Jie Bai

Signaling pathways involved in oxidative stress-induced inhibition of osteoblast differentiation are not known. We showed in this report that H(2)O(2) (0.1-0.2mM)-induced oxidative stress suppressed the osteoblastic differentiation process of primary rabbit bone marrow stromal cells (BMSC) and calvarial osteoblasts, manifested by a reduction of differentiation markers including alkaline phosphatase (ALP), type I collagen, colony-forming unit-osteoprogenitor (CFU-O) formation, and nuclear phosphorylation of Runx2. H(2)O(2) treatment stimulated phospholipase C-gamma1 (PLC-gamma1), extracellular signal-regulated kinase 1/2 (ERK1/2), and NF-kappaB signaling but inhibited p38 mitogen-activated protein kinase (MAPK) activation. In the presence of 20microM PD98059 or 50microM caffeic acid phenethyl ester (CAPE), specific inhibitor for ERKs or NF-kappaB, respectively, could significantly reverse the decrease of above-mentioned osteoblastic differentiation markers elicited by H(2)O(2) (0.1mM). Furthermore, PD98059 also suppressed H(2)O(2)-stimulated NF-kappaB signaling in this process. These data suggest that ERK and ERK-dependent NF-kappaB activation is required for oxidative stress-induced inhibition of osteoblastic differentiation in rabbit BMSC and calvarial osteoblasts.

Anti-programmed death-1 (PD-1) monotherapy induces a high response rate in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but complete remission (CR) is infrequently observed. As decitabine is known to boost T-cell function, we assessed the safety and efficacy of anti-PD-1 camrelizumab alone versus decitabine-primed camrelizumab in patients with relapsed/refractory cHL.This two-arm, open-label, phase II study enrolled patients with relapsed/refractory cHL who had received at least two lines of previous therapy. Anti-PD-1 treatment-naïve patients were randomly assigned (1:2) to camrelizumab (200 mg) monotherapy or decitabine (10 mg/d, days 1 to 5) plus camrelizumab (200 mg, day 8) combination therapy every 3 weeks. Patients who were previously treated with anti-PD-1 were assigned combination therapy. Primary end point was CR rate and safety.Overall, 86 patients were enrolled and evaluated for response, with a median follow-up of 14.9 months. In anti-PD-1-naïve patients, CR rate was 32% (six of 19 patients) with camrelizumab monotherapy versus 71% (30 of 42 patients) who were administered decitabine plus camrelizumab (P = .003). At the time of analysis, the response duration rate at 6 months was 76% on camrelizumab monotherapy versus 100% on decitabine plus camrelizumab. For patients who were previously treated with anti-PD-1, 28% achieved CR and 24% partial response after decitabine plus camrelizumab. Ten patients maintained a response at more than 6 months and 81% of responders were estimated to have a response at more than 1 year. For both treatments, the most common adverse events were clinically inconsequential cherry hemangiomas and leukocytopenia that were self-limiting.CR rate in patients with relapsed/refractory cHL who were clinically naïve to PD-1 blockade was significantly higher with decitabine plus camrelizumab than with camrelizumab alone. Decitabine plus camrelizumab may reverse resistance to PD-1 inhibitors in patients with relapsed/refractory cHL.

Thioredoxin (Trx), a redox enzyme with a conserved active site (Cys-32-Gly-Pro-Cys-35), is induced and secreted into circulation in response to inflammation. Studies here demonstrate that elevating Trx levels in circulation either by i.v. injection of recombinant Trx or stimulating Trx release in Trx-transgenic mice dramatically blocks lipopolysaccharide (LPS)-stimulated neutrophil migration in the murine air pouch chemotaxis model. Furthermore, we show that leukocyte recruitment induced by the murine chemokines KC/GROalpha, RANTES (regulated upon activation, normal T cell expressed and secreted), and monocyte chemoattractant protein-1 (MCP-1) is suppressed also in Trx-transgenic mice. Addressing the mechanism responsible for this suppression, we show that circulating Trx blocks (i) the LPS-stimulated in vitro activation of neutrophil p38 mitogen-activated protein kinase, (ii) the normal down-regulation of CD62L on neutrophils migrating into the LPS-stimulated air pouch, and (iii) the in vitro adhesion of LPS-activated neutrophils on endothelial cells. However, as we also show, Trx does not alter the expression of endothelial cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, CD62P, and CD62E) within 3 h. Collectively, these findings indicate that elevated levels of circulating Trx interfere with chemotaxis by acting directly on neutrophils. We discuss these findings in the context of recent studies reporting beneficial effects of acutely elevated Trx in ischemic injury and negative effects associated with chronically elevated Trx in HIV disease.

To evaluate the effects and safety of 300-600 mg α-lipoic acid (ALA) given i.v. for diabetic peripheral neuropathy (DPN).We searched the databases of Medline, Embase, and Cochrane central register of Controlled Trials and Chinese biological medicine for clinical trials of ALA in the treatment of DPN. Data were extracted to examine methodological quality and describe characteristics of studies. The primary outcomes were efficacy, median motor nerve conduction velocity (MNCV), median sensory nerve conduction velocity (SNCV), peroneal MNCV, and peroneal SNCV. Secondary outcomes were adverse events.Fifteen randomized controlled trials met the inclusion criteria. The treatment group involved the administration of ALA 300-600 mg i.v. per day. And the control group used the same interventions except for ALA. Compared with the control group, nerve conduction velocities increased significantly in the treatment group. The weighted mean differences in nerve conduction velocities were 4.63 (95% confidence interval 3.58-5.67) for median MNCV, 3.17 (1.75-4.59) for median SNCV, 4.25 (2.78-5.72) for peroneal MNCV, and 3.65 (1.50-5.80) for peroneal SNCV in favor of the treatment group. The odds ratio in terms of efficacy was 4.03 (2.73-5.94) for ALA. Furthermore, no serious adverse events were observed during the treatment period.The results of this meta-analysis provide evidence that treatment with ALA (300-600 mg/day i.v. for 2-4 weeks) is safe and that the treatment can significantly improve both nerve conduction velocity and positive neuropathic symptoms. However, the evidence may not be strong because most of the studies included in this meta-analysis have poor methodological quality.

Immune checkpoint blockades, such as inhibitors against programmed death 1 (PD-1) and its ligand (PD-L1), have received extensive attention in the past decade because of their dramatic clinical outcomes in advanced malignancies.However, both primary and acquired resistance becomes one of the major obstacles, which greatly limits the long-lasting effects and wide application of PD-1/PD-L1 blockade therapy.PD-1/PD-L1 both regulates and is regulated by cellular signaling pathways and epigenetic modification, thus inhibiting the proliferation and effector function of T and B cells.The lack of tumor antigens and effective antigen presentation, aberrant activation of oncogenic pathways, mutations in IFN-γ signaling, immunosuppressive tumor microenvironment such as regulatory T cells, myeloid-derived suppressor cells, M2 macrophages, and immunoinhibitory cytokines can lead to resistance to PD-1/PD-L1 blockade.In this review, we describe PD-1 related signaling pathways, essential factors contributing to the resistance of PD-1 blockade, and discuss strategies to increase the efficacy of immunotherapy.Furthermore, we discuss the possibility of combined epigenetic therapy with PD-1 blockade as a potential promising approach for cancer treatment.

Endoplasmic reticulum (ER) stress has been implicated in Parkinson disease. We previously reported that thioredoxin 1 (Trx-1) suppressed the ER stress caused by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine; however, its molecular mechanism remains largely unknown. In the present study, we showed that 1-methyl-4-phenylpyridinium ion (MPP(+)) induced ER stress by activating glucose-regulated protein 78 (GRP78), inositol-requiring enzyme 1α (IRE1α), tumor necrosis factor receptor-associated factor 2 (TRAF2), c-Jun N-terminal kinase (JNK), caspase-12, and C/EBP homologous protein (CHOP) in PC12 cells. The downregulation of Trx-1 aggravated the ER stress and further increased the expression of the above molecules induced by MPP(+). In contrast, overexpression of Trx-1 attenuated the ER stress and repressed the expression of the above molecules induced by MPP(+). More importantly, the overexpression of Trx-1 in transgenic mice suppressed ER stress by inhibiting the activation of these molecules. We present, for the first time, the molecular mechanism of Trx-1 suppression of endoplasmic reticulum stress in Parkinson disease in vitro and in vivo. Based on our findings, we conclude that Trx-1 plays a neuroprotective role in Parkinson disease by suppressing ER stress by regulating the activation of GRP78, IRE1α, TRAF2, JNK, caspase-12, and CHOP.

MicroRNAs (miRNAs) play important roles in the progression of human cancer. Although previous reports have shown that miR-145-5p is down-regulated in esophageal squamous cell carcinoma (ESCC), the roles and mechanisms of down-regulation of miR-145-5p in ESCC are still largely unknown. Using microRNA microarray and Gene Expression Omnibus (GEO) datasets, we confirmed that miR-145-5p was down-regulated in ESCC tissues. In vitro assays revealed that ectopic miR-145-5p expression repressed cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT). miR-145-5p also reduced the expressions of cell cycle genes including cyclin A2 (CCNA2), cyclin D1 (CCND1) and cyclin E1 (CCNE1), the EMT-associated transcription factor Slug, and matrix metalloproteinases (MMPs) including MMP2, MMP7 and MMP13. Furthermore, miR-145-5p mimics reduced candidate target gene specificity protein 1 (Sp1) and nuclear factor κ B (NF-κB) (p65) both in mRNA and protein levels. Knockdown of Sp1 phenocopied the effects of miR-145-5p overexpression on cell cycle regulators, EMT and the expression of NF-κB (p65). Importantly, inhibition of the NF-κB signaling pathway or knockdown of NF-κB (p65) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells. In conclusion, our results suggested that miR-145-5p plays tumor-suppressive roles by inhibiting esophageal cancer cell migration, invasion and EMT through regulating the Sp1/NF-κB signaling pathway.

Abstract Background Gestational diabetes mellitus (GDM) is a temporary form of diabetes during pregnancy, which influences the health of maternal-child in clinical practice. It is still urgent to develop new effective treatment for GDM. Naringenin is a bioactive ingredient with multiple activities including anti-diabetic. In current study, the effects of naringenin on GDM symptoms, insulin tolerance, inflammation, and productive outcomes were evaluated and the underlying mechanisms were explored. Methods We administrated naringenin to GDM mice and monitored the GDM symptoms, glucose and insulin tolerance, inflammation and productive outcomes. We established tumor necrosis factor alpha (TNF-α)-induced insulin resistance skeletal muscle cell model and evaluated the effects of naringenin on reactive oxygen species (ROS) production, glucose uptake and glucose transporter type 4 (GLUT4) membrane translocation. Results We found that naringenin ameliorated GDM symptoms, improved glucose and insulin tolerance, inhibited inflammation, and improved productive outcomes. It was further found that naringenin inhibited TNF-α-induced ROS production, enhanced GLUT4 membrane translocation, and glucose uptake, which were abolished by inhibition of AMP-activated protein kinase (AMPK). Conclusion Naringenin improves insulin sensitivity in gestational diabetes mellitus mice in an AMPK-dependent manner.

Ferroptosis is a new form of programmed cell death with characteristic accumulation of reactive oxygen species (ROS) resulting from iron accumulation and lipid peroxidation. Ferroptosis is involved in many diseases, including cancer, and induction of ferroptosis has shown attractive antitumour activities. In this review, we summarize recent findings on the regulatory mechanisms of key regulators of ferroptosis, including the catalytic subunit solute carrier family 7 member 11 (SLC7A11), the glutathione peroxidase 4 (GPX4), p53 and non-coding RNAs, the correlations between ferroptosis and iron homeostasis or autophagy, ferroptosis-inducing agents and nanomaterials and the diagnostic and prognostic value of ferroptosis-associated genes in TCGA data.

Background The isocitrate dehydrogenase (IDH) genotype and 1p/19q codeletion status are key molecular markers included in glioma pathologic diagnosis. Advanced diffusion models provide additional microstructural information. Purpose To compare the diagnostic performance of histogram features of multiple diffusion metrics in predicting glioma IDH and 1p/19q genotyping. Materials and Methods In this prospective study, participants were enrolled from December 2018 to December 2020. Diffusion-weighted imaging was performed by using a spin-echo echo-planar imaging sequence with five b values (500, 1000, 1500, 2000, and 2500 sec/mm2) in 30 directions for every b value and one b value of 0. Diffusion metrics of diffusion-tensor imaging (DTI), diffusion-kurtosis imaging (DKI), neurite orientation dispersion and density imaging (NODDI), and mean apparent propagator (MAP) were calculated, and their histogram features were analyzed in regions that included the entire tumor and peritumoral edema. Comparisons between groups were performed according to IDH genotype and 1p/19q codeletion status. Logistic regression analysis was used to predict the IDH and 1p/19q genotypes. Results A total of 215 participants (115 men, 100 women; mean age, 48 years ± 13 [standard deviation]) with grade II (n = 68), grade III (n = 35), and grade IV (n = 112) glioma were included. Among the DTI, DKI, NODDI, MAP, and total diffusion models, there were no significant differences in the areas under the receiver operating characteristic curve (AUCs) for predicting IDH mutations (AUC, 0.76, 0.82, 0.78, 0.81, and 0.82, respectively; P > .05) and 1p/19q codeletion in gliomas with IDH mutations (AUC, 0.83, 0.81, 0.82, 0.83, and 0.88, respectively; P > .05). A regression model with an R2 value of 0.84 was used for the Ki-67 labeling index and histogram features of the diffusion metrics. Conclusion Whole-tumor histogram analysis of multiple diffusion metrics is a promising approach for glioma isocitrate dehydrogenase and 1p/19q genotyping, and the performance of diffusion-tensor imaging is similar to that of advanced diffusion models. Clinical trial registration no. ChiCTR2100048119 © RSNA, 2021 Online supplemental material is available for this article.An earlier incorrect version appeared online. This article was corrected on December 14, 2021.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Its molecular mechanism is still unclear, and pharmacological treatments are unsatisfactory. Transient receptor potential vanilloid 4 (TRPV4) is a nonselective Ca2+ channel. It has recently emerged as a critical risk factor in the pathophysiology of neuronal injuries and cerebral diseases. Our previous study reported that TRPV4 contributed to endoplasmic reticulum (ER) stress in the MPP+-induced cell model of PD. In the present study, we detected the role and the mechanism of TRPV4 in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice.Intracerebral injection of an adeno-associated virus (AAV) into the substantia nigra (SN) of mice was used to knockdown or upregulate the expression of TRPV4 and intraperitoneal injection of MPTP. Rotarod and pole tests were used to evaluate the locomotor ability of mice. We used immunohistochemistry, Nissl staining and Western blot to detect the alterations in the number of tyrosine hydroxylase (TH)-positive neurons, Nissl-positive neurons, the levels of ER stress-associated molecules and proinflammatory cytokines in the SN.The SN was transfected with AAV for 3 weeks and expressed the target protein with green fluorescence. Knockdown of TRPV4 via injection of a constructed AAV-TRPV4 shRNAi into the SN alleviated the movement deficits of PD mice. Upregulation of TRPV4 via injection of a constructed AAV-TRPV4 aggravated the above movement disorders. The expression of TRPV4 was upregulated in the SN of MPTP-treated mice. Injection of AAV-TRPV4 shRNAi into the SN rescued the number of TH-positive and Nissl-positive neurons in the SN decreased by MPTP, while injection of AAV-TRPV4 induced the opposite effect. Moreover, MPTP-decreased Sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) and pro-cysteinyl aspartate specific proteinase-12 (procaspase-12), MPTP-increased Glucose-regulated protein 78 (GRP78), Glucose-regulated protein 94 (GRP94) and C/EBP homologous protein (CHOP) were inhibited by AAV-TRPV4 shRNAi infection, and enhanced by AAV-TRPV4. In the same way, MPTP-decreased procaspase-1, MPTP-increased Interleukin-18 (IL-18), Cyclooxgenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) were inhibited by AAV-TRPV4 shRNAi, or further exacerbated by AAV-TRPV4.These results suggest that TRPV4 mediates ER stress and inflammation pathways, contributing to the loss of dopamine (DA) neurons in the SN and movement deficits in PD mice. Moreover, this study provides a new perspective on molecular targets and gene therapies for the treatment of PD in the future.

Thioredoxin (TRX) is induced by a variety of oxidative stimuli and shows cytoprotective roles against oxidative stress. To clarify the possibility of clinical application, we examined the effects of intravenously administered TRX in a model of transient focal cerebral ischemia in this study. Mature male C57BL/6j mice received either continuous intravenous infusion of recombinant human TRX (rhTRX) over a range of 1-10 mg/kg, bovine serum albumin, or vehicle alone for 2 h after 90-min transient middle cerebral artery occlusion (MCAO). Twenty-four hours after the transient MCAO, the animals were evaluated neurologically and the infarct volumes were assessed. Infarct volume, neurological deficit, and protein carbonyl contents, a marker of protein oxidation, in the brain were significantly ameliorated in rhTRX-treated mice at the dose of 3 and 10 mg/kg versus these parameters in control animals. Moreover, activation of p38 mitogen-activated protein kinase, whose pathway is involved in ischemic neuronal death, was suppressed in the rhTRX-treated mice. Further, rhTRX was detected in the ischemic hemisphere by western blot analysis, suggesting that rhTRX was able to permeate the blood-brain barrier in the ischemic hemisphere. These data indicate that exogenous TRX exerts distinct cytoprotective effects on cerebral ischemia/reperfusion injury in mice by means of its redox-regulating activity.

Background Vandetanib is a multikinase inhibitor that is under assessment for the treatment of various cancers. QTc interval prolongation is one of the major adverse effects of this drug, but the reported incidence varies substantially among clinical trials. We performed a systematic review and meta-analysis to obtain a better understanding in the risk of QTc interval prolongation among cancer patients administered vandetanib. Methodology and Principal Findings Eligible studies were phase II and III prospective clinical trials that involved cancer patients who were prescribed vandetanib 300 mg/d and that included data on QTc interval prolongation. The overall incidence and risk of QTc interval prolongation were calculated using random-effects or fixed-effects models, depending on the heterogeneity of the included studies. Nine trials with 2,188 patients were included for the meta-analysis. The overall incidence of all-grade and high-grade QTc interval prolongation was 16.4% (95% CI, 8.1–30.4%) and 3.7% (8.1–30.4%), respectively, among non-thyroid cancer patients, and 18.0% (10.7–28.6%) and 12.0% (4.5–28.0%), respectively, among thyroid cancer patients. Patients with thyroid cancer who had longer treatment duration also had a higher incidence of high-grade events, with a relative risk of 3.24 (1.57–6.71), than patients who had non-thyroid cancer. Vandetanib was associated with a significantly increased risk of all-grade QTc interval prolongation with overall Peto odds ratios of 7.26 (4.36–12.09) and 5.70 (3.09–10.53) among patients with non-thyroid cancer and thyroid cancer, respectively, compared to the controls. Conclusions/Significance Treatment with vandetanib is associated with a significant increase in the overall incidence and risk of QTc interval prolongation. Different cancer types and treatment durations may affect the risk of developing high-grade QTc interval prolongation.

Panax notoginseng, a traditional Chinese medicine, has been used for thousands of years to treat ischemic patients. More than 20 saponin components have been isolated from P. notoginseng root and identified chemically. However, these different chemical components have different roles. In this study we compared the neuroprotective mechanisms of ginsenosides Rg1, Rb1, Rg1/Rb1, and panax notoginsenoside (PNS) against injuries caused by cerebral ischemia–reperfusion (I/R). Our results show that all of these treatments significantly reduced infarction volume and alleviated neurological deficits caused by cerebral I/R. The increase in malondialdehyde (MDA) concentration was inhibited by these treatments in the hippocampus. The decreased expressions of thioredoxin-1 (Trx-1), copper–zinc superoxide dismutase (SOD-1), protein kinase B (PKB/Akt), and nuclear factor-kappa B (NF-κB) caused by cerebral I/R were restored by these treatments. The expression of heat shock protein 70 (HSP70) was enhanced in the middle cerebral artery occlusion (MCAO) group, as well as in all of the treatment groups. These results suggest that Rg1 and Rb1 have similar roles in protecting the brain from ischemic damage; however, neither Rg1/Rb1 nor PNS have synergistic effects, thus either Rg1 or the Rb1 monomer should be considered as a pharmacological neuroprotective strategy for use in the case of ischemic stroke.

Recent studies have shown that interferon-γ (IFN-γ)-induced galectin-9 expression in Kupffer cells plays an essential role in modulatingthe microenvironment of hepatitis-associated hepatocellular carcinoma (HCC). However, whether or not IFN-γ induces galectin-9 expression in HCC cells, its biological role and regulatory mechanism in HCC development and progression are poorly defined. Quantitative PCR and western blotting analysis were used to detect galectin-9 and EZH2 levels in HCC cell lines stimulated with IFN-γ. Bioinformatics analysis and luciferase reporter assay were utilized to confirmthe binding ofmiR-22 to the 3′ untranslated region (3’-UTR) of galectin-9. The methylation status of miR-22 promoter was analyzed by MSP (Methylation specific PCR) and BSP (bisulfite sequencing PCR), while chromatin immunoprecipitation (ChIP) assay identify the occupation status of EZH2 and H3K27me3 at the promoter. Furthermore, the effect of ectopic expression of galectin-9 and miR-22 on cell proliferation, migration, invasion and cell apoptosis was assessed by using CCK-8, transwell assays and flow cytometric analysis, respectively. IFN-γ induces up-regulation of galectin-9 and EZH2 in HCC cell lines. Galectin-9 is a target of miR-22 and EZH2 facilitates galectin-9 expression by tri-methylation of H3K27 on miR-22 promoter but not hyper-methylation status of DNA. MiR-22 overexpression suppressed HCC cell growth, invasion, and metastasis both in vitro and in vivo. Interestingly, galectin-9 also exhibited antitumor effects, and restoring galectin-9 expression in miR-22 overexpressing cells strengthened its antitumor effects. These findings indicated that EZH2 facilitates galectin-9 expression by epigenetically repressing miR-22 and that galectin-9, which is known as an immunosuppressant, also functions as a tumor suppressor in HCC.

MicroRNAs (miRNAs) play important roles in the progression of human cancer including esophageal squamous cell carcinoma (ESCC). Although previous reports showed that miR-125b-5p was down-regulated in ESCC, the roles and mechanisms of loss of function of miR-125b-5p in ESCC were still unknown. Using microRNA microarray and GEO datasets, we found and confirmed that miR-125b-5p was down-regulated in ESCC tissues. In-vitro assays showed that ectopic miR-125b-5p expression repressed cell proliferation, migration and invasion, and induced cell senescence. We also found that miR-125b-5p reduced the expressions of cell cycle regulatory genes including CCNA2, CCND1 and CCNE1, and regulated the markers of epithelial to mesenchymal transition (EMT) including E-cadherin, N-cadherin and EMT associated transcription factor Slug, and also decreased the MMPs including MMP2, MMP7 and MMP13. Furthermore, the candidate target gene HMGA2 was negatively regulated by miR-125b-5p both in mRNA and protein levels. Importantly, knockdown of HMGA2 partially phenocopied the effects of miR-125b-5p overexpression on cell cycle regulators and EMT markers. In conclusion, our results suggested that overexpression of miR-125b-5p inhibited cell proliferation, migration and invasion partially by down-regulating HMGA2 in ESCC.

Solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and apoptosis inducing factor mitochondria associated 2 (AIFM2) are the key regulators in ferroptosis. However, the expression patterns and prognostic roles of these genes in pan-cancer are still largely unclear. The expression patterns and prognostic roles of SLC7A11, GPX4, and AIFM2 and the relationships between the expression levels of these genes and immune infiltration levels in pan-cancer were analyzed by using TIMER, gene expression profiling interactive analysis (GEPIA), Oncomine, and Kaplan–Meier databases. Our results showed that both SLC7A11 and GPX4 were overexpressed in colorectal cancer, and SLC7A11 was overexpressed in lung cancer. High levels of SLC7A11 and AIFM2 were significantly linked with the shortened disease-free survival and overall survival (OS) in adrenocortical carcinoma (ACC), respectively. And high expression of SLC7A11, GPX4, and AIFM2 were significantly correlated with the shortened OS of acute myeloid leukemia patients. In esophageal carcinoma (ESCA), GPX4 expression was significantly associated with the infiltration of macrophage and myeloid dendritic cell, and AIFM2 expression was significantly associated with the infiltration of CD4 + T cell. Importantly, GPX4 expression was positively correlated with the expression levels of monocyte markers (CD14 and CD115) and M2 macrophage markers (VSIG4 and MS4A4A) both in ESCA and in head and neck squamous cell carcinoma (HNSC). In summary, SLC7A11, GPX4, and AIFM2 are dysregulated in many types of cancers, and are candidate prognostic biomarkers for many types of cancers, and can be used to evaluate the infiltration of immune cells in tumor tissues.

Thioredoxin (TRX) has a role in a variety of biological processes, including cytoprotection and the activation of transcription factors. Nerve growth factor (NGF) is a major survival factor of sympathetic neurons and promotes neurite outgrowth in rat pheochromocytoma PC12 cells. In this study, we showed that NGF induces TRX expression at protein and mRNA levels. NGF activated the TRX gene through a regulatory region positioned from -263 to -217 bp, containing the cAMP-responsive element (CRE). Insertion of a mutation in the CRE in this region abolished the response to NGF. NGF induced binding of CRE-binding protein to the CRE of the TRX promoter in an electrophoretic mobility shift assay. NGF also induced nuclear translocation of TRX. 2'-Amino-3'-methoxyflavone, an inhibitor of mitogen-activated protein kinase kinase, which is a known inhibitor of NGF-dependent differentiation in PC12 cells, suppressed the NGF-dependent expression and nuclear translocation of TRX. Overexpression of mutant TRX (32S/35S) or TRX antisense vector blocked the neurite outgrowth of PC12 cells by NGF. Overexpression of mutant TRX (C32S/C35S) suppressed the NGF-dependent activation of the CRE-mediated c-fos reporter gene. These results suggest that TRX plays a critical regulatory role in NGF-mediated signal transduction and outgrowth in PC12 cells.

Exposure to excessive light induces retinal photoreceptor cell damage, leading to development and progression of various retinal diseases. We tested the effect of geranylgeranylacetone (GGA), an acyclic polyisoprenoid, on light-induced retinal damage in mice. Oral treatment with GGA (1.0 mg/d) for 5 d induced thioredoxin (Trx) and heat shock protein 72 (Hsp72) predominantly in the retinal pigment epithelium (RPE). After white light exposure (8000 lux for 2 h), the percentage of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive photoreceptor cells decreased significantly at 24 and 96 h, and the number of photoreceptor cell nuclei at 96 h and the electroretinographic amplitudes of the a- and b-waves at 4 and 10 d increased significantly in GGA-pretreated mice compared with saline-pretreated mice. Light-induced upregulations of 8-hydroxy-2-deoxyguanosine and 4-hydroxy-2-nonenal-modified protein, markers of oxidative stress, were inhibited by GGA pretreatment. To elucidate the cytoprotective mechanism of GGA and Trx, we used human K-1034 RPE cells and mouse photoreceptor-derived 661W cells. In K-1034 cells, GGA (10 μ m ) induced intracellular Trx, Hsp72, and extracellular Trx but not extracellular Hsp72. Extracellular Trx (0.75 n m ) attenuated H 2 O 2 (200 μ m )-induced cell damage in 661W cells. Pretreatment with GGA and overexpression of Trx in K-1034 cells counteracted H 2 O 2 (50 μ m )-induced attenuation of cellular latex bead incorporation. Protection of phagocytotic activity through induction of Trx and possibly Hsp72 in RPE cells and elimination of oxidative stress in the photoreceptor layer through release of Trx from RPE cells may be mechanisms of GGA-mediated cytoprotection. Therefore, Trx is a neurotrophic factor released from RPE cells and plays a crucial role in maintaining photoreceptor cell integrity.

Panaxatriol saponins (PTS), the main constituents extracted from Panax notoginseng, a Chinese herbal medicine, has been shown to be an effective agent on various diseases. Our previous study has demonstrated that PTS is an inducer of thioredoxin-1 (Trx-1) and has a possible potential as a therapeutic agent for Parkinson's disease (PD). However, the effect of PTS on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in vivo is unknown. Using locomotor activity test and traction test, we detected the effect of PTS on MPTP-induced behavioral impairment. Tyrosine hydroxylase, Trx-1, cyclooxygenase-2, pro-caspase-9, pro-caspase-12 and caspase-3 expressions in the anatomical region of substantia nigra pars compacta (SNc) were tested by Western blot. PTS provided neuroprotection against the loss of dopaminergic neurons and behavioral impairment caused by MPTP. MPTP-induced neuronal death in the SNc was suppressed by PTS through increasing Trx-1 expression, suppressing cyclooxygenase-2 over-expression and inhibiting mitochondria-mediated apoptosis. PTS, an inducer of Trx-1, has pluripharmacological properties in the protection against PD including enhancing antioxidant activity, acting as neurotrophic factor, modulating inflammation and inhibiting mitochondria-mediated apoptosis.

Abstract A cell-in-cell process refers to the invasion of one living cell into another homotypic or heterotypic cell. Different from non-apoptotic death processes of internalized cells termed entosis or cannibalism, we previously reported an apoptotic cell-in-cell death occurring during heterotypic cell-in-cell formation. In this study, we further demonstrated that the apoptotic cell-in-cell death occurred only in internalized immune killer cells expressing granzyme B (GzmB). Vacuole wrapping around the internalized cells inside the target cells was the common hallmark during the early stage of all cell-in-cell processes, which resulted in the accumulation of reactive oxygen species and subsequent mitochondrial injury of encapsulated killer or non-cytotoxic immune cells. However, internalized killer cells mediated rapid bubbling of the vacuoles with the subsequent degranulation of GzmB inside the vacuole of the target cells and underwent the reuptake of GzmB by killer cells themselves. The confinement of GzmB inside the vacuole surpassed the lysosome-mediated cell death occurring in heterotypic or homotypic entosis processes, resulting in a GzmB-triggered caspase-dependent apoptotic cell-in-cell death of internalized killer cells. On the contrary, internalized killer cells from GzmB-deficient mice underwent a typical non-apoptotic entotic cell-in-cell death similar to that of non-cytotoxic immune cells or tumor cells. Our results thus demonstrated the critical involvement of immune cells with cytotoxic property in apoptotic cell-in-cell death, which we termed as emperitosis taken from emperipolesis and apoptosis. Whereas entosis or cannibalism may serve as a feed-on mechanism to exacerbate and nourish tumor cells, emperitosis of immune killer cells inside tumor cells may serve as an in-cell danger sensation model to prevent the killing of target cells from inside, implying a unique mechanism for tumor cells to escape from immune surveillance.

Sall4 is a novel oncogene found upregulated in several malignancies including colon cancer. However, its upstream regulatory miRNA is still undefined. miR-219-5p is regarded as a tumor-related miRNA in cancer research. Nevertheless, its actual role of whether inhibiting or promoting tumorigenesis is unclear in colon cancer. Potential interaction between Sall4 and miR-219-5p is predicted by TargetScan. CCK-8 test was used for evaluation of cell proliferation and cell survival rates. Western blot analysis and real-time PCR were applied for detection of target molecules. Luciferase assay was a direct confirmation of mutual interaction. Wound healing assay and transwell assay were conducted for cell migration and invasion tests. Flow cytometry was used for cell apoptosis analysis. Tissue specimens and cell lines were explored for miR-219-5p inhibition on colon cancer proliferation, migration, invasion, apoptosis and drug resistance by targeting Sall4. The results show that miR-219-5p inhibited carcinogenesis of colon cancer by targeting oncogene Sall4.

<h2>Abstract</h2><h3>Background</h3> We previously reported elsewhere of a follicular lymphoma patient suffering from persistent COVID-19 pneumonia that was still ongoing at 2 months after onset. <h3>Materials and Methods</h3> We provide a follow-up report of the case along with a literature review of immunocompromised lymphoma patients experiencing prolonged COVID-19 infections. <h3>Results</h3> Although requiring a full 1 year, the presented case eventually achieved spontaneous resolution of COVID-19 pneumonia. Anti-SARS-CoV-2 antibodies could not be detected throughout the disease course, but COVID-19-directed T-cell response was found to be intact. The patient also developed secondary immune thrombocytopenia subsequent to COVID-19 pneumonia. We found 19 case reports of immunocompromised lymphoma patients with prolonged COVID-19 infections in the literature. All 5 patients who died did not receive convalescent plasma therapy, whereas resolution of COVID-19 infection was achieved in 8 out of 9 patients who received convalescent plasma therapy. <h3>Conclusions</h3> We demonstrate through the presented case that while time-consuming, resolution of COVID-19 infections may be achieved without aid from humoral immunity if cellular immunity is intact. Immunocompromised lymphoma patients are at risk of a prolonged disease course of COVID-19, and convalescent plasma therapy may be a promising approach in such patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine-induced adaptive responses have been well investigated. However, the effects of sex, age, and ethnic background on the immune responses elicited by the mRNA vaccine remain unclear. Here, we performed comprehensive analyses of adaptive immune responses elicited by the SARS-CoV-2 mRNA vaccine. Vaccine-induced antibody and T cell responses declined over time but persisted after 3 months, and switched memory B cells were even increased. Spike-specific CD4+ T and CD8+ T cell responses were decreased against the B.1.351 variant, but not against B.1.1.7. Interestingly, T cell reactivity against B.1.617.1 and B.1.617.2 variants was decreased in individuals carrying HLA-A24, suggesting adaptive immune responses against variants are influenced by different HLA haplotypes. T follicular helper cell responses declined with increasing age in both sexes, but age-related decreases in antibody levels were observed only in males, and this was associated with the decline of T peripheral helper cell responses. In contrast, vaccine-induced CD8+ T cell responses were enhanced in older males. Taken together, these findings highlight that significant differences in the reactogenicity of the adaptive immune system elicited by mRNA vaccine were related to factors including sex, age, and ethnic background.

Significance: Thioredoxin 1 (Trx1) is a ubiquitous protein that is found in organisms ranging from prokaryotes to eukaryotes. Trx1 acts as reductases in redox regulation and protects proteins from oxidative aggregation and inactivation. Trx1 helps the cells to cope with various environmental stresses and inhibits programmed cell death. It is beneficial to neuroregeneration and resistance against oxidative stress-associated neuron damage. Trx1 also plays important roles in suppressing neurodegenerative disorders. Recent Advances: Trx1 is a redox regulating protein involved in neuronal protection. According to a previous study, Trx1 expression is increased by nerve growth factor (NGF) and necessary for neurite outgrowth of PC12 cells. Trx1 has been shown to promote the growth of neurons. Trx1 knockout or knockdown has the worse impact on cell viability and survival. Critical Issues: Trx1 has functions in central nervous system. Trx1 plays the defensive roles against oxidative stress in neurodegenerative diseases. Future Directions: In this review, we focus on the structure of Trx1 and basic functions of Trx1. Trx1 plays a neuroprotective role by suppressing endoplasmic reticulum stress in Parkinson's disease. Neurodegenerative diseases have no cure and carry a high cost to the health care system and patient's families. Trx1 may be taken as a new target for neurodegenerative disorder therapy. Further studies of the Trx1 roles and mechanisms on neurodegenerative diseases are needed. Antioxid. Redox Signal. 36, 1023–1036.

To ensure the safety of railway transportation, it is necessary to promote the defect detection of track fasteners. However, most current inspections focus on coarse-grained detection of defects, while neglecting the potential fine-grained defects, such as looseness and subtle deformation. To solve this problem, this paper proposes a method for fine-grained defect detection of track fasteners using RGB-D images. The proposed method is divided into two stages: coarse-grained detection, which detects defects such as missing or loose elastic strips, and fine-grained detection, which detects potential defects such as loose fasteners. By combining coarse-grained detection and fine-grained detection, more excellent defect detection of track fasteners has been achieved The proposed method achieves 99.6% accuracy of coarse-grained detection and 90.6% accuracy of fine-grained detection at 23.3 FPS.

Parkinson's disease (PD) is characterized by the formation of Lewy body in dopaminergic neurons in the substantia nigra pars compacta (SNpc). Alpha-synuclein (α-syn) is a major component of Lewy body. Autophagy eliminates damaged organelles and abnormal aggregated proteins. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays roles in protecting dopaminergic neurons against neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the relationship between Trx-1 and α-syn in PD is still unknown. In the present study, the movement disorder and dopaminergic neurotoxicity in MPTP-treated mice were improved by Trx-1 overexpression and were aggravated by Trx-1 knockdown in the SNpc in mice. The expression of α-syn was increased in the SNpc of MPTP-treated mice, which was inhibited by Trx-1 overexpression and was exacerbated in Trx-1 knockdown mice. Autophagosomes was increased under electron microscope after MPTP treatment, which were recovered in Trx-1 overexpressing mice and were further increased in Trx-1 knockdown in the SNpc in mice. The expressions of phosphatase and tensin homolog deleted on chromosome ten (PTEN)-induced putative kinase 1 (PINK1), Parkin, LC3 II and p62 were increased by MPTP, which were blocked in Trx-1 overexpressing mice and were further increased in Trx-1 knockdown mice. Cathepsin D was decreased by MPTP, which was restored in Trx-1 overexpressing mice and was further decreased in Trx-1 knockdown mice. The mRFP-GFP-LC3 green fluorescent dots were increased by 1-methyl-4-phenylpyridinium (MPP+) and further increased in Trx-1 siRNA transfected PC12 cells, while mRFP-GFP-LC3 red fluorescent dots were increased in Trx-1 overexpressing cells. These results indicate that Trx-1 may eliminate α-syn in PD mice through potentiating autophagy-lysosome pathway.

To evaluate the performance of multiparametric neurite orientation dispersion and density imaging (NODDI) radiomics in distinguishing between glioblastoma (Gb) and solitary brain metastasis (SBM).In this retrospective study, NODDI images were curated from 109 patients with Gb (n = 57) or SBM (n = 52). Automatically segmented multiple volumes of interest (VOIs) encompassed the main tumor regions, including necrosis, solid tumor, and peritumoral edema. Radiomics features were extracted for each main tumor region, using three NODDI parameter maps. Radiomics models were developed based on these three NODDI parameter maps and their amalgamation to differentiate between Gb and SBM. Additionally, radiomics models were constructed based on morphological magnetic resonance imaging (MRI) and diffusion imaging (diffusion-weighted imaging [DWI]; diffusion tensor imaging [DTI]) for performance comparison.The validation dataset results revealed that the performance of a single NODDI parameter map model was inferior to that of the combined NODDI model. In the necrotic regions, the combined NODDI radiomics model exhibited less than ideal discriminative capabilities (area under the receiver operating characteristic curve [AUC] = 0.701). For peritumoral edema regions, the combined NODDI radiomics model achieved a moderate level of discrimination (AUC = 0.820). Within the solid tumor regions, the combined NODDI radiomics model demonstrated superior performance (AUC = 0.904), surpassing the models of other VOIs. The comparison results demonstrated that the NODDI model was better than the DWI and DTI models, while those of the morphological MRI and NODDI models were similar.The NODDI radiomics model showed promising performance for preoperative discrimination between Gb and SBM.The NODDI radiomics model showed promising performance for preoperative discrimination between Gb and SBM, and radiomics features can be incorporated into the multidimensional phenotypic features that describe tumor heterogeneity.• The neurite orientation dispersion and density imaging (NODDI) radiomics model showed promising performance for preoperative discrimination between glioblastoma and solitary brain metastasis. • Compared with other tumor volumes of interest, the NODDI radiomics model based on solid tumor regions performed best in distinguishing the two types of tumors. • The performance of the single-parameter NODDI model was inferior to that of the combined-parameter NODDI model.

Geranylgeranylacetone (GGA) has been introduced into the clinical field as an anti-ulcer drug. In addition to protective effects on gastric mucosal cells, GGA also has anti-apoptotic effects against ischemia and reperfusion injury in hepatocytes and intestinal cells. However, the molecular mechanisms of the cytoprotective or anti-apoptotic effect of GGA are largely unknown. To explore the molecular mechanism of GGA action, we focused on thioredoxin (TRX), an endogenous-redox-acting molecule. We have demonstrated that GGA induces the messenger RNA and protein of TRX and affects the activation of transcription factors, AP-1 and NF-kappaB, and that GGA blunted ethanol-induced cytotoxicity of cultured hepatocytes. These results provide evidence suggesting that a possible novel molecular mechanism of GGA is to protect cells via the induction of TRX and the activation of transcription factors such as NF-kappaB and AP-1.

Thioredoxin (TRX) is a redox-active protein which plays a cytoprotective role against oxidative stress. Geranylgeranylacetone (GGA), used widely as an anti-ulcer drug, has been reported to induce TRX as well as heat shock protein 70 (HSP70) in hepatocytes and other cells. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes dopaminergic denervation and Parkinsonism in humans. The 1-methyl-4-phenylpyridinium ion (MPP+), an active metabolite of MPTP, induces cell death in a rat pheochromocytoma cell line (PC12 cells). We found that MPP+ suppresses TRX expression in PC12 cells. Overexpression or administration of TRX attenuates MPP+-induced neurotoxicity on PC12 cells. Moreover, GGA induces expression of TRX and HSP70 and attenuates MPP+-induced toxicity in PC12 cells. These results indicate that TRX and GGA have a possible potential as new therapeutic agents for Parkinson disease.

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), characteristic motor symptoms and cognitive impairment. Thioredoxin-1 (Trx-1) is a redox protein and protects neurons from various injuries. Our previous study has shown that Trx-1 overexpression attenuates movement disorder in PD. However, whether Trx-1 ameliorates cognitive deficits in PD is still unknown. In the present study, we investigated the effects of Trx-1 on learning and memory in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in mice. We demonstrated that deficits in learning and memory were induced by MPTP in mice through the elevated plus-maze test. We found that the retention transfer latency time was shorten, escape latency was decreased and the number of platform crossings was increased in the Morris water maze (MWM) in Trx-1 transgenic (TG) mice when compared with wild type mice. The expressions of tyrosine hydroxylase (TH) and dopamine D1 receptor (D1R) were decreased by MPTP, which were restored in Trx-1 TG mice. The expression of N-methyl-D-aspartate receptor 2B subunit (NR2B), the levels of phosphorylation of extracellular signal-regulated kinase (ERK1/2) and cAMP-response element binding protein (CREB) in the hippocampus were decreased by MPTP, which were reversed in Trx-1 TG mice. These results suggest that Trx-1 ameliorates learning and memory deficits in MPTP-induced PD model in mice via modulating the D1R and the NMDAR-ERK1/2-CREB pathway. Trx-1 may be a therapy target for learning and memory deficits in PD.

The tumor microenvironment orchestrates the sustained growth, metastasis and recurrence of cancer. As an indispensable component of the tumor microenvironment, cancer‐associated fibroblasts (CAF) are considered as an essential synthetic machine producing various tumor components, leading to cancer sustained stemness, drug resistance and tumor recurrence. Here, we developed a sustainable primary culture of lung cancer cells fed with lung cancer‐associated fibroblasts, resulting in enrichment and acquisition of drug resistance in cancer cells. Moreover, IGF2/AKT/Sox2/ABCB1 signaling activation in cancer cells was observed in the presence of CAF, which induces upregulation of P‐glycoprotein expression and the drug resistance of non‐small cell lung cancer cells. Our results demonstrated that CAF cells constitute a mechanism for cancer drug resistance. Thus, traditional chemotherapy combined with insulin‐like growth factor 2 (IGF2) signaling inhibitor may present an innovative therapeutic strategy for non‐small cell lung cancer therapy.

Brain-derived neurotrophic factor (BDNF) is one of the neurotrophic factors that are vital to the survival and proliferation of neuron. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays various roles in regulating transcript factors and inhibiting apoptosis. It has been reported that Trx-1 is required for nerve growth factor-mediated signal transduction and neurite outgrowth, and is involved in synaptic protein expression induced by BDNF. However, the molecular mechanism on BDNF inducing Trx-1 expression has not been fully verified. The present study investigated the expression of Trx-1 after treatment with BDNF in SH-SY5Y cells. We first demonstrated that cell viability and the expression of Trx-1 were increased by BDNF in SH-SY5Y cells, which were inhibited by the tyrosine kinase B (TrkB) inhibitor, K252a, and the phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002. Moreover, BDNF increased the activity of cAMP response element-binding protein (CREB) through TrkB/PI3-K/Akt pathway. Whereas the expression of Trx-1 induced by BDNF was suppressed by CREB siRNA. Thus, our data suggest that BDNF induces the expression of Trx-1 through the TrkB/Akt/CREB pathway.

Abstract Oesophageal squamous cell carcinoma (ESCC) is a common and aggressive malignancy. Although many molecular alterations have been observed in ESCC, the mechanisms underlying the development and progression of this disease remain unclear. In the present study, miR-1224-5p was identified to be downregulated in ESCC tissues compared to normal tissues, and its low expression was correlated with shorter survival time in patients. In vitro experiments showed that miR-1224-5p inhibited the proliferation, colony formation, migration and invasion of ESCC cells. Mechanistic investigation revealed that miR-1224-5p directly targeted TNS4 and inhibited its expression, which led to the inactivation of EGFR-EFNA1/EPHA2-VEGFA (vascular endothelial growth factor A) signalling. Experiments in vivo confirmed the suppressive effect of miR-1224-5p on oesophageal cancer cells. By immunohistochemistry analysis of ESCC specimens, we found that TNS4 expression was positively correlated with that of VEGFA, and was significantly associated with lymph node metastasis and shorter survival time in patients. Together, our data suggest that miR-1224-5p downregulation is a frequent alteration in ESCC that promotes cell proliferation, migration, invasion and tumour growth by activating the EGFR-EFNA1/EPHA2-VEGFA signalling pathway via inhibition of TNS4 expression. Decreased miR-1224-5p and elevated TNS4 are unfavourable prognostic factors for ESCC patients.

Background and purposeThis study aimed to evaluate the efficacy of radical radiotherapy and assess prognostic factors in metachronous oligometastatic esophageal cancer (MOEC) patients after initial treatment with curative-intent surgery and/or chemoradiotherapy.Materials and methodsMOEC Patients during 2009–2018 in Mianyang Central Hospital were retrospectively analyzed. Each patient had ≤5 oligometastatic lesions, and the primary lesions were controlled in this study. Patients were devided into radiotherapy (RT) and non-radiotherapy (NRT) groups. The study endpoints were overall survival (OS) and treatment toxicities.ResultsThis study included 82 patients who underwent intensity-modulated radiotherapy for MOEC. Median OS were 14 (95% confidence interval [CI], 11.0–17.0) and 7 (95% CI, 4.5–9.5) months for the RT and NRT groups, respectively (P = 0.016). Median OS were 18 (95% CI, 13.6–22.4) and 10 (95% CI, 5.1–14.9) months for lung and bone metastases, respectively (P = 0.010). Median OS were 15 (95% CI, 12.4–17.6) and 10 (95% CI, 7.6–12.4) months for interval time from initial diagnosis to metastasis ≥12 and <12 months, respectively (P = 0.026). Median OS were 16 (95% CI, 12.2–19.8) and 10 (95% CI, 5.0–15.0) months for biological effective dose (BED10) ≥ 60 Gy and BED10 < 60 Gy, respectively (P = 0.033). Cox multivariate regression analysis showed that treatment modality (RT vs. NRT) was an independent prognostic factor for MOEC patients (hazard ratio: 1.8, 95% CI: 1.1–3.0; P = 0.022). No toxic side effects greater than grade 3 were observed in all patients.ConclusionsRadiotherapy is a feasible and positive treatment for MOEC patients after initial treatment, a radical radiation dose with BED10 ≥ 60 Gy has benefits in extending survival. Radical radiotherapy should thus be considered for MOEC patients.

Formaldehyde (FA), a common environmental pollutant, has toxic effects on central nervous system. The detailed mechanisms on FA-induced neurotoxicity have not been fully elucidated. In this study, we found that glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) expression, biomarkers of endoplasmic reticulum (ER) stress, were increased and pro-caspase-12 was decreased after PC12 cells exposure to FA. These results suggest that FA actually induces ER stress. Thioredoxin-1 (Trx-1) has various biological activities, including the control of redox balance, the modulation of ER stress and inhibition of apoptosis. In the present study, Trx-1 expression was increased at early stage, but decreased at late stage after FA treatment. Knockdown of Trx-1 expression increased the susceptibility of PC12 cells to FA-induced neurotoxicity. We also found that ginsenoside Rg1 had the potential to induce Trx-1 expression and attenuated neurotoxicity induced by FA. ER stress caused by FA was suppressed by ginsenoside Rg1. These data indicate that Trx-1 is a therapeutic candidate for protecting against FA-induced neurotoxicity.

Enhancer of zeste homologue 2 (EZH2) is crucially involved in epigenetic silencing by acting as a histone methyltransferase. Although EZH2 is overexpressed in many cancers and is involved in malignant cell proliferation and invasion, the role of EZH2 in senescence induced by DNA damage has up to now remained largely unknown. In this study, we sought to explore the outcome of EZH2 depletion along with exposure of doxorubicin (DOX), and related mechanisms, in gastric cancer cells.Here, senescence induced by DNA damage was achieved in gastric cancer cells by DOX treatment. EZH2 was downregulated by transfection with siRNA or treated with (-)-epigallocatechin-3-gallate, a targeted inhibitor. Senescence-associated β galactosidase (SA-β-gal) and formation of senescence-associated heterochromatin foci were used to identify cell senescence. To investigate effects of EZH2 depletion on the cell cycle, apoptosis and proliferation, flow cytometry and MTT analysis were employed. Changes in p53-p21 axis activation were detected by Western blotting.We found that cell proliferative arrest caused by DOX could be promoted by EZH2 depletion. Mechanistically, EZH2 depletion not only worked in coordination with DNA damage during the progression of cell senescence but also promoted apoptosis in p53 mutant cells. However, it had no cooperative relationship with DOX in p53 wild-type cells.These data help unravel a crucial role for EZH2 in senescence and apoptosis in gastric cancer cells and that p53 genomic status was associated with different cell responses to EZH2 silencing.

The phosphoinositide 3-kinase/Akt pathway activation commonly occurs in various types of human cancer and has an important role in chemoresistance. Combination of traditional chemotherapy drugs and molecular-targeted agents is a promising strategy for cancer therapy, which has shown enhanced cytotoxicity and lower drug resistance. The present study found that the Akt inhibitor, MK-2206, can increase the effect of cisplatin in the gastric cancer cell line AGS, which has higher Akt phosphorylation, but exhibited a poor combination effect in MKN-45 and MGC-803 cells, which have limited Akt activation. The MTT assay demonstrated that sequential treatment of cisplatin, followed by the Akt inhibitor, MK-2206, caused a synergistic effect of proliferation inhibition, and the apoptosis assay by propidium iodide/fluorescein isothiocyanate staining also showed that combination treatment induced more apoptosis compared to the monotherapy groups. Using western blot analysis, MK-2206 was shown to significantly suppress the phosphorylation of Akt (Ser473), however, the expression of total Akt remained the same, and the combination treatment also increased the expression of cleaved poly adenosine diphosphate ribose polymerase, which contributed to apoptosis.

Liraglutide has been shown to improve glucose tolerance and lose weight in individuals with type 2 diabetes. To date, no meta-analysis of liraglutide's safety and efficacy in individuals without diabetes has been conducted.The aim of this study is to carry out a meta-analysis to assess the efficacy and safety of liraglutide in the obese, non-diabetic individuals.A literature review was performed to identify all published randomised control trials (RCT) of liraglutide for the treatment of obesity in non-diabetic individuals. The search included the following databases: EMBASE, MEDLINE and the Cochrane Controlled Trials Register.We included five publications involving a total of 4,754 patients that compared liraglutide with placebo and found that liraglutide to be an effective and safe treatment for weight loss in individuals without diabetes. Primary efficacy end points: mean weight loss (MD = -5.52, 95% CI = -5.93 to -5.11, p<0.00001); lost more than 5% of body weight (OR = 5.46, 95% CI=3.57 to 8.34, p<0.00001) and key secondary efficacy end points: SBP decreased (the MD = -2.56, 95% CI = -3.28 to -1.84, p<0.00001). Safety assessments included the proportion of individuals who were withdrawn due to AE (OR = 2.85, 95% CI= 0.84 to 9.62, p=0.009), and nausea indicated that liraglutide was well tolerated.This systematic review and meta-analysis indicates that liraglutide to be an effective and safe treatment for weight loss in the obese, non-diabetic individuals.

Abstract Metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic long noncoding RNA that has been found to promote carcinogenesis and metastasis in many tumors. However, the underlying role of MALAT1 in the progression and metastasis of hepatocellular carcinoma (HCC) remains unclear. In this study, aberrantly elevated levels of MALAT1 were detected in both HCC specimens and cell lines. We found that knockdown of MALAT1 caused retardation in proliferation, migration, and invasion both in vivo and in vitro. Mechanistic investigations showed that Snail family transcriptional repressor 1 (SNAI1) is a direct target of microRNA (miR)‐22 and that MALAT1 modulates SNAI1 expression by acting as a competing endogenous RNA for miR‐22. Inhibition of miR‐22 restored SNAI1 expression suppressed by MALAT1 knockdown. Furthermore, MALAT1 facilitated the enrichment of enhancer of zeste homolog 2 (EZH2) at the promoter region of miR‐22 and E‐cadherin, which was repressed by MALAT1 knockdown. Cooperating with EZH2, MALAT1 positively regulated SNAI1 by repressing miR‐22 and inhibiting E‐cadherin expression, playing a vital role in epithelial to mesenchymal transition. In conclusion, our results reveal a mechanism by which MALAT1 promotes HCC progression and provides a potential target for HCC therapy.

To investigate the association between clinic-radiological features and glioma-associated epilepsy (GAE), we developed and validated a radiomics nomogram for predicting GAE in WHO grade II~IV gliomas.This retrospective study consecutively enrolled 380 adult patients with glioma (266 in the training cohort and 114 in the testing cohort). Regions of interest, including the entire tumor and peritumoral edema, were drawn manually. The semantic radiological characteristics were assessed by a radiologist with 15 years of experience in neuro-oncology. A clinic-radiological model, radiomic signature, and a combined model were built for predicting GAE. The combined model was visualized as a radiomics nomogram. The AUC was used to evaluate model classification performance, and the McNemar test and Delong test were used to compare the performance among the models. Statistical analysis was performed using SPSS software, and p < 0.05 was regarded as statistically significant.The combined model reached the highest AUC with the testing cohort (training cohort, 0.911 [95% CI, 0.878-0.942]; testing cohort, 0.866 [95% CI, 0.790-0.929]). The McNemar test revealed that the differences among the accuracies of the clinic-radiological model, radiomic signature, and combined model in predicting GAE in the testing cohorts (p > 0.05) were not significantly different. The DeLong tests showed that the difference between the performance of the radiomic signature and the combined model was significant (p < 0.05).The radiomics nomogram predicted seizures in patients with glioma non-invasively, simply, and practically. Compared with the radiomics models, comprehensive clinic-radiological imaging signs observed by the naked eye have non-discriminatory performance in predicting GAE.

A meta-analysis study was conducted to measure the consequence of diabetic foot ulcers (DFUs) and other risk factors (RFs) on the prevalence of lower extremity amputation (LEA). A comprehensive literature inspection till February 2023 was applied and 2765 interrelated studies were reviewed. Of the 32 chosen studies enclosed, 9934 subjects were in the chosen studies' starting point, and 2906 of them were with LEA. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to compute the value of the effect of DFUs and other RFs on the prevalence of LEA by the continuous and dichotomous approaches and a fixed or random effect model. Male gender (OR, 1.30; 95% CI, 1.17-1.44, P < .001), smoking (OR, 1.24; 95% CI, 1.01-1.53, P = .04), previous foot ulcer (OR, 2.69; 95% CI, 1.93-3.74, P < .001), osteomyelitis (OR, 3.87; 95% CI, 2.28-6.57, P < .001), gangrene (OR, 14.45; 95% CI, 7.03-29.72, P < .001), hypertension (OR, 1.17; 95% CI, 1.03-1.33, P = .01), and white blood cells count (WBCC) (MD, 2.05; 95% CI, 1.37-2.74, P < .001) were significantly shown to be an RF in LEA in subjects with DFUs. Age (MD, 0.81; 95% CI, -0.75 to 2.37, P = .31), body mass index (MD, -0.55; 95% CI, -1.15 to 0.05, P = .07), diabetes mellitus type (OR, 0.99; 95% CI, 0.63-1.56, P = .96), and glycated haemoglobin (MD, 0.33; 95% CI, -0.15 to 0.81, P = .17) were not shown to be an RF in LEA in subjects with DFUs. Male gender, smoking, previous foot ulcer, osteomyelitis, gangrene, hypertension, and WBCC were significantly shown to be an RF in LEA in subjects with DFUs. However, age and diabetes mellitus type were not shown to be RF in LEA in subjects with DFUs. However, caused of the small sample sizes of several chosen studies for this meta-analysis, care must be exercised when dealing with its values.

Although PARP inhibitor (PARPi) has been proven to be a promising anticancer drug in cancer patients harboring BRCA1/2 mutation, it provides limited clinical benefit in colorectal cancer patients with a low prevalence of BRCA1/2 mutations. In our study, we found PARPi talazoparib significantly induced cellular senescence via inhibiting p53 ubiquitination and activating p21. Furthermore, CDK4/6i palbociclib amplified this therapy-induced senescence (TIS) in vitro and in vivo. Mechanistically, talazoparib and palbociclib combination induced senescence-associated secretory phenotype (SASP), and characterization of SASP components revealed type I interferon (IFN)-related mediators, which were amplified by cGAS/STING signaling. More importantly, RNA sequencing data indicated that combination therapy activated T cell signatures and combination treatment transformed the tumor microenvironment (TME) into a more antitumor state with increased CD8 T cells and natural killer (NK) cells and decreased macrophages and granulocytic myeloid-derived suppressor cells (G-MDSCs). Moreover, clearance of the TIS cells by αPD-L1 promoted survival in immunocompetent mouse colorectal cancer models. Collectively, we elucidated the synergistic antitumor and immunomodulatory mechanisms of the talazoparib-palbociclib combination. Further combination with PD-L1 antibody might be a promising "one-two punch" therapeutic strategy for colorectal cancer patients.

Sepsis is the main cause of death in critically ill patients, pathogenesis of which is still unclear. The nuclear factor κB (NF-κB) inflammatory signal pathway mediated by endoplasmic reticulum stress is involved in sepsis. Thioredoxin-1 (Trx-1) is an important protein of regulating oxidative stress. It plays a crucial role in the anti-oxidation, anti-apoptosis, and anti-inflammation. However, the role and the mechanism of Trx-1 in sepsis have not been extensively studied. In the present study, we showed that the survival was longer in sepsis induced by cecal ligation and puncture in Trx-1 overexpression transgenic (Tg) mice compared with wild-type mice. Wet/dry lung weight ratio was decreased in Trx-1 Tg mice. The levels of TNF-α and IL-1β in plasma and lung tissue were inhibited in Tg mice. The expressions of glucose-regulated protein 78, inositol-requiring enzyme 1α (IRE1α), tumor necrosis factor receptor-associated factor 2, C/EBP homologous protein, NF-κB, and inhibitors of NF-κBα were increased in lung tissue. More importantly, the overexpression of Trx-1 in transgenic mice suppressed NF-κB inflammatory signal pathway by inhibiting the activation of molecules involved in ER stress. Our results suggest that Trx-1 may play protective role in extending survival in sepsis by regulating inflammatory response through suppressing ER stress.

Background/Aims: Acute ST-segment elevation of myocardial infarction (STEMI) is the most severe type of acute coronary syndrome (ACS). Particular attention has been focused on studying the pathogenesis of STEMI, and how to prevent thrombosis, reduce inflammatory reaction, stabilize plaques and improve vascular endothelial functions to preserve the survived myocardium. This study aimed to compare the anti-inflammatory endothelium-protective effects, clinical prognosis, and relevant bleeding risks of ticagrelor versus clopidogrel in patients with STEMI who underwent urgent percutaneous coronary intervention (PCI) and provide certain experimental evidence and a theoretical basis for the selection of safe and effective drugs and their proper dosage, thereby further guiding clinical medication. Methods: We sequentially enrolled 193 patients (104 males and 89 females) admitted to hospital due to acute STEMI. These patients underwent urgent PCI between December 2013 and May 2015 and met the inclusion criteria. They were assigned (1: 1) into two groups according to different treatments, 97 patients in the ticagrelor group (treatment group), and 96 patients in the clopidogrel group (control group). Levels of hypersensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), and endothelial cell-specific molecule 1 (ESM-1) taken at admission and 24 h, 4 days, and 7 days after administration, as well as the correlation between the levels of IL-6, hs-CRP, and ESM-1, were determined in the two groups. At the same time, the effects of treatment with ticagrelor and clopidogrel on the efficacy endpoint events (ischemic and safety) were explored. Results: No statistically significant difference was found in the levels of hs-CRP, IL-6, or ESM-1 at admission between the two groups (P&gt; 0.05); Their levels were significantly elevated 24 h after administration, with statistical differences between two groups (P&lt; 0.05). Furthermore, a downward trend with statistically significant differences was found on Day 4 and Day 7 (P&lt; 0.05); ESM-1 levels increased along with increases of hs-CRP and IL-6 levels, indicating ESM-1 was positively correlated with hs-CRP (r=0.523, P&lt; 0.001) and IL-6 (r=0.431, P&lt; 0.001); and the occurrence rates of ischemic endpoint events at 30 days were lower in the treatment group than in the control group. The occurrence of safety endpoint events was higher than in the control group; however, no statistically significant difference was found (P&gt; 0.05). Conclusions: Compared with clopidogrel, ticagrelor appears to rapidly reduce the prevalence of inflammatory reactions and stabilize the functions of vascular endothelium to improve the stability of atherosclerotic plaque and decrease the occurrence rate of thrombosis as well as ischemic outcome events without any obvious increase in the risk of bleeding in patients with acute STEMI receiving urgent PCI. This renders it a potential drug for clinical practice. At the same time, measurement of ESM-1, a new biological marker for vascular endothelial function disorder, could possibly become a simple, effective, and practical new method for clinical evaluation of risk stratification of patients with acute STEMI at admission.

We show that 1-methyl-4-phenylpyridinium ion (MPP+), an active metabolite of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), induces cytotoxicity via endoplasmic reticulum (ER)- and mitochondria–mediated pathways, and thioredoxin-1 (TRX-1), a redox-active protein, prevents MPTP-induced neurotoxicity. TRX-1 overexpression suppressed reactive oxygen species and the ATP decline caused by MPP+ in HepG2 cells. MPP+ activated caspase-12 in PC12 cells and induced cytotoxicity in HeLa-ρ0 cells lacking mitochondrial DNA, as well as in the parental HeLa-S3 cells. TRX-1–transgenic mice demonstrated significant resistance to caspase-12 activation and the apoptotic decrease of dopaminergic neurons after MPTP administration, compared with wild-type C57BL/6 mice.

Background Osteopontin (OPN) is one kind of cytokine which can play a number of roles in promoting activation of T lymphocyte, regulating balance between Th1 and Th2, participating in cell-induced immunologic response and stimulating B lymphocyte to express multi-clone antibodies. Some researches have showed that OPN may be involved in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate possible association of a single nucleotide polymorphism (SNP) at position 9250 in exon 7 of the OPN gene (OPN gene 9250) with SLE in Chinese patients. Methods Totally 158 patients (18 males and 140 females) fulfilled the revised criteria for SLE by the American College of Rheumatology in 1982 and 180 healthy volunteer controls (34 males and 146 females), all from the south of China, consented to participate in the study. OPN gene 9250 polymorphism was detected by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Results The frequency of TT genotype of the OPN gene 9250 was significantly lower (52.5% vs 70%, P<0.05) and the frequency of TC genotype of the OPN gene 9250 was significantly higher (43.7% vs 29.4%, P<0.05) in SLE patients than in controls. There were significant differences in OPN gene 9250 allele and phenotype frequencies between the SLE patients and controls (P<0.05). When the SLE patients and controls were separated into men and women, significant differences of frequencies were noted in TT genotype, TC genotype and allele of the OPN gene 9250 in women (P<0.05) but not in men (P>0.05). Conclusions OPN gene 9250 polymorphism appears to be associated with susceptibility to SLE in Chinese Han ethnic population.

1. Leptin, an important adipose-derived hormone, can be associated with cardiac pathophysiology; however, the role of leptin in cardiomyocyte apoptosis is poorly understood. The present study examines serum-deprivation-induced apoptosis in primary cultured cardiomyocytes treated with leptin. 2. Cardiomyocytes were subjected to serum deprivation in the presence or absence of leptin (5 or 50 nmol/L) for 48 h. Apoptosis was determined by Hoechst 33258 and Annexin V-FITC/propidium iodide dual staining. Cell viability, malondialdehyde (MDA) content, caspase 3 activation, and the expression and enzyme activity of superoxide dismutase (SOD) were measured. Small interference RNA (siRNA) targeting SOD1 and SOD2 were used to knockdown their expression and measure apoptosis. 3. Serum deprivation caused nearly 30% of apoptosis in cardiomyocytes, and an approximately 60% decrease in cell viability. The mRNA levels and the activated form of caspase 3 were greatly increased. In the presence of leptin, the apoptotic rate was reduced to approximately 15%, cell viability was increased and the activation of caspase 3 was partially inhibited. Additionally, the augmented lipid peroxidation (MDA formation) was abolished, and the impaired activities of SOD1 and SOD2 were restored by leptin. The mRNA expression of SOD2, but not SOD1, was stimulated by leptin. Transfection with siRNA that cause deficiency of either SOD1 or SOD2 attenuated the anti-apoptotic effects of leptin. 4. The results suggest that leptin inhibits serum-deprivation-induced apoptosis in cardiomyocytes by activating SOD. The present study outlines the direct actions of leptin in cardiac disorders that are related to elevated leptin levels.

To evaluate the association between visual acuity (VA) and 4-year mortality in an older population-based cohort.Five thousand and fifty-seven persons aged 50 to 96 years (91.0% of the eligible population) residents of the Southern Harbin, Heilongjiang Provence, China participated in the study. At baseline (2006), the main ocular diseases were diagnosed from a basic ocular examination including presenting and best-corrected VA. Of the 5,057 participants in the baseline survey, those who died after the study were identified and the death certificate was checked. The physicians in charge of the health of the village population were asked for the presumed cause of death. The rate of death was determined in the follow-up survey in 2010. We evaluated the association of visual impairment (VI) and mortality using multiple logistic regression.Between the baseline examination and the censoring cutpoint study, a total of 214 subjects (4.2%) were dead. Females with VI were less likely to have died relative to male gender with VI (P<0.05). Compared with participants who reported better presenting VA (VA ≥ 20/60), the risk of mortality was significantly higher for those reporting moderate VI (20/400 ≤ VA < 20/60) (Odds Ratio [OR], 2.1; 95% confidence interval [CI],1-4.1) and those reporting severe VI (VA < 20/400) (OR,3.6; 95% CI, 2.0-6.6). Similar associations were obtained for best-corrected VA in the better eye (OR, 3.1; 95% CI: 1.5-6.4 and 3.9; 95%CI: 2.1-7.2, respectively).In this Chinese population-based cohort we found that visual impairment predicted a significantly elevated mortality.

There are few efficacious interventions to combat morphine dependence. Thioredoxin-1 (Trx-1) and heat shock protein 70 (Hsp70) are emerging as important modulators of neuronal function. They have been shown to be involved in cellular protective mechanisms against a variety of toxic stressors. This study was designed to investigate the effects of geranylgeranylacetone (GGA), a pharmacological inducer of Trx-1 and Hsp70, on morphine-induced hyperlocomotion, rewarding effect, and withdrawal syndrome. Trx-1 and Hsp70 expression was increased in the frontal cortex, hippocampus, ventral tegmental area, and nucleus accumbens of mice after GGA treatment. GGA administration reduced morphine-induced motor activity and inhibited conditioned place preference. GGA markedly attenuated the morphine–naloxone-induced withdrawal signs, including jumping, rearing, and forepaw tremor. Furthermore, the activation of cAMP-responsive element-binding protein and the expression of ΔFosB and cyclin-dependent kinase 5 were decreased in the nucleus accumbens by GGA treatment after morphine withdrawal. In the nucleus accumbens, GGA enhanced morphine-induced expression of Trx-1 and Hsp70 after morphine withdrawal. These results suggest that strengthening the expression of Trx-1 and Hsp70 in the brain by using noncytotoxic pharmacological inducers may provide a novel therapeutic strategy for morphine dependence. GGA could be a safe and novel therapeutic agent for morphine dependence.

Objective Elevated plasma total homocysteine (tHcy) acts synergistically with hypertension to exert a multiplicative effect on cardiovascular diseases risk. The aim of this study was to determine the relationship between tHcy concentration and blood pressure, and to evaluate the role of plasma tHcy in arterial stiffness and wave reflection in hypertension. Methods In this cross-sectional study, a community-based sample of 1680 subjects (mean age 61.6 years) was classified into four groups according to tHcy level (<21.6 vs. ≥21.6 µmol/l) and blood pressure (hypertensive vs. normotensive). Levels of plasma tHcy and other biochemical parameters (e.g., lipids, glucose) were determined. Central arterial blood pressure, reflected pressure wave, and carotid-femoral pulse wave velocity (cf-PWV) were assessed by tonometry within 2 days of obtaining the blood specimen. Results Neither peripheral nor central blood pressure differed according to tHcy levels in normotensive and hypertensive subjects. Differences in cf-PWV according to tHcy were observed only in hypertensive subjects; differences in cf-PWV in normotensive subjects were not significant after adjusting for confounding factors. Central augmentation index did not differ according to tHcy level in either normotensive or hypertensive subjects. Results of univariate analysis revealed significant correlations between blood pressure parameters and tHcy concentration only among normotensive subjects; however, these correlations were not significant in a partial correlation analysis. Results of multiple regression analysis showed that plasma tHcy levels were independently correlated with cf-PWV in hypertensive subjects (β = 0.713, P = 0.004). The independent relationship between tHcy and central augmentation index was not significant by further multiple analyses in normotensive or hypertensive individuals. Conclusions Plasma tHcy level is strongly and independently correlated with arterial stiffness measured as cf-PWV only in hypertensive subjects. Thus, hypertension is a major link between tHcy and aortic arterial stiffness.

Cellular senescence, which can be defined as a stress response preventing the propagation of cells that have accumulated potentially oncogenic alterations, is invariably associated with a permanent cell cycle arrest. Enhancer of zeste homolog 2 (EZH2) as a member of polycomb group proteins and its targets include cell cycle regulatory proteins, which govern cell cycle progression and cellular senescence. In this study, we report that EZH2 depletion promotes the senescent state in human gastric cancer cells SGC-7901. We found that EZH2 functionally suppressed the senescent state in human gastric cancer cells SGC-7901. EZH2 depletion inhibited cell proliferation, arrested cellular cycle, restored features of a cellular senescence phenotype, and promoted doxorubicin-induced senescence. To prove that EZH2 expression contributes substantially to the change of key cell cycle regulators, we showed that p21 and p16 were activated to a certain extent upon EZH2 depletion and activation of p21 was in a p53-independent manner. Taken together, our data suggest that EZH2 depletion promotes the progression of senescence by mediating the activation of tumor suppressor genes p21 and p16, and could serve as a potential epigenetic target for gastric cancer therapy.

Ephedrine (Eph) is one of alkaloids that has been isolated from the ancient herb ephedra (ma huang) and is used as the treatment of asthma, hypotension and fatigue. However, its molecular mechanism remains unknown. Thioredoxin-1 (Trx-1) is a redox regulating protein, which has various biological activities, including regulating transcription factor DNA binding activity and neuroprotection. In this study, we found that Eph induced Trx-1 expression, which was inhibited by propranolol (β-adrenergic receptor inhibitor), but not by phenoxybenzamine (α-adrenergic receptor inhibitor) in rat pheochromocytoma PC12 cells. Moreover, the increase of Trx-1 expression was inhibited by SQ22536 (adenylyl cyclase inhibitor) and H-89 (protein kinase A inhibitor). Interestingly, the effect of Eph on dopamine- and cyclic AMP-regulated phosphoprotein (DARPP-32) was similar to Trx-1. Thus, the relationship between Trx-1 and DARPP-32 was further studied. The DARPP-32 siRNA significantly reduced Trx-1 expression, but Trx-1 siRNA did not exchange DARPP-32. These results suggested that Eph induced the Trx-1 expression through β-adrenergic receptor/cyclic AMP/PKA/DARPP-32 signaling pathway. Furthermore, Eph induced PKA-mediated cyclic AMP response element-binding protein (CREB) phosphorylation. Down-regulation of DARPP-32 expression decreased phosphorylated CREB. In addition, Eph had a significant effect on the viability of the rat pheochromocytoma PC12 cells through β-adrenergic receptors. Trx-1 may play an important role in the actions of Eph.

Growth differentiation factor 11 (GDF-11) has been implicated in reverse effects of ageing on the central nervous system of humans. β2-microglobulin (β2-MG) has been reported to negatively regulate cognition. However, there is a lot of controversy about the role of GDF-11 and β2-MG in ageing and cognitive regulation. To examine the involvement of GDF-11 and β2-MG in the ageing process and cognitive dysfunction, a total of 51 healthy subjects and 41 elderly patients with different degrees of age-related cognitive impairment participated in the study. We measured plasma GDF-11 and β2-MG levels using ELISA and immunoturbidimetry, respectively. The results were statistically analyzed to evaluate the associations between levels of GDF-11 and β2-MG, and ageing and cognitive impairments. Circulating GDF-11 levels did not decline with age or correlate with ageing in healthy Chinese males. We did not detect differences in circulating GDF-11 levels amongst the healthy advanced age and four cognitive impairment groups. β2-MG levels increased with age, but there was no significant difference between healthy elderly males and advanced age males. Increased levels of β2-MG were observed in the dementia group compared with the healthy advanced age group. Our results suggest that circulating GDF-11 may not exert a protective effect during the ageing process or on cognitive function, and β2-MG may play a role in ageing and cognitive impairment. However, it is possible that the relatively small sample size in the present study affected the quality of the statistical analysis, and future studies are needed to further validate our findings.

Abstract Background The role of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) is not clear in early‐stage nonsmall‐cell lung cancer (NSCLC) patients. This meta‐analysis aims to compare the efficacy and safety of EGFR‐TKIs as adjuvant therapy with chemotherapy or placebo in NSCLC patients harboring EGFR mutations. Patients and Methods Pubmed, Embase, and Cochrane databases were searched for randomized controlled trials. The hazard ratio (HR) of disease‐free survival (DFS) and overall survival (OS) as well as the risk ratio (RR) of severe adverse events were merged. Results Seven articles from five studies from 1843 records, a total of 1227 patients, were included in the analysis. The HR for DFS was 0.38 (95% confidence interval [CI] 0.22–0.63), in favor of EGFR‐TKIs. However, no significant benefit of OS was seen (HR = 0.61, 95% CI 0.31–1.22). Treatment benefit was more pronounced in patients with advanced disease stage and longer duration of medication, EGFR exon 19 deletion mutation, and treatment with third‐generation EGFR‐TKIs. Adjuvant targeted therapy may cause few adverse events compared with chemotherapy (RR = 0.28, 95% CI 0.09–0.94). The possibility of severe adverse events for the first‐generation drugs was significantly lower than for third‐generation drugs. Conclusion In EGFR mutation‐positive patients with stage IB–IIIA NSCLC, compared with adjuvant chemotherapy or placebo, adjuvant EGFR‐TKIs should effectively improve the patient's DFS, but not effectively improve OS. Disease stage, treatment duration, mutation types, and therapeutic drugs could affect the degree of benefit. Adjuvant EGFR‐TKIs had more favorable tolerability than chemotherapy, especially with the usage of first‐generation drugs.

Thioredoxin-1 has various biologic activities, including the control of redox balance and the inhibition of apoptosis. The current study was designed to examine the effects of panaxatriol saponins (PTS) extracted from Panax notoginseng on thioredoxin-1 expression and 1-methyl-4-phenylpyridinium ion-induced injury.Using PC12 cells and Kunming mice, we test thioredoxin-1 expression after PTS treatment by Western blot. The protective effect of PTS against 1-methyl-4-phenylpyridinium ion-induced injury was assessed by MTT assay and LDH release assay.PTS induced thioredoxin-1 expression in vitro and in vivo, and attenuated 1-methyl-4-phenylpyridinium ion-induced cell death of PC12 cells.PTS is a new inducer of thioredoxin-1 and has a possible potential as a therapeutic agent for neurodegenerative diseases including Parkinson's disease.

Oxymatrine is one of the alkaloids extracted from the Chinese herb Sophora japonica (Sophora flavescens Ait.) with anti-inflammatory, immune reaction inhibiting, antiviral, and hepatocyte and antihepatic fibrosis protective activities. However, the effect of oxymatrine on heart failure is not yet known. In this study, the effect of oxymatrine on heart failure was investigated using a Sprague-Dawley rat model of chronic heart failure. Morphological findings showed that in the group treated with 50 and 100 mg/kg of oxymatrine; intermyofibrillar lysis disappeared, myofilaments were orderly, closely and evenly arranged; and mitochondria contained tightly packed cristae compared with the heart failure group. We investigated the cytosolic Ca2+ transients and sarcoplasmic reticulum (SR) Ca2+ content, and assessed the expression of ryanodine receptor (RyR2), SR-Ca2+ ATPase (SERCA2a), and L-type Ca2+ channel (dihydropyridine receptor, DHPR). We found that the cytosolic Ca2+ transients were markedly increased in amplitude in the medium- (ΔF/F 0 = 26.22 ± 2.01) and high-dose groups (ΔF/F 0 = 29.49 ± 1.17) compared to the heart failure group (ΔF/F 0 = 12.12 ± 1.35, P < 0.01), with changes paralleled by a significant increase in the SR Ca2+ content (medium-dose group: ΔF/F 0 = 32.20 ± 1.67, high-dose group: ΔF/F 0 = 32.57 ± 1.29, HF: ΔF/F 0 = 17.26 ± 1.05, P < 0.01). Moreover, we demonstrated that the expression of SERCA2a and cardiac DHPR was significantly increased in the medium- and high-dose group compared with the heart failure rats. These findings suggest that oxymatrine could improve heart failure by improving the cardiac function and that this amelioration is associated with upregulation of SERCA2a and DHPR.

<h2>Abstract</h2><h3>Objectives</h3> Arterial stiffness predicts an increased risk of future cardiovascular events, possibly via myocardial damage. Minimally elevated levels of plasma cardiac troponin T (TnT), a marker of cardiomyocyte injury, can be detected by the high-sensitivity TnT (hsTnT) assay. The current study investigated the relationship between plasma hsTnT levels and alterations in arterial stiffness in a community-based population. <h3>Methods</h3> We related levels of plasma hsTnT to measures of arterial stiffness (carotid–femoral pulse wave velocity [PWV], office pulse pressure [PP] and carotid–radial PWV) in 1479 participants (mean age, 62.3 years; 619 men, 860 women) from a community-based population in Beijing, China. <h3>Results</h3> In multiple logistic regression models, carotid–femoral PWV (OR: 1.84; 95% CI: 1.06–3.17; <i>P</i>=0.028) and office PP (OR: 2.02; 95% CI: 1.31–3.11; <i>P</i>=0.002) were associated with a higher likelihood of detectable hsTnT. In addition, carotid–femoral PWV (OR: 2.34; 95% CI: 1.03–5.30; <i>P</i>=0.042) and office PP (OR: 2.30; 95% CI: 1.13–4.66; <i>P</i>=0.022) were significantly related to elevated hsTnT levels. A subsequent subgroup analysis found that, in subjects aged 60 years and older, the associations between carotid–femoral PWV and office PP and hsTnT levels were strengthened. The associations between hsTnT with any of the arterial stiffness measures were not present in the younger subgroup (<60 years old). <h3>Conclusions</h3> Carotid–femoral PWV and office PP are associated with minimally elevated hsTnT levels in the elderly, indicating a relationship between central artery stiffness and subclinical myocardial damage.

Platelet function has been described by many laboratory assays, and PL-11 is a new point-of-care platelet function analyzer based on platelet count drop method, which counts platelet before and after the addition of agonists in the citrated whole blood samples. The present study sought to compare PL-11 with other three major more established assays, light transmission aggregometry (LTA), VerifyNow™ aspirin system and thromboelastography (TEG), for monitoring the short-term aspirin responses in healthy individuals. Ten healthy young men took 100 mg/d aspirin for 3-day treatment. Platelet function was measured via PL-11, LTA, VerifyNow and TEG, respectively. The blood samples were collected at baseline, 2 hour, 1 day during the aspirin treatment and 1 day, 5 ± 1 days, 8 ± 1 days after the aspirin withdrawal. Moreover, 90 additional healthy subjects were recruited to establish a reference range for PL-11. Platelet function of healthy subjects decreased significantly 2 hours after 100 mg/d aspirin intake and began to recover during 4–6 days after the aspirin withdrawal. Correlations between methods were PL-11 vs. LTA (r = 0.614, p < 0.01); PL-11 vs. VerifyNow (r = 0.829, p < 0.01); PL-11 vs. TEG (r = 0.697, p < 0.001). There was no significant bias between PL-11 and LTA at baseline (bias = 1.94%, p = 0.804) using Bland-Altman analysis, while the data of PL-11 were significantly higher than LTA (bias = 24.02%, p < 0.001) during the aspirin therapy. The reference range for PL-11 in healthy young individuals was from 66.8 to 90.5% (95%CI). When aspirin low-responsiveness was defined as LTA > 20%, the cut-off values for each method were, respectively: PL-11 > 50%, VerifyNow > 533 ARU, TEG > 60.2%. The results of different platelet function assays were uninterchangeable for monitoring aspirin response and correlations among them were also varied. Correlations among PL-11 and other three major assays suggested the ability of PL-11 to assess the treatment effects of aspirin. But a large cohort study is needed to confirm the cut-off value of aspirin response detected by PL-11.

Despite growing evidence that N-terminal pro-brain natriuretic peptide (NT-proBNP) has an important prognostic value for patients with cardiovascular disease, chronic kidney disease, etc, the prognostic significance of NT-proBNP levels in the general population has not been established. The aim of this study was to evaluate the clinical significance of NT-proBNP in a community population.This is a community-based prospective survey of residents from two communities in Beijing conducted for a routine health status checkup. Out of 1,860 individuals who were eligible for inclusion from 2007 to 2009, 1,499 completed a follow-up and were assessed for the prognostic value of NT-proBNP in 2013. A questionnaire was used for end point events. Anthropometry and blood pressure were measured. Plasma NT-proBNP, creatinine, lipids, and glucose were determined.A total of 1,499 subjects with complete data were included in the analysis. Participants were divided into four groups according to baseline NT-proBNP levels (quartile 1, <19.8 pg/mL; quartile 2, 19.8-41.6 pg/mL; quartile 3, 41.7-81.8 pg/mL; quartile 4, ≥81.9 pg/mL). During a median 4.8-year follow-up period, the all-cause mortality rate rose from 0.8% in the lowest concentration NT-proBNP group (<19.8 pg/mL) to 7.8% in the highest NT-proBNP group (≥81.9 pg/mL; P<0.001). The incidence of major adverse cardiovascular events (MACEs) increased from 3.1% in the lowest NT-proBNP group to 18.9% in the highest group (P<0.001). Individuals in the highest NT-proBNP group (≥81.9 pg/mL) were associated with higher risk of all-cause death and MACEs compared with the lowest NT-proBNP group using Kaplan-Meier survival curves and the Cox proportional hazard model after adjusting for age, sex, and traditional risk factors.The plasma NT-proBNP level is a strong and independent prognosis factor for all-cause death and MACEs in the community population. The NT-proBNP cut-point for the prognostic value remains to be further studied. NT-proBNP is a strong and independent prognostic factor for all-cause death and MACEs in individuals older than 65 years and MACEs in individuals younger than 65 years.

The study aimed to evaluate the relationship between anthropometric and metabolic indices, inflammatory cytokines, and adipocyte fatty acid-binding protein (A-FABP) in obese patients with newly diagnosed type 2 diabetes. The study included 48 nonobese subjects with newly diagnosed type 2 diabetes, 42 obese subjects with newly diagnosed type 2 diabetes, 30 simple obese subjects, and 30 matched normal subjects. Serum A-FABP was assessed by enzyme-linked immunosorbent assay. Pearson's correlations and multiple linear regression stepwise analysis were used to analyze correlations of A-FABP with anthropometric and metabolic indices and inflammatory cytokines. Obese subjects with newly diagnosed type 2 diabetes had elevated A-FABP compared to normal control, nondiabetic obese patients, and nonobese diabetic patients. A-FABP was significantly correlated with glycated hemoglobin A1C (HbA1C), BMI, triglyceride, Homeostasis Model Assessment Index (HOMA-IR), waist hip rate, C-reactive protein, IL-6, and HDL-C in obese subjects with type 2 diabetes. In multiple linear regression stepwise analysis, BMI, HbA1C, and HOMA-IR were significantly independent determinants for A-FABP. BMI, HbA1C, and HOMA-IR are independently associated with A-FABP in obese subjects with newly diagnosed type 2 diabetes. A-FABP may be related to insulin resistance and inflammation in type 2 diabetes and concomitant obesity.

Nondestructive detection of mutton freshness based on a single indicator has limitations and poor applicability. Hyperspectral imaging technology can detect a variety of information in the process of mutton freshness changes, but the establishments of spectral feature extraction and evaluation model have greater impacts on the final evaluation results. To improve the applicability and accuracy of nondestructive detection of mutton freshness, this paper proposes a multi-indicator correlation maximization spectral feature extraction algorithm and self-adaptive BP neural network classification model to detect mutton freshness nondestructively. In the experiments, 400–1000 nm hyperspectral images are collected from 140 mutton samples, and the standard values of total volatile basic nitrogen (TVB-N) and total aerobic plate count (TAC) are determined by laboratory methods. The representative spectra of mutton samples are extracted in the region of interests (ROIs). The spectral feature information is extracted using the feature of multi-indicator correlation maximization, which is proposed in this paper. The samples of calibration set and the prediction set are divided at a ratio of 3:1, and the improved three-layer BP neural network is used to evaluate the freshness of mutton. The results show that the final overall classification accuracy (OA) is 0.9378, the Kappa coefficient is 0.9096, and the AUC values for the three freshness classification results are 0.8192, 0.6766 and 0.7483, respectively. The root means square error (RMSE) of the evaluation results is 0.279. The research shows that the method proposed in this paper can achieve more accurate nondestructive detection of mutton freshness. Moreover, the research provides a new method to obtain spectral information of multiple detection indicators with hyperspectral imaging technology, which can improve the applicability and robustness of the evaluation model of single indicator.

PurposeThe aim of the present study is to investigate the association of the polymorphism of two genes in CXC chemokine family, interleukin-8 (IL-8) and interferon-inducible protein 10 (IP-10), with both susceptibility and progression of DR in T2D population of northern China.Patients and methodsA total of 1043 eligible type 2 diabetic patients from Heilongjiang of northern China were recruited for this study. They were grouped into: with diabetic retinopathy (DR, 528 cases) and without diabetic retinopathy (DNR, 515 cases). Single nucleotide polymorphism (SNP) genotyping of IL-8(-251T/A) and IP-10(-1596C/T) was performed by polymerase chain reaction. Multivariate analysis and stepwise multiple logistic progression analysis were conducted to evaluate the association between gene SNP and DR susceptibility and progression. Pooled odds ratio (OR) with 95% confidence interval (CI) was applied to assess the strength of the association among study groups.ResultsThe occurring of IL-8(-251) AA genotype was correlated with susceptibility (OR: 2.286, 95% CI: 1.382-3.782, P=0.001) and progression of high-risk proliferative diabetic retinopathy (PDR) (OR: 0.354, 95% CI: 0.162-0.770, P=0.009). Reversely, T allele of IP-10 (-1596) C/T was correlated with a reduced risk of DR (OR: 0.341, 95% CI: 0.249-0.466, P<0.001). However, gene polymorphisms of IL-8-251T/A and IP-10-1596C/T were not associated with diabetic macular edema (DME)(P>0.05).ConclusionsAA genotype of IL-8-251T/A was closely correlated to DR and high-risk proliferative diabetic retinopathy (PDR). -1596T allele of the IP-10 is a beneficial genotype for DR.

Antioxidant and hepatoprotective activities in vitro of saffron petals were examined in this study for better utilizing saffron (Crocus sativus L.) biowaste. Using the DPPH and ABTS radical scavenging method, we compared the antioxidant activity and the content of total flavonoid extracts from petals (TFESP), stamens (TFESS), and both saffron petals and stamens (TFEMS). The results showed that the antioxidant capacity and the flavonoid content of TFESP were higher than those of TFESS and TFEMS. Then, the hepatoprotective activity of TFESP was determined, and the silymarin was used as a positive control. The main components of TFESP were analysed by ultrahigh performance liquid chromatography (UPLC) photodiode array (PDA)/mass spectrometry (MS) and nuclear magnetic resonance (NMR). The result showed that (1) TFESP could release oxidative liver injury induced by tert-butyl hydroperoxide (t-BHP). (2) TFESP could reduce the accumulation of reactive oxygen species (ROS); enhance the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH); and then improve the total antioxidant capacity (T-AOC) in BRL-3A cells. (3) TFESP could enhance the expression of B-cell lymphoma-2 (BCL-2) and decrease the expression of caspase-3 and caspase-9; increase the expression of Kelch-like ECH-associated protein-1 (Keap-1), nuclear factor, erythroid 2-related factor 2 (Nrf2), superoxide dismutase, and heme oxygenase 1 (HO-1); and downregulate inducible nitric oxide synthase (INOS), interleukin-6 (IL-6), and nuclear factor kappa B-9 (NF-κB-9). (4) The main hepatoprotective component of TFESP was identified as kaempferol-3-o-sophoroside. The mechanism may be that kaempferol-3-o-sophoroside can protect t-BHP-induced cell injury by regulating the expression of antioxidant, antiapoptotic, and anti-inflammatory genes. Thus, saffron petals are a potential hepatoprotective resource worthy of development.

Lung cancer is the most common cancer malignancy worldwide. With the continuous spread of the coronavirus disease 2019 (COVID-19) globally, it is of great significance to explore the impact of this disease on the clinical characteristics of lung cancer. Thus, we aimed to investigate whether the COVID-19 pandemic had any influence on the clinical characteristics and diagnosis of patients with lung cancer. We collected clinical and demographic data of patients who were newly diagnosed with lung cancer at our hospital between February 2019 and July 2020. Overall, 387 patients with lung cancer were divided into two groups for analysis: epidemic group (from February to July 2020) and pre-epidemic group (from February to July 2019). The source of diagnosis and clinical characteristics of the two groups were analysed. T-test and Mann-Whitney U were used for continuous variables, and Chi-squared or Fisher’s exact test for categorical variable. We found that during the epidemic period, 110 cases of lung cancer were incidentally diagnosed during COVID-19 screening, accounting for 47.6% of all newly diagnosed lung cancer cases at our hospital. The proportions of patients who were diagnosed based on symptoms and physical examination in the epidemic group were 34.2 and 18.2%, respectively, while that in the pre-epidemic group were 41.7 and 58.3%, respectively. There was significant difference in the source of diagnosis between the two groups. In a subgroup analysis of the epidemic group, the average tumour volume of the patients diagnosed with COVID-19 screening was significantly smaller than that of the patients diagnosed with symptoms and physical examination. In conclusion, the continuation of the COVID-19 pandemic may impact the screening and clinical characteristics of lung cancer and require large-scale and longer-term observation.

This study was conducted in order to investigate the association between radiomics features and frontal glioma-associated epilepsy (GAE) and propose a reliable radiomics-based model to predict frontal GAE.This retrospective study consecutively enrolled 166 adult patients with frontal glioma (111 in the training cohort and 55 in the testing cohort). A total 1,130 features were extracted from T2 fluid-attenuated inversion recovery images, including first-order statistics, 3D shape, texture, and wavelet features. Regions of interest, including the entire tumor and peritumoral edema, were drawn manually. Pearson correlation coefficient, 10-fold cross-validation, area under curve (AUC) analysis, and support vector machine were adopted to select the most relevant features to build a clinical model, a radiomics model, and a clinical-radiomics model for GAE. The receiver operating characteristic curve (ROC) and AUC were used to evaluate the classification performance of the models in each cohort, and DeLong's test was used to compare the performance of the models. A two-sided t-test and Fisher's exact test were used to compare the clinical variables. Statistical analysis was performed using SPSS software (version 22.0; IBM, Armonk, New York), and p <0.05 was set as the threshold for significance.The classification accuracy of seven scout models, except the wavelet first-order model (0.793) and the wavelet texture model (0.784), was <0.75 in cross-validation. The clinical-radiomics model, including 17 magnetic resonance imaging-based features selected among the 1,130 radiomics features and two clinical features (patient age and tumor grade), achieved better discriminative performance for GAE prediction in both the training [AUC = 0.886, 95% confidence interval (CI) = 0.819-0.940] and testing cohorts (AUC = 0.836, 95% CI = 0.707-0.937) than the radiomics model (p = 0.008) with 82.0% and 78.2% accuracy, respectively.Radiomics analysis can non-invasively predict GAE, thus allowing adequate treatment of frontal glioma. The clinical-radiomics model may enable a more precise prediction of frontal GAE. Furthermore, age and pathology grade are important risk factors for GAE.

Abstract We report two cases with tiny ferromagnetic intraocular foreign bodies (FBs) that were demonstrated only on magnetic resonance imaging (MRI) and confirmed by subsequent ophthalmologic operation. Both of the patients had a history of ocular trauma and their clinical symptoms were compatible with an intraocular FB. Plain x‐ray film, 3 mm slice thickness computed tomography (CT) scans (Toshiba TXT 600 system and GERP22 system), B‐scan ultrasonography, and an MRI study (Siemens Impact 1.0 MR system) were acquired. MR examinations were performed using spin‐echo (SE) T1, T2, and PD‐weighted axial and sagittal or coronal images with 3 mm slice thickness. Plain x‐ray film, 3 mm slice thickness CT scans and B‐scan ultrasonography all failed to demonstrate any tiny intraocular FBs in these two patients, whereas MRI revealed tiny ferromagnetic FBs due to their characteristic magnetic susceptibility artifact. A ferromagnetic FB was found in the vitreous body of each patient, which were 0.375 × 0.3 × 0.15 mm and 0.5 × 0.4 × 0.2 mm, respectively, and there was no evidence of MR‐induced damage. We suggest that tiny ferromagnetic fragments with a diameter below 0.5 mm, which are too small to be visualized by x‐ray plain films and CT images, may be visualized on MR images. These tiny ferromagnetic particles may not be large enough to cause ocular damage during a 1.0T MRI examination. MRI may be a useful tool in the evaluation of tiny intraocular ferromagnetic FBs if other imaging modalities such as plain s‐ray, CT scan, and ultrasonography failed to do so. Further evaluation with a large‐scale study (in vitro and in vivo animal study) for the safety of detecting tiny (&lt;0.5 mm) intraocular ferromagnetic particles is warranted. J. Magn. Reson. Imaging 2009;29:704–707. © 2009 Wiley‐Liss, Inc.

Purpose: To examine the distribution and causes of corneal blindness in a rural Chinese population. Methods: Cluster sampling of populations age > 50 was used. The protocol consisted of a detailed interview, visual acuity (VA) testing, and clinical examinations. An eye was considered to have cornea blindness if the visual acuity was < 20/400 due to a corneal disease. Results: A total of 5057 eligible subjects agreed to participate, giving an attendance rate of 91.0%. Corneal blindness in at least one eye was present in 48 participants, prevalence of 0.949% (95% CI: 0.682–1.216%) in at least one eye, which included 0.16% prevalence of corneal blindness in both eyes. The most frequent causes of corneal blindness in at least one eye included keratitis during childhood (39.6%), keratitis during adulthood (27.1%), and trauma (20.8%). We found that aging and male gender were associated with prevalence of corneal blindness. Multivariate analysis shows a higher OR of corneal blindness in subjects age 70 and older (1.746) and male gender (1.177). Conclusions: Corneal blindness is a public health problem in southern Harbin, the majority of which is either preventable or treatable. Eye care planning must focus on corneal blindness as well as cataract.

Giant pituitary adenomas (GPAs) remain a therapeutic challenge with high mortality and morbidity. We described our experience in a consecutive series of GPAs with extensive suprasellar extension.A series of 15 consecutive patients with maximum dimension of more than 4cm was enrolled in present study. These cases were microsurgically treated through diverse transcranial approach in our neurosurgical department from January 2006 to January 2011. Four different transcranial microsurgical approaches were selected based on tumor localization and expansion as well as neurosurgeon's experience.Gross total removal (GTR) was achieved in 10 of all patients (67%), subtotal removal was achieved in 5 of 15 (33%). Nine patients experienced visual improvement postoperatively compared with those of preoperative symptom (82%), no intraoperative or postoperative death was observed in present series. The most striking features of this study indicate that an experienced team can reach 67% with no mortality, no panhypopituitarism and no permanent diabetes insipidus dealing with GPAs. No recurrent tumor was found in the GPAs with GTR, adjuvant radiation therapy had been performed in 5 patients and the continuous shrinkage of the residual adenomas was achieved in 2 out of 5 with radiotherapy.Transcranial approach was still a relatively reliable and safe management for complex GPAs with extensive suprasellar extension.

Introduction: This study was designed to investigate the relationship between serum adiponectin and testosterone in patients with type 2 diabetes.

Abstract Background &amp; Aims Acetaminophen ( APAP ) is widely used as an antipyretic agent which is safe at therapeutic doses. However, overdose of APAP induces fatal and non‐fatal hepatic necroses. The chemical reactive metabolites of APAP initiate toxicity and inflammatory response within the liver and lead to acute liver failure. However, the mechanism underlying APAP ‐induced liver injury is unknown. Thioredoxin‐1 ( TRX ‐1) is an important redox regulator, which plays roles in resisting oxidative stress, regulating inflammation and inhibiting apoptosis. Panaxatriol saponin ( PTS ) is one of the biologically active fractions of Panax notoginseng which is a traditional Chinese medicine. The aim of this study was to investigate the mechanism on PTS protecting liver from APAP hepatotoxicity. Methods Mice were divided into three groups, control group, APAP group and APAP combined with PTS group. Alanine aminotransferase ( ALT ) and tumour necrosis factor‐alpha ( TNF ‐α) were detected by ELISA . TRX ‐1 and pro‐caspase‐12 were examined by Western blotting. Results Our results showed PTS inhibited the levels of ALT and TNF ‐α by APAP . Pretreatment with PTS ameliorated liver injury induced by APAP . The decrease in TRX ‐1 expression was restored by PTS , as well as decreased pro‐caspase‐12 expression was inhibited by PTS . These data suggest that PTS has roles in suppressing the hepatotoxicity by APAP . Conclusion Panaxatriol saponin ameliorated liver injury by APAP through restoring the expression TRX ‐1 and inhibiting pro‐caspase‐12 decrease.

SALL4 is a novel oncogene mediating tumorigenesis in multiple carcinomas. However, its actual role and mechanisms participating in the development of colorectal cancer remains unclear.Immunohistochemical staining and Western blot were conducted to detect the expression of SALL4 and other molecules. siRNA of SALL4 was transfected to silence SALL4 expression in Caco-2 cell line. Flow cytometry was used for cell cycle and apoptosis analysis. Wound healing and transwell assay were used for invasion test. CCK-8 test was employed for cell proliferation and drug sensitivity assessment.By inhibition of SALL4 expression, the proliferation, invasiveness and drug resistance were dramatically reduced while apoptosis rate was up-regulated. Gli1 was found to decrease its expression in SALL4 silencing cells. Moreover, the inhibition on tumorigenesis of Caco-2 by SALL4 silencing was antagonized by Gli1 up-regulation, suggesting Gli1 as a downstream target of SALL4 in cancer development.SALL4 inhibition limited oncogenesis on colorectal cancer by reducing Gli1 expression.

Sepsis is a serious public health issue and the leading cause of death in critically ill patients in intensive care units. Thioredoxin-1 (Trx-1) is a protein of regulating redox, as well as a modulator of inflammation and apoptosis. Our previous study reported that Trx-1 decreased endoplasmic reticulum-mediated inflammation involved in lung in a model of experimental sepsis. However, its effect on mitochondrial-mediated apoptosis in spleen has not been reported. We studied whether Trx-1 could prevent spleen cells apoptosis in sepsis. In the present study, we showed that the apoptosis in spleen was decreased in sepsis induced by cecal ligation and puncture (CLP) in Trx-1 overexpression transgenic (Tg) mice compared with wild-type mice. Colony forming units in the peritoneal cavity and the level of procalcitonin in plasma were significantly decreased in Trx-1 Tg mice 12 h after CLP. The expressions of c-jun-N-terminal kinase, Bax, caspase-9, and caspase-3 were increased in spleen, which were suppressed in Trx-1 Tg mice. However, the decreased Bcl-2 expression in sepsis was recovered in Trx-1 Tg mice. Our results suggest that overexpression of Trx-1 provides protection against sepsis through suppressing mitochondria-induced apoptosis pathway in spleen. This study may provide a new target for clinical intervention, as well potential strategies for treatment of sepsis.

Parkinson’s disease (PD) is a neurodegenerative disease. Nicotine has been reported to have the role in preventing Parkinson’s disease. However, its mechanism is still unclear. In present study we found that nicotine suppressed 1-methyl-4-phenylpyridinium ion(MPP+) toxicity in PC12 cells by MTT assay. The expression of thioredoxin-1(Trx-1) was decreased by MPP+, which was restored by nicotine. The nicotine suppressed expressions of Glucose-regulated protein 78(GRP78/Bip) and C/EBP homologous protein (CHOP) induced by MPP+. The methyllycaconitine (MLA), the inhibitor of α7nAChR and LY294002, the inhibitor of phosphatidylinositol 3-kinase (PI3K) blocked the suppressions of above molecules, respectively. Consistently, pretreatment with nicotine ameliorated the motor ability, restored the declines of Trx-1 and tyrosine hydroxylase (TH), and suppressed the expressions of Bip and CHOP induced by 1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Our results suggest that nicotine plays role in resisting MPP+/MPTP neurotoxicity through activating the α7nAChR/PI3K/Trx-1 pathway and suppressing ER stress.

Over the past decade, mini-laparoscopic cholecystectomy (MLC) and single-port laparoscopic cholecystectomy (SILC) have been the two main successful mini-invasive surgical interventions for the treatment of cholecystolithiasis since the advent of laparoscopic cholecystectomy (LC). In this study, we conducted a meta-analysis to compare the two treatment alternatives.We searched PubMed, CNKI and the Cochrane library for trials that compared MLC and SILC. Risk difference (RD) and mean difference (MD) were calculated with a 95% confidence interval (CI).Four randomized controlled trials (RCTs) and 2 non-randomized comparative studies (nRCSs) involving 2764 patients were identified. A longer operating time (MD -10.49; 95% CI -18.10, -2.88; P = 0.007) and a shorter wound length (MD 3.65; 95% CI 0.51, 6.78; P = 0.02) were found to be associated with SILC compared with MLC. No significant differences were revealed in conversion, hospital stay, pain relief and cosmetic results. Although a lower incidence of complications was observed with MLC (8.2%) compared with SILC (15.9%), but the difference was not statistically significant (RD -0.06; 95% CI -0.12, 0.00; P = 0.07).MLC has an advantage over SILC in terms of operating time rather than hospital stay, pain relief, cosmetic results. Though conversion and complication rates were higher with SILC, there existed no statistically differences in the two measures between the two procedures. Whether MLC confers any benefits in terms of conversion or complications still warrants further studies.

The prevalence of dyslipidemia is rising alarmingly in elderly Han Chinese male patients with type 2 diabetes mellitus (T2DM). The genetic factors that contribute to the development of diabetic dyslipidemia remain incompletely identified. This study was conducted to assess the association between vitamin D receptor (VDR) polymorphisms and development of dyslipidemia in the Han elderly male population with T2DM in North China.A total of 242 T2DM patients with dyslipidemia (DH group, n=108) or without dyslipidemia (DO group, n=134) and 100 controls were genotyped for ApaI, TaqI and FokI single nucleotide polymorphisms (SNPs) of the VDR gene using polymerase chain reaction-restriction fragment length polymorphism and sequencing. The frequency and distribution of the SNPs were compared between cases and controls.The distribution of genotypes of VDR-FokI was significantly different between the control and DM group (P=0.033), as well as between the control and DH subgroup (P=0.011) but not DO subgroup (P=0.111). The frequency of C allele and CC genotype of FokI was significantly higher in the DH patients than in the controls (P=0.015 and P=0.003, respectively). Logistic regression analysis in a dominant model homozygous for the C allele of the FokI SNP showed that CC genotype was associated with DH patients (OR =1.797, 95% CI: 1.077-2.999, P=0.025). Significant associations of the ApaI and TaqI SNPs with either DO or DH subjects were not observed.These findings suggest that CC genotype of VDR-FokI is a risk factor for T2DM patients with dyslipidemia in elderly males in North China.

Polycomb group proteins are epigenetic transcriptional repressors that function through recognition and modification of histone methylation and chromatin structure. As a member of PcG proteins, enhancer of zeste homolog 2 (EZH2) targets cell cycle regulatory proteins which govern cell cycle progression and cellular senescence. In previous work, we reported that EZH2 depletion functionally induced cellular senescence in human gastric cancer cells with mutant p53. However, whether EZH2 expression contributes to the change of key cell cycle regulators and the mechanism involved are still unclear. To address this issue, we investigated the effects of EZH2 depletion on alteration of histone methylation pattern. In gastric cancer cells, INK4/ARF locus was activated to certain extent in consequence of a decrease of H3K27me3 along it caused by EZH2 silence, which contributed substantially to an increase in the expression of p15(INK4b), p14(ARF) and p16(INK4a) and resulted in cellular senescence ultimately. Furthermore, MKN28 cells, which did not express p16(INK4a) and p21(cip), could be induced to senescence via p15(INK4b) activation and suppression of p15(INK4b) reversed senescence progression induced by EZH2 downregulated. These data unravel a crucial role of EZH2 in the regulation of INK4/ARF expression and senescence procedure in gastric cancer cells, and show that the cellular senescence could just depend on the activation of p15(INK4b)/Rb pathway, suggesting the cell-type and species specificity involved in the mechanisms of senescence inducement.

The aim of the present study was to observe and investigate the changes in the serum level of high-sensitivity C-reactive protein (hs-CRP), the endothelial cell-specific molecule-1 (ESM-1) and short-term prognosis of patients with ST-segment elevation myocardial infarction (STEMI) treated by ticagrelor. We enrolled 107 patients with acute STEMI who were admitted in the Department of Cardiology for the first time with occurrence of symptoms, and we successfully performed emergency operation of percutaneous coronary intervention. The patients were divided into two groups, 54 patients in the ticagrelor group (treatment group) and 53 patients in the clopidogrel group (control group), according to the administration of ticagrelor or clopidogrel in dual anti-platelet therapy. Then, we observed the changes at the time of admission, at 24 h, and 4th and 7th day after administration and investigated the correlations between them and the effect of ticagrelor on the short-term prognosis of acute STEMI patients. Significant increases of the serum levels of hs-CRP and ESM-1 were seen in patients of the two groups 24 h after administration of drugs with statistically significant differences between the groups (P<0.05), and on the 4th and 7th day we found a downward trend with statistically significant differences (P<0.05). The level of ESM-1 enhanced the increase of hs-CRP, indicating there was a positive correlation between ESM-1 and hs-CRP (r=0.535, P<0.001). A comparison of the occurrence rates of ischemic outcome event, bleeding and overall adverse events between the two groups yielded no statistically significant difference (P>0.05). In conclusion, the present study demonstrates that ticagrelor can reduce the prevalence of inflammatory reactions rapidly and stabilize the functions of vascular endothelium to improve the stability of atherosclerosis plaque and decrease the occurrence rate of thrombosis as well as ischemic outcome event without any obvious increase in the risk of bleeding. Thus, ticagrelor should be recommended in clinical practices for the treatment of patients with STEMI.

Methamphetamine (METH) has been reported to induce endoplasmic reticulum (ER) stress and neuronal apoptosis in the central nervous system (CNS) during the development of addiction. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays an important role in inhibiting apoptosis and protects neurons from cytotoxicity through ER and mitochondria-mediated pathways. Our previous study has been reported that Trx-1 protects mice from METH-induced rewarding effect. However, whether Trx-1 plays the role in resisting METH injury is still unclear. Here, we aim to investigate whether Trx-1 participates in the regulation of METH-induced CNS injury via ER stress and mitochondria-mediated pathways. Our study first repeated the conditioned place preference expression induced by METH. Then we detected and found that METH increased the expression of N-methyl-d-asparate (NMDA) receptor subunit 2B (NR2B) and the level of glutamate (Glu) in the ventral tegmental area (VTA) and nucleus accumbens (NAc), while Trx-1 overexpression suppressed the increases. We further examined ER stress-related proteins and mitochondrial apoptosis pathway in the VTA and NAc, and found that METH increased the expressions of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and Bax, as same time decreased the expressions of procaspase12, Bcl-2, and procaspase3, while Trx-1 overexpression blocked these changes. These results indicate that Trx-1 blocks METH-induced injury by suppressing ER stress and mitochondria-mediated apoptosis in the VTA and NAc via targeting glutamatergic system.

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder. Its molecular mechanism is still unclear. Endoplasmic reticulum (ER) stress has been highlighted in PD. Transient receptor potential vanilloid 4 (TRPV4) is a kind of nonselective calcium cation channel. A defined role for TRPV4 in PD has not been reported. The purpose of the present research was to investigate the molecular mechanisms by which TRPV4 regulates ER stress induced by the 1-methyl-4-phenylpyridinium ion (MPP+) in PC12 cells.PC12 cells were pretreated with the TRPV4-specific antagonist HC067047 or transfected with TRPV4 siRNA followed by treatment with MPP+. Cell viability was measured by the CCK-8 Assay. The expression of TRPV4, sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2), glucose-regulated protein 78 (GRP78), glucose-regulated protein 94 (GRP94), C/EBP homologous protein (CHOP), procaspase-12, and tyrosine hydroxylase (TH) was detected by western blot and RT-PCR.The expression of TRPV4 was upregulated, while cell viability was decreased by MPP+, which was reversed by HC067047. The ER stress common molecular signature SERCA2 was depressed by MPP+. Moreover, MPP+ induced upregulation of GRP78, GRP94, CHOP, and decrease in procaspase-12 and TH. HC067047 and TRPV4 siRNA reversed MPP+-induced ER stress and restored TH production.TRPV4 functions upstream of ER stress induced by MPP+ and holds promise as a prospective pharmacotherapy target for PD.

This study aimed to investigate the performance of Pulsatilla saponin A (PsA) in diffuse large B-cell lymphoma (DLBCL) cells.Proliferation, ELISA, apoptosis, cell cycle analysis, and assays were carried out to detect the growth and apoptosis in DLBCL cells. Western blotting was used to identify the change in the protein.In cell assays, PsA significantly inhibited the growth and apoptosis in DLBCL cells. The IL-10 and TNF-α of OCI-LY10 and U2932 cells were reduced after 24 h PsA treatment. Bax, cleaved PARP, and cleaved Caspase-3 were increased, while Bcl-2 and C-Myc decreased after PsA treatment. IL-10 may regulate the expression of C-Myc protein in cells by activating the JAK2/STAT3 signaling pathway. PsA can inhibit the overexpression of p-JAK2 and p- STAT3 signaling pathways induced by IL-10 stimulants. The proliferation and apoptosis induced by PsA were confirmed in DLBCL cells.Our findings revealed that PsA may exert its antitumor effect by causing G1 arrest and apoptosis in DLBCL cells. The mechanism of PsA regulating apoptosis in DLBCL cells is probably through the JAK2/STAT3 signaling pathway in vitro.

Abstract Olfaction is a crucial sense that is essential for the well-being and survival of individuals. Olfactory bulb (OB) is the first olfactory relay station, and its function depends on newly generated neurons from the subventricular zone (SVZ). These newly born neurons constantly migrate through the rostral migratory stream to integrate into existing neural networks within the OB, thereby contributing to olfactory information processing. However, the mechanisms underlying the contribution of SVZ adult neurogenesis to OB neurogenesis remain largely elusive. Adult neurogenesis is a finely regulated multistep process involving the proliferation of adult neural stem cells (aNSCs) and neural precursor cells, as well as the migration and differentiation of neuroblasts, and integration of newly generated neurons into preexisting neuronal circuitries. Recently, extensive studies have explored the mechanism of SVZ and OB neurogenesis. This review focused on elucidating various molecules and signaling pathways associated with OB neurogenesis dependent on the SVZ function. A better understanding of the mechanisms underlying the OB neurogenesis on the adult brain is an attractive prospect to induce aNSCs in SVZ to generate new neurons to ameliorate olfactory dysfunction that is involved in various diseases. It will also contribute to developing new strategies for the human aNSCs-based therapies.

Fasteners are a critical part of the rail and are used to fix the rail, which are important for train operation. Rail vibrations during train operation can cause anomalies in fasteners. At present, the 3D structured light camera is used to detect anomalies on the railway sites, but there is a lack of sufficient mining of three-dimensional data and effective fusion of multi-sensor data. To address this issue, this paper proposes a novel approach for railway fastener anomaly detection via multi-sensor fusion and self-driven loss reweighting. First, a pixel-level attention mechanism multi-sensor fusion method is applied, where the depth map is used as an attention factor to highlight edge contours and enhance abrupt changes in the gray level. Second, a feature fusion-decoupled module is proposed to obtain the dense feature maps and then decouple the detection task to output class, location and confidence, respectively. Finally, given the characteristics of the sample imbalance in the fastener dataset, a dynamic self-driven loss reweighting method is used to improve the detection accuracy of difficult samples. The experimental results show that the proposed method can achieve 86.6% precision and 61.72 FPS detection speed, better than other state-of-the-art algorithms.

This study aimed to assess the value of diffusion kurtosis imaging (DKI)-based radiomics models in differentiating glioblastoma (GB) from single brain metastasis (SBM) and compare their diagnostic performance with that of routine magnetic resonance imaging (MRI) models.A total of 110 patients who underwent DKI and were pathologically diagnosed with GB (n = 58) or SBM (n = 52) were enrolled in this study. Radiomics features were extracted from the manually delineated region of interest of the lesion. A training set for model development was constructed from the images of 88 random patients, and 22 patients were reserved for independent validation. Seven single-DKI-parametric models and a multi-DKI-parametric model were constructed using six classifiers, whereas four single-routine-sequence models (based on T2 weighted imaging, apparent diffusion coefficient, T2-dark-fluid, and contrast-enhanced T1 magnetization prepared rapid gradient echo) and a multisequence routine MRI model were constructed for comparison. Receiver operating characteristic curve analysis was conducted to assess the diagnostic performance. The areas under the curve (AUCs) of different models were compared using the DeLong test.The AUCs of the single-DKI-parametric models ranged from 0.800 to 0.933 (mean kurtosis [MK] model). The multi-DKI-parametric model had a slightly higher AUC (0.958) than the MK model; however, the difference was not statistically significant (P = 0.688). In comparison, the AUCs of the routine MRI models ranged from 0.633 to 0.733 (multisequence routine MRI model). The AUC of the multi-DKI-parametric model was significantly higher than that of the multisequence routine MRI model (P = 0.042).The multi-DKI-parametric radiomics model exhibited better performance than that of the single-DKI-parametric models and routine MRI models in distinguishing GB from SBM.

Metro intrusion seriously affects the safety of metro operation. Semantic segmentation is the main content of the research on metro intrusion. Tunnels account for a large proportion of metro lines, by processing the images captured by the vehicle front camera, the state of the elements in the tunnel can be obtained, among which the perception and understanding of the whole scene is an important part of the image processing. For on-board cameras, we propose a lightweight semantic segmentation algorithm for metro to satisfy the real-time requirements. Finally, for a 2048 × 1024 input, the algorithm achieves 75.21% MIoU on the metro tunnel data set with speed of 54FPS (Frames Per Second) on NVIDIA 3090 Ti card.

In order to enhance the real-time perception of the environment of the train and ensure safety, it is necessary to detect intrusion. Most of the intrusion detection algorithms have large parameters and slow speed, so they cannot be well applied in high-speed trains. Therefore, this paper proposes a lightweight pedestrian intrusion detection algorithm with on-board video. First, the lightweight object detection algorithm is used to realize pedestrian detection in the whole scene. Second, the railway track area is extracted by a lightweight semantic segmentation algorithm. Finally, by judging the coordinate position, the pedestrian intrusion detection in the railway track area is realized. In experiments, the positive detection rate is 94.84%, and the missing detection rate is 0.97%, and the false detection rate is 0.81%, which can effectively detect the pedestrian intrusion in the railway track and further improve the intelligent perception system of railway operation environment, which has practical significance and application value for railway safety.

It often occurs that foreign objects hang on railway overhead lines especially in windy days, which may lead to the delay of train, and even cause loss of life and property. With the gradual maturity of computer vision, railway foreign object detection has made great progress. This paper focuses on foreign object in railway overhead lines, and proposes a foreign object detection method based on few-shot learning. The proposed method consists of two stages: general training and fine-tuning training. In the first stage, the data-abundant common classes dataset is used to train the entire detector to obtain the underlying model parameters. In the fine-tuning stage, we make a balanced dataset consisting of common classes and enhanced railway classes, and fine-tune the last layer of the detector to accomplish few-shot foreign object detection. Finally, this proposed method is tested on images of overhead lines intrusions taken in actual railway scenario, and achieves 79% mAP in railway classes.

Real-time awareness of the service status of facilities and equipment in metro tunnels is essential for the safe movement of trains. For low illumination underground tunnel environments where objects have high similarity characteristics and are difficult to distinguish, this paper proposes a framework for tracking high similarity objects along the rail line based on on-board visual perception devices. The framework mainly consists of two stages: object detection and object association. In the first stage, an object detection algorithm is used to detect potentially faulty objects in the video, and this paper takes the continuous occurrence of insulated steel supports on the line as the high similarity research object. In the second stage a matching strategy is used to associate the same object in the video sequence and assign the same ID (identity document). Finally, the proposed framework was tested on metro tunnel video and achieved an accuracy of 95.64 and a detection performance of 25 FPS (frames per second), 82.17 MOTA (multiple object tracking accuracy) and 88.46 MOTP (multiple object tracking precision) tracking performance.

OBJECTIVE: Try to create a dose gradient function (DGF) and test its effectiveness in reducing radiation induced lung injury in breast cancer radiotherapy. MATERIALS AND METHODS: Radiotherapy plans of 30 patients after breast-conserving surgery were included in the study. The dose gradient function was defined as D G H = V D V p 3 , then the area under the DGF curve of each plan was calculated in rectangular coordinate system, and the minimum area was used as the trigger factor, and other plans were triggered to optimize for area reduction. The dosimetric parameters of target area and organs at risk in 30 cases before and after re-optimization were compared. RESULTS: On the premise of ensuring that the target dose met the clinical requirements, the trigger factor obtained based on DGF could further reduce the V5, V10, V20, V30 and mean lung dose (MLD) of the ipsilateral lung in breast cancer radiotherapy, P &lt; 0.01. And the D2cc and mean heart dose (MHD) of the heart were also reduced, P &lt; 0.01. Besides, the NTCPs of the ipsilateral lung and the heart were also reduced, P &lt; 0.01. CONCLUSION: The trigger factor obtained based on DGF is efficient in reducing radiation induced lung injury in breast cancer radiotherapy.

Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignant tumors, and the mechanisms underlying the anti-ferroptosis of esophageal cancer cells are still largely unclear. This study aims to explore the roles of amplified protein kinase C iota (PKCiota) in the ferroptosis of ESCC cells. Cell viability, colony formation, MDA assay, Western blotting, co-IP, PLA, and RNA-seq technologies are used to reveal the roles and mechanisms underlying the PKCiota-induced resistance of ESCC cells to ferroptosis. We showed here that PKCiota was amplified and overexpressed in ESCC and decreased during RSL3-induced ferroptosis of ESCC cells. PKCiota interacted with GPX4 and the deubiquitinase USP14 and improved the protein stability of GPX4 by suppressing the USP14-mediated autophagy–lysosomal degradation pathway. PKCiota was negatively regulated by miR-145-5p, which decreased in esophageal cancer, and also regulated by USP14 and GPX4 by a positive feedback loop. PKCiota silencing and miR-145-5p overexpression suppressed tumor growth of ESCC cells in vivo, respectively; even a combination of silencing PKCiota and RSL3 treatment showed more vital suppressive roles on tumor growth than silencing PKCiota alone. Both PKCiota silencing and miR-145-5p overexpression sensitized ESCC cells to RSL3-induced ferroptosis. These results unveiled that amplified and overexpressed PKCiota induced the resistance of ESCC cells to ferroptosis by suppressing the USP14-mediated autophagic degradation of GPX4. Patients with PKCiota/USP14/GPX4 pathway activation might be sensitive to GPX4-targeted ferroptosis-based therapy.

Background and purpose The differential diagnosis between solid glioma and brain inflammation is necessary but sometimes difficult. We assessed the effectiveness of multiple diffusion metrics of diffusion-weighted imaging (DWI) in differentiating solid glioma from brain inflammation and compared the diagnostic performance of different DWI models. Materials and methods Participants diagnosed with either glioma or brain inflammation with a solid lesion on MRI were enrolled in this prospective study from May 2016 to April 2023. Diffusion-weighted imaging was performed using a spin-echo echo-planar imaging sequence with five b values (500, 1,000, 1,500, 2000, and 2,500 s/mm 2 ) in 30 directions for each b value, and one b value of 0 was included. The mean values of multiple diffusion metrics based on diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), mean apparent propagator (MAP), and neurite orientation dispersion and density imaging (NODDI) in the abnormal signal area were calculated. Comparisons between glioma and inflammation were performed. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) of diffusion metrics were calculated. Results 57 patients (39 patients with glioma and 18 patients with inflammation) were finally included. MAP model, with its metric non-Gaussianity (NG), shows the greatest diagnostic performance (AUC = 0.879) for differentiation of inflammation and glioma with atypical MRI manifestation. The AUC of DKI model, with its metric mean kurtosis (MK) are comparable to NG (AUC = 0.855), followed by NODDI model with intracellular volume fraction (ICVF) (AUC = 0.825). The lowest value was obtained in DTI with mean diffusivity (MD) (AUC = 0.758). Conclusion Multiple diffusion metrics can be used in differentiation of inflammation and solid glioma. Non-Gaussianity (NG) from mean apparent propagator (MAP) model shows the greatest diagnostic performance for differentiation of inflammation and glioma.

Abstract Perimenopausal period causes a significant amount of bone loss, which results in primary osteoporosis (OP). The Periostin (Postn) may play important roles in the pathogenesis of OP after ovariectomized (OVX) rats. To identify the roles of Postn in the bone marrow mesenchymal stem cell derived osteoblasts (BMSC-OB) in OVX rats, we investigated the expression of Wnt/β-catenin signaling pathways in BMSC-OB and the effects of Postn on bone formation by development of BMSC-OB cultures. Twenty-four female Sprague–Dawley rats at 6 months were randomized into 3 groups: sham-operated (SHAM) group, OVX group and OVX+Postn group. The rats were killed after 3 months, and their bilateral femora and tibiae were collected for BMSC-OB culture, Micro-CT Analysis, Bone Histomorphometric Measurement, Transmission Electron Microscopy and Immunohistochemistry Staining. The dose/time-dependent effects of Postn on the proliferation, differentiation and mineralization of BMSC-OB and the expression of osteoblastic markers were measured in in vitro experiments. We found increased Postn increased bone mass, promoted bone formation of trabeculae, Wnt signaling and the osteogenic activity in osteoblasts in sublesional femur. Postn have the function to enhance cell proliferation, differentiation and mineralization at a proper concentration and incubation time. Interestingly, in BMSC-OB from OVX rats treated with the different dose of Postn, the osteoblastic markers expression and Wnt/β-catenin signaling pathways were significantly promoted. The direct effect of Postn may lead to inhibit excessive bone resorption and increase bone formation through the Wnt/β-catenin signaling pathways after OVX. Postn may play a very important role in the pathogenesis of OP after OVX.

Neurological brain disorders are a series of conditions with damage or loss of neurons, such as Parkinson's disease (PD), Alzheimer's disease (AD), or drug dependence. These individuals have gradual deterioration of cognitive, motor, and other central nervous system functions affected. This degenerative trajectory is intricately associated with dysregulations in neurotransmitter systems. Positron Emission Tomography (PET) imaging, employing radiopharmaceuticals and molecular imaging techniques, emerges as a crucial tool for detecting brain biomarkers. It offers invaluable insights for early diagnosis and distinguishing neurological brain disorders. This article comprehensively reviews the application and progress of conventional and novel PET imaging agents in diagnosing neurological brain disorders. Furthermore, it conducts a thorough analysis on merits and limitations. The article also provides a forward-looking perspective in the future development directions of PET imaging agents for diagnosing neurological brain disorders and proposes potential innovative strategies. It aims to furnish clinicians and researchers with an all-encompassing overview of the latest advancements and forthcoming trends in the utilization of PET imaging for diagnosing brain disorders.