April 2022 | Microorganisms, Vol. 10, No. 5Biochemical response of Ficopomatus enigmaticus adults after exposure to organic and inorganic UV filtersMarine Pollution Bulletin, Vol. 178Mercaptophos impacts on redox status biomarkers of common carp (Cyprinus carpio) as an endocrine disruptorAquaculture Reports, Vol. 22Reactive Oxygen Species, Antioxidant Responses and Implications from a Microbial Modulation Perspective18 January 2022 | Biology, Vol. 11, No. 2Glutaredoxin Interacts with GR and AhpC to Enhance Low-Temperature Tolerance of Antarctic Psychrophile Psychrobacter sp. ANT20624 January 2022 | International Journal of Molecular Sciences, Vol. 23, No. 3Co-Exposure with an Invasive Seaweed Exudate Increases Toxicity of Polyamide Microplastics in the Marine Mussel Mytilus galloprovincialis18 January 2022 | Toxics, Vol. 10, No. 2Will climate changes enhance the impacts of e-waste in aquatic systems?Chemosphere, Vol. 288Impacts of oxidants and antioxidants on the emergence and progression of Alzheimer's diseaseNeurochemistry International, Vol. 153Comparative structural and techno‐functional elucidation of full‐fat and defatted flaxseed extracts: implication of atmospheric pressure plasma jet21 July 2021 | Journal of the Science of Food and Agriculture, Vol. 102, No. 2Monitoring of Paralytic Shellfish Toxins Using Biological Assays4 August 2022Plant Proteoforms Under Environmental Stress: Functional Proteins Arising From a Single Gene14 December 2021 | Frontiers in Plant Science, Vol. 12Increased plasma disequilibrium between pro- and anti-oxidants during the early phase resuscitation after cardiac arrest is associated with increased levels of oxidative stress end-products24 October 2021 | Molecular Medicine, Vol. 27, No. 1Carbonyl Composition and Electrophilicity in Vaping Emissions of Flavored and Unflavored E-Liquids9 December 2021 | Toxics, Vol. 9, No. 12Impact on Porphyromonas gingivalis of antimicrobial photodynamic therapy with blue light and Rose Bengal in plaque-disclosing solutionPhotodiagnosis and Photodynamic Therapy, Vol. 36Insight into the Antibacterial Activity of Selected Metal Nanoparticles and Alterations within the Antioxidant Defence System in Escherichia coli, Bacillus cereus and Staphylococcus epidermidis30 October 2021 | International Journal of Molecular Sciences, Vol. 22, No. 21Salinity influences on the response of Mytilus galloprovincialis to the rare-earth element lanthanumScience of The Total Environment, Vol. 794Effect of disinfection of non-hardened Salmo trutta eggs with Chloramine T®, Wofasteril®, and hydrogen peroxide on embryo and larvae viability, microorganism load, lipid peroxidation, and protein carbonylation7 June 2021 | Aquaculture International, Vol. 29, No. 5Antioxidant compounds from Annona crassiflora fruit peel reduce lipid levels and oxidative damage and maintain the glutathione defense in hepatic tissue of Triton WR-1339-induced hyperlipidemic miceBiomedicine & Pharmacotherapy, Vol. 142A role for zinc transporter gene SLC39A12 in the nervous system and beyondGene, Vol. 799Lipid-Based Drug Delivery Systems in Regenerative Medicine17 September 2021 | Materials, Vol. 14, No. 18Iron deficiency exacerbates cisplatin- or rhabdomyolysis-induced acute kidney injury through promoting iron-catalyzed oxidative damageFree Radical Biology and Medicine, Vol. 173Metabolic effects of CoCr-enriched medium on shear-stressed endothelial cell and osteoblasts: A possible mechanism involving a hypoxic condition on bone healingMaterials Science and Engineering: C, Vol. 128Targeting Bacterial Gyrase with Cystobactamid, Fluoroquinolone, and Aminocoumarin Antibiotics Induces Distinct Molecular Signatures in Pseudomonas aeruginosamSystems, Vol. 6, No. 4Copper chloride inhibits brush border membrane enzymes, alters antioxidant and metabolic status and damages DNA in rat intestine: a dose-dependent study10 April 2021 | Environmental Science and Pollution Research, Vol. 28, No. 32Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes4 August 2021 | International Journal of Molecular Sciences, Vol. 22, No. 16Role of Melatonin in Angiotensin and Aging31 July 2021 | Molecules, Vol. 26, No. 15Antioxidant properties of anthocyanins and their mechanism of action in atherosclerosisFree Radical Biology and Medicine, Vol. 172Oxidative modification impairs SERCA activity in Drosophila and human cell models of Parkinson's diseaseBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Vol. 1867, No. 7Ganoderma lucidum Induces Myogenesis Markers to Avert Damage to Skeletal Muscles in Rats Exposed to Hypobaric Hypoxia Arti Jatwani and Rajkumar Tulsawani17 June 2021 | High Altitude Medicine & Biology, Vol. 0, No. 0Exposure to pesticides and oxidative stress in Brazilian agricultural communities14 June 2021 | Biomarkers, Vol. 10Ocean Warming May Enhance Biochemical Alterations Induced by an Invasive Seaweed Exudate in the Mussel Mytilus galloprovincialis28 May 2021 | Toxics, Vol. 9, No. 6Fasting ameliorates oxidative stress: A review of physiological strategies across life history events in wild vertebratesComparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, Vol. 256How do life-history traits influence the fate of intertidal and subtidal Mytilus galloprovincialis in a changing climate?Environmental Research, Vol. 196Therapeutic effects of biochanin A, phloretin, and epigallocatechin-3-gallate in reducing oxidative stress in arsenic-intoxicated mice6 January 2021 | Environmental Science and Pollution Research, Vol. 28, No. 16Investigation of nitrogen purging prior to UV treatment on quality of milk19 November 2020 | International Journal of Food Engineering, Vol. 17, No. 3Effect of pulsed light on microbial inactivation, sensory properties and protein structure of fresh ricotta cheeseLWT, Vol. 139Blue light protection, part II—Ingredients and performance testing methods19 December 2020 | Journal of Cosmetic Dermatology, Vol. 20, No. 3Signaling Toward Reactive Oxygen Species-Scavenging Enzymes in Plants1 February 2021 | Frontiers in Plant Science, Vol. 11Sublethal effects of triclosan and triclocarban at environmental concentrations in silver catfish (Rhamdia quelen) embryosChemosphere, Vol. 263The protective effect of piperine on oxidative stress and hepatic damage induced by diisononyl phthalate in rat8 November 2021 | Egyptian Journal of Basic and Applied Sciences, Vol. 8, No. 1The influence of post-translational modification of mitochondrial and cytoplasmic proteins of the placenta on the development of fetal growth restrictionProblemy reproduktsii, Vol. 27, No. 2Association of Tumour Microenvironment with Protein Glycooxidation, DNA Damage, and Nitrosative Stress in Colorectal Cancer1 August 2021 | Cancer Management and Research, Vol. Volume 13In Vitro Methodologies for Toxicological Assessment of Drug Delivery Nanocarriers14 April 2021Inflammation response, oxidative stress and DNA damage caused by urban air pollution exposure increase in the lack of DNA repair XPC proteinEnvironment International, Vol. 145Mitochondrial defects in the respiratory complex I contribute to impaired translational initiation via ROS and energy homeostasis in SMA motor neurons22 December 2020 | Acta Neuropathologica Communications, Vol. 8, No. 1In Vitro and In Vivo Models for Evaluating the Oral Toxicity of Nanomedicines31 October 2020 | Nanomaterials, Vol. 10, No. 11Inactivation of the mitochondrial protease Afg3l2 results in severely diminished respiratory chain activity and widespread defects in mitochondrial gene expression19 October 2020 | PLOS Genetics, Vol. 16, No. 10Cytoprotective effects of antioxidant supplementation on mesenchymal stem cell therapy2 April 2020 | Journal of Cellular Physiology, Vol. 235, No. 10Post-translational modifications contribute to neoepitopes in Type-1 diabetes: Challenges for inducing antigen-specific toleranceBiochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1868, No. 10Sulforaphane ameliorates serum starvation‐induced muscle atrophy via activation of the Nrf2 pathway in cultured C2C12 cells9 July 2020 | Cell Biology International, Vol. 44, No. 9Evaluation of biochemical parameters in Rubus tereticaulis treated rats and its implications in wound healing10 June 2020 | Molecular and Cellular Biochemistry, Vol. 472, No. 1-2An integrated omics approach to investigate summer mortality of New Zealand Greenshell™ mussels11 September 2020 | Metabolomics, Vol. 16, No. 9Functions and effects of reactive oxygen species in male fertilityAnimal Reproduction Science, Vol. 220TAK1 preserves skeletal muscle mass and mitochondrial function through redox homeostasis7 August 2020 | FASEB BioAdvances, Vol. 2, No. 9Effects of Feeding Increasing Levels of Yerba Mate on Lamb Meat Quality and Antioxidant Activity20 August 2020 | Animals, Vol. 10, No. 9How to Improve the Antioxidant Defense in Asphyxiated Newborns—Lessons from Animal Models21 September 2020 | Antioxidants, Vol. 9, No. 9Anticancer Properties of Platinum Nanoparticles and Retinoic Acid: Combination Therapy for the Treatment of Human Neuroblastoma Cancer16 September 2020 | International Journal of Molecular Sciences, Vol. 21, No. 18Fibrinogen Modification and Fibrin Formation in Patients with an End-Stage Renal Disease Subjected to Peritoneal Dialysis10 August 2020 | Biochemistry (Moscow), Vol. 85, No. 8Albumin Protects Lung Cells against Acrolein Cytotoxicity and Acrolein-Adducted Albumin Increases Heme Oxygenase 1 Transcripts12 June 2020 | Chemical Research in Toxicology, Vol. 33, No. 7Evolution of cellular stress response mechanisms23 January 2020 | Journal of Experimental Zoology Part A: Ecological and Integrative Physiology, Vol. 333, No. 6Long-term intake of the reactive metabolite methylglyoxal is not toxic in miceFood and Chemical Toxicology, Vol. 141Aberrant energy metabolism and redox balance in seizure onset zones of epileptic patientsJournal of Proteomics, Vol. 223Effects of atmospheric pressure plasma jet on the physicochemical, functional, and antioxidant properties of flaxseed protein11 June 2020 | Journal of Food Science, Vol. 85, No. 7Carbonyl Cytotoxicity Affects Plant Cellular Processes and Detoxifying Enzymes Scavenge These Compounds to Improve Stress Tolerance13 May 2020 | Journal of Agricultural and Food Chemistry, Vol. 68, No. 23Selenium and selenoproteins: it’s role in regulation of inflammation6 March 2020 | Inflammopharmacology, Vol. 28, No. 3Toxic consequences and oxidative protein carbonylation from chloropicrin exposure in human corneal epithelial cellsToxicology Letters, Vol. 322Effect of Curcumin on Protein Damage Induced by Rotenone in Dopaminergic PC12 Cells16 April 2020 | International Journal of Molecular Sciences, Vol. 21, No. 8Identification of oxidant susceptible proteins in Salmonella Typhimurium19 February 2020 | Molecular Biology Reports, Vol. 47, No. 3Behavior and biochemical responses of the polychaeta Hediste diversicolor to polystyrene nanoplasticsScience of The Total Environment, Vol. 707Hypercapnia Impairs Na,K-ATPase Function by Inducing Endoplasmic Reticulum Retention of the β-Subunit of the Enzyme in Alveolar Epithelial Cells21 February 2020 | International Journal of Molecular Sciences, Vol. 21, No. 4Mitochondria, Oxidative Stress, Cancer, and Aging30 January 2020Survival strategies of Wuchang bream (Megalobrama amblycephala) juveniles for chronic ammonia exposure: Antioxidant defense and the synthesis of urea and glutamineComparative Biochemistry and Physiology Part C: Toxicology & PharmacologyChlorinated effluent organic matter causes higher toxicity than chlorinated natural organic matter by inducing more intracellular reactive oxygen speciesScience of The Total Environment, Vol. 701High day-to-day and diurnal variability of oxidative stress and inflammation biomarkers in people with type 2 diabetes mellitus and healthy individuals21 July 2020 | Redox Report, Vol. 25, No. 1Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration11 December 2019 | Frontiers in Neuroscience, Vol. 13Polyvinylalcohol-carbazate (PVAC) reduces red blood cell hemolysis6 December 2019 | PLOS ONE, Vol. 14, No. 12Pro-oxidant versus anti-oxidant effects of seeds aglycone extracts of Lepidium sativum and Eruca vesicaria Linn., in vitro, and on neutrophil nitro-oxidative functions14 August 2019 | Journal of Food Science and Technology, Vol. 56, No. 12Host Cytoskeleton Remodeling throughout the Blood Stages of Plasmodium falciparum4 September 2019 | Microbiology and Molecular Biology Reviews, Vol. 83, No. 4Effects of different ageing methods on colour, yield, oxidation and sensory qualities of Australian beef loins consumed in Australia and JapanFood Research International, Vol. 125Use of modified CUPRAC and dinitrophenylhydrazine colorimetric methods for simultaneous measurement of oxidative protein damage and antioxidant defense against oxidationTalanta, Vol. 204The Impact of Oxidative Stress on Ribosomes: From Injury to Regulation2 November 2019 | Cells, Vol. 8, No. 11Oxidative Stress and Inflammation Interdependence in Multiple Sclerosis1 November 2019 | Journal of Clinical Medicine, Vol. 8, No. 11Microglia morphology and proinflammatory signaling in the nucleus accumbens during nicotine withdrawalScience Advances, Vol. 5, No. 10Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta15 October 2019 | eLife, Vol. 8Modified semi‐continuous fermentation for resuscitating nongrowing cells during high‐temperature gluconic acid production by Acetobacter senegalensis9 August 2019 | Journal of Applied Microbiology, Vol. 127, No. 4Impairment of production and posttranslational changes of placental nuclear and membrane proteins with complicated pregnancy1 January 2019 | Biomeditsinskaya Khimiya, Vol. 65, No. 6Hepatoprotective Effects of Fadogia ancylantha (Makoni Tea) on Ethanol-Induced Liver Damage in Wistar Rats23 December 2019 | Journal of Biologically Active Products from Nature, Vol. 9, No. 5Celastrol pretreatment as a therapeutic option against cisplatin-induced nephrotoxicity12 August 2019 | Toxicology Research, Vol. 8, No. 5Role of redox imbalance and cytokines in mediating oxidative damage and disease progression of patients with rheumatoid arthritis8 July 2019 | Free Radical Research, Vol. 53, No. 7Chronic exposure to 35% carbamide peroxide tooth bleaching agent induces histological and hematological alterations, oxidative stress, and inflammation in mice24 April 2019 | Environmental Science and Pollution Research, Vol. 26, No. 17Ecotoxicological effects of lanthanum in Mytilus galloprovincialis: Biochemical and histopathological impactsAquatic Toxicology, Vol. 211Antimicrobial photodynamic therapy using a plaque disclosing solution on Streptococcus mutansPhotodiagnosis and Photodynamic Therapy, Vol. 26Improvement of Muscle Quality of Grass Carp (Ctenopharyngodon idellus) With a Bio-Floating Bed in Culture Ponds31 May 2019 | Frontiers in Physiology, Vol. 10TRPV1 Contributes to Cerebral Malaria Severity and Mortality by Regulating Brain InflammationOxidative Medicine and Cellular Longevity, Vol. 2019Gene therapy for the mitochondrial genome: Purging mutations, pacifying ailmentsMitochondrion, Vol. 46Antioxidant effects of curcumin in models of neurodegeneration, aging, oxidative and nitrosative stress: A reviewNeuroscience, Vol. 406Fourier transform infrared microspectroscopy detects biochemical changes during C. elegans lifespanVibrational Spectroscopy, Vol. 102Sperm protein carbonylation13 January 2019 | Andrologia, Vol. 51, No. 4Evidence of Blood and Muscle Redox Status Imbalance in Experimentally Induced Renal Insufficiency in a Rabbit ModelOxidative Medicine and Cellular Longevity, Vol. 2019Prolonged erythrocyte auto-incubation as an alternative model for oxidant generation systemToxicology in Vitro, Vol. 56In vitro anthelmintic effect of biologically synthesized silver nanoparticles on liver amphistome, Gigantocotyle explanatumExperimental Parasitology, Vol. 198The impacts of warming on the toxicity of carbon nanotubes in musselsMarine Environmental Research, Vol. 145Irreversible plasma and muscle protein oxidation and physical exercise4 December 2018 | Free Radical Research, Vol. 53, No. 2Oxidant-Mediated Protein Amino Acid Conversion25 February 2019 | Antioxidants, Vol. 8, No. 2Oxidative Stress and Antioxidant Supplementation on Immunity in Hansen’s Disease (Leprosy)27 October 2019Are the effects induced by increased temperature enhanced in Mytilus galloprovincialis submitted to air exposure?Science of The Total Environment, Vol. 647Biochemical and molecular evidence on the role of vaspin in early detection of the insulin resistance in a rat model of high-fat diet and use of diazinonToxicology, Vol. 411Caffeine inhibits hypoxia-induced renal fibroblast activation by antioxidant mechanism16 July 2019 | Cell Adhesion & Migration, Vol. 13, No. 1Reviews in AquacultureThe Effect of Mesedin on the Content of Oxidative Stress Biomarkers in the Brain Tissue in Ischemia29 April 2019 | Neurochemical Journal, Vol. 13, No. 1Oxidative Medicine and Cellular Longevity, Vol. 2019International Journal of Molecular Sciences, Vol. 20, No. 17Pathophysiological mechanisms of diabetic cardiomyopathy and the therapeutic potential of epigallocatechin-3-gallateBiomedicine & Pharmacotherapy, Vol. 109Protective effects of farnesol on a Rhizobium strain exposed to cadmiumEcotoxicology and Environmental Safety, Vol. 165Investigating the Glycating Effects of Glucose, Glyoxal and Methylglyoxal on Human Sperm13 June 2018 | Scientific Reports, Vol. 8, No. 1Brazilian Curcuma longa L. attenuates comorbidities by modulating adipose tissue dysfunction in obese rats5 December 2018 | Nutrire, Vol. 43, No. 1Insights into the respiratory chain and oxidative stress2 October 2018 | Bioscience Reports, Vol. 38, No. 5Phenelzine reduces the oxidative damage induced by peroxynitrite in plasma lipids and proteins19 December 2017 | Archives of Physiology and Biochemistry, Vol. 124, No. 5The Protective Roles of Dietary Selenium Yeast and Tea Polyphenols on Growth Performance and Ammonia Tolerance of Juvenile Wuchang Bream (Megalobrama amblycephala)2 October 2018 | Frontiers in Physiology, Vol. 9The possible ameliorative effect of Olea europaea L. oil against deltamethrin-induced oxidative stress and alterations of serum concentrations of thyroid and reproductive hormones in adult female ratsEcotoxicology and Environmental Safety, Vol. 161Investigation of Metal-Catalyzed Antibody Carbonylation With an Improved Protein Carbonylation AssayJournal of Pharmaceutical Sciences, Vol. 107, No. 10Effect of Dietary Selenium on Protein and Lipid Oxidation and the Antioxidative Potential of Selected Chicken Culinary Parts during Frozen StorageJournal of Chemistry, Vol. 2018Scavenging of lipid peroxyl radicals protects plasma lipids and proteins from peroxynitrite7 September 2018 | Biomedical ReportsAre the impacts of carbon nanotubes enhanced in Mytilus galloprovincialis submitted to air exposure?Aquatic Toxicology, Vol. 202Identification and characterization of protein cross-links induced by oxidative reactions27 August 2018 | Expert Review of Proteomics, Vol. 15, No. 8Photoinactivation of Pseudomonas syringae pv. actinidiae in kiwifruit plants by cationic porphyrins11 May 2018 | Planta, Vol. 248, No. 2Natural Phytotherapeutic Antioxidants in the Treatment of Mercury Intoxication-A Review29 August 2018 | Advanced Pharmaceutical Bulletin, Vol. 8, No. 3Upregulation of Nrf2 and Decreased Redox Signaling Contribute to Renoprotective Effects of Chemerin Receptor Blockade in Diabetic Mice19 August 2018 | International Journal of Molecular Sciences, Vol. 19, No. 8The 4‑hydroxynonenal mediated oxidative damage of blood proteins and lipids involves secondary lipid peroxidation reactions6 July 2018 | Experimental and Therapeutic MedicineComparative study of oxidative status in blood of asthmatic patients20 March 2018 | Comparative Clinical Pathology, Vol. 27, No. 4Protein and cell wall polysaccharide carbonyl determination by a neutral pH 2,4-dinitrophenylhydrazine-based photometric assayRedox Biology, Vol. 17Celastrol ameliorates acetaminophen-induced oxidative stress and cytotoxicity in HepG2 cells6 October 2017 | Human & Experimental Toxicology, Vol. 37, No. 7Intermittent Hypoxia Induced Formation of “Endothelial Cell-Colony Forming Units (EC-CFUs)” Is Affected by ROS and Oxidative Stress14 June 2018 | Frontiers in Neurology, Vol. 9Protective potential of thymoquinone against peroxynitrite induced modifications in histone H2A: In vitro studiesInternational Journal of Biological Macromolecules, Vol. 112Endoplasmic Reticulum Chaperone GRP78 Protects Heart From Ischemia/Reperfusion Injury Through Akt ActivationNovelty and Significance18 April 2018 | Circulation Research, Vol. 122, No. 11Origin and pathophysiology of protein carbonylation, nitration and chlorination in age-related brain diseases and aging17 May 2018 | Aging, Vol. 10, No. 5Competing trends of ROS and RNS-mediated protein modifications during hypoxia as an alternate mechanism of NO benefitsBiochimie, Vol. 148Inhibition efficiency of a newly isolated flavonoid compound from Vitex negundo L. leaves against cattle-endosymbiont Setaria cervi : Phytomedicine for lymphatic filariasisParasite Epidemiology and Control, Vol. 3, No. 2Molecular responses to therapeutic proteasome inhibitors in multiple myeloma patients are donor-, cell type- and drug-dependent20 March 2018 | Oncotarget, Vol. 9, No. 25Salivary biomarkers for the diagnosis and monitoring of neurological diseasesBiomedical Journal, Vol. 41, No. 2Metabolomics approach discriminates toxicity index of pyrazinamide and its metabolic products, pyrazinoic acid and 5-hydroxy pyrazinoic acid20 April 2017 | Human & Experimental Toxicology, Vol. 37, No. 4The use of quetiapine in the treatment of major depressive disorder: Evidence from clinical and experimental studiesNeuroscience & Biobehavioral Reviews, Vol. 86Transcriptional Landscape and Regulatory Roles of Small Noncoding RNAs in the Oxidative Stress Response of the Haloarchaeon Haloferax volcanii9 April 2018 | Journal of Bacteriology, Vol. 200, No. 9Protective role of exogenous phytohormones on redox status in pea seedlings under copper stressJournal of Plant Physiology, Vol. 221Oxidative Stress in Urothelial Carcinogenesis: Measurements of Protein Carbonylation and Intracellular Production of Reactive Oxygen Specie

Microbes make methane from coal Methane associated with coal beds is an important global resource of natural gas. Much of the methane in coal comes from microbial methanogenesis. Mayumi et al. characterized a strain of Methermicoccus shengliensis that, unexpectedly, is capable of making methane from the dozens of methoxylated aromatic compounds found in a variety of coal types (see the Perspective by Welte). Isotope tracer experiments showed that this organism could also incorporate carbon dioxide into methane. Science , this issue p. 222 ; see also p. 184

The effects of interferon (IFN) treatment and the post-IFN treatment α-fetoprotein (AFP) levels on risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC) are unknown. To determine the relationship between AFP and alanine transaminase (ALT) levels and HCC risk, a cohort consisting of 1,818 patients histologically proven to have CHC treated with IFN were studied. Cumulative incidence and HCC risk were analyzed over a mean follow-up period of 6.1 years using the Kaplan-Meier method and Cox proportional hazard analysis. HCC developed in 179 study subjects. According to multivariate analysis, older age, male gender, advanced fibrosis, severe steatosis, lower serum albumin levels, non sustained virological response (non-SVR), and higher post-IFN treatment ALT or AFP levels were identified as independent factors significantly associated with HCC development. Cutoff values for ALT and AFP for prediction of future HCC were determined as 40 IU/L and 6.0 ng/mL, respectively, and negative predictive values of these cutoffs were high at 0.960 in each value. The cumulative incidence of HCC was significantly lower in patients whose post-IFN treatment ALT and AFP levels were suppressed to less than the cutoff values even in non-SVR patients. This suppressive effect was also found in patients whose post-IFN treatment ALT and AFP levels were reduced to less than the cutoff values despite abnormal pretreatment levels. Conclusion: Post-IFN treatment ALT and AFP levels are significantly associated with hepatocarcinogenesis. Measurement of these values is useful for predicting future HCC risk after IFN treatment. Suppression of these values after IFN therapy reduces HCC risk even in patients without HCV eradication. (Hepatology 2013;58:1253–1262)

To probe the physiological role of calsequestrin in excitation-contraction coupling, transgenic mice overexpressing cardiac calsequestrin were developed.Transgenic mice exhibited 10-fold higher levels of calsequestrin in myocardium and survived into adulthood, but had severe cardiac hypertrophy, with a twofold increase in heart mass and cell size.In whole cell-clamped transgenic myocytes, Ca 2 ϩ channelgated Ca 2 ϩ release from the sarcoplasmic reticulum was strongly suppressed, the frequency of occurrence of spontaneous or Ca 2 ϩ current-triggered "Ca 2 ϩ sparks" was reduced, and the spark perimeter was less defined.In sharp contrast, caffeine-induced Ca 2 ϩ transients and the resultant Na ϩ -Ca 2 ϩ exchanger currents were increased 10-fold in transgenic myocytes, directly implicating calsequestrin as the source of the contractile-dependent pool of Ca 2 ϩ .Interestingly, the proteins involved in the Ca 2 ϩ -release cascade (ryanodine receptor, junctin, and triadin) were downregulated, whereas Ca 2 ϩ -uptake proteins (Ca 2 ϩ -ATPase and phospholamban) were unchanged or slightly increased.The parallel increase in the pool of releasable Ca 2 ϩ with overexpression of calsequestrin and subsequent impairment of physiological Ca 2 ϩ release mechanism show for the first time that calsequestrin is both a storage and a regulatory protein in the cardiac muscle Ca 2 ϩ -signaling cascade.Cardiac hypertrophy in these mice may provide a novel model to investigate the molecular determinants of heart failure.(

Exposure of human plasma to gas-phase (but not to whole) cigarette smoke (CS) produces oxidative damage to lipids [Frei, Forte, Ames & Cross (1991) Biochem. J. 277, 133-138], which is prevented by ascorbic acid. The ability of CS to induce protein damage was measured by the carbonyl assay and by loss of enzyme activity and protein -SH groups. Both whole and gas-phase CS caused formation of carbonyls in human plasma, which was partially inhibited by GSH but not by ascorbic acid or metal-ion-chelating agents. Isolated albumin exposed to CS showed much faster carbonyl formation (per unit protein) than did whole plasma; damage to isolated albumin was partially prevented by chelating agents. Isolated creatine kinase (CK) lost activity upon exposure to CS much faster than did CK in plasma. Direct addition to plasma of mixtures of some or all of the aldehydes reported to be present in CS caused protein carbonyl formation and inactivation of CK, but neither occurred to the extent produced by CS exposure.

Nuclear factor kappa B (NF-kappa B) is believed to play an important role in the activation of a human immunodeficiency virus (HIV) which causes acquired immunodeficiency syndrome (AIDS). Recent findings suggesting an involvement of reactive oxygen species in signal transduction pathways leading to NF-kappa B activation have ensured the possible clinical use of antioxidants in blocking HIV activation. The present study examined the effects of vitamin E derivatives on the tumor necrosis factor-alpha (TNF-alpha) induced NF-kappa B activation. Incubation of human Jurkat T cells with vitamin E acetate or alpha-tocopheryl succinate (10 microM to 1 mM) exhibited a concentration dependent inhibition of NF-kappa B activation. alpha-Tocopherol or succinate at these concentrations had no apparent effects. 2,2,5,7,8-Pentamethyl-6-hydroxychromane (PMC) was extremely effective, causing complete inhibition of NF-kappa B activation at 10 microM. Oct-1 binding activity was inactivated by alpha-tocopheryl succinate whereas other derivatives had no effects, suggesting that the effects of alpha-tocopheryl succinate are not specific to NF-kappa B. HPLC measurements demonstrated that treatment of cells with TNF-alpha had no effects on cellular alpha-tocopherol, but vitamin E acetate treatment increased the alpha-tocopherol content. Cell viability was not affected by any of the vitamin E derivatives. These results indicate a possible use of vitamin E derivatives in AIDS therapeutics.

Acquired immunodeficiency syndrome (AIDS) results from infection with a human immunodeficiency virus (HIV). The long terminal repeat (LTR) region of HIV proviral DNA contains binding sites for nuclear factor κB (NF-κB), and this transcriptional activator appears to regulate HIV activation. Recent findings suggest an involvement of reactive oxygen species (ROS) in signal transduction pathways leading to NF-κB activation. The present study was based on reports that antioxidants which eliminate ROS should block the activation of NF-κB and subsequently HIV transcription, and thus antioxidants can be used as therapeutic agents for AIDS. Incubation of Jurkat T cells (1 × 106 cells/ml) with a natural thiol antioxidant, α-lipoic acid, prior to the stimulation of cells was found to inhibit NF-κB activation induced by tumor necrosis factor-α (25 ng/ml) or by phorbol 12-myristate 13-acetate (50 ng/ml). The inhibitory action of α-lipoic acid was found to be very potent as only 4 mM was needed for a complete inhibition, whereas 20 mM was required for N-acetylcysteine. These results indicate that α-lipoic acid may be effective in AIDS therapeutics.

Obstructive sleep apnea (OSA) has emerged as a major public health problem and increasing evidence indicates that untreated OSA can lead to the development of various cardiovascular disorders. One important mechanism by which OSA may promote cardiovascular diseases is intermittent hypoxia, in which patients are subjected to repeated episodes of brief oxygen desaturation in the blood, followed by reoxygenation. Such cycles of hypoxia/reoxygenation may result in the generation of reactive oxygen species. Some studies have demonstrated the presence of oxidative stress in OSA patients as well as in animals subjected to intermittent hypoxia. Further, modulations of nitric oxide and biothiol status might also play important roles in the pathogenesis of OSA-associated diseases. Reactive oxygen species and redox events are also involved in the regulation of signal transduction for oxygen-sensing mechanisms. This review summarizes currently available information on the evidence for and against the occurrence of oxidative stress in OSA and the role of reactive oxygen species in cardiovascular changes associated with OSA.

Thioctic acid (TA) and its reduced form dihydrolipoic acid (DHLA) have recently gained somc recognition as useful biological antioxidants. In particular, the ability of DHLA to inhibit lipid peroxidation has been reported. In the present study, the effects of TA and DHLA on reactive oxygen species (ROS) generated in the aqueous phase have been investigated. Xanthine plus xanthine oxidase-generated superoxide radicals (O2), detected by electron spin resonance spectroscopy (ESR) using DMPO as a spin trap. were eliminated by DHLA but not by TA. The sulhydryl content of DHLA, measured using Ellman's reagent decreased subsequent to the incubation with xanthine plus xanthine oxidase confirming the interaction between DHLA and O2-. An increase of hydrogen peroxide concentration accompanied the reaction between DHLA and O2x, suggesting the reduction of O2- by DHLA. Competition of O2- with epinephrine allowed us to estimate a second order kinetic constant of the reaction between O2- and DHLA, which was found to be a 3.3 × 105 M-1 s-1. On the other hand, the DMPO signal of hydroxyl radicals (HO ·) generated by Fenton's reagent were eliminated by both TA and DHLA. Inhibition of the Fenton reaction by TA was confirmed by a chemiluminescence measurement using luminol as a probe for HO ·. There was no electron transfer from Fe2+ to TA or from DHLA to Fe3 + detected by measuring the Fe2+ -phenanthroline complex. DHLA did not potentiate the DMPO signal of HO · indicating no prooxidant activity of DHLA. These results suggest that both TA and DHLA possess antioxidant properties. In particular. DHLA is very effective as shown by its dual capability by eliminating both O2-; and HO ·.

There is now considerable evidence supporting a mitogenic action of serotonin (5-HT) on vascular smooth muscle cells (SMC) that might participate in pulmonary hypertension (PH). Our previous studies have demonstrated that 5-HT–induced proliferation depends on the generation of reactive oxygen species and activation of extracellular signal-regulated kinase (ERK) 1/ERK2. Activation of Rho kinase (ROCK) in SMC also may be important in PH. We undertook the present study to assess the role of Rho A/ROCK and its possible relation to ERK1/ERK2 in 5-HT–induced pulmonary artery SMC proliferation. We found that this stimulation of SMC proliferation requires Rho A/ROCK as inhibition with Y27632, a ROCK inhibitor, or dominant negative (DN) mutant Rho A blocks 5-HT–induced proliferation, cyclin D1 expression, phosphorylation of Elk, and the DNA binding of transcription factors, Egr-1 and GATA-4. 5-HT activated ROCK, and the activation was blocked by GR 55562 and GR127935, 5-HT 1B/1D receptor antagonists, but not by serotonin transport (SERT) inhibitors. Activation of Rho kinase by 5-HT was independent of activation of ERK1/ERK2, and 5-HT activated ERK1/ERK2 independently of ROCK. Treatment of SMC with Y27632 and expression of DNRho A in cells blocked translocation of ERK1/ERK2 to the cellular nucleus. Depolymerization of actin with cytochalasin D (CD) and latrunculin B (latB) failed to block the translocation of ERK, suggesting that the actin cytoskeleton does not participate in the translocation. The studies show for the first time to our knowledge combinational action of SERT and a 5-HT receptor in SMC growth and Rho A/ROCK participation in 5-HT receptor 1B/1D-mediated mitogenesis of vascular SMCs through an effect on cytoplasmic to nuclear translocation of ERK1/ERK2.

Anthracyclines are effective cancer chemotherapeutic agents but can induce serious cardiotoxicity. Understanding the mechanism of cardiac damage by these agents will help in development of better therapeutic strategies against cancer. The GATA-4 transcription factor is an important regulator of cardiac muscle cells. The present study demonstrates that anthracyclines can down-regulate GATA-4 activity. Treatment of HL-1 cardiac muscle cells or isolated adult rat ventricular myocytes with anthracyclines such as daunorubicin and doxorubicin decreased the level of GATA-4 DNA-binding activity. The mechanism of decreased GATA-4 activity acts at the level of the GATA-4 gene, because anthracyclines caused significantly decreased levels of GATA-4 protein and mRNA. The rate of decline in GATA-4 transcript levels in the presence of actinomycin D was unaltered by anthracyclines, indicating that these agents may affect directly GATA-4 gene transcription. To determine whether decreased GATA-4 levels are functionally related to cardiac muscle cell death that can be induced by anthracyclines, the ability of ectopic GATA factors to rescue anthracycline-induced apoptosis was tested. Adenovirus-mediated expression of either GATA-4 or GATA-6 was sufficient to attenuate the incidence of apoptosis. Furthermore, suppression of GATA-4 DNA-binding activity by a dominant negative mutant of GATA-4 induced the apoptosis. These results suggest that the mechanism of anthracycline-induced cardiotoxicity may involve the down-regulation of GATA-4 and the induction of apoptosis.

Reactive oxygen species serve as second messengers for signal transduction; however, molecular targets of oxidant signaling have not been defined. Here, we show that ligand–receptor–mediated signaling promotes reactive oxygen species–dependent protein carbonylation. Treatment of pulmonary artery smooth muscle cells with endothelin-1 increased protein carbonyls. Carbonylation of the majority of proteins occurred transiently, suggesting that there is also a mechanism for decarbonylation induced by endothelin-1. Decarbonylation was suppressed by inhibition of thioredoxin reductase, and cellular thioredoxin was upregulated during the decarbonylation phase. These results indicate that endothelin-1 promotes oxidant signaling as well as thioredoxin-mediated reductive signaling to regulate carbonylation and decarbonylation mechanisms. In cells treated with endothelin receptor antagonists, hydrogen peroxide scavengers, or an iron chelator, we identified, via mass spectrometry, proteins that are carbonylated in a receptor- and Fenton reaction–dependent manner, including annexin A1, which promotes apoptosis and suppresses cell growth. Carbonylation of annexin A1 by endothelin-1 was followed by proteasome-dependent degradation of this protein. We propose that carbonylation and subsequent degradation of annexin A1 may play a role in endothelin-mediated cell growth and survival, important events in pulmonary vascular remodeling. Protein carbonylation in response to ligand–receptor interactions represents a novel mechanism in redox signaling.

Reactive oxygen species (ROS) serve as mediators of signal transduction. However, mechanisms of how ROS influence the target molecules to elicit signaling event have not been defined. Our laboratory recently accumulated evidence for the role of protein carbonylation in the mechanism of ROS signaling. This concept originated from experiments in which pulmonary artery smooth muscle cells were treated with endothelin-1 to understand the mechanism of cell growth. Endothelin-1 was found to promote protein carbonylation in an endothelin receptor- and Fenton reaction-dependent manner. Mass spectrometry identified proteins that are carbonylated in response to endothelin-1, including annexin A1. Our experiments generated a hypothesis that endothelin-1-mediated carbonylation and subsequent degradation of annexin A1 promote cell growth. This mechanism was found also to occur in response to other signaling activators such as serotonin and platelet-derived growth factor in smooth muscle cells of pulmonary circulation, systemic circulation, and the airway, as well as in cardiac muscle cells, suggesting the universal role of this pathway. We also discovered a process of decarbonylation that defines transient kinetics of carbonylation signals in certain conditions. We propose that protein carbonylation and decarbonylation serve as a mechanism of signal transduction. Antioxid. Redox Signal. 12, 393–404.

Juglone (5-hydroxyl-1,4-naphthoquinone) is a phenolic compound found in walnuts. Because of the antioxidant capacities of phenolic compounds, juglone may serve to combat oxidative stress, thereby protecting against the development of various diseases and aging processes. However, being a quinone molecule, juglone could also act as a redox cycling agent and produce reactive oxygen species. Such prooxidant properties of juglone may confer health effects, such as by killing cancer cells. Further, recent studies revealed that juglone influences cell signaling. Notably, juglone is an inhibitor of Pin1 (peptidyl-prolyl cis/trans isomerase) that could regulate phosphorylation of Tau, implicating potential effects of juglone in Alzheimer’s disease. Juglone also activates mitogen-activated protein kinases that could promote cell survival, thereby protecting against conditions such as cardiac injury. This review describes recent advances in the understanding of the effects and roles of juglone in oxidative stress and cell signaling.

Pulmonary hypertension is a devastating disorder without any available treatment strategies that satisfactorily promote the survival of patients. The identification of new therapeutic strategies to treat patients with pulmonary hypertension is warranted.Human studies have provided evidence that there is increased oxidative stress (lipid peroxidation, protein oxidation, DNA oxidation, and the depletion of small-molecule antioxidants) in patients with pulmonary hypertension. A variety of compounds with antioxidant properties have been shown to have beneficial therapeutic effects in animal models of pulmonary hypertension, possibly supporting the hypothesis that reactive oxygen species (ROS) are involved in the progression of pulmonary hypertension. Thus, understanding the molecular mechanisms of ROS actions could contribute to the development of optimal, antioxidant-based therapy for human pulmonary hypertension. One such mechanism includes action as a second messenger during cell-signaling events, leading to the growth of pulmonary vascular cells and right ventricular cells.The molecular mechanisms behind promotion of cell signaling for pulmonary vascular cell growth and right ventricular hypertrophy by ROS are not well understood. Evidence suggests that iron-catalyzed protein carbonylation may be involved.Understanding precise mechanisms of ROS actions should be useful for designing preclinical animal experiments and human clinical trials of the use of antioxidants and/or other redox compounds in the treatment of pulmonary hypertension.

Alzheimer's disease is a chronic neurodegenerative disorder and represents the main cause of dementia globally. Currently, the world is suffering from the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of patients with Alzheimer's disease. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer's disease and ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease, and brains with the disease examined in this study also exhibited higher carbonylated proteins, as well as an increased thiol oxidation state of peroxiredoxin 6 (Prx6). A moderate positive correlation was found between the increased ACE2 protein expression and oxidative stress in brains with Alzheimer's disease. In summary, the present study reveals the relationships between Alzheimer's disease and ACE2, the receptor for SARS-CoV-2. These results suggest the importance of carefully monitoring patients with both Alzheimer's disease and COVID-19 in order to identify higher viral loads in the brain and long-term adverse neurological consequences.

Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. So far, 60 million people have been infected with SARS-CoV-2, and 1.4 million people have died because of COVID-19 worldwide, causing serious health, economical, and sociological problems. However, the mechanism of the effect of SARS-CoV-2 on human host cells has not been defined. The present study reports that the SARS-CoV-2 spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in lung vascular cells. The treatment of human pulmonary artery smooth muscle cells or human pulmonary artery endothelial cells with recombinant SARS-CoV-2 spike protein S1 subunit (Val16 - Gln690) at 10 ng/ml (0.13 nM) caused an activation of MEK phosphorylation. The activation kinetics was transient with a peak at 10 min. The recombinant protein that contains only the ACE2 receptor-binding domain of the SARS-CoV-2 spike protein S1 subunit (Arg319 - Phe541), on the other hand, did not cause this activation. Consistent with the activation of cell growth signaling in lung vascular cells by the SARS-CoV-2 spike protein, pulmonary vascular walls were found to be thickened in COVID-19 patients. Thus, SARS-CoV-2 spike protein-mediated cell growth signaling may participate in adverse cardiovascular/pulmonary outcomes, and this mechanism may provide new therapeutic targets to combat COVID-19.

The world is suffering from the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 uses its spike protein to enter the host cells. Vaccines that introduce the spike protein into our body to elicit virus-neutralizing antibodies are currently being developed. In this article, we note that human host cells sensitively respond to the spike protein to elicit cell signaling. Thus, it is important to be aware that the spike protein produced by the new COVID-19 vaccines may also affect the host cells. We should monitor the long-term consequences of these vaccines carefully, especially when they are administered to otherwise healthy individuals. Further investigations on the effects of the SARS-CoV-2 spike protein on human cells and appropriate experimental animal models are warranted.

Cold snare polypectomy (CSP) has become the standard resection method for small colorectal polyps (<10 mm). Sessile serrated lesions (SSL) have low prevalence of advanced histology irrespective of size, and thus could be amenable to CSP. In this study, we evaluated the safety and efficacy of CSP for SSLs ≥10 mm.Between November 2018 and January 2020, we prospectively enrolled 300 consecutive patients who underwent CSP for 474 SSLs ≥10 mm. To delineate SSL borders, indigo carmine chromoendoscopy and/or image-enhanced endoscopy was conducted. Piecemeal CSP (pCSP) was performed in cases where en-bloc resection was difficult. Biopsy specimens were obtained from the margins of the post-polypectomy defect to confirm complete resection. Surveillance colonoscopy was performed to screen for local recurrence.All lesions were successfully resected using CSP without submucosal injection. The median diameter of the resected lesions was 14 mm, and pCSP was used to resect 106 (22%) lesions. Post-polypectomy biopsies revealed residual serrated tissue in only one case (0.2%). Adverse events included immediate bleeding in 8 (3%) patients; no delayed bleeding events occurred, irrespective of the use of antithrombotic drugs. During a 7-month median follow-up period, surveillance colonoscopies were performed for 384 lesions (81%), and no local recurrences were detected.CSP without submucosal injection is a safe and effective treatment for SSLs ≥10 mm. UMIN Clinical Trials, Number: UMIN000034763.

In addition to the well-known property of reactive oxygen species (ROS) to cause non-specific cellular damage, the potential role of ROS in regulation of signal transduction has been recognized. Studies of vascular smooth muscle cells strongly suggest that ROS are required for cell growth signaling. The IP3-induced Ca2+ release from vascular smooth muscle can be selectively stimulated by ROS which may enhance signal transduction for muscle contraction and gene expression. The subunit-subunit contact within the ryanodine receptor complex, as well as intermolecular interactions between the ryanodine receptor and triadin, are redox sensitive, suggesting that ROS may regulate cardiac muscle Ca(2+)-signaling events. The biochemistry of ROS and thiol regulation may allow for specific interactions between ROS and target molecules during redox regulation.

To evaluate the clinical usefulness of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) compared with histopathological grading, clinical stage and serum prostatic specific antigen (PSA) level in the detection and characterization of prostate cancer.Forty-four patients with histologically proven prostate cancer and five control subjects with benign prostatic hyperplasia (BPH) were prospectively investigated with FDG-PET prior to treatment.By visual inspection, FDG accumulation was positive in 28 patients with prostate cancer (sensitivity 64%), whereas all were negative in the control group. FDG-PET in three patients with lymph node metastases did not show any high intrapelvic accumulations corresponding to metastatic sites. Among 12 patients with multiple bone metastases which were detected with 99m-HMDP bone scintigraphy, nine (75%) showed moderate to high FDG accumulation at the sites of bone metastases. Quantitatively, FDG accumulation in prostate cancer was significantly higher than in BPH and there was a tendency for FDG uptake of tumors to be higher with higher histological Gleason grades. Furthermore, FDG uptake in tumors with lymph node and/or bone metastasis was significantly higher than that of localized stages. However, the correlation between PSA and FDG uptake in the prostate cancer was very weak for clinical relevance.Although FDG-PET was not sensitive enough to detect prostate cancer in clinical use, it is suggested that glucose metabolism in prostate cancer tended to be higher in patients with tumors of advanced stages.

Abstract Reactive oxygen species are thought to be messengers for nuclear factor (NF)-kappa B activation because its activation can be abrogated by antioxidants. However, this study identifies, for the first time, NF-kappa B activators that are insensitive to antioxidants. NF-kappa B activation that is induced by either calyculin A or okadaic acid (inhibitors of serine/threonine protein phosphatases 1 and 2A) is not blocked by N-acetylcysteine or dihydrolipoate in Jurkat and U937 cells. Nonetheless, these antioxidants block induction by TNF-alpha, lymphotoxin, and PMA. Unlike okadaic acid and calyculin A, neither TNF-alpha, lymphotoxin, nor PMA inhibited activities of phosphatases 1 and 2A. NF-kappa B activation induced by okadaic acid or calyculin A was not blocked by a myosin light chain kinase inhibitor, but was prevented by a protease inhibitor. The mitochondrial inhibitor, rotenone, also inhibited NF-kappa B activation by calyculin A; however, this inhibition was accompanied by a depletion of cellular ATP. These results suggest that 1) phosphatase inhibitors either target a component of signal transduction, which occurs downstream to an antioxidant-sensitive step or use distinct signaling pathways; 2) inhibition of phosphatases 1 and 2A is not a step in the pathway of TNF-alpha-, lymphotoxin-, or PMA-induced NF-kappa B activation; 3) myosin light chain kinase does not participate in NF-kappa B activation; and 4) activation of NF-kappa B by phosphatase inhibitors is controlled by proteases.

A variety of cellular activities, including metabolism, growth, and death, are regulated and modulated by the redox status of the environment. A biphasic effect has been demonstrated on cellular proliferation with reactive oxygen species (ROS)-especially hydrogen peroxide and superoxide-in which low levels (usually submicromolar concentrations) induce growth but higher concentrations (usually >10-30 micromolar) induce apoptosis or necrosis. This phenomenon has been demonstrated for primary, immortalized and transformed cell types. However, the mechanism of the proliferative response to low levels of ROS is not well understood. Much of the work examining the signal transduction by ROS, including H(2)O(2), has been performed using doses in the lethal range. Although use of higher ROS doses have allowed the identification of important signal transduction pathways, these pathways may be activated by cells only in association with ROS-induced apoptosis and necrosis, and may not utilize the same pathways activated by lower doses of ROS associated with increased cell growth. Recent data has shown that low levels of exogenous H(2)O(2) up-regulate intracellular glutathione and activate the DNA binding activity toward antioxidant response element. The modulation of the cellular redox environment, through the regulation of cellular glutathione levels, may be a part of the hormetic effect shown by ROS on cell growth.

Hepatocyte growth factor (HGF) is released in response to myocardial infarction and may play a role in regulating cardiac remodeling. Recently, HGF was found to inhibit the apoptosis of cardiac muscle cells. Because GATA-4 can induce cell survival, the effects of HGF on GATA-4 activity were investigated. Treatment of HL-1 cells or primary adult rat cardiac myocytes with HGF, at concentrations that can be detected in the human serum after myocardial infarction, rapidly enhances GATA-4 DNA-binding activity. The enhanced DNA-binding activity is associated with the phosphorylation of GATA-4. HGF-induced phosphorylation and activation of GATA-4 is abolished by MEK inhibitors or the mutation of the ERK phosphorylation site (S105A), suggesting that HGF activates GATA-4 via MEK-ERK pathway-dependent phosphorylation. HGF enhances the expression of anti-apoptotic Bcl-x_L, and this is blocked by dominant negative mutants of MEK or GATA-4. Forced expression of wild-type GATA-4, but not the GATA-4 mutant (S105A) increases the expression of Bcl-x_L. Furthermore, expression of the GATA-4 mutant (S105A) suppresses HGF-mediated protection of cells against daunorubicin-induced apoptosis. These results demonstrate that HGF protects cardiac muscle cells against apoptosis via a signaling pathway involving MEK/ERK-dependent phosphorylation of GATA-4.

Obstructive sleep apnea is associated with increased risk for cardiovascular diseases. As obstructive sleep apnea is characterized by episodic cycles of hypoxia and normoxia during sleep, we investigated effects of intermittent hypoxia (IH) on ischemia-reperfusion-induced myocardial injury. C57BL/6 mice were subjected to IH (2 min 6% O 2 and 2 min 21% O 2 ) for 8 h/day for 1, 2, or 4 wk; isolated hearts were then subjected to ischemia-reperfusion. IH for 1 or 2 wk significantly enhanced ischemia-reperfusion-induced myocardial injury. However, enhanced cardiac damage was not seen in mice treated with 4 wk of IH, suggesting that the heart has adapted to chronic IH. Ischemia-reperfusion-induced lipid peroxidation and protein carbonylation were enhanced with 2 wk of IH, while, with 4 wk, oxidative stress was normalized to levels in animals without IH. H 2 O 2 scavenging activity in adapted hearts was higher after ischemia-reperfusion, suggesting the increased antioxidant capacity. This might be due to the involvement of thioredoxin, as the expression level of this protein was increased, while levels of other antioxidant enzymes were unchanged. In the heart from mice treated with 2 wk of IH, ischemia-reperfusion was found to decrease thioredoxin. Ischemia-reperfusion injury can also be enhanced when thioredoxin reductase was inhibited in control hearts. These results demonstrate that IH changes the susceptibility of the heart to oxidative stress in part via alteration of thioredoxin.

&lt;i&gt;Objectives:&lt;/i&gt; The aim of this study was to investigate the relationships between early changes in the tumor markers α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), and antitumor response in the early period following administration of sorafenib in patients with advanced hepatocellular carcinoma (HCC). &lt;i&gt;Methods:&lt;/i&gt; Forty-eight advanced HCC patients were evaluated. AFP and DCP were measured at baseline, and after 2 and 4 weeks, and the antitumor responses were evaluated according to the RECIST criteria 4 weeks after starting sorafenib therapy. The ratios of each tumor marker were compared by stratifying the patients into the partial response (PR) + stable disease (SD) group or the progressive disease (PD) group. &lt;i&gt;Results:&lt;/i&gt; Both 2 and 4 weeks after starting sorafenib therapy, the AFP ratio in the PR + SD group (n = 32) was significantly lower than in the PD group (n = 16; p = 0.002, p = 0.002). DCP was elevated in both the PR + SD group and the PD group 2 weeks and 4 weeks after starting sorafenib therapy. &lt;i&gt;Conclusions:&lt;/i&gt; Evaluation of AFP ratios 2 and 4 weeks after starting sorafenib therapy may be useful for predicting antitumor response. On the other hand, early elevation of DCP does not necessarily suggest treatment failure by sorafenib, as DCP elevation can occur despite therapeutic efficacy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the current pandemic of coronavirus disease 2019 (COVID-19) that have killed over one million people worldwide so far. To date, over forty million people have officially been identified to be infected with this virus with less than 3% death rate. Since many more people are expected to have been infected with this virus without the official diagnosis, the number of people who have recovered from the SARS-CoV-2 infection should be substantial. Given the large number of people recovered from either the mild SARS-CoV-2 infection or more severe COVID-19 conditions, it is critical to understand the long-term consequences of the infection by this virus. Our histological evaluations revealed that patients died of COVID-19 exhibited thickened pulmonary vascular walls, one important hallmark of pulmonary arterial hypertension (PAH). By contrast, such pulmonary vascular remodeling lesions were not found in patients died of SARS-CoV-1 during the 2002–2004 SARS outbreak or due to the infection by H1N1 influenza. The advancement in the treatment for the human immunodeficiency virus (HIV) infection has been remarkable that HIV-infected individuals now live for a long time, in turn revealing that these individuals become susceptible to developing PAH, a fatal condition. We herein hypothesize that SARS-CoV-2 is another virus that is capable to triggering the increased susceptibility of infected individuals to developing PAH in the future. Given the large number of people being infected with SARS-CoV-2 during this pandemic and that most people recover from severe, mild or asymptomatic conditions, it is imperative to generate scientific information on how the health of recovered individuals may be affected long-term. PAH is one lethal consequence that should be considered and needs to be monitored. This may also foster the research on developing therapeutic agents to prevent PAH, which has not so far been successful.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. The aim of this study was to determine the recent prevalence and clinical characteristics of NAFLD in Japan.This study initially included 410 061 retrospectively enrolled adults from the medical health checkup registry for metabolic syndrome, chronic kidney disease, and fatty liver in Japan (MIRACLE-J; UMIN-CTR no. UMIN000049419), who were evaluated between 2014 and 2018 at 13 health centers in Japan. Individuals consuming >20 g of alcohol/day or with chronic liver disease were excluded. Fatty liver was diagnosed by ultrasonography. The probability of NAFLD with advanced fibrosis was estimated based on the fibrosis-4 index and NAFLD fibrosis score.A total of 71 254 participants were included in the final analysis. The overall prevalence of NAFLD was 25.8%. There was a significant, twofold difference in NAFLD prevalence between men (37.4%) and women (18.1%). Nonalcoholic fatty liver disease prevalence increased linearly with body mass index, triglycerides, and low-density lipoprotein cholesterol regardless of threshold values, even in the absence of obesity. Among patients with NAFLD, 14% had diabetes mellitus, 31% had hypertension, and 48% had dyslipidemia. The estimated prevalence of NAFLD with advanced fibrosis was 1.7% and 1.0% according to the fibrosis-4 index and NAFLD fibrosis score, respectively.The prevalence of NAFLD was approximately one-quarter of the general population in Japan. There was a linear relationship between NAFLD prevalence and various metabolic parameters, even in nonobese participants. The prevalence of NAFLD with advanced fibrosis was estimated to be 1%-2%.

The central plain of Thailand was formed over the last 8–7 kyr mainly by the deltaic processes of two major rivers, the Chao Phraya and the Mae Klong. The delta plain is the third largest delta plain in Southeast Asia after that of the Mekong and the Irrawaddy. On the basis of sedimentological and paleontological analyses of samples from three boreholes and an open-pit survey, the evolution of the delta was clarified with high-resolution 14C dating. After the maximum transgression at between 8 and 7 cal kyr BP, the delta system migrated southward into the paleo-Gulf of Ayutthaya. A large mud shoal (the Sananivate Mud Shoal) formed near the mouth of the paleo-gulf between 7 and 3 cal kyr BP and facilitated its infilling. As a result, the delta has prograded rapidly particularly during the last 2 kyr. Deltaic sediment volume for the last 7.5±0.5 kyr shows that the average rate of sedimentation was 23.1±3.6 million t/yr, which is nearly the same as the present total sediment discharge from both rivers. The comparatively wide delta plain relative to sediment discharge resulted from the stable sea level, the shallow paleo-gulf acting as a receiving basin, and effective sediment trapping because of the mud shoal.

Hepatocyte growth factor (HGF) has been proposed as an endogenous cardioprotective agent against oxidative stress. The mechanism of HGF action in the heart, however, has not yet been elucidated. The present study demonstrates that HGF protects adult cardiac myocytes against oxidative stress-induced apoptosis. HGF, at the concentrations which can be detected in the plasma of humans subsequent to myocardial infarction, effectively attenuated death of isolated adult rat cardiac myocytes and cultured HL-1 cardiac muscle cells induced by apoptosis-inducing oxidative stress stimuli such as daunorubicin, serum deprivation, and hydrogen peroxide. We identified expression of c-Met HGF receptor in adult cardiac myocytes, which can be rapidly tyrosine phosphorylated in response to HGF treatment. HGF also activated MEK, p44/42 MAPK, and p90RSK. To determine if MEK-MAPK pathway may be involved in the mechanism of HGF-mediated cardiac myocyte protection, effects of a specific MEK inhibitor, PD98059, were studied. Pretreatment of cells with PD98059 partially blocked HGF signaling for protection against hydrogen peroxide-induced cell death. Thus, HGF protects cardiac myocytes against oxidative stress, in part, via activating MEK-MAPK pathway.

The charge carrier transport properties of neat thin films of red-, green- and blue-phosphorescence Ir complexes have been investigated in terms of time-of-flight transient photocurrent measurement. Bis(2-(2'-benzo[4,5-a]thienyl)pyridinato- N , C 3' )iridium(acetylacetonate) (btp 2 Ir(acac)) (red-phosphorescence emitter) and iridium(III) bis[(4,6-di-fluorophenyl)-pyridinato- N , C 2' ]picolinate (FIrpic) (blue-phosphorescence emitter) thin films exhibit bipolar charge transport. In contrast, the electron and hole transit signals of fac -tris(2-phenylpyridine)iridium(III) (Ir(ppy) 3 ) (green-phosphorescence emitter) thin films are unobservable. The charge carrier transport properties of thin films of an Ir-complex-doped 4,4'- N , N '-dicarbazole-biphenyl (CBP) and the appropriateness of FIrpic as a triplet-exciton and hole blocking layer are shown.

GATA4 is a member of the GATA family of zinc finger transcription factor, which regulates gene transcription by binding to GATA elements. GATA4 was originally discovered as a regulator of cardiac development and subsequently identified as a major regulator of adult cardiac hypertrophy. GATA4 regulates gene expression of various genes, which are involved in cardiac development and cardiac hypertrophy and heart failure. In addition to the heart, GATA4 plays important roles in the reproductive system, gastrointestinal system, respiratory system and cancer. Positive and negative regulations of GATA4 therefore are important components of biologic functions. The activation of GATA4 occurs via various cell signaling events. Earlier studies have identified protein-protein interactions of GATA4 with other factors. The discovery of interactions of GATA4 with nuclear factor for activated T cells (NFAT) revealed the importance of calcium signaling in the activation of GATA4. GATA4 can also be phosphorylated by mitogen activated protein kinases and protein kinase A. Lysine modifications also occur on the GATA4 molecule including acetylation and sumoylation. Both reactive oxygen-dependent and -independent antioxidant-sensitive pathways for GATA4 activation have also been demonstrated. The GATA4 activity is also regulated by modulating the level of GATA4 expression via transcriptional as well as translational mechanisms. This work summarizes the current understanding of regulatory mechanisms for modulating GATA4 activity.

Although most chemotherapeutic drugs have the potential to exert cardiotoxicity, these drugs have been chosen for use in cancer treatment because survival and curability benefits outweigh the risk of these complications. Anthracyclines, for example, are a powerful class of chemotherapeutic agents; however, their use is restricted by dose-related cardiotoxicity. Experimental evidence strongly supports the role of reactive oxygen species in this process, suggesting that antioxidants may be effective in protecting the heart from toxicity. Clinical use of antioxidants to protect the heart during anthracycline chemotherapy has been controversial due to the potential for reduced cytotoxic efficacy toward cancer cells. Results from randomized clinical trials addressing whether antioxidants either reduce the incidence of clinical heart failure among patients undergoing anthracycline-based chemotherapy or reduce the response rates to anthracycline-based chemotherapy have been unclear. While anthracyclines are by far the most well-studied antitumor agents with cardiotoxic properties, evidence now shows that reactive oxygen species may play roles in cardiotoxicity induced by other chemotherapeutic agents such as cyclophosphamide, cisplatin, 5-fluorouracil, and trastuzumab. Thus, in the new era of combination therapy and long-term survival of cancer patients, the use of antioxidants to support cancer therapy should be revisited.

A new predictive biomarker for determining prognosis in patients with hepatocellular carcinoma (HCC) who receive sorafenib is required, because achieving a reduction in tumor size with sorafenib is rare, even in patients who have a favorable prognosis. Vascular endothelial growth factor (VEGF) receptor is a sorafenib target. In the current study, the authors examined changes in plasma VEGF concentrations during sorafenib treatment and determined the clinical significance of VEGF as a prognostic indicator in patients with HCC.Plasma VEGF concentrations were serially measured in 63 patients with advanced HCC before and during sorafenib treatment. A plasma VEGF concentration that decreased >5% from the pretreatment level at 8 weeks was defined as a "VEGF decrease." An objective tumor response was determined using modified Response Evaluation Criteria in Solid Tumors 1 month after the initiation of therapy and every 3 months thereafter.Patients who had a VEGF decrease at week 8 (n=14) had a longer median survival than those who did not have a VEGF decrease (n=49; 30.9 months vs 14.4 months; P=.038). All patients who had a VEGF decrease survived for >6 months, and the patients who had both a VEGF decrease and an α-fetoprotein response (n=6) survived during the observation period (median, 19.7 months; range, 6.5-31.0 months). In univariate analyses, a VEGF decrease, radiologic findings classified as progressive disease, and major vascular invasion were associated significantly with 1-year survival; and, in multivariate analysis, a VEGF decrease was identified as an independent factor associated significantly with survival.A plasma VEGF concentration decrease at 8 weeks after starting sorafenib treatment may predict favorable overall survival in patients with advanced HCC.

Innate immunity plays an important role in host antiviral response to hepatitis C viral (HCV) infection. Recently, single nucleotide polymorphisms (SNPs) of IL28B and host response to peginterferon α (PEG-IFNα) and ribavirin (RBV) were shown to be strongly associated. We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment. We genotyped IL28B SNPs (rs8099917 and rs12979860) in 88 chronic hepatitis C patients treated with PEG-IFNα-2b/RBV and quantified expressions of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), related ubiquitin E3-ligase (RNF125), modulators (ISG15 and USP18), and IL28 (IFNλ). Both IL28B SNPs were 100% identical; 54 patients possessed rs8099917 TT/rs12979860 CC (IL28B major patients) and 34 possessed rs8099917 TG/rs12979860 CT (IL28B minor patients). Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients (≈ 3.3-fold, P < 0.001). However, expression of IPS-1 was significantly lower in IL28B minor patients (1.2-fold, P = 0.028). Expressions of viral sensors and modulators were significantly higher in nonvirological responders (NVR) than that in others despite stratification by IL28B genotype (≈ 2.6-fold, P < 0.001). Multivariate and ROC analyses indicated that higher RIG-I and ISG15 expressions and RIG-I/IPS-1 expression ratio were independent factors for NVR. IPS-1 down-regulation in IL28B minor patients was confirmed by western blotting, and the extent of IPS-1 protein cleavage was associated with the variable treatment response.Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFNα/RBV. Both IL28B minor allele and higher RIG-I and ISG15 expressions and RIG-I/IPS-1 ratio are independent factors for NVR.

Ligand/receptor stimulation of cells promotes protein carbonylation that is followed by the decarbonylation process, which might involve thiol-dependent reduction (C.M. Wong et al., Circ. Res. 102:301-318; 2008). This study further investigated the properties of this protein decarbonylation mechanism. We found that the thiol-mediated reduction of protein carbonyls is dependent on heat-labile biologic components. Cysteine and glutathione were efficient substrates for decarbonylation. Thiols decreased the protein carbonyl content, as detected by 2,4-dinitrophenylhydrazine, but not the levels of malondialdehyde or 4-hydroxynonenal protein adducts. Mass spectrometry identified proteins that undergo thiol-dependent decarbonylation, which include peroxiredoxins. Peroxiredoxin-2 and -6 were carbonylated and subsequently decarbonylated in response to the ligand/receptor stimulation of cells. siRNA knockdown of glutaredoxin inhibited the decarbonylation of peroxiredoxin. These results strengthen the concept that thiol-dependent decarbonylation defines the kinetics of protein carbonylation signaling.

Pulmonary arterial hypertension (PAH) remains a lethal disease with pronounced narrowing of pulmonary vessels due to abnormal cell growth. Agents that can reduce the pulmonary vascular thickness thus have therapeutic potential. The present study investigated the efficacy of carfilzomib (CFZ), a proteasome inhibitor and a cancer chemotherapeutic drug, on reversing PAH.In two rat models of PAH, SU5416/hypoxia and SU5416/ovalbumin, CFZ effectively reversed pulmonary vascular remodelling with the promotion of apoptosis and autophagy. In human pulmonary artery smooth muscle cells, knocking down mediators of autophagy attenuated CFZ-induced cell death. The cell death role of autophagy was promoted by the participation of tumour protein p53-inducible nuclear protein 1. CFZ increased the protein ubiquitination, and siRNA knockdown of ubiquitin inhibited cell death, suggesting that CFZ-induced cell death is ubiquitin-dependent. Mass spectrometry demonstrated the ubiquitination of major vault protein and heat shock protein 90 in response to CFZ. The siRNA knockdown of these proteins enhanced CFZ-induced cell death, revealing that they are cell survival factors. CFZ reduced right-ventricular pressure and enhanced the efficacy of a vasodilator, sodium nitroprusside. While no indications of CFZ toxicity were observed in the right ventricle of PAH rats, apoptosis was promoted in the left ventricle. Apoptosis was prevented by dexrazoxane or by pifithrin-α without interfering with the efficacy of CFZ to reverse pulmonary vascular remodelling.The addition of anti-tumour agents such as CFZ along with cardioprotectants to currently available vasodilators may be a promising way to improve PAH therapy.

Aim Although the viral markers hepatitis B surface antigen (HBsAg) and hepatitis B core‐related antigen (HbcrAg) could reflect intrahepatic hepatitis B virus (HBV) replication activity and constitute important biomarkers for hepatocellular carcinoma (HCC), the value of using these two markers in combination for assessing HCC risk has not been clarified in detail. Methods Four hundred and forty‐nine consecutive patients with chronic HBV infection were included in the study and the association of HBsAg and HBcrAg with HCC risk was investigated cross‐sectionally, as well as longitudinally. Results When the high value cut‐offs of HBsAg and HBcrAg were defined as 3.0 log IU/mL and 3.0 log U/mL, respectively, patients with a history of HCC were found frequently in the low HBsAg group ( P = 0.002) and high HBcrAg group ( P &lt; 0.001). When HBsAg and HBcrAg were combined, an HCC history was most frequent in the subset with low HBsAg and high HBcrAg, among the HBeAg‐negative patients (odds ratio [OR], 7.83; P &lt; 0.001), irrespective of nucleos(t) ide analogue (NA) therapy (NA: OR, 4.76; P &lt; 0.001; non‐NA: OR, 9.60; P &lt; 0.001). In a longitudinal analysis of the subsequent development of HCC, carried out on the 338 patients without an HCC history at enrollment, HCC developed significantly more frequently in the low HBsAg/high HBcrAg group ( P = 0.005). Conclusions Patients with low HBsAg/high HBcrAg values are at high risk of developing HBV‐related HCC, according to this cross‐sectional and longitudinal analysis, indicating that the combination of HBsAg and HBcrAg values is an excellent biomarker for assessing HCC risk.

Abstract Alzheimer’s disease is a chronic neurodegenerative disorder and represents the main cause of dementia. Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of Alzheimer’s disease patients. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer’s disease and the ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer’s disease, and Alzheimer’s disease brains examined in this study also exhibited higher carbonylated proteins as well as increased thiol oxidation state of peroxiredoxin 6 (Prx6). The positive correlation was found between the increased ACE2 protein expression and oxidative stress in Alzheimer’s disease brain. Thus, the present study reveals the relationships between Alzheimer’s disease and ACE2, the receptor for SARS-CoV-2. These results warrant monitoring Alzheimer’s disease patients with COVID-19 carefully for the possible higher viral load in the brain and long-term adverse neurological consequences.

Neurological disorders have been reported in a large number of coronavirus disease 2019 (COVID-19) patients, suggesting that this disease may have long-term adverse neurological consequences. COVID-19 occurs from infection by a positive-sense single-stranded RNA virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The membrane fusion protein of SARS-CoV-2, the spike protein, binds to its human host receptor, angiotensin-converting enzyme 2 (ACE2), to initiate membrane fusion between the virus and host cell. The spike protein of SARS-CoV-2 contains the furin protease recognition site and its cleavage enhances the infectivity of this virus. The binding of SARS-CoV-2 to the ACE2 receptor has been shown to downregulate ACE2, thereby increasing the levels of pathogenic angiotensin II (Ang II). The furin protease cleaves between the S1 subunit of the spike protein with the binding domain toward ACE2 and the S2 subunit with the transmembrane domain that anchors to the viral membrane, and this activity releases the S1 subunit into the blood circulation. The released S1 subunit of the spike protein also binds to and downregulates ACE2, in turn increasing the level of Ang II. Considering that a viral particle contains many spike protein molecules, furin-dependent cleavage would release many free S1 protein molecules, each of which can downregulate ACE2, while infection with a viral particle only affects one ACE2 molecule. Therefore, the furin-dependent release of S1 protein would dramatically amplify the ability to downregulate ACE2 and produce Ang II. We hypothesize that this amplification mechanism that the virus possesses, but not the infection per se, is the major driving force behind COVID-19-associated neurological disorders.

Exposure of human plasma to ozone produces oxidative protein damage, measured as protein carbonyl formation. Isolated human albumin or creatine phosphokinase are oxidized much faster than are total proteins. Consideration must be given to proteins as targets of oxidative injury by ozone in vivo.

Nuclear factor kappa B (NF-kappa B) is believed to play an important role in the activation of human immunodeficiency virus (HIV) which causes acquired immunodeficiency syndrome (AIDS). Recent findings suggesting an involvement of reactive oxygen species in signal transduction pathways leading to NF-kappa B activation have encouraged the possible clinical use of antioxidants in blocking HIV activation. We have examined the effects of vitamin E and alpha-lipoate derivatives on NF-kappa B activation, and have observed that each of these antioxidants behave differently. Here we propose mechanisms of antioxidant actions in influencing cell signalling for NF-kappa B activation.

Charge carrier generation and transport in fac tris (2-phenylpyridine) iridium (III) (Ir(ppy)3) doped in 4,4′-N,N′-dicarbazole-biphenel (CBP) thin films have been studied in terms of time-of-flight and time-resolved photoluminescence spectroscopies. It is found that the excitation energy rapidly transfer from CBP to Ir(ppy)3, and that the charge carriers are generated on Ir(ppy)3 sites. With increasing Ir(ppy)3 concentration, the electron drift mobility is slightly decreased, while the hole transit signals become unobservable. The electron and hole transport properties of Ir(ppy)3 doped CBP thin films result from the energy levels of the lowest unoccupied molecular orbital and the highest occupied molecular orbital of Ir(ppy)3 with respect to those of CBP.

The relationships between structure and antioxidant activity of dihydrolipoic acid (DHLA) were studied using homologues of DHLA: bisonor-DHLA (a derivative which lacks two carbons in the hydrophobic tail), tetranor-DHLA (which lacks four carbons) and a methyl ester derivative. It was observed that: i) DHLA homologues with shorter hydrocarbon tails (i.e., bisnor- and tetranor-DHLA) had greater ability to quench superoxide radicals (O-2); ii) no differences among homologues with different chain lengths were found for peroxyl radical (ROO) scavenging in aqueous solution, and iii) DHLA was the best membrane antioxidant in terms of ROO scavening and lipid peroxidation inhibition. Differences among the DHLA homologues in their antioxidant properties in polar and apolar environments generally agreed with differences in their partition coefficients. The methyl ester was the least effective antioxidant both in aqueous phase and in membranes. Tetranor-DHLA was found not only to be less effective in preventing ROO-induced lipid peroxidation, but also to induce lipid peroxidation in the presence of residual iron. Thus, the complexity of biological systems seems to complicate generalizations on the correlation of molecular structure with antioxidant activity of DHLA.

Serotonin (5-hydroxytryptamine (5-HT)) is a mitogen of pulmonary artery smooth muscle cells (PASMC) and plays an important role in the development of pulmonary hypertension. Signal transduction initiated by 5-HT involves serotonin transporter-dependent generation of reactive oxygen species and activation of the MEK-ERK pathway. However, the downstream transcriptional regulatory components have not been identified. In systemic smooth muscle cells, GATA-6 has been shown to regulate mitogenesis by driving cells into a quiescent state, and the down-regulation of GATA-6 induces mitogenesis. Thus, the present study tested the hypothesis that 5-HT induces mitogenesis of PASMC by down-regulating GATA-6. Quiescent bovine PASMC were treated with 5-HT, and the binding activity of nuclear extracts toward GATA DNA sequence was monitored. Surprisingly, PASMC express GATA-4, and 5-HT up-regulates the GATA DNA binding activity. Pretreatment of cells with inhibitors of serotonin transporter, reactive oxygen species, and MEK blocks GATA-4 activation by 5-HT. GATA-4 is not activated when the ERK phosphorylation site is mutated, indicating that 5-HT phosphorylates GATA-4 via the MEK/ERK pathway. GATA up-regulation is also induced by other mitogens of PASMC such as endothelin-1 and platelet-derived growth factor. Dominant negative mutants of GATA-4 suppress cyclin D2 expression and cell growth, indicating that GATA-4 activation regulates PASMC proliferation. Thus, GATA-4 mediates 5-HT-induced growth of PASMC and may be an important therapeutic target for the prevention of pulmonary hypertension.

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Reactive oxygen species (ROS) mediate various cell signaling processes, but the mechanism for how ROS promote cell signaling is poorly understood. Protein carbonylation occurs because of the direct metal-catalyzed oxidation of amino acid side chains (primary protein carbonylation) or the addition of reactive aldehydes to amino acid side chains (secondary protein carbonylation). We hypothesize that primary protein carbonylation plays a role in the mechanism of ROS signaling. Specifically, we propose that (i) primary protein carbonylation mediates cell signaling and (ii) primary protein carbonylation is reversible.

Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. Because iron is an important regulator of ROS biology, this study examined the effects of iron chelation on the development of pulmonary vascular remodeling. The administration of an iron chelator, deferoxamine, to rats prevented chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. Various iron chelators inhibited the growth of cultured pulmonary artery smooth muscle cells. Protein carbonylation, an important iron-dependent biological event, was promoted in association with pulmonary vascular remodeling and cell growth. A proteomic approach identified that Rho GDP-dissociation inhibitor (a negative regulator of RhoA) is carbonylated. In human plasma, the protein carbonyl content was significantly higher in patients with idiopathic pulmonary arterial hypertension than in healthy controls. These results suggest that iron plays an important role in the ROS-dependent mechanism underlying the development of pulmonary hypertension.

Right ventricular (RV) failure is the major cause of death among patients with pulmonary arterial hypertension (PAH). However, the mechanism of RV failure has not been defined.This study examined mechanisms and consequences of RV myocyte apoptosis and fibrosis in response to PAH. Rats were injected with SU5416 (vascular endothelial growth factor inhibitor), followed by hypoxia for 3 weeks, and subsequently maintained in normoxia for 2, 5, or 14 weeks (5-, 8-, and 17-week time points after the SU5416 injection, respectively). RV systolic pressure (RVSP) was elevated to >70 mmHg at 5-week time point, and this pressure was sustained thereafter. Significant RV myocyte apoptosis and fibrosis were observed at 8- and 17-week time points. Apoptosis was associated with downregulated Bcl-xL (anti-apoptotic protein), downregulated GATA4 (transcriptional regulator of Bcl-xL), and upregulated p53 (negative regulator of GATA4 gene transcription). PAH-mediated RV apoptosis and fibrosis were attenuated in p53 knock-out rats. Despite the major loss of cardiomyocytes, RV contractility was enhanced, suggesting that the remaining myocytes can perform improved contractile functions. Improved RV contractility is associated with the increased expression of contractile and sarcoplasmic reticulum Ca(2+) uptake proteins. In contrast, the expression of calsequestrin 2 (CSQ2) was downregulated. The siRNA knockdown of CSQ2 improved RV contractility and increased the expression of contractile and Ca(2+) uptake proteins.These results suggest that RV decompensation is associated with the death of cardiomyocytes, resulting in fibrosis. However, the remaining myocytes are capable of sustaining RV contractility through the mechanism that involves CSQ2.

The brain is sensitive to aging-related morphological changes, where many neurodegenerative diseases manifest accompanied by a reduction in memory. The hippocampus is especially vulnerable to damage at an early stage of aging. The present transmission electron microscopy study examined the synapses and synaptic mitochondria of the CA1 region of the hippocampal layer in young-adult and old rats by means of a computer-assisted image analysis technique. Comparing young-adult (10 months of age) and old (22 months) male Fischer (CDF) rats, the total numerical density of synapses was significantly lower in aged rats than in the young adults. This age-related synaptic loss involved degenerative changes in the synaptic architectonic organization, including damage to mitochondria in both pre- and post-synaptic compartments. The number of asymmetric synapses with concave curvature decreased with age, while the number of asymmetric synapses with flat and convex curvatures increased. Old rats had a greater number of damaged mitochondria in their synapses, and most of this was type II and type III mitochondrial structural damage. These results demonstrate age-dependent changes in the morphology of synaptic mitochondria that may underlie declines in age-related synaptic function and may couple to age-dependent loss of synapses.

The current pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While this respiratory virus only causes mild symptoms in younger healthy individuals, elderly people and those with cardiovascular diseases such as systemic hypertension are susceptible to developing severe conditions that can be fatal. SARS-CoV-2 infection is also associated with an increased incidence of cardiovascular diseases such as myocardial injury, acute coronary syndrome, and thromboembolism. Understanding the mechanisms of the effects of this virus on the cardiovascular system should thus help develop therapeutic strategies to reduce the mortality and morbidity associated with SARS-CoV-2 infection. Since this virus causes severe and fatal conditions in older individuals with cardiovascular comorbidities, effective therapies targeting specific populations will likely contribute to ending this pandemic. In this review article, the effects of various viruses—including other coronaviruses, influenza, dengue, and human immunodeficiency virus—on the cardiovascular system are described to help provide molecular mechanisms of pathologies associated with SARS-CoV-2 infection and COVID-19. The goal is to provide mechanistic information from the biology of other viral infections in relation to cardiovascular pathologies for the purpose of developing improved vaccines and therapeutic agents effective in preventing and/or treating the acute and long-term consequences of SARS-CoV-2 and COVID-19.

Apoptosis of cardiac muscle cells plays important roles in the development of various heart diseases including myocardial infarction and anthracycline-induced cardiomyopathy. Understanding the regulatory mechanisms of cardiac myocyte apoptosis and survival is important for establishing therapeutic strategies against heart disease. Our recent experiments demonstrate that the GATA-4 transcription factor not only mediates cardiac hypertrophy, but also regulates apoptosis and survival of adult cardiac muscle cells. Apoptosis induced by anthracyclines is associated with decreased expression of GATA-4, while the restoration of GATA-4 levels via ectopic expression attenuated the apoptosis. Survival factors of cardiac myocytes such as hepatocyte growth factor and endothelin-1 activate GATA-4, and this signal transduction mechanism at least in part serves to protect the heart against oxidative stress.

Reactive oxygen intermediates (ROI) have been implicated in a variety of pathophysiological conditions, and vascular smooth muscle may be a site of damage in such oxygen toxicity. Mechanisms of the effects of these intermediates on vascular smooth muscle at the cellular level, however, have not been well studied. We have previously shown that xanthine oxidase (XO)-generated superoxide radicals (O2-.) inhibited the Ca(2+)-adenosine triphosphatase of vascular smooth muscle sarcoplasmic reticulum (SR) through mechanisms that do not involve H2O2 or hydroxyl radicals. In the present study, we report that the D-myo-inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release from bovine aortic SR was also affected by O2-(.). Hypoxanthine (100 microM) plus XO (10 mU/ml) in the presence of catalase (100 U/ml) stimulated the IP3-induced Ca2+ release from SR monitored using arsenazo III. At 10 microM IP3, the release was doubled by O2-. treatment. As a consequence of using the higher SR protein concentrations required to observe the Ca2+ release, this effect was independent of Ca2+ uptake inhibition induced by O2-(.). Since the effect of O2-. was not seen when a nonhydrolyzable analogue of IP3 was used to induce Ca2+ release, O-2. may be inhibiting the degradation processes of IP3.

Effects of reactive oxygen intermediates generated by hypoxanthine plus xanthine oxidase on the Ca(2+)-adenosinetriphosphatase (ATPase) of sarcoplasmic reticulum from bovine aortic smooth muscle were studied. Exogenous hypoxanthine (0.1-100 microM) plus xanthine oxidase (10 mU/ml) produced an hypoxanthine concentration-dependent inhibition of the Ca(2+)-ATPase. The inhibition could be completely blocked by superoxide dismutase (100 U/ml) but not by either mannitol (20 mM) or deferoxamine (100 microM). Direct addition of hydrogen peroxide in the micromolar range did not cause significant inhibition. These results suggest that superoxide is the primary damaging species. Cysteine blocked this inhibition, suggesting possible involvement of sulfhydryl groups in the inhibition mechanism. Additionally, 1.16 +/- 0.17 mU/g wet wt of xanthine oxidase activity was detected in the postnuclear supernatant of bovine aortic smooth muscle, suggesting the existence of a possible intracellular source of superoxide. This value was calculated to be approximately 5 mU/ml by using a usual value of vascular smooth muscle cellular volume. Thus the level of endogenous xanthine oxidase in vascular smooth muscle is comparable with the level of exogenous xanthine oxidase used in the present study. These findings suggest a potential role of xanthine oxidase-generated superoxide in oxidative damage to vascular smooth muscle during a number of pathophysiological conditions.

Abstract We studied orchiectomy specimens from 130 patients immuhistochemically with testicular germ cell tumor (TGCT) using anti‐core 2 N ‐acetylglucosaminyltransferase‐1 (C2GnT‐1) antibody. The incidence of C2GnT‐1 positivity in stage I disease (29.5%, 21/71) was significantly lower than that in higher stages (84.7%, 50/59) ( P &lt; 0.001, χ 2 test). This significant difference was also found when the cases were divided into seminoma and NSGCT according to histopathological classification. Kaplan‐Meier plots and the log rank test showed that in the patients with stage I seminoma, C2GnT‐1‐positive cases had a higher risk for recurrence ( P &lt; 0.001). This was also the case with the patients with stage I NSGCT ( P &lt; 0.001). To determine whether C2GnT‐1 promotes aggressive behavior of cancer cells, a C2GnT‐1‐negative human TGCT cell line, JKT‐1, was stably transfected with a mammalian expression vector containing C2GnT‐1 cDNA. In vitro assays revealed that JKT‐1‐C2 cells are more invasive than mock transfectants, although there are no differences in proliferation activity. When orthotopically inoculated into athymic nude mice, JKT‐1‐C2 cells produced larger testicular tumors extending to the retroperitoneum with mesenteric metastasis, while mock transfectants produced small tumors without metastasis ( P &lt; 0.01, Mann‐Whitney's U ‐test). When injected via the tail vein, JKT‐1‐C2 cells produced a number of metastatic lung foci. In contrast, mock transfectants produced a small number of nodules ( p &lt; 0.01, Mann‐Whitney's U ‐test). These results strongly suggest that C2GnT‐1 enhances the metastatic potential of TGCT and may be a reliable biomarker for aggressive potential of TGCT.

The major cause of death among pulmonary hypertension patients is right heart failure, but the biology of right heart is not well understood. Previous studies showed that mechanisms of the activation of GATA4, a major regulator of cardiac hypertrophy, in response to pressure overload are different between left and right ventricles. In the left ventricle, aortic constriction triggers GATA4 activation via posttranslational modifications without influencing GATA4 expression, while pulmonary artery banding enhances GATA4 expression in the right ventricle. We found that GATA4 expression can also be increased in the right ventricle of rats treated with chronic hypoxia to induce pulmonary hypertension and investigated the mechanism of increased GATA4 expression. Examination of Gata4 promoter revealed that CCAAT box plays an important role in gene activation, and hypoxic pulmonary hypertension promoted the binding of CCAAT-binding factor/nuclear factor-Y (CBF/NF-Y) to CCAAT box in the right ventricle. We found that CBF/NF-Y forms a complex with annexin A1, which inhibits DNA binding activity. In response to hypoxic pulmonary hypertension, annexin A1 gets degraded, resulting in CBF/NF-Y-dependent activation of Gata4 gene transcription. The right ventricle contains a higher level of CBF/NF-Y compared to the left ventricle, and this may allow for efficient activation in response to annexin A1 degradation. Signaling via iron-catalyzed protein oxidation mediates hypoxic pulmonary hypertension-induced annexin A1 degradation, Gata4 gene transcription, and right ventricular hypertrophy. These results establish a right heart-specific signaling mechanism in response to pressure overload, which involves metal-catalyzed carbonylation and degradation of annexin A1 that liberates CBF/NF-Y to activate Gata4 gene transcription.

Background A genome-wide association study revealed an association between variants of the inosine triphosphatase ( ITPA) gene and ribavirin (RBV)-induced anaemia. The aim of this study was to replicate this finding in an independent Japanese cohort and to define a method to allow pretreatment prediction of anaemia in combination with other factors. Methods Genotype 1b chronic hepatitis C patients ( n=132) treated with pegylated interferon (PEG-IFN)-α and RBV for 48 weeks were genotyped for ITPA rs1127354 and examined for anaemia and treatment outcome. Results Variants of the ITPA gene protected against severe anaemia throughout the 48-week treatment period and were associated with lower incidence of anaemia-related RBV dose reduction. A combination of the ITPA genotype with baseline haemoglobin (Hb) and creatinine clearance (CLcr) levels predicted severe anaemia with high accuracy (90% sensitivity and 62% specificity). Among a subset of patients with the IL28B genotype of TT at rs8099917, patients with variants of the ITPA gene were associated with a higher rate of receiving &gt;80% of the expected RBV dose, a higher rate of sustained virological response (SVR), and a lower rate of relapse. Conclusions The variants of the ITPA gene, which could protect against haemolytic anaemia and RBV dose reduction, were associated with a high rate of SVR by standard PEG-IFN and RBV therapy in a subset of Japanese patients with the favourable TT genotype at rs8099917 of IL28B. A combination of ITPA genetic polymorphisms with baseline Hb and CLcr levels further improves the predictive accuracy of severe anaemia.

High-mobility metal-oxide-semiconductor field-effect transistors (MOSFETs) consisting of stripe-shaped local germanium-on-insulator (GOI) structures were fabricated by lateral liquid-phase epitaxy (LLPE). The effective hole mobility of back-gate LLPE-grown GOI MOSFETs was accurately and reliably evaluated with a split capacitance-voltage (C-V) method. The superior effective hole mobility of the GOI devices throughout a wide range of accumulated carrier densities over that for a reference silicon-on-insulator device was demonstrated. A very high peak hole mobility of 511 cm2/Vs and an on/off current ratio of 106, together with phonon scattering limited carrier mobility at high temperatures, indicated not only the excellent crystalline quality of LLPE-grown GOI but also surprisingly good interface quality between Ge and the buried oxide.

Pulmonary arterial hypertension remains a devastating disease without a cure. The major complication of this disease is the abnormal growth of vascular cells, resulting in pulmonary vascular remodeling. Thus, agents, which affect the remodeled vessels by killing unwanted cells, should improve treatment strategies. The present study reports that antitumor drugs selectively kill vascular cells in remodeled pulmonary vessels in rat models of pulmonary hypertension.After developing pulmonary vascular remodeling in chronic hypoxia or chronic hypoxia/SU-5416 models, rats were injected with antitumor drugs including proteasome inhibitors (bortezomib and MG-132) and daunorubicin. Within 1 to 3 days, these agents reduced the media and intima thickness of remodeled pulmonary vascular walls, but not the thickness of normal pulmonary vessels. These drugs also promoted apoptotic and autophagic death of vascular cells in the remodeled vessels, but not in normal vessels. We provide evidence that the upregulation of annexin A1, leading to GATA4-dependent downregulation of Bcl-xL, is a mechanism for specific apoptotic killing, and for the role of parkin in defining specificity of autophagic killing of remodeled vascular cells. The reversal of pulmonary vascular remodeling increased the capacity of vasodilators to reduce pulmonary arterial pressure.These results suggest that antitumor drugs can specifically kill cells in remodeled pulmonary vascular walls and may be useful for improving the efficacy of current therapeutic strategies to treat pulmonary arterial hypertension.

Because of recent advances in deep sequencing technology, detailed analysis of hepatitis C virus (HCV) quasispecies and their dynamic changes in response to direct antiviral agents (DAAs) became possible, although the role of quasispecies is not fully understood. In this study, to clarify the evolution of viral quasispecies and the origin of drug-resistant mutations induced by interferon (IFN)-based protease inhibitor therapy, the nonstructural-3 (NS3) region of genotype 1b HCV in 34 chronic hepatitis patients treated with telaprevir (TVR)/pegylated interferon (PEG-IFN)/ribavirin (RBV) was subjected to a deep sequencing study coupled with phylogenetic analysis. Twenty-six patients (76.5%) achieved a sustained viral response (SVR), while 8 patients did not (non-SVR; 23.5%). When the complexity of the quasispecies was expressed as the mutation frequency or Shannon entropy value, a significant decrease in the IFNL3 (rs8099917) TT group and a marginal decrease in the SVR group were found soon (12 h) after the introduction of treatment, whereas there was no decrease in the non-SVR group and no significant decrease in mutation frequency in the IFNL3 TG/GG group. In the analysis of viral quasispecies composition in non-SVR patients, major populations greatly changed, accompanied by the appearance of resistance, and the compositions were unlikely to return to the pretreatment composition even after the end of therapy. Clinically TVR-resistant variants were observed in 5 non-SVR patients (5/8, 62.5%), all of which were suspected to have acquired resistance by mutations through phylogenetic analysis. In conclusion, results of the study have important implications for treatment response and outcome in interferon-based protease inhibitor therapy.In the host, hepatitis C virus (HCV) consists of a variety of populations (quasispecies), and it is supposed that dynamic changes in quasispecies are closely related to pathogenesis, although this is poorly understood. In this study, recently developed deep sequencing technology was introduced, and changes in quasispecies associated with telaprevir (TVR)/pegylated interferon (PEG-IFN)/ribavirin (RBV) triple therapy and their clinical significance were investigated extensively by phylogenetic tree analysis. Through this study, the associations among treatment response, changes in viral quasispecies complexity in the early stage of treatment, changes in the quasispecies composition, and origin of TVR-resistant variant HCV were elucidated.

Background Pulmonary arterial hypertension ( PAH ) is a serious disease without cure. Elevated pulmonary vascular resistance puts strain on the right ventricle ( RV ) and patients die of RV failure. Subjecting Sprague–Dawley rats to SU 5416 injection and hypoxia promotes severe PAH with pulmonary vascular lesions similar to human disease and has been well utilized to investigate pulmonary vascular pathology. However, despite exhibiting severe RV fibrosis, these rats do not die. Recently, subjecting Fischer ( CDF ) rats to the same treatment to promote PAH was found to result in mortality. Thus, the present study performed detailed morphological characterizations of Fischer rats with PAH . Methods and Results Rats were subjected to SU 5416 injection and hypoxia for 3 weeks, followed by maintenance in normoxia. More than 90% of animals died within 6 weeks of the SU 5416 injection. Necropsy revealed the accumulation of fluid in the chest cavity, right ventricular hypertrophy and dilatation, hepatomegaly, and other indications of congestive heart failure. Time course studies demonstrated the progressive thickening of pulmonary arteries with the formation of concentric lamellae and plexiform lesions as well as RV fibrosis in PAH rats. Transmission electron microscopy demonstrated the destruction of the myofilaments, T‐tubules, and sarcoplasmic reticulum. RV mitochondrial damage and fission were found in Fischer rats, but not in Sprague–Dawley rats, with PAH . Conclusions These results suggest that the destruction of RV mitochondria plays a role in the mechanism of PAH ‐induced death. The SU 5416/hypoxia model in Fischer rats should be useful for further investigating the mechanism of RV failure and finding effective therapeutic agents to increase the survival of PAH patients.

Background and Aims Traction methods have been reported to speed up endoscopic submucosal dissection (ESD). We used the multiloop (M-loop) method as a traction method for colorectal ESD and recorded the submucosal dissection time (SDT) and submucosal dissection speed (SDS). Methods From January to August 2018, we used the M-loop method for colorectal ESD procedures and timed the duration and recorded the outcomes. Two experts and eight nonexperts performed the procedures, which were carried out at a tertiary endoscopic center in Japan. Results A total of 50 patients were treated by colorectal ESD using the M-loop method. The mean SDT was 42.1 ± 4.16 minutes and the mean SDS was 28.0 ± 2.89 mm2/minutes. The mean SDS was 38.9 ± 6.9 mm2/minutes for experts and 25.3 ± 3.1 mm2/minutes for nonexperts. En bloc resection was achieved in 100% of cases. There were 3 adverse events and unfavorable outcomes. Conclusions Traction by the M-loop method improved SDS in colorectal ESD. The method can be an effective tool to assist colorectal ESD. Further evaluation of the usefulness of the M-loop method is required in direct comparison with conventional ESD. Traction methods have been reported to speed up endoscopic submucosal dissection (ESD). We used the multiloop (M-loop) method as a traction method for colorectal ESD and recorded the submucosal dissection time (SDT) and submucosal dissection speed (SDS). From January to August 2018, we used the M-loop method for colorectal ESD procedures and timed the duration and recorded the outcomes. Two experts and eight nonexperts performed the procedures, which were carried out at a tertiary endoscopic center in Japan. A total of 50 patients were treated by colorectal ESD using the M-loop method. The mean SDT was 42.1 ± 4.16 minutes and the mean SDS was 28.0 ± 2.89 mm2/minutes. The mean SDS was 38.9 ± 6.9 mm2/minutes for experts and 25.3 ± 3.1 mm2/minutes for nonexperts. En bloc resection was achieved in 100% of cases. There were 3 adverse events and unfavorable outcomes. Traction by the M-loop method improved SDS in colorectal ESD. The method can be an effective tool to assist colorectal ESD. Further evaluation of the usefulness of the M-loop method is required in direct comparison with conventional ESD.

Reactive oxygen species are known to cause attenuation of cardiac muscle contraction. This attenuation is usually preceded by transient augmentation of twitch amplitude as well as cytosolic Ca2+. The present study examines the role of an endogenous antioxidant, glutathione in the mechanism of H2O2-mediated augmentation of Ca2+ release from the sarcoplasmic reticulum. Whole-cell patch-clamped single rat ventricular myocytes were dialyzed with the Cs+-rich internal solution containing 200 μM fura-2 and 2 mM glutathione (reduced form). After equilibration of the myocyte with intracellular dialyzing solution, Ca2+ current-induced Ca2+ release from the sarcoplasmic reticulum was monitored. Rapid perfusion with H2O2 (100 μM or 1 mM) for 20 s inhibited Ca2+ current, but enhanced the intracellular Ca2+ transients for 3–4 min. Thus, the efficacy of Ca2+-induced Ca2+ release mechanism was augmented in 71% of myocytes (n = 7). This enhancement ranged between 1.5- to threefold as the concentrations of H2O2 were raised from 100 μM to 1 mM. If glutathione were excluded from the patch pipette or replaced with glutathione disulfide, the enhancement of Ca2+-induced Ca2+ release was seen in only a minority (20%) of the myocytes. H2O2 exposure did not increase the basal intracellular Ca2+ levels, suggesting that the mechanism of H2O2 action was not mediated by inhibition of the sarcoplasmic reticulum Ca2+ uptake or activation of passive Ca2+ leak pathway. H2O2-mediated stimulation of Ca2+-induced Ca2+ release was also observed in myocytes dialyzed with dithiothreitol (0.5 mM). Therefore, reduced thiols support the action of H2O2 to enhance the efficacy of Ca2+-induced Ca2+ release, suggesting that redox reactions might regulate Ca2+ channel-gated Ca2+ release by the ryanodine receptor.

Nonenzymatic glycation has been found to increase in a variety of proteins in diabetic patients. The present study examined a possibility of preventing glycation and subsequent structural modifications of proteins by α-lipoic acid (thioctic acid) as lipoate, a substance which has gained attention as a potential therapeutic agent for diabetes-induced complications. Incubation of bovine serum albumin (BSA) at 2 mg/ml with glucose (500 mM) in a sterile condition at 37°C for seven days caused glycation and structural modifications of BSA observed by SDS-PAGE, near UV absorption, tryptophan and nontryptophan fluorescence, and fluorescence of an extrinsic probe, TNS (6-(p-toluidinyl) naphthalene-2-sulfonate). When BSA and glucose were incubated in the presence of lipoate (20 mM), glycation and structural modifications of BSA were significantly prevented. Glycation and inactivation of lysozyme were also prevented by lipoate. These results suggest a potential for the therapeutic use of lipoic acid against diabetes-induced complications.

Nitecapone [3-(3,4-dihydroxy-5-nitrophenyl)methylene-2,4-pentanedione] [OR-462] is a catechol-O-methyltransferase inhibitor with gastroprotective properties. Recently, its antioxidant properties have been discovered: It scavenges peroxyl radicals (ROO.) and thus spares glutathione. Further examination of the properties of nitecapone demonstrated a remarkable ability of this compound to act as an antioxidant: (1) to scavenge ROO. in solution with a stoichiometry factor of 2: (2) to scavenge ROO. in membranes; (3) to inhibit lipid peroxidation; (4) to act as a competitive inhibitor for xanthine oxidase with Ki of 8.8 μM; (5) to scavenge O2− with a second order kinetic rate constant of 1.0 × 104 M−1 s−1; and (6) to scavenge HO.. Nitecapone also interacts with oxidation product of ascorbate to participate in recycling of vitamin E. Thus, nitecapone potentially is an effective therapeutic antioxidant, and the use of this compound in a combination with other antioxidants may be beneficial.

Charge-carrier transport and triplet exciton diffusion in iridium(III) bis[(4,6-di-fluoropheny)-pyridinato-N,C2′]picolinate (FIrpic) doped in 4,4′-N, N′-dicarbazole-biphenyl (CBP) thin films have been studied by time-of-flight (TOF) transient photocurrent and steady-state photocurrent measurements. With increasing FIrpic concentration, hole TOF transients become highly dispersive and the hole drift mobility is decreased. In contrast, the electron transit signals become unobservable. The TOF results are found to be consistent with those of steady-state photocurrent measurements of FIrpic-doped CBP thin films; the photocurrent spectra are symbatic and antibatic when the illuminated electrode is positively and negatively biased, respectively. The diffusion lengths of triplet excitons in FIrpic-doped CBP thin films are determined from the symbatic photocurrent spectra.

Intermittent hypoxia (IH) with repeated episodes of hypoxia-normoxia cycle has been shown to exert preconditioning-like cardioprotective effects. To understand the mechanism of these events, we investigated the changes in cardiac gene expression in response to acute IH. Mice were subjected to five cycles of 2 min of 10% O(2) plus 2 min of 21% O(2). RNA was isolated, and gene array analysis was performed. Results show that the expression of antiapoptotic genes, such as Bcl-2 and Bcl-x(L), were increased after acute IH. GATA-4 regulates transcription of these genes, and, consistently, GATA-4 activity was increased by acute IH. Although the phosphorylation of GATA-4 has been shown to regulate its activity, no changes in GATA-4 phosphorylation status by acute IH were noted. Gene transcription of gata4 was increased by acute IH, and this might be responsible for the enhanced GATA activity. To understand the mechanism of acute IH activation of gata4 gene transcription, we identified a promoter region of the mouse gata4 gene that is 1,000 bp immediately upstream from the transcriptional start site. In cardiac muscle cells, truncation of 1,000 to 250 bp did not alter the transcriptional activity, suggesting that the proximal 250-bp region contains important transcriptional regulatory sites. We further found that acute IH activates factors which bind to the proximal 100-bp region. Thus acute IH activates not yet identified factors that bind to the proximal 100-bp region of the gata4 promoter and, in turn, increases gata4 gene transcription, leading to enhanced expression of Bcl-2 and Bcl-x(L).

The chronic phase of pulmonary arterial hypertension (PAH) is associated with vascular remodeling, especially thickening of the smooth muscle layer of large pulmonary arteries and muscularization of small pulmonary vessels, which normally have no associated smooth muscle. Serotonin (5-hydroxytryptamine, 5-HT) has been shown to induce proliferation and hypertrophy of pulmonary artery smooth muscle cells (PASMC), and may be important for in vivo pulmonary vascular remodeling. Here, we show that 5-HT stimulates migration of pulmonary artery PASMC. Treatment with 5-HT for 16h increased migration of PASMC up to four-fold as monitored in a modified Boyden chamber assay. Increased migratory responses were associated with cellular morphological changes and reorganization of the actin cytoskeleton. 5-HT-induced alterations in morphology were previously shown in our laboratory to require cAMP [Lee SL, Fanburg BL. Serotonin produces a configurational change of cultured smooth muscle cells that is associated with elevation of intracellular cAMP. J Cell Phys 1992;150(2):396-405], and the 5-HT4 receptor was pharmacologically determined to be the primary activator of cAMP in bovine PASMC [Becker BN, Gettys TW, Middleton JP, Olsen CL, Albers FJ, Lee SL, et al. 8-Hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells. Mol Pharmacol 1992;42(5):817-25]. We examined the role of the 5-HT4 receptor and cAMP in 5-HT-induced bovine PASMC migration. PASMC express 5-HT4 receptor mRNA, and a 5-HT4 receptor antagonist and a cAMP antagonist completely blocked 5-HT-induced cellular migration. Consistent with our previous report that a cAMP-dependent Cl(-) channel is required for 5-HT-induced morphological changes in PASMC, phenylanthranilic acid, a Cl(-) channel blocker, inhibited actin cytoskeletal reorganization and migration produced by 5-HT. We conclude that 5-HT stimulates PASMC migration and associated cytoskeletal reorganization through the 5-HT4 receptor and cAMP activation of a chloride channel.

Obstructive sleep apnea (OSA) is associated with cardiovascular diseases such as hypertension through mechanisms involving intermittent hypoxia (IH). However, it is not yet clear whether IH directly affects the heart. In a mouse model of OSA, we found that IH causes time-dependent alterations of the susceptibility of the heart to oxidative stress. Acute IH can exert preconditioning-like cardioprotection, in part, through the transcriptional activation of genes such as bcl-xL and gata4. We cloned the mouse gata4 promoter and identified an IH-responsive region. The exposure of mice to prolonged IH results in the increased susceptibility of the heart to ischemia–reperfusion injury by increasing the oxidative stress status. This might resemble conditions of OSA patients. In our mouse model, further exposure to prolonged IH allowed reversal of the enhancement of myocardial damage. Understanding the complex effects of IH on the heart should help ultimately to develop therapeutic strategies against OSA-induced complications.

Anthracyclines such as daunorubicin (DNR) and doxorubicin are effective cancer chemotherapeutic agents, but can induce cardiotoxicity. GATA4 has been shown to serve as a survival factor of cardiac muscle cells, and anthracyclines promote apoptosis in part by down-regulating GATA4. The present study investigated the mechanism of anthracycline action to down-regulate GATA4.DNR inhibited the transcriptional activity exhibited by the 250 bp conserved region immediately upstream from the transcriptional start site of the Gata4 gene. Mapping this region identified that the CCAAT-binding factor/nuclear factor-Y (CBF/NF-Y) binding to the CCAAT box was inhibited by DNR in HL-1 cardiac muscle cells and in perfused isolated mouse hearts. The DNR action on the Gata4 promoter was found to be dependent on p53, since DNR promoted nuclear binding of p53 to CBF/NF-Y and pifithrin-α (a p53 inhibitor) attenuated DNR down-regulation of GATA4.Anthracycline down-regulation of GATA4 is mediated by the inhibition of Gata4 gene transcription via a novel mechanism that involves the p53-dependent inhibition of CBF/NF-Y binding to the CCAAT box within the Gata4 promoter.

An autopsy of a 23-year-old woman with progressive muscular weakness and wasting showed a unique muscle abnormality with segmental involvement of individual fibers by peculiar inclusions. Electron microscopically, these inclusions resembled cytoplasmic bodies, being formed of two concentric zones of filamentous materials. They seemed to arise from filaments of myofibrils that were fragmented and highly disorganized in affected areas.

The oral adsorbent AST-120 has the potential to delay dialysis initiation and improve survival of patients on dialysis. We evaluated the effect of AST-120 on dialysis initiation and its potential to improve survival in patients with chronic kidney disease. The present retrospective pair-matched study included 560 patients, grouped according to whether or not they received AST-120 before dialysis (AST-120 and non-AST-120 groups). The cumulative dialysis initiation free rate and survival rate were compared by the Kaplan-Meier method. Multivariate analysis was used to determine the impact of AST-120 on dialysis initiation. Our results showed significant differences in the 12- and 24-month dialysis initiation free rate (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>P</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.001</mml:mn></mml:mrow></mml:math>), although no significant difference was observed in the survival rate between the two groups. In conclusion, AST-120 delays dialysis initiation in chronic kidney disease (CKD) patients but has no effect on survival. AST-120 is an effective therapy for delaying the progression of CKD.

Right heart failure is the major cause of death among patients with pulmonary arterial hypertension (PAH). Understanding the biology of the right ventricle (RV) should help developing new therapeutic strategies. Rats subjected to the injection of Sugen5416 (an inhibitors of vascular endothelial growth factor receptor) plus the ovalbumin immunization had increased pulmonary arterial pressure and severe vascular remodeling. RVs of these rats were hypertrophied and had severe cardiac fibrosis. No apoptosis was, however, detected. Metabolomics analysis revealed that oxidized glutathione, xanthine and uric acid had increased in PAH RVs, suggesting the production of reactive oxygen species by xanthine oxidase. PAH RVs were also found to have a 30-fold lower level of α-tocopherol nicotinate, consistent with oxidative stress decreasing antioxidants and also demonstrating for the first time that the nicotinate ester of vitamin E is endogenously expressed. Oxidative/nitrosative protein modifications including S-glutathionylation, S-nitrosylation and nitrotyrosine formation, but not protein carbonylation, were found to be increased in RVs of rats with PAH. Mass spectrometry identified that S-nitrosylated proteins include heat shock protein 90 and sarcoplasmic reticulum Ca2+-ATPase. These results demonstrate that RV failure is associated with the promotion of specific oxidative and nitrosative stress.

Objectives This study was aimed to reveal risk factors for delayed bleeding after endoscopic resection (ER) of superficial non‐ampullary duodenal epithelial tumors (SNADETs) and at exploring measures to prevent this complication. Methods A total of 235 consecutive patients with 249 SNADETs who had undergone ER were enrolled in this study. They were divided into two groups: OTSC group, consisting of the initial 114 cases in which the defects were closed only using OTSCs; and OTSC‐c group, consisting of the later 135 cases in which conventional clips were additionally used to cover the inverted submucosa after post‐procedure defect closure using OTSCs. The therapeutic outcomes were then compared between the OTSC and OTSC‐c groups. Results All lesions were successfully resected en‐bloc , and the R0 resection rate was 92.4%. The complete defect closure rate was 90.0% and no delayed perforation occurred when successful defect closure was achieved. The rate of delayed bleeding was significantly higher in the OTSC group than in OTSC‐c group (11.4% vs. 1.5%, P = 0.001). Multivariate logistic regression analyses revealed that tumor location distal to the ampulla (OR 10.0; 95% CI 1.24–81.0, P = 0.03) and use of a DOAC (OR 8.83; 95% CI 1.13–68.7, P = 0.04) were significant independent predictors of delayed bleeding. Propensity score‐matching analysis revealed that additional use of conventional clips was associated with a significantly reduced risk of delayed bleeding ( P = 0.003). Conclusions Additional use of conventional clips after prophylactic defect closure using OTSCs appears to be useful to reduce the risk of delayed bleeding after ER of SNADETs. UMIN Clinical Trials (No. 000035478).

Severe acute respiratory syndrome coronavirus 2 has been causing the pandemic of coronavirus disease 2019 (COVID-19) that has so far resulted in over 450 million infections and six million deaths. This respiratory virus uses angiotensin-converting enzyme 2 as a receptor to enter host cells and affects various tissues in addition to the lungs. The present study reports that the placental arteries of women who gave birth to live full-term newborns while developing COVID-19 during pregnancy exhibit severe vascular wall thickening and the occlusion of the vascular lumen. A morphometric analysis of the placental arteries stained with hematoxylin and eosin suggests a 2-fold increase in wall thickness and a 5-fold decrease in the lumen area. Placental vascular remodeling was found to occur in all of SARS-CoV-2-positive mothers as defined by RT-PCR. Immunohistochemistry with α-smooth muscle actin and the Kv11.1 channel as well as Masson’s trichrome staining showed that such placental vascular remodeling in COVID-19 is associated with smooth muscle proliferation and fibrosis. Placental vascular remodeling may represent a response mechanism to the clinical problems associated with childbirth in COVID-19 patients.

Recently, pemafibrate and a low-carbohydrate diet (LCD) have each been reported to improve fatty liver disease. However, it is unclear whether their combination improves fatty liver disease and is equally effective in obese and non-obese patients.In 38 metabolic-associated fatty liver disease (MAFLD) patients, classified by baseline body mass index (BMI), changes in laboratory values, magnetic resonance elastography (MRE), and magnetic resonance imaging-proton density fat fraction (MRI-PDFF) were studied after 1 year of combined pemafibrate plus mild LCD.The combination treatment resulted in weight loss (P = 0.002), improvement in hepatobiliary enzymes (γ-glutamyl transferase, P = 0.027; aspartate aminotransferase, P < 0.001; alanine transaminase [ALT], P < 0.001), and improvement in liver fibrosis markers (FIB-4 index, P = 0.032; 7 s domain of type IV collagen, P = 0.002; M2BPGi, P < 0.001). Vibration-controlled transient elastography improved from 8.8 to 6.9 kPa (P < 0.001) and MRE improved from 3.1 to 2.8 kPa (P = 0.017) in the liver stiffness. MRI-PDFF improved from 16.6% to 12.3% in liver steatosis (P = 0.007). In patients with a BMI of 25 or higher, improvements of ALT (r = 0.659, P < 0.001) and MRI-PDFF (r = 0.784, P < 0.001) were significantly correlated with weight loss. However, in patients with a BMI below 25, the improvements of ALT or PDFF were not accompanied by weight loss.Combined treatment with pemafibrate and a low-carbohydrate diet resulted in weight loss and improvements in ALT, MRE, and MRI-PDFF in MAFLD patients. Although such improvements were associated with weight loss in obese patients, the improvements were observed irrespective of weight loss in non-obese patients, indicating this combination can be effective both in obese and non-obese MAFLD patients.

Atezolizumab plus bevacizumab combination therapy (AB) was the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). IFN-γ-induced protein 10 (IP-10/CXCL10) is a chemokine to inhibit HCC proliferation by promoting the migration of cytotoxic T cells. We focused on the relationship between plasma IP-10/CXCL10 levels and the initial therapeutic response in patients receiving AB therapy.Forty-six patients receiving AB therapy were enrolled. Plasma IP-10/CXCL10 levels were measured at baseline, 3-7 days, 3 weeks, 6 weeks, and 8-12 weeks after the start of AB therapy. The initial therapeutic response was evaluated at 8-12 weeks.The baseline IP-10/CXCL10 levels of partial response (PR) group was higher than that of stable disease (SD) or progressive disease (PD) group. Patients with the baseline IP-10/CXCL10 of 84 pg/mL or higher were likely to present PR than patients below (71 vs. 35%, p = 0.031), but prediction of PD using the baseline IP-10/CXCL10 levels was difficult. In contrast, IP-10/CXCL10 ratio of the PR group was lower than that of the SD/PD group at 3, 6, and 8-12 weeks. Patients with the 3, 6, and 8-12 weeks IP-10/CXCL10 ratio of 1.3, 0.4, and 0.4 or lower were likely to present PR than patients with ≥1.3, 0.4, and 0.4 (88, 35, 35 vs. 30, 3.8, 0%, p &lt; 0.001, 0.011, 0.002). In other hand, the 3, 6, and 8-12 weeks IP-10/CXCL10 ratio for PD group was higher than that for non-PD group. Patients with the 3, 6, and 8-12 weeks IP-10/CXCL10 ratio of 1.3, 1.7, and 1.9 or higher were likely to present PD than patients below (85, 62, 57 vs. 32, 23, 14%, p = 0.002, 0.034, 0.009).High baseline IP-10/CXCL10 levels may be associated with better outcome, and high IP-10/CXCL10 ratio after 3-12 weeks may be associated with worse outcome in u-HCC patients receiving AB therapy.

H2O2 has been proposed as a second messenger involved in cell signaling for NF-kappa B activation. In the present study, this hypothesis was tested by transiently overexpressing catalase, a specific scavenger of H2O2, in COS-1 cells. A mammalian expression vector was constructed by incorporating catalase gene from pCAT10 clone into the unique EcoRI site of the pSG5 vector which contains the SV-40 promoter. Transient transfection of the catalase expression vector by the DEAE-dextran method led to a four-fold increase in catalase activity and catalase content as detected by immunoblot analysis. This level of increase was detected in both nuclear/mitochondrial- and cytosolic/microsomal fractions. Overexpression of catalase, however, did not block TNF- or PMA-induced NF-kappa B activation. These results weaken the hypothesis that H2O2 is a second messenger for TNF- and PMA-signaling for NF-kappa B activation.

Pulmonary hypertension is characterized by thickened pulmonary arterial walls due to increased number of pulmonary artery smooth muscle cells (PASMC). Apoptosis of PASMC may play an important role in regulating the PASMC number and may be useful for reducing pulmonary vascular thickening. The present study examined the regulation of an anti-apoptotic protein Bcl-x(L). Bcl-x(L) expression was found to be increased in the pulmonary artery of chronic hypoxia-treated rats with pulmonary vascular remodeling. Adenovirus-mediated gene transfer of Bcl-x(L) indeed showed that this protein has anti-apoptotic activities in PASMC. Treatment of remodeled pulmonary artery with sodium nitroprusside (SNP) reduced Bcl-x(L) expression by targeting the bcl-x(L) promoter. The bcl-x(L) promoter contains two GATA elements, and SNP decreases the GATA-4 DNA-binding activity. Overexpression of GATA-4 attenuated the SNP-mediated suppression of Bcl-x(L) expression, providing direct evidence for the role of GATA-4 in Bcl-x(L) gene transcription. We established that SNP targets the 250 proximal region of the gata4 promoter and suppresses its gene transcription. Thus, inducers of pulmonary hypertension enhance anti-apoptotic Bcl-x(L) gene transcription, which can be suppressed by targeting gata4 gene transcription.

The development of immunosuppressive techniques has helped overcome the ABO incompatibility barrier. However, the outcomes of ABO-incompatible (ABOi) kidney transplantation remain a controversial issue with the advent of the anti-CD20 chimeric antibody rituximab. Herein, we report the outcomes of ABOi kidney transplantation with low-dose rituximab.Between June 2006 and April 2013, 42 patients underwent living-related kidney transplantation at our hospital. The patients were divided into 2 groups: ABO-compatible (ABOc; n = 29) and ABOi kidney transplants using low-dose rituximab (100 mg/m(2)) without splenectomy (n = 13). The basic immunosuppression regimen (calcineurin inhibitor [CNI], mycophenolate mofetil [MMF], and steroids) was the same for both groups, except for the use of rituximab and therapeutic apheresis in the ABOi group. We compared post-transplantation renal function, incidents of virus infection, episodes of rejection, and graft survival between the 2 groups.In our hospital, 30% of recipients received ABOi kidney transplants. The estimated glomerular filtration rate (eGFR) did not differ between the groups. Rejection episodes confirmed by biopsy in the ABOc and ABOi groups were 8 (28%) and 4 (31%) patients (P = .833), acute antibody-mediated rejection was observed in 1 (3.5%) and 2 (15%) patients (P = .165), and virus infection was observed in 14 (48%) and 3 (23%) patients (P = .252), respectively. The 5-year patient survival rate was 100% in both groups, and the 5-year graft survival rates were 95% for ABOc and 100% for ABOi transplants (P = .527).These results suggest that the outcomes of ABOi kidney transplantation with low-dose rituximab are similar to those of ABOc kidney transplantation. Further study is necessary to address the efficacy and safety of ABOi kidney transplantation.

Reactive free radicals contained in cigarette smoke (CS) and compromised phagocytic antimicrobial activities including those of polymorphonuclear leukocytes (PMNs) have been implicated in the pathogenesis of severe CS-related pulmonary disorders. In CS-exposed buffer solutions, O2-. was the predominant generated reactive oxygen species, as demonstrated by lucigenin-amplified chemiluminescence and electron spin resonance (ESR) spin-trapping with 5,5-dimethyl-1-pyrroline N-oxide (DMPO). When PMNs were incubated in this buffer, phorbol 12-myristate 13-acetate (PMA)-stimulated active oxygen production and coupled O2 consumption were strongly impaired without appreciably affecting PMN viability (1-min exposure inhibited active oxygen production by 75%). Superoxide dismutase (SOD) totally protected and an iron chelator, diethylenetriaminepentaacetic acid (DETAPAC), also protected the CS-exposed PMNs, suggesting that generated O2-. was an initiating factor in the impairment and OH. generation was a subsequent injurious factor. Pretreatment of PMNs with antioxidants such as alpha-tocopherol and dihydrolipoic acid (DHLA) was partially protective. The results suggest that (i) O2-. is probably generated in the upper and lower respiratory tract lining fluid when they come in contact with CS; (ii) such generated O2-. can primarily impair PMN capabilities to generate reactive oxygen species; and (iii) since these effects may contribute to the pathogenesis of CS-related lung diseases, prior supplementation with antioxidants such as alpha-tocopherol or DHLA might be successful in preventing these deleterious effects.

Chiral cationic palladium[bond]phosphinooxathiane complexes have been found to be effective catalysts for enantioselective Diels-Alder (DA) reaction of cyclopentadiene with acyl-1,3-oxazolidin-2-ones to give the corresponding DA adducts in good yield and high enantioselectivity up to 93% ee.

RS-61443, a morpholinoethyl ester of mycophenolic acid, has been shown to prevent renal allograft rejection in dogs when administered in combination with low-dose cyclosporine and prednisolone. The purpose of this study was to test whether high-dose RS-61443 can reverse acute renal allograft rejection. Mongrel dogs receiving a renal allograft were treated with baseline immunosuppression consisting of RS-61443 10 mg/kg, cyclosporine 5 mg/kg, and prednisolone 0.1 mg/kg. All animals developed acute allograft rejection. Dogs in group I (n = 11) received 14, 7, and 3.5 mg/kg methylprednisolone intravenously on 3 consecutive days after the diagnosis of rejection. Dogs in group II (n = 16) were given RS-61443 80 mg/kg twice daily. After rejection treatment, RS-61443 was increased to 20 mg/kg in all animals; cyclosporine and prednisolone were continued as before. In group I, five of 11 dogs developed uncontrollable rejection; in six of 11 dogs only a temporary reversal occurred. None of the dogs in group I survived for more than 20 days after the diagnosis of rejection. In group II rejection was completely reversed in 14 of 16 dogs (87.5%), resulting in a return of serum creatinine to prerejection levels. Thus, high-dose therapy with RS-61443 can successfully reverse acute kidney allograft rejection in dogs in a high proportion of cases.

Cationic palladium (Pd)- and platinum (Pt)-phosphinooxazolidine catalysts 13a-c, 15a-d, 17a-c, and 19a-c were prepared from phosphinooxazolidine ligands 1-3, MCl(2) (M = Pd and Pt), and counterions, and the activities of the catalysts in the asymmetric Diels-Alder (DA) reactions of cyclic or acyclic dienes with imide dienophiles were investigated. These catalysts demonstrated high levels of catalytic activity. The cationic Pd-POZ complex 13c provided particularly excellent enantioselectivity (98% ee) in the DA reactions of cyclopentadiene with acryloyl-, crotonyl-, and fumaroyl-1,3-oxazolidin-2-ones (20a-c).

Hepatocyte growth factor (HGF) is upregulated in response to lung injury and has been implicated in tissue repair through its antiapoptotic and proliferative activities. Cyclooxygenase-2 (COX-2) is an inducible enzyme in the biosynthetic pathway of prostaglandins, and its activation has been shown to play a role in cell growth. Here, we report that HGF induces gene transcription of COX-2 in human bronchial epithelial cells (HBEpC). Treatment of HBEpC with HGF resulted in phosphorylation of the HGF receptor (c-Met), activation of Akt, and upregulation of COX-2 mRNA. Adenovirus-mediated gene transfer of a dominant negative (DN) Akt mutant revealed that HGF increased COX-2 mRNA in an Akt-dependent manner. COX-2 promoter analysis in luciferase reporter constructs showed that HGF regulation required the β-catenin-responsive T cell factor-4 binding element (TBE). The HGF activation of the COX-2 gene transcription was blocked by DN mutant of β-catenin or by inhibitors that blocked activation of Akt. Inhibition of p42/p44 MAPK pathway blocked HGF-mediated activation of β-catenin gene transcription but not Akt activation, suggesting that p42/p44 MAPK acts in a parallel mechanism for β-catenin activation. We also found that inhibition of COX-2 with NS-398 blocked HGF-induced growth in HBEpC. Together, the results show that the HGF increases COX-2 gene expression via an Akt-, MAPK-, and β-catenin-dependent pathway in HBEpC.

Aim Real‐time tissue elastography ( RTE ) is a non‐invasive method for the measurement of tissue elasticity using ultrasonography. Liver fibrosis ( LF ) index is a quantitative method for evaluation of liver fibrosis calculated by RTE image features. This study aimed to investigate the significance of LF index for predicting liver fibrosis in chronic hepatitis C patients. Methods In this prospective study, 115 patients with chronic hepatitis C who underwent liver biopsy were included, and the diagnostic accuracy of LF index and serum fibrosis markers was evaluated. Results RTE imaging was successfully performed on all patients. Median LF index in patients with F 0–1, F 2, F 3 and F 4 were 2.61, 3.07, 3.54 and 4.25, respectively, demonstrating a stepwise increase with liver fibrosis progression ( P &lt; 0.001). LF index (odds ratio [ OR ] = 5.3, 95% confidence interval [ CI ] = 2.2–13.0) and platelet count ( OR = 0.78, 95% CI = 0.68–0.89) were independently associated with the presence of advanced fibrosis ( F 3–4). Further, LF index was independently associated with the presence of minimal fibrosis ( F 0–1) ( OR = 0.25, 95% CI = 0.11–0.55). The area under the receiver–operator curve ( AUROC ) of LF index for predicting advanced fibrosis (0.84) was superior to platelets (0.82), FIB ‐4 index (0.80) and aspartate aminotransferase/platelet ratio index ( APRI ) (0.76). AUROC of LF index (0.81) was superior to platelets (0.73), FIB ‐4 index (0.79) and APRI (0.78) in predicting minimal fibrosis. Conclusion LF index calculated by RTE is useful for predicting liver fibrosis, and diagnostic accuracy of LF index is superior to serum fibrosis markers.

Reactive oxygen species (ROS) mediate cell-signaling processes in response to various ligands and play important roles in the pathogenesis of cardiovascular diseases. The present study reports that interleukin-22 (IL-22) elicits signal transduction in vascular smooth muscle cells (SMCs) through a ROS-dependent mechanism. We find that pulmonary artery SMCs express IL-22 receptor alpha 1 and that IL-22 activates STAT3 through this receptor. IL-22-induced signaling is found to be mediated by NADPH oxidase, as indicated by the observations that the inhibition and siRNA knock-down of this enzyme inhibit IL-22 signaling. IL-22 triggers the oxidative modifications of proteins through protein carbonylation and protein glutathionylation. Mass spectrometry identified some proteins that are carbonylated in response to IL-22 stimulation, including α-enolase, heat shock cognate 71 kDa protein, mitochondrial 60 kDa heat shock protein, and cytoplasmic 2 actin and determined that α-tubulin is glutathionylated. Protein glutathionylation and STAT3 phosphorylation are enhanced by the siRNA knock-down of glutaredoxin, while IL-22-mediated STAT3 phosphorylation is suppressed by knocking down thioredoxin interacting protein, an inhibitor of thioredoxin. IL-22 is also found to promote the growth of SMCs via NADPH oxidase. In rats, pulmonary hypertension is found to be associated with increased smooth muscle IL-22 expression. These results show that IL-22 promotes the growth of pulmonary vascular SMCs via a signaling mechanism that involves NADPH oxidase-dependent oxidation.

Substantial experimental evidence suggests the usefulness of antioxidants for the treatment of various forms of pulmonary hypertension. However, no recommendations have yet been made if patients with pulmonary hypertension should receive pharmacologic and/or dietary antioxidants. Our understanding of antioxidants has evolved greatly over the last two decades, from the primitive use of natural antioxidant vitamins to the modulation of vascular oxidases, such as NAD(P)H oxidases. These oxidases and their products not only regulate pulmonary vascular tone and intimal and smooth muscle thickening, but also modulate the adaptation of the right ventricle to increased afterload. It is important that well-designed randomized clinical trials be conducted to test the importance of oxidase-reactive oxygen species activation in the pathogenesis and treatment of pulmonary hypertension. The purpose of this Forum on Pulmonary Hypertension is to summarize the available preclinical information, which may aid in designing and conducting future randomized clinical trials for evaluating the efficacy of antioxidants for the treatment of pulmonary hypertension. The complexity of oxidative pathways contributed to the tremendous difficulties and challenges in selecting agents, doses, and designing clinical trials. Further studies using human, animal, and cell culture models may be needed to define optimal trials. This Forum on Pulmonary Hypertension should stimulate new thinking and provide essential background information to better define the challenges of developing successful randomized clinical trials in the near future.

Vitamin E refers to a family of compounds that function as lipid-soluble antioxidants capable of preventing lipid peroxidation. Naturally occurring forms of vitamin E include tocopherols and tocotrienols. Vitamin E in dietary supplements and fortified foods is often an esterified form of α-tocopherol, the most common esters being acetate and succinate. The vitamin E esters are hydrolyzed and converted into free α-tocopherol prior to absorption in the intestinal tract. Because its functions are relevant to many chronic diseases, vitamin E has been extensively studied in respect to a variety of diseases as well as cosmetic applications. The forms of vitamin E most studied are natural α-tocopherol and the esters α-tocopheryl acetate and α-tocopheryl succinate. A small number of studies include or focus on another ester form, α-tocopheryl nicotinate, an ester of vitamin E and niacin. Some of these studies raise the possibility of differences in metabolism and in efficacy between vitamin E nicotinate and other forms of vitamin E. Recently, through metabolomics studies, we identified that α-tocopheryl nicotinate occurs endogenously in the heart and that its level is dramatically decreased in heart failure, indicating the possible biological importance of this vitamin E ester. Since knowledge about vitamin E nicotinate is not readily available in the literature, the purpose of this review is to summarize and evaluate published reports, specifically with respect to α-tocopheryl nicotinate with an emphasis on the differences from natural α-tocopherol or α-tocopheryl acetate.

Major vault protein forms a hollow, barrel-like structure in the cell called the vault, whose functions and regulation are not well understood. The present study reports that major vault protein regulates growth/survival signaling in human airway smooth muscle cells through oxidative modifications. The promotion of protein S-glutathionylation by asthma mediators such as interleukin-22 and platelet-derived growth factor or by knocking down glutaredoxin-1 or thioredoxin activated cell growth signaling. Mass spectrometry identified that major vault protein is glutathionylated. Major vault protein knockdown enhanced cell death and inhibited STAT3 and Akt signaling. We identified a protein partner of major vault protein that is regulated by glutaredoxin-1, namely myosin-9, which was found to serve as a cell death factor. Knocking down myosin-9 or promoting protein S-glutathionylation by knocking down glutaredoxin-1 inhibited the death of airway smooth muscle cells by heating to simulate bronchial thermoplasty, a clinically successful procedure for the treatment of severe asthma. These results establish a novel signaling pathway in which ligand/receptor-mediated oxidation promotes the S-glutathionylation of major vault protein, which in turn binds to myosin-9 to suppress the heating-induced death of airway smooth muscle cells.

This study reveals the hydrocarbon generation potential and thermal maturity of coal and coaly mudstones from the Eocene Urahoro Group in the Kushiro coal basin (Kushiro Basin) of eastern Hokkaido (Japan). The coal is classified as subbituminous or high volatile C bituminous, and characterized by high hydrogen content (6.1 ± 0.4 wt%, 1σ, dry ash free basis). The hydrogen index (HI = 180–409 mg hydrocarbon/g total organic carbon) and random mean vitrinite reflectance (VRr = 0.42–0.56%) indicate that the coal and coaly mudstones in the Urahoro Group are gas- and oil-prone or oil-prone. Based on the HI and VRr values, the effective oil window starts at vitrinite reflectance ranges of 0.55 to 0.80%. The vitrinite reflectance of coal samples from the Kushiro Coal Mine is inversely proportional to the HI value, although each coal seam has the identical thermal history. This result suggests that the vitrinite reflectance of the samples in the Kushiro Coal Mine is suppressed. Based on the corrected vitrinite reflectance (non-suppressed vitrinite reflectance), the maturity of the coal in the Kushiro Basin increases towards the north. The non-suppressed vitrinite reflectance of the samples from the northernmost part of the basin (Hokuyo Area) was approximately 0.8%, which is within the start of the oil window. The maturity of the coal-bearing strata in the northern area of the basin could be affected by volcanic activity along the volcanic front. In the Hokuyo Area, the Urahoro Group overlies a sequence of Cretaceous–Eocene marine clastic rocks (Nemuro Group), which are about 3000–4000 m in total thickness, suggesting that the organic matter in the marine clastic rocks should reach higher maturity (VRr > 0.8%).

Total body irradiation (TBI) can result in death associated with hematopoietic insufficiency. Although radiation causes apoptosis of white blood cells, red blood cells (RBC) undergo hemolysis due to hemoglobin denaturation. RBC lysis post-irradiation results in the release of iron into the plasma, producing a secondary toxic event. We investigated radiation-induced iron in the spleens of mice following TBI and the effects of the radiation mitigator captopril. RBC and hematocrit were reduced ~7 days (nadir ~14 days) post-TBI. Prussian blue staining revealed increased splenic Fe3+ and altered expression of iron binding and transport proteins, determined by qPCR, western blotting, and immunohistochemistry. Captopril did not affect iron deposition in the spleen or modulate iron-binding proteins. Caspase-3 was activated after ~7-14 days, indicating apoptosis had occurred. We also identified markers of iron-dependent apoptosis known as ferroptosis. The p21/Waf1 accelerated senescence marker was not upregulated. Macrophage inflammation is an effect of TBI. We investigated the effects of radiation and Fe3+ on the J774A.1 murine macrophage cell line. Radiation induced p21/Waf1 and ferritin, but not caspase-3, after ~24 h. Radiation ± iron upregulated several markers of pro-inflammatory M1 polarization; radiation with iron also upregulated a marker of anti-inflammatory M2 polarization. Our data indicate that following TBI, iron accumulates in the spleen where it regulates iron-binding proteins and triggers apoptosis and possible ferroptosis.

Cardiovascular complications are seen among human immunodeficiency virus (HIV)-positive individuals, who now survive longer due to successful antiretroviral therapies. Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased blood pressure in the lung circulation. The prevalence of PAH in the HIV-positive population is dramatically higher than that in the general population. While HIV-1 Group M Subtype B is the most prevalent subtype in western countries, the majority of HIV-1 infections in eastern Africa and former Soviet Union countries are caused by Subtype A. Research on vascular complications in the HIV-positive population in the context of subtype differences, however, has not been rigorous. Much of the research on HIV has focused on Subtype B, and information on the mechanisms of Subtype A is nonexistent. The lack of such knowledge results in health disparities in the development of therapeutic strategies to prevent/treat HIV complications. The present study examined the effects of HIV-1 gp120 of Subtypes A and B on human pulmonary artery endothelial cells by performing protein arrays. We found that the gene expression changes caused by gp120s of Subtypes A and B are different. Subtype A is a more potent downregulator of perostasin, matrix metalloproteinase-2, and ErbB than Subtype B, while Subtype B is more effective in downregulating monocyte chemotactic protein-2 (MCP-2), MCP-3, and thymus- and activation-regulated chemokine proteins. This is the first report of gp120 proteins affecting host cells in an HIV subtype-specific manner, opening up the possibility that complications occur differently in HIV patients throughout the world.

Atezolizumab plus bevacizumab (AB) combination therapy is the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). The management of immune-related adverse events (irAEs) is an important issue associated with achieving a good therapeutic response in patients receiving AB therapy. However, few studies have reported irAE development in patients receiving AB therapy. This study focused on the association between irAE development and autoantibodies at baseline in patients receiving AB therapy.Sixty-one patients receiving AB therapy were enrolled. For autoantibodies, the following antibodies were tested before the start of AB therapy: antinuclear antibodies, rheumatoid factor (RF), anti-thyroglobulin antibodies, thyroid peroxidase antibodies, anti-thyroid stimulating hormone receptor antibodies, and acetylcholine receptor antibodies. A patient was considered to have pre-existing antibodies if any of the listed antibodies were present at baseline.Ten patients (16%) developed irAEs during the observation period. The irAEs included liver injury, hypothyroidism, adrenal insufficiency, adrenocorticotropic hormone deficiency, and rhabdomyolysis. Patients with irAE (n = 10) were more likely to be positive for any autoantibody (hazard ratio [HR] 3.7, p = 0.047) and RF at baseline (HR 5.4, p = 0.035) and to achieve complete response (HR 5.8, p = 0.027) than those without. The presence of autoantibodies at baseline was an independent factor associated with irAE development.In the real world, 16% of patients receiving AB therapy for u-HCC developed irAEs. Patients with autoantibodies at baseline are at high risk of developing irAEs and require cautious follow-up.

Falls are caused by a combination of factors, including loss of lower limb muscle strength (LMS), and associated with declined performance status (PS). Age-related sarcopenia is generally associated with decreased muscle mass and strength of lower limb muscle but without a noticeable loss of those of upper limb or trunk muscle. However, no reports have focused on falls or LMS in chronic liver disease (CLD) patients. This study is the first to analyze the risk factors for falls in patients with CLD, focusing on LMS measurement using the Locomoscan. This study enrolled 315 CLD patients whose LMS was measured. The patients who experienced falls more than 1 year ago or during the observation period were classified as those who experienced falls. We found that risk factors for falls were PS1/2 and decreased LMS (< 0.32 N/kg). The group with sarcopenia had a higher frequency of decreased LMS (54 vs. 26%, p = 0.001) and falls (24 vs. 4.4%, p < 0.001) compared to the non-sarcopenia group. This study found that decreased LMS was an independent risk factor for falls. Assessment of LMS may be used as a better marker associated with the risk of falls in patients with CLD.

Objective: &#x0D; Local ablation therapies (radiofrequency ablation (RFA), and microwave ablation (MWA)) are important as curative treatment option in patient with early-stage hepatocellular carcinoma (HCC) and option for intrahepatic tumor volume reduction in those with unresectable HCC. Various techniques; contrast-enhanced ultrasound (CEUS), real-time virtual sonography (RVS), artificial pleural and ascites fluid infusion, and body position change (BPC) have been used to accurately and safely perform local ablation therapies. However, there have been few reports on the usefulness of BPC. Therefore, this study focused on the usefulness of BPC during local ablation therapies in patients with HCC.&#x0D; Methods: &#x0D; We evaluated the technical success rates, treatment time, and prognosis of 283 nodules treated with local ablation therapies. Furthermore, we defined nodules adjacent to large vessels or extrahepatic organs, or poorly visible nodules using US as HCC in high-risk locations. High-risk locations HCC were classified into phase 1 (before active use of BPC, January 2018 to December 2019) and phase 2 (after active use of BPC, January 2020 to January 2022).&#x0D; Results: &#x0D; One hundred seventy-six nodules (62%) were classified as high-risk location group. Compared to non-high risk HCC, treatment-assist techniques, such as BPC (61 vs. 24 %, p&amp;lt;0.001), artificial pleural fluid infusion (24 vs. 5.6%, p&amp;lt;0.001), artificial ascites infusion (50 vs. 11%, p&amp;lt;0.001), fusion imaging (28 vs. 8.4%, p&amp;lt;0.001) and CEUS (26 vs. 4.7%, p&amp;lt;0.001) were performed more frequently for high-risk HCC.&#x0D; The technical success rates were 96% (271/283 nodules), 96% (167/173 nodules) and 95% (102/107 nodules), for all nodules, the high-risk location group and the non-high risk location group, respectively. In the high-risk location group, the technical success rates of the group without BPC were lower than that with BPC (91 vs. 99%, p=0.015). Only BPC was a related factor for the technical success rate for high-risk locations HCC (OR 10 (1.2-86), p=0.034). In contrast, no differences were found in the treatment time, the local tumor progression rates, intrahepatic distant recurrence rates, and overall survival between the group with BPC and that without BPC in the high-risk location HCC.&#x0D; Conclusion: &#x0D; BPC during local ablation therapies in patients with HCC in high-risk locations was safe and efficient. Body position should be adjusted for HCC in high-risk locations to maintain good US visibility and ensure safe puncture route in patients undergoing local ablation therapies.