Ning Wei

The cyclin-dependent kinase Cdk2 associates with cyclins A, D, and E and has been implicated in the control of the G1 to S phase transition in mammals. To identify potential Cdk2 regulators, we have employed an improved two-hybrid system to isolate human genes encoding Cdk-interacting proteins (Cips). CIP1 encodes a novel 21 kd protein that is found in cyclin A, cyclin D1, cyclin E, and Cdk2 immunoprecipitates. p21CIP1 is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclin A-Cdk2, cyclin E-Cdk2, cyclin D1-Cdk4, and cyclin D2-Cdk4 complexes. Cotransfection experiments indicate that CIP1 and SV40 T antigen function in a mutually antagonistic manner to control cell cycle progression.

Chronic inflammation is a well-known risk factor for cancer. Proinflammatory mediators such as prostaglandin E2 (PGE2) promote colorectal tumor growth by stimulating angiogenesis, cell invasion, and cell growth, and inhibiting apoptosis. Molecules that regulate tumor-associated angiogenesis provide promising therapeutic targets for treatment of colorectal cancer (CRC) as indicated by the recent development of the novel anti-angiogenic agent bevacizumab (Avastin). However, use of this drug only prolongs survival by several months, highlighting the importance of finding more effective treatment regimens. We report here that PGE2 induces expression of CXCL1 (growth-regulated oncogene α), a pro-angiogenic chemokine, in human CRC cells. More importantly, CXCL1 released from carcinoma cells induces microvascular endothelial cell migration and tube formation in vitro. Furthermore, PGE2 promotes tumor growth in vivo by induction of CXCL1 expression, which results in increased tumor microvessel formation. These results have potential clinical significance because we found that CXCL1 expression correlates with PGE2 levels in human CRCs. Collectively, our findings show for the first time that CXCL1 is regulated by PGE2 and indicate that CXCL1 inhibitors should be evaluated further as potential anti-angiogenic agents for treatment of CRC.

Peroxisome proliferator-activated receptor (PPAR) δ is a member of the nuclear hormone receptor superfamily. PPARδ may ameliorate metabolic diseases such as obesity and diabetes. However, PPARδ's role in colorectal carcinogenesis remains controversial. Here, we present genetic and pharmacologic evidence demonstrating that deletion of PPARδ decreases intestinal adenoma growth in Apc Min/+ mice and inhibits tumor-promoting effects of a PPARδ agonist GW501516. More importantly, we found that activation of PPARδ up-regulated VEGF in colon carcinoma cells. VEGF directly promotes colon tumor epithelial cell survival through activation of PI3K–Akt signaling. These results not only highlight concerns about the use of PPARδ agonists for treatment of metabolic disorders in patients who are at high risk for colorectal cancer, but also support the rationale for developing PPARδ antagonists for prevention and/or treatment of cancer.

The glutathione peroxidases, a family of selenocysteine-containing redox enzymes, play pivotal roles in balancing the signaling, immunomodulatory, and deleterious effects of reactive oxygen species (ROS). The glutathione peroxidase GPX3 is the only extracellular member of this family, suggesting it may defend cells against ROS in the extracellular environment. Notably, GPX3 hypermethylation and underexpression occur commonly in prostate, gastric, cervical, thyroid, and colon cancers. We took a reverse genetics approach to investigate whether GPX3 would augment inflammatory colonic tumorigenesis, a process characterized by oxidative stress and inflammation, comparing Gpx3(-/-) mice in an established two-stage model of inflammatory colon carcinogenesis. Gpx3-deficient mice exhibited an increased tumor number, though not size, along with a higher degree of dysplasia. In addition, they exhibited increased inflammation with redistribution toward protumorigenic M2 macrophage subsets, increased proliferation, hyperactive WNT signaling, and increased DNA damage. To determine the impact of acute gene loss in an established colon cancer line, we silenced GPX3 in human Caco2 cells, resulting in increased ROS production, DNA damage and apoptosis in response to oxidative stress, combined with decreased contact-independent growth. Taken together, our results suggested an immunomodulatory role for GPX3 that limits the development of colitis-associated carcinoma.

Although endocannabinoid signaling is important for certain aspects of gastrointestinal homeostasis, the role of the cannabinoid receptors (CB) in colorectal cancer has not been defined. Here we show that CB1 expression was silenced in human colorectal cancer due to methylation of the CB1 promoter. Our genetic and pharmacologic studies reveal that loss or inhibition of CB1 accelerated intestinal adenoma growth in Apc(Min/+) mice whereas activation of CB1 attenuated intestinal tumor growth by inducing cell death via down-regulation of the antiapoptotic factor survivin. This down-regulation of survivin by CB1 is mediated by a cyclic AMP-dependent protein kinase A signaling pathway. These results indicate that the endogenous cannabinoid system may represent a potential therapeutic target for prevention or treatment of colorectal cancer.

Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions.

Selenium (Se) is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD). Epidemiological studies have inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS)-induced colitis, and azoxymethane (AOM) followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-β pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC) had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis.

Although epidemiologic and experimental evidence strongly implicates chronic inflammation and dietary fats as risk factors for cancer, the mechanisms underlying their contribution to carcinogenesis are poorly understood. Here we present genetic evidence demonstrating that deletion of peroxisome proliferator-activated receptor δ (PPARδ) attenuates colonic inflammation and colitis-associated adenoma formation/growth. Importantly, PPARδ is required for dextran sodium sulfate induction of proinflammatory mediators, including chemokines, cytokines, COX-2, and prostaglandin E2 (PGE2), in vivo. We further show that activation of PPARδ induces COX-2 expression in colonic epithelial cells. COX-2-derived PGE2 stimulates macrophages to produce proinflammatory chemokines and cytokines that are responsible for recruitment of leukocytes from the circulation to local sites of inflammation. Our results suggest that PPARδ promotes colonic inflammation and colitis-associated tumor growth via the COX-2-derived PGE2 signaling axis that mediates cross-talk between tumor epithelial cells and macrophages.

Protein kinase D (PKD) signaling plays a critical role in the regulation of DNA synthesis, proliferation, cell survival, adhesion, invasion/migration, motility, and angiogenesis. To date, relatively little is known about the potential role of PKD in the development and/or progression of human colorectal cancer. We evaluated the expression of different PKD isoforms in colorectal cancer and investigated the antitumor activity of PKD inhibitors against human colorectal cancer. PKD2 was the dominant isoform expressed in human colon cancer cells. PKD3 expression was also observed but PKD1 expression, at both the RNA and protein levels, was not detected. Suppression of PKD using the small molecule inhibitors CRT0066101 and kb-NB142-70 resulted in low micromolar in vitro antiproliferative activity against multiple human colorectal cancer cell lines. Drug treatment was associated with dose-dependent suppression of PKD2 activation. Incubation with CRT0066101 resulted in G(2)-M phase arrest and induction of apoptosis in human colorectal cancer cells. Further studies showed that CRT0066101 treatment gave rise to a dose-dependent increase in expression of cleaved PARP and activated caspase-3, in addition to inhibition of AKT and ERK signaling, and suppression of NF-κB activity. Transfection of PKD2-targeted siRNAs resulted in similar effects on downstream pathways as observed with small molecule inhibitors. Daily administration of CRT0066101 resulted in significant inhibition of tumor growth in HCT116 xenograft nude mice. Taken together, our studies show that PKD plays a significant role in mediating growth signaling in colorectal cancer and may represent a novel chemotherapeutic target for the treatment of colorectal cancer.

LncRNA ZFAS1 (ZNFX1 antisense RNA1) plays key roles in the occurrence and progression of various cancers, including colorectal cancer, glioma, lung cancer, gastric cancer, and so on. To date, relatively little is known about its potential role in development and/or progression of clear cell renal cell carcinoma (ccRCC). Expression level of ZFAS1 and miR-10a in 60 ccRCC and 20 adjacent non-tumor tissues were determined by using qRT-PCR. The effect of knockdown of ZFAS1 on cell proliferation, migration and invasion were measured by CCK-8 assay, transwell migration and invasion assay, respectively. The correlation of ZFAS1 and miR-10a was analyzed by bioinformatics DIANA TOOLS. Protein and mRNA expression of spindle and kinetochore-associated protein 1(SKA1) were determined by western blot and qRT-PCR analysis, respectively. Interactions between ZFAS1 and miR-10a were verified by luciferase reporter assay and RNA immunoprecipitation (RIP) assay, and interactions between miR-10a and SKA1 was verified by a luciferase reporter assay. We observed that high-level expression of ZFAS1 is positively correlated with poor prognosis and shorter overall survival (OS) in patients with ccRCC. Knockdown of ZFAS1 significantly suppressed proliferation, migration and invasion of ccRCC cells. Furthermore, miR-10a was identified as a target of ZFAS1. Silencing miR-10a could attenuate the ability of ZFAS1 in promoting proliferation and metastasis of ccRCC. Subsequently, our studies validated that SKA1, as a key downstream target protein for miR-10a, is responsible for the biological role of ZFAS1. ZFAS1 positively regulated SKA1 expression via sponging miR-10a. Taken together, our findings suggest that ZFAS1 promotes growth and metastasis of ccRCC via targeting miR-10a/SKA1 pathway, which may represent a novel therapeutic target or biomarker for ccRCC.

This study investigated the in vitro and in vivo antiproliferative activity of esculetin against hepatocellular carcinoma, and clarified its potential molecular mechanisms. Cell viability was determined by the MTT (tetrazolium) colorimetric assay. In vivo antitumor activity of esculetin was evaluated in a hepatocellular carcinoma mouse model. Seventy-five C57BL/6J mice were implanted with Hepa1-6 cells and randomized into five groups (n=15 each) given daily intraperitoneal injections of vehicle (physiological saline), esculetin (200, 400, or 700 mg·kg-1·day-1), or 5-Fu (200 mg·kg-1·day-1) for 15 days. Esculetin significantly decreased tumor growth in mice bearing Hepa1-6 cells. Tumor weight was decreased by 20.33, 40.37, and 55.42% with increasing doses of esculetin. Esculetin significantly inhibited proliferation of HCC cells in a concentration- and time-dependent manner and with an IC50 value of 2.24 mM. It blocked the cell cycle at S phase and induced apoptosis in SMMC-7721 cells with significant elevation of caspase-3 and caspase-9 activity, but did not affect caspase-8 activity. Moreover, esculetin treatment resulted in the collapse of mitochondrial membrane potential in vitro and in vivo accompanied by increased Bax expression and decreased Bcl-2 expression at both transcriptional and translational levels. Thus, esculetin exerted in vitro and in vivo antiproliferative activity in hepatocellular carcinoma, and its mechanisms involved initiation of a mitochondrial-mediated, caspase-dependent apoptosis pathway.

Insulin degrading enzyme (IDE) is believed to act as a junction point of Type 2 diabetes (T2D) and Alzheimer's disease (AD); however, the underlying mechanism was not completely clear yet. Transgenic APPSwe/PS1 mice were used as the AD model and were treated with streptozocin/streptozotocin (STZ) to develop a mixed mice model presenting both AD and T2D. Morris Water Maze (MWM) and recognition task were performed to trace the cognitive function. The detection of fasting plasma glucose (FPG) and plasma insulin concentration, and oral glucose tolerance test (OGTT) were used to trace the metabolism evolution. Aβ40 and Aβ42 were quantified by colorimetric ELISA kits. The mRNA or protein expression levels were determined by quantitative real-time RT-PCR and Western blotting analysis respectively. T2D contributes to the AD progress by accelerating and worsening spatial learning and recognition impairments. Metabolic parameters and glucose tolerance were significantly changed in the presence of the AD and T2D. The expression levels of IDE, PPARγ, and AMPK were down-regulated in mice with AD and T2D. PPARγ activator rosiglitazone (RSZ) or AMPK activator AICAR increased the expression level of IDE and decreased Aβ levels in mice with AD and T2D. RSZ or AICAR treatment also alleviated the spatial learning and recognition impairments in AD and T2D mice. Our results found that, in the mice with T2D and AD, the activators of PPARγ/AMPK signaling pathway significantly increased the expression level of IDE, and decreased the accumulation of Aβ40 and Aβ42, as well as alleviated the spatial learning and recognition impairments.

Aurora kinase A (Aurora-A), a serine/threonine kinase, plays a pivotal role in various cellular processes, including mitotic entry, centrosome maturation and spindle formation. Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer, including lung cancer, colorectal cancer, and breast cancer. Alteration of Aurora-A impacts multiple cancer hallmarks, especially, immortalization, energy metabolism, immune escape and cell death resistance which are involved in cancer progression and resistance. This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance, including chemoresistance (taxanes, cisplatin, cyclophosphamide), targeted therapy resistance (osimertinib, imatinib, sorafenib, etc.), endocrine therapy resistance (tamoxifen, fulvestrant) and radioresistance. Specifically, the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair, feedback activation bypass pathways, resistance to apoptosis, necroptosis and autophagy, metastasis, and stemness. Noticeably, our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1, ARID1A and MYC gene mutation tumors, and potential synergistic strategy for mTOR, PAK1, MDM2, MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase. In addition, we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.

The world wide proliferation of mobile phones raises the concern about the health effects of 1800-MHz microwaves on the brain. The present study assesses the effects of microwave exposure on the function of cultured hippocampal neurons of rats using whole cell patch-clamp analysis combined with immunocytochemistry. We showed that chronic exposure (15 min per day for 8 days) to Global System for Mobile Communication (GSM) 1800-MHz microwaves at specific absorption rate (SAR) of 2.4 W/kg induced a selective decrease in the amplitude of alpha-amino-3-hydroxy-5-methyl-4-soxazole propionic acid (AMPA) miniature excitatory postsynaptic currents (mEPSCs), whereas the frequency of AMPA mEPSCs and the amplitude of N-methyl-D-aspartate (NMDA) mEPSCs did not change. Furthermore, the GSM microwave treatment decreased the expression of postsynaptic density 95 (PSD95) in cultured neurons. Our results indicated that 2.4 W/kg GSM 1800-MHz microwaves may reduce excitatory synaptic activity and the number of excitatory synapses in cultured rat hippocampal neurons.

<h3>Objective</h3> Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD. <h3>Design</h3> We determined <i>BVES</i> promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured <i>BVES</i> mRNA levels in a tissue microarray consisting of normal colons and CAC samples. <i>Bves^−/−</i> and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels. <h3>Results</h3> <i>BVES</i> mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, <i>BVES</i> promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, <i>Bves</i> was underexpressed in experimental inflammatory carcinogenesis, and <i>Bves^−/−</i> mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of <i>Bves</i>^−/− tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction. <h3>Conclusion</h3> Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. <i>BVES</i> promoter methylation status may serve as a CAC biomarker.

Clinical studies have reported that patients with gastroesophageal reflux disease (GERD) have a higher prevalence of hypertension.To performed a bidirectional Mendelian randomization (MR) analysis to investigate the causal link between GERD and essential hypertension.Eligible single nucleotide polymorphisms (SNPs) were selected, and weighted median, inverse variance weighted (IVW) as well as MR egger (MR-Egger) regression were used to examine the potential causal association between GERD and hypertension. The MR-Pleiotropy RESidual Sum and Outlier analysis was used to detect and attempt to reduce horizontal pleiotropy by removing outliers SNPs. The MR-Egger intercept test, Cochran's Q test and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of single instrumental variable.IVW analysis exhibited an increased risk of hypertension (OR = 1.46, 95%CI: 1.33-1.59, P = 2.14E-16) in GERD patients. And the same result was obtained in replication practice (OR = 1.002, 95%CI: 1.0008-1.003, P = 0.000498). Meanwhile, the IVW analysis showed an increased risk of systolic blood pressure (β = 0.78, 95%CI: 0.11-1.44, P = 0.021) and hypertensive heart disease (OR = 1.68, 95%CI: 1.36-2.08, P = 0.0000016) in GERD patients. Moreover, we found an decreased risk of Barrett's esophagus (OR = 0.91, 95%CI: 0.83-0.99, P = 0.043) in essential hypertension patients.We found that GERD would increase the risk of essential hypertension, which provided a novel prevent and therapeutic perspectives of essential hypertension.

Enhanced UV radiation can change plant biology, especially secondary metabolites, yet the effects on postharvest medicinal plant tissues are now rarely researched. Therefore, our study was aimed to explore changes of secondary metabolites and pharmacological activities involved in the response to enhanced UV-A and UV-B radiation induction in freshly collected flower buds of Lonicera japonica Thunb. We found that after UV-A and UV-B radiation, the content of seven compounds dramatically increased. We identified these compounds by HPLC–MS, which were four kinds of iridoid and three kinds of isochlorogenic acid. Antioxidant experiment showed that the antioxidant power of methanol extracts from the flower buds represented enhancement to a certain extent after UV-A and UV-B radiation, compared to control group. Featured by the shorter period required, the fewer experimental costs as well as the easier procedures to carry out, UV radiation would be a novel and feasible method to increase the health-related compounds of fresh postharvest medicinal plant tissues. Our study examined the feasibility of short-term and enhanced UV radiation application as emerging technology for enhancing health-promoting phytochemicals in freshly postharvest Lonicera japonica Thunb. Comparing with some other biotic factors, like cell engineering which is also an effective way to stimulate secondary metabolic compounds, UV radiation stimulating plant organs has several advantages. For example, shorter period required, the easier procedures to carry out and the fewer experimental costs are featured. Our study showed that short-term and enhanced UV radiation could be applied to enhance the phytochemical compounds in freshly postharvest Lonicera japonica Thunb. In addition, the convenient and feasible method to enhance the phytochemical concentration in fresh nature products could be used as both postharvest treatment of crops or medical plants and pretreatment of processing industry to obtain the concentration of health-related compounds.

Alzheimer's disease (AD) is accompanied by enhanced oxidative stress and excess free radicals. Phosphodiesterase 9 inhibitors (PDE-9Is) showed memory improving effects in many pharmacological deficit models. However, whether BAY 73-6691 (a selective PDE-9I) may attenuate the oxidative stress during the development of AD is still unclear. For this purpose, primary cultures of SH-SY5Y cells were incubated with 20μM beta-amyloid25-35 (Aβ25-35), followed by exposure to different concentrations (50, 100, 150 and 200μg/ml) of BAY 73-6691. Furthermore, the antioxidant effect of BAY 73-6691 was evaluated in mice subjected to intracerebroventricular injection of Aβ25-35 (day 0) and treatment with BAY 73-6691 by intraperitoneal injection once daily (days 1-10). Our results elucidated that treatment with BAY 73-6691 attenuated the Aβ25-35-induced cytotoxicity and oxidative stress in SH-SY5Y cells. In vivo, BAY 73-6691 protected Aβ25-35-induced oxidative damage in hippocampus, associated with the attenuation of impairments in hippocampal neurons. Administration of BAY 73-6691 improved learning and memory in the Morris water maze test, and restored several hippocampal memory-associated proteins. Our study identified a neuroprotective role for BAY 73-6691 against Aβ25-35-induced oxidative stress in vivo and in vitro, harboring therapeutic potential for the treatment of AD by alleviating the impairments in spatial memory and hippocampal neurons.

Inflammatory bowel diseases (IBD) are a chronic inflammatory disease, which affects almost all tissues in the body. Previous studies mainly focused on breathing, fecal, and urine samples of patients with IBD. However, there is no comprehensive metabolomic analysis of the serum, colon, heart, liver, kidney, cortex, hippocampus, and brown fat tissues. Therefore, the aim of our study is to evaluate the utility metabolomic analysis of target tissues in the pathogenesis of IBD in exploring new biomarkers for early diagnosis and treatment.Male Sprague-Dawley rats were randomly allocated to control and DSS-treated groups (n = 7). Dextran sulfate sodium (DSS) was orally administered for 6 weeks. Gas chromatography-mass spectrometry (GC-MS) was used for metabolite determination, multivariate statistical analysis was used to identify metabolites that were differentially expressed in two groups.Our results showed that 3, 11, 12, 6, 5, 13, 13, and 11 metabolites were differentially expressed between the DSS treatment group and the control group in the serum, colon, heart, liver, kidney, cortex, hippocampus, and brown fat tissues, respectively. The most significant change of metabolites in the study was amino acid (L-alanine, L-glutamic acid, L-phenylalanine, L-proline, L-lysine, L-isoleucine, L-tryptophan, L-norleucine, L-valine, glycine, serine, L-threonine), organic acid (citric acid, 3-hydroxybutyric acid, propanoic acid), glucide (D-arabinose, D-fructose) and purine (9H-purin-6-ol, D-ribose) profiles. Several pathways were affected according to the integrated pathway analysis. These pathways ranged from amino acid metabolism (such as alanine, aspartate, and glutamate metabolism, glutathione metabolism) to purine metabolism (aminoacyl-tRNA biosynthesis).Using GC-MS-based profiling of metabolite changes, these results may provide a more comprehensive view for IBD and IBD-related diseases and improve the understanding of IBD pathogenesis.

Colorectal cancer (CRC) is a heterogeneous disease with a myriad of alterations at the cellular and molecular levels. Kristen rat sarcoma (KRAS) mutations occur in up to 40% of CRCs and serve as both a prognostic and predictive biomarker. Oncogenic mutations in the KRAS protein affect cellular proliferation and survival, leading to tumorigenesis through RAS/MAPK pathways. Until recently, only indirect targeting of the pathway had been investigated. There are now several KRAS allele-specific inhibitors in late-phase clinical trials, and many newer agents and targeting strategies undergoing preclinical and early-phase clinical testing. The adequate treatment of KRAS-mutated CRC will inevitably involve combination therapies due to the existence of robust adaptive resistance mechanisms in these tumors. In this article, we review the most recent understanding and findings related to targeting KRAS mutations in CRC, mechanisms of resistance to KRAS inhibitors, as well as evolving treatment strategies for KRAS-mutated CRC patients.

Currently, multi-drug resistance (MDR) to anticancer drugs is a major obstacle to successful treatment of cancer. Looking for novel compounds with anti-MDR activity is an effectively way to overcome cancer drug resistance. Here, we found that H1, a novel derivate of Tetrandrine, displayed anti-MDR activity in vitro and in vivo. Average resistant factor of H1 is only 1.6. In KB and KBv200 cancer cells xenograft mice, H1 also displayed favorable anti-MDR activity. It could induce typical apoptosis as indicated by morphologic changes, DNA fragmentation in sensitive and resistant cancer cells. Further studies showed that H1 treatment resulted in the increase of ROS generation, elevation of the Bax/Bcl-2 ratio, loss of mitochondrial transmembrane potential (ΔΨ(m)), release of cytochrome c and AIF from mitochondria into cytosol, and activation of caspase-9 and caspase-3, but had no effect on activation of caspase-8 and the expression of Fas/FasL. On the other hand, H1 also inhibited survival pathways such as the activation of Erk1/2 and Akt1/2. In conclusion, H1 exerts good anti-MDR activity in vitro and in vivo, its mechanisms may be associated with initiating intrinsic apoptosis pathway and inhibiting the activation of Erk1/2 and Akt1/2. These findings further support the potential of H1 to be used in clinical trial of MDR cancer treatment.

Abstract Myeloid Translocation Gene, Related-1 (MTGR1) CBFA2T2 is a member of the Myeloid Translocation Gene (MTG) family of transcriptional corepressors. The remaining two family members, MTG8 (RUNX1T1) and MTG16 (CBFA2T3) are identified as targets of chromosomal translocations in acute myeloid leukemia (AML). Mtgr1−/− mice have defects in intestinal lineage allocation and wound healing. Moreover, these mice show signs of impaired intestinal stem cell function. Based on these phenotypes, we hypothesized that MTGR1 may influence tumorigenesis arising in an inflammatory background. We report that Mtgr1−/− mice were protected from tumorigenesis when injected with azoxymethane (AOM) and then subjected to repeated cycles of dextran sodium sulfate (DSS). Tumor cell proliferation was comparable, but Mtgr1−/− tumors had significantly higher apoptosis rates. These phenotypes were dependent on epithelial injury, the resultant inflammation, or a combination of both as there was no difference in aberrant crypt foci (ACF) or tumor burden when animals were treated with AOM as the sole agent. Gene expression analysis indicated that Mtgr1−/− tumors had significant upregulation of inflammatory networks, and immunohistochemistry (IHC) for immune cell subsets revealed a marked multilineage increase in infiltrates, consisting predominately of CD3+ and natural killer T (NKT) cells as well as macrophages. Transplantation of wild type (WT) bone marrow into Mtgr1−/− mice, and the reciprocal transplant, did not alter the phenotype, ruling out an MTGR1 hematopoietic cell-autonomous mechanism. Our findings indicate that MTGR1 is required for efficient inflammatory carcinogenesis in this model, and implicate its dysfunction in colitis-associated carcinoma. This represents the first report functionally linking MTGR1 to intestinal tumorigenesis. Cancer Res; 71(4); 1302–12. ©2011 AACR.

Ginkgo biloba L. (ginkgo) is generally regarded as a tolerant species to environmental stresses. However, its tolerance mechanisms are not well understood, particularly for salt stress. To evaluate the species’ physiological responses to salt stress, 3-year-old ginkgo seedlings were exposed to a range of salinity levels (0% to 1.0% NaCl). A significant reduction in maximum ( F v / F m ) and actual (Φ PSII ) quantum yields of photosystem II (PSII) photochemistry and the nonphotochemical quenching (q N ) coefficient only occurred in late treatment stages at the salinity levels of 0.6% to 1.0%. As salt concentration increased, the response time and chlorophyll (Chl) fluorescence indices decreased. Overall, the activities of superoxide dismutase (SOD) and peroxidase (POD); contents of catalase (CAT), reduced glutathione (GSH), and flavonoids; and scavenging rate of free radicals enhanced under salinity stress. These data indicate that ginkgo seedlings are tolerant to low salt stress, and enzymatic and nonenzymatic antioxidant systems seem to work synergistically to reduce lipid oxidation under NaCl stress because malondialdehyde (MDA) content did not increase. Correlation and principal component analyses determined that water potential, Chl fluorescence parameters, activities of POD and SOD, contents of CAT and flavonoids, and hydroxyl (•OH) and diphenyl picrylhydrazyl (DPPH) free radical scavenging capability were sensitive to salt stress. These parameters can be used for in vitro or rapid and nondestructive monitoring of the responses of ginkgo seedlings to salinity stress. It is of significance to understand the tolerance mechanisms of ginkgo to salt stress, reduce the harm of NaCl and other snow-melting agents to ginkgo as shade trees, and develop new salt-tolerant varieties.

Currently, non-small cell lung carcinoma (NSCLC) is remaining a major worldwide health problem. Meanwhile, accumulating evidences indicate that Histone deacetylase (HDACs) activation could induce PD-L1 expression in various types of cancer, especially in myeloma and B-cell lymphomas. Therefore, we hypothesized that high-level expression of HDAC10 is associated with PD-L1 induction and poor prognosis in patients with NSCLC. Totally, 180 NSCLC patients receiving complete pulmonary resection and systematic lymph node dissection were enrolled from April 2004 to August 2009. The patients with integrated clinicopathological records were followed up. The expression level of HDAC10 and PD-L1 in tissue samples was determined by immunohistochemistry. We observed that HDAC10 expression in lung cancer tissue is significantly higher than that in corresponding para-cancer tissue. Moreover, HDAC10 expression positively correlated with the expression level of PD-L1 (r=0.213, P<0.05) in NSCLC patients. In the subgroup, multivariate analysis showed that the expression level of HDAC10 can be an independent prognostic factor and high-level expression of HDAC10 indicated a poor overall survival in pulmonary carcinoma (r=0.540, P<0.001). Our findings suggest that the expression level of HDAC10 is positively associated with PD-L1 expression and may predict outcome of patients with NSCLC.

Radix Angelicae dahuricae is a well-known medicinal herb in a number of herb preparations for medical uses. In this study, a rapid and selective method using liquid chromatography with tandem mass spectrometry was developed for the separation and simultaneous quantitation of nine furanocoumarins from Radix A. dahuricae, namely imperatorin, isoimperatorin, oxypeucedanin hydrate, bergapten, oxypeucedanin, xanthotoxol, xanthotoxin, isopimpinellin, and psoralen. Chromatographic separation was achieved on a CAPCELL PAK MG II C18 analytical column. Detection was performed using positive electrospray ion source in the multiple reaction monitoring mode. The method was fully validated for analyzing these principles in rat plasma with a lower limit of quantification from 0.5 to 5 ng/mL. The intra- and interbatch precisions were less than 10%, and the accuracies ranged from -7.5 to 8.0%. The extraction recovery of the analytes was above 70% without a significant matrix effect. The method was used to determine the oral and intravenous pharmacokinetic profiles of these furanocoumarins after dosing with Radix A. dahurica extract. The bioavailability of these furanocoumarins ranged from 10.1 to 82.8%. These data provide critical information for a better understanding of the pharmacological mechanisms and herb-drug interaction potential of Radix A. dahurica.

Type 2 diabetes (T2D) may play a relevant role in the development of Alzheimer's disease (AD), however, the underlying mechanism was not clear yet. We developed an animal model presenting both AD and T2D, morris water maze (MWM) test and recognition task were performed to trace the cognitive function. Fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT) were determined to trace the metabolism evolution. TUNEL assay and apoptosis-related protein levels were analyzed for the detection of neuronal apoptosis. Cyclic adenosine monophosphate (cAMP) agonist bucladesine or protein kinase (PKA) inhibitor H-89 were used to determine the effects of cAMP/PKA signaling pathway on IDE expression and neuronal apoptosis. The results showed that T2D contributes to the AD progress by accelerating and worsening spatial memory and recognition dysfunctions. Metabolic parameters and glucose tolerance were significantly changed in the presence of the AD and T2D. The significantly induced neuronal apoptosis and increased pro-apoptotic proteins in mice with AD and T2D were also observed. We showed the decreased expression level of IDE and the activating of cAMP/PKA signaling pathway in AD and T2D mice. Further studies indicated that cAMP agonist decreased the expression level of IDE and induced the neuronal apoptosis in mice with AD and T2D; whereas PKA inhibitor H-89 treatment showed the completely opposite results. Our study indicated that, in the T2D and AD mice, cAMP/PKA signaling pathway and IDE may participate in the contribute role of T2D in accelerating the pathological process of AD via causing the accumulation of Aβ and neuronal apoptosis.

Metastatic colorectal cancer (mCRC) remains a major public health problem, and diagnosis of metastatic disease is usually associated with poor prognosis.The multi-kinase inhibitor regorafenib was approved in 2013 in the U.S. for the treatment of mCRC patients who progressed after standard therapies.However, the clinical efficacy of regorafenib is quite limited.One potential strategy to improve mCRC therapy is to combine agents that target key cellular signaling pathways, which may lead to synergistic enhancement of antitumor efficacy and overcome cellular drug resistance.Protein kinase D (PKD), a family of serine/threonine kinases, mediates key signaling pathways implicated in multiple cellular processes.Herein, we evaluated the combination of regorafenib with a PKD inhibitor in several human CRC cells.Using the Chou-Talalay model, the combination index values for this combination treatment demonstrated synergistic effects on inhibition of cell proliferation and clonal formation.This drug combination resulted in induction of apoptosis as determined by flow cytometry, increased PARP cleavage, and decreased activation of the anti-apoptotic protein HSP27.This combination also yielded enhanced inhibition of ERK, AKT, and NF-κB signaling.Taken together, PKD inhibition in combination with regorafenib appears to be a promising strategy for the treatment of mCRC.

Oxygen therapy is important during the management of high-risk neonatal infants, such as those with preterm birth, low birth weight, and asphyxia. However, prolonged exposure to high oxygen concentrations can readily lead to diffuse nonspecific inflammation, which promotes airway remodeling and pulmonary fibrosis. The Rho/Rho-associated coiled-coil kinase (Rho/ROCK) signaling pathway plays an important role in numerous developmental and proliferative diseases. This study was performed to determine the efficacy of ROCK inhibitor fasudil in blocking the development of hyperoxia-induced lung injury and fibrosis in neonatal rats.Neonatal rats were randomly divided into four groups: air + saline group, air + fasudil group, hyperoxia + saline group, and hyperoxia + fasudil group. The hyperoxia + saline and Hyp + fasudil groups were exposed to 95% oxygen for 21 days and administered intraperitoneal saline or fasudil once daily. The air + saline and air + fasudil group were exposed to 21% oxygen (room air) and administered the same volume of intraperitoneal saline or fasudil.Fasudil-treated rats exhibited improved histopathological changes and decreased lung hydroxyproline content. Fasudil attenuated the protein level of alpha-smooth muscle actin, transforming growth factor-β1, and connective tissue growth factor. Additionally, fasudil reduced the activation of ROCK1 and myosin phosphatase targeting subunit 1 protein in the Rho/ROCK signaling pathway.Fasudil may be a potentially effective therapeutic drug for hyperoxia-induced pulmonary fibrosis.

Targeting TopoisomeraseII (TopoII) and generate enzyme mediated DNA damage is an effective strategy for treatment of breast cancer. TopoII is known as a validated target for drug discovery and cancer chemotherapy. XWL-1-48, a new orally podophyllotoxin derivative, was designed and synthesized. The effect of XWL-1-48 on TopoII binding and activity was determined by molecular docking software and kDNA-decatenation assay, respectively. In vitro and in vivo breast cancer models were used to document the antitumor activity of XWL-1-48. Cellular apoptosis, cell cycle and ROS were analyzed by flow cytometry. Alteration of XWL-1-48-mediated downstream pathways was determined by western blot analysis. The cytotoxicity of XWL-1-48 is more potent than that of its congener GL331. Molecular docking demonstrated that XWL-1-48 could bind to TopoII through forming two strong hydrogen bonds and potential pi-pi interactions. Noticeably, XWL-1-48 exerts potent antitumor activity in in vitro and in vivo breast cancer model. Treatment with XWL-1-48 caused ROS generation and triggered DNA damage through induction of γ-H2AX and activation of ATM/p53/p21 pathway. Further studies showed that XWL-1-48 led to S-phase arrest and mitochondrial apoptosis. Meanwhile, XWL-1-48 significantly blocked PI3K/Akt/Mdm2 pathway and enhanced Mdm2 degradation. XWL-1-48 may be a promising orally topoII inhibitor, its mechanisms are associated with suppression of TopoII, induction of DNA damage and apoptosis, blockage of PI3K/AKT/Mdm2 pathway.

To manage glaucoma, timolol is currently delivered via eye drop solution in high doses due to poor ocular bioavailability. The silicone contact lenses can be used to control the release of timolol ...

Abstract Background: Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US, and it remains a significant public health burden. Metastatic CRC (mCRC) is usually treated with combination chemotherapy and targeted therapy regimens, but eventually becomes chemotherapy refractory. Thus, novel and more effective treatments for mCRC are urgently needed. Cyclin-dependent kinase 9 (CDK9) is a key activator of RNA Pol II transcription and promotes the expression of many cancer driver genes, making CDK9 a promising target for cancer therapy. Methods: Human CRC cell lines, patient-derived organoids (PDOs), cell line xenografts, and patient-derived xenografts were used to investigate the efficacy and mechanisms of action of the CDK9 inhibitors AZD4573, enitociclib, and NVP-2, as well as the BRAF inhibitors encorafenib and dabrafenib. In vitro viability was measured by chemical cell proliferation assays and in vivo tumor sizes were measured by calipers. In vitro mechanisms of action were assessed by RNA sequencing, real time polymerase chain reaction, and Western blotting. In vivo mechanisms of action were assessed by immunohistochemistry. Results: CDK9 inhibitors potently inhibited CRC cells and PDOs. In contrast to hematologic malignancies, we did not observe consistent suppression of the oncogenes c-MYC and MCL-1 by CDK9 inhibitor treatment. Instead, CDK9 inhibitors suppressed several other key cancer pathways in CRC, such as MAPK, mTOR, and PI3K signaling pathways. Importantly, multiple targets within the MAPK pathway were strongly suppressed, including EGFR, KRAS, and BRAF. We hypothesized that combination treatment with CKD9 inhibitors and MAPK pathway inhibitors can synergistically treat CRC. As proof-of-concept, we investigated the combination of CDK9 and BRAF inhibitors in models of BRAF-mutant CRC, a particularly aggressive type of CRC. We found this combination to synergistically suppress CRC growth in vitro and in vivo. Compared to single agents, combination treatment led to significantly stronger induction of apoptosis and suppression of MAPK pathway signaling. Our results suggest that concurrent treatment with CDK9 inhibitors plus established MAPK pathway inhibitors, such as BRAF inhibitors, can significantly improve upon single agent treatment. Conclusions: We have found CDK9 inhibitors to potently suppress CRC growth and survival through a unique mechanism of action, by vertical suppression of the MAPK signaling pathway. We demonstrate that CDK9 inhibitors can synergize with BRAF inhibitors in the treatment of BRAF-mutant CRC models. Thus, CDK9 inhibitors are a promising class of drugs warranting further investigation, including early-phase clinical trials, in mCRC. Citation Format: Chaoyuan Kuang, Ning Wei, Mahshid Mohammadi, Muzaffer A. Bhat, Terence Li, Priyanka Patil, Othon Wiltz, Renee Huang, Kohtaro Ooka, Melanie Quintal, Edward Chu. CDK9 inhibitors modulate the transcriptional landscape of colorectal cancer to suppress MAPK signaling and synergizes with BRAF inhibitors to treat BRAF-mutant colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1218.

PUMA (p53 unregulated modulator of apoptosis), a BH3-only Bcl-2 family member, can be induced by p53-dependent and p53-independent manners. It plays an important role as regulator of cellular apoptosis. Herein, we evaluate the effects of H1 (a derivative of tetrandrine) on induction of PUMA and underlie its potential mechanism in p53-independent cytotoxic response. Anti-proliferative activity and evidently cytotoxic activity of H1 were observed in wild-type and p53 null cells. Further studies demonstrated that H1 resulted in an increase of cleaved PARP, decease of survivin and elevation of p-H2AX. What is more, H1 significantly induced PUMA expression in a concentration- and time-dependent manner and caused an increase of Bax/Bcl-2 ratio in p53 null cells. Of note, knockdown of PUMA attenuated cytotoxic activity of H1. Further studies demonstrated that inhibition of AKT/FoxO3a signaling contributed to H1-mediated PUMA induction. Targeted suppression of AKT/FoxO3a signaling by siRNA could overcome H1-mediated PUMA induction. In addition, H1 significantly suppressed NF-κB activity and caused an increase of early apoptotic and late apoptotic cells, and elevated caspase-3 activity. Taken together, we found that inhibition of AKT/FoxO3a signaling may contribute to H1-mediated PUMA induction, suggesting that inhibition of AKT/FoxO3a signaling result in PUMA expression in response to p53-independent cytotoxic effects of H1.

Cellular protein synthesis is accelerated in human colorectal cancer (CRC), and high expression of protein synthesis regulators in CRC patients is associated with poor prognosis. Thus, inhibition of protein synthesis may be an effective therapeutic strategy for CRC. We previously demonstrated that the quassinoid bruceantinol (BOL) had antitumor activity against CRC. Herein, potent tumor growth suppression (>80%) and STAT3 inhibition was observed in two different mouse models following BOL administration. Loss of body and spleen weight was observed but was eliminated upon nanoparticle encapsulation while maintaining strong antitumor activity. STAT3 siRNA knockdown exhibited modest suppression of cell proliferation. Surprisingly, STAT3 inhibition using a PROTAC degrader (SD-36) had little effect on cancer cell proliferation suggesting the possibility of additional mechanism(s) of action for quassinoids. BOL-resistant (BR) cell lines, HCT116BR and HCA7BR, were equally sensitive to standard CRC therapeutic agents and known STAT3 inhibitors but resistant to homoharringtonine (HHT), a known protein synthesis inhibitor. The ability of quassinoids to inhibit protein synthesis was dependent on the structure of the C15 sidechain. Of note, BOL did not inhibit protein synthesis in normal human colon epithelial cells whereas HHT and napabucasin remained effective in these normal cells. Novel quassinoids were designed, synthesized, and evaluated in pre-clinical CRC models. Treatment with the most potent analog, 5c, resulted in significant inhibition of cell proliferation and protein synthesis at nanomolar concentrations. These quassinoid analogs may represent a novel class of protein synthesis inhibitors for the treatment of human CRC.

A previous study has shown that CTN (Citrinin) inhibits mouse testosterone production. In this study, the mechanism by which testosterone production is inhibited by CTN in rat Leydig cells was investigated, and the morphological evidence of apoptosis, including nuclei fragmentation and phosphatidylserine (PS) exposure on cell surfaces, was clearly observed 36h after CTN exposure. The results showed that citrinin at 50 and 100μM significantly suppressed testosterone secretion by human chorionic gonadotropin (hCG) at 10IU/ml. Western blotting results showed that CTN induced formation of processed p53, caspase-9, and caspase-3 proteins in a dose-dependent manner; CTN also induced a dose-dependent increase in caspase-3 catalytic activity. Western blot assays also showed that CTN decreased expression of three key enzymes (P450scc, 3β-HSD-1, and StAR) of testosterone production. Taken together, these results suggested that CTN reduced testosterone secretion by inducing apoptosis in rat Leydig cells, a mechanism that might account for CTN stimulation of p53 expression followed by activation of multiple caspases.

A novel podophyllotoxin derivative, XWL-1-48, was synthesized as an oral topoisomerase II inhibitor. kDNA decatenation assay indicated that XWL-1-48 significantly inhibited topoisomerase II activity in a concentration-dependent manner. Moreover, the cytotoxicity of XWL-1-48 is more potent than its congener GL331 and the IC50 values are from 0.34 ± 0.21 to 3.54 ± 0.54 µM in 10 cancer cell lines including KBV200 cells with P-gp overexpression. Noticeably, XWL-1-48 exerted potent antitumor activity in in vitro and in vivo human hepatocellular carcinoma (HCC) model. Further studies demonstrated that treatment of XWL-1-48 induced γ-H2AX and p-ATM expression, and further triggered DNA damage response through activation of ATM-p53-p21 and ATM-Chk2-Cdc25A pathways. Targeted inhibition of ATM by siRNA attenuated the ability of XWL-1-48 on inducing DNA damage. XWL-1-48 significantly suppressed Cyclin A and p-Cdk2 (Thr160) expression, increased p-Cdk2 (Thr14), led to inactivation of Cyclin A/Cdk2 complex, arrested cell cycle at S phase. Finally, XWL-1-48 elevated the ratio of Bax/Bcl2 and induced Fas and FasL, initiated mitochondria- and death receptor-mediated apoptosis pathway. Meanwhile, XWL-1-48 evidently enhanced degradation of Mdm2, blocked PI3K/Akt/Mdm2 pathway and suppressed HCC cell survival. Thus, XWL-1-48 may be a promising orally topoisomerase II inhibitor for treatment of HCC.

MiR-155 can inhibit the formation of atherosclerosis by interfering with the transformation of macrophages into foam cells that plays a critical role in the pathogenesis of atherosclerosis, but the precise mechanisms of miR-155 are still unknown. Herein, we observed that mRNA and protein expression levels of CEH were significantly upregulated in a dose- and time-dependent manner by transfected with miR-155 mimics in THP-1 macrophages. Further studies showed that overexpression of miR-155 can significantly inhibit foam cells formation, reduce intracellular CE accumulation and enhance the efflux of FC and cholesterol, result in a decrease of intracellular lipid accumulation; while this effect was significantly reversed by siCEH. Meanwhile, we found that Tim-3 is associated with miR-155-mediated CEH expression in THP-1 macrophage-derived foam cells. Overexpression of Tim-3 can attenuate miR-155-mediated CEH induction. Taken together, our findings demonstrated that miR-155 can inhibit the transformation of macrophages into foam cells by enhancing CEH signaling pathway in macrophages, this effect is likely to be achieved by inhibiting the expression of Tim-3.

To evaluate the effects of global system for mobile communications (GSM) 1800 MHz microwaves on dendritic filopodia, dendritic arborization, and spine maturation during development in cultured hippocampal neurons in rats. The cultured hippocampal neurons were exposed to GSM 1800 MHz microwaves with 2.4 and 0.8 W/kg, respectively, for 15 min each day from 6 days in vitro (DIV6) to DIV14. The subtle structures of dendrites were displayed by transfection with farnesylated enhanced green fluorescent protein (F-GFP) and GFP-actin on DIV5 into the hippocampal neurons. There was a significant decrease in the density and mobility of dendritic filopodia at DIV8 and in the density of mature spines at DIV14 in the neurons exposed to GSM 1800 MHz microwaves with 2.4 W/kg. In addition, the average length of dendrites per neuron at DIV10 and DIV14 was decreased, while the dendritic arborization was unaltered in these neurons. However, there were no significant changes found in the neurons exposed to the GSM 1800 MHz microwaves with 0.8 W/kg. These data indicate that the chronic exposure to 2.4 W/kg GSM 1800 MHz microwaves during the early developmental stage may affect dendritic development and the formation of excitatory synapses of hippocampal neurons in culture.

The novel, chemically stabilized disorazole analog, (-)-CP2-disorazole C1 (1) displayed potent anti-proliferative activity against a broad-spectrum of human colorectal cancer cells. HCT15 and H630R1 cell lines expressing high basal levels of the ABCB1 protein, known to cause multi-drug resistance, were also sensitive to growth inhibition by 1 but were resistant to both vincristine and docetaxel, two commonly used microtubule inhibitors. Compound 1 exhibited strong inhibition of tubulin polymerization at a level comparable to vincristine. In addition, treatment with 1 resulted in decreased protein levels of β-tubulin but not α-tubulin. An analysis of cellular proteins known to interact with microtubules showed that 1 caused decreased expression of c-Myc, APC, Rb, and additional key cellular signaling pathways in CRC cells. Treatment with compound 1 also resulted in G2/M cell cycle arrest and induction of apoptosis, but not senescence. Furthermore, endothelial spheroid sprouting assays demonstrated that 1 suppressed angiogenesis and can, therefore, potentially prevent cancer cells from spreading and metastasizing. Taken together, these findings suggest that the microtubule disruptor 1 may be a potential drug candidate for the treatment of mCRC.

The lncRNA AFAP1-AS1, oriented from an antisense direction to the protein-coding gene AFAP1 in the opposite strand, was upregulated in a variety of tumors and associated with poor prognosis, including lung cancer, breast cancer, ovarian cancer, and so on. However, the biological role of AFAP1-AS1 in clear cell renal cell carcinoma (ccRCC) is still unknown. We observed that AFAP1-AS1 expression was significantly upregulated in ccRCC tissues and that patients with high-level expression of AFAP1-AS1 had a shorter overall survival. Knockdown of AFAP1-AS1 markedly suppressed the progression of proliferation, invasion, migration, and EMT in ccRCC cells. Downregulation of AFAP1-AS1 resulted in an increase in E-cadherin and a decrease in vimentin. Noticeably, we found that PTEN has a negative correlation with the lncRNA AFAP1-AS1 expression. Further studies verified that PTEN deficiency effectively attenuated the ability of AFAP1-AS1 in promoting ccRCC cell proliferation, invasion, migration, and EMT. Moreover, the similar biological response of silencing AFAP1-AS1 was observed in our ccRCC mice model. Knockdown of AFAP1-AS1 evidently suppressed tumor growth. Taken together, our results provide the evidences that silencing of AFAP1-AS1 inhibits cell proliferation, EMT, and metastasis through PTEN-dependent signaling, and our findings elucidate a novel potential therapeutic target or biomarker for the treatment of ccRCC.

Diabetic retinopathy (DR) is a common problem in the diabetic patients due to the high blood glucose level. DR affects more number of diabetic patients worldwide with irreversible vision loss.The current investigation was focused to reveal the therapeutic actions of nimbolide against the streptozotocin (STZ)-provoked DR in rats through inhibition of TLR4/NF-κB pathway.DR was provoked to the rats through administering a single dose of STZ (60 mg/kg) intraperitoneally. The DR rats were then supplemented with the 50 mg/kg of nimbolide for 60 days. The bodyweight and blood glucose level was measured using standard methods. The lipid profiles (cholesterol, TG, LDL, and HDL), inflammatory markers, and antioxidants level was detected using respective kits. The level of MCP-1, VEGF, and MMP-9 was quantified using kits. The morphometric analysis of retinal tissues were done. The mRNA expressions of target genes were studied using RT-PCR assay.Nimbolide treatment effective decreased the food intake and blood glucose, and improved the bodyweight of STZ-provoked animals. The levels of pro-inflammatory mediators, cholesterol, TG, LDL, and HDL, MCP-1, VEGF, and MMP-9 was remarkably suppressed by the nimbolide treatment. Nimbolide also improved the antioxidants, retinal thickness and cell numbers. The TLR4/NF-κB pathway was appreciably inhibited by the nimbolide.Overall, our findings demonstrated that the nimbolide attenuated the STZ-provoked DR in rats through inhibiting the TLR4/NF-κB pathway.

Observational studies suggest that Parkinson's disease (PD) is related with the risk of cardio and cerebrovascular disease. However, the causality is not yet fully established. Therefore, we employed Mendelian randomization to assess whether PD is related to risk of ischemic stroke (IS), IS subtypes, coronary artery disease (CAD) and myocardial infarction (MI).Eighty-eight and eleven single nucleotide polymorphisms associated with PD at the genome-wide significance level, were used as instrumental variables for PD in European and East Asian population respectively. Using a 2-sample MR, we examined associations with IS, IS related subtypes, CAD and MI in European population. We also assessed the causal association of PD with IS and CAD in East Asian population. The primary MR analyses were performed by using the random-effects inverse variance weighted approach.In European population, genetic predisposition to PD was related to higher risk of IS (odds ratio [OR], 1.03 per doubling in odds of PD; 95% confidence interval [CI], 1.01-1.05; P = 0.002) and cardioembolic stroke (OR, 1.08 per doubling in odds of PD; 95% CI, 1.04-1.12; P = 1.29 × 10-4), but not large artery stroke, small vessel stroke, CAD and MI. In East Asian population, we found no evidence of causal effect of PD on the risk of IS and CAD.This study found that genetic predisposition to PD is related to higher risk of IS and cardioembolic stroke in European population.

The laterals of both shoots and roots often maintain a particular angle with respect to the gravity vector, and this angle can change during organ development and in response to environmental stimuli. However, the cellular and molecular mechanisms of the lateral organ gravitropic response are still poorly understood. Here it is demonstrated that the young siliques of Arabidopsis thalinana plants subjected to 3-D clinostat rotation exhibited automorphogenesis with increased growth angles between pedicels and the main stem. In addition, the 3-D clinostat rotation treatment significantly influenced the development of vascular bundles in the pedicel and caused an enlargement of gap cells at the branch point site together with a decrease in KNAT1 expression. Comparisons performed between normal and empty siliques revealed that only the pedicels of siliques with normally developing seeds could change their growth angle under the 3-D clinostat rotational condition, while the pedicels of the empty siliques lost the ability to respond to the altered gravity environment. These results indicate that the response of siliques to altered gravity depends on the normal development of seeds, and may be mediated by vascular bundle cells in the pedicel and gap cells at branch point sites.

We aimed to compare mediastinoscopy-assisted esophagectomy (MAE) with the Ivor Lewis procedure in T2 middle and lower thoracic esophageal carcinoma patients in fields of perioperative complications and overall survival (OS).The clinical data of 112 T2 esophageal cancer patients who received MAE (n = 31) or Ivor Lewis procedure (n = 81) from January 2010 to December 2015 were retrospectively analyzed in propensity score analysis. Thirty-eight T2 esophageal cancer patients who underwent MAE (n = 19) and Ivor Lewis procedure (n = 19) were included in this study. The perioperative conditions and OS were analyzed.The MAE group showed shorter operation time (143.2 ± 20.6 vs 176.8 ± 31.1 min, P = 0.001), less drainage in 24 h (119.2 ± 235.1 vs 626.3 ± 396.3 mL, P < 0.001), less retention time of thoracic tube (27.8 ± 24.0 vs 101.2 ± 54.6 h, P < 0.001), and less hemorrhage during operation (255.4 ± 159.8 vs 367.4 ± 150.9 mL, P = 0.059) compared with the Ivor Lewis group. Less dissected lymph nodes were detected in the MAE group (12.2 ± 5.4 vs 16.8 ± 5.8, P = 0.044) than in the Ivor Lewis group, especially in the upper mediastinum (1.8 ± 2.1 vs 3.5 ± 2.3, P < 0.001) and middle mediastinum (2.5 ± 2.0 vs 5.3 ± 3.2, P = 0.027). The mean survival time was 59.1 and 53.3 months for the MAE group and Ivor Lewis group, respectively (P = 0.635). The results of Cox regression indicated that the nodal stage (P = 0.016) was an independent prognostic factor and the surgical method was not an independent prognostic factor for these patients (P = 0.290).MAE procedure showed less surgical trauma compared with the Ivor Lewis procedure. The mediastinal lymphadenectomy of T2 esophageal carcinoma patients who underwent MAE was inferior to those who underwent Ivor Lewis procedure. The perioperative complications and OS of the MAE group were no worse than that of the Ivor Lewis group.

Aim: We investigated the role of GOLPH2 in non-small-cell lung cancer (NSCLC). Methods: We analyzed the relationship between the expression of GOLPH2 and the clinical pathological characteristics of patients with NSCLC. The function of GOLPH2 in NSCLC cell lines was also explored through overexpression and knockdown studies. Results: The positive expression rate of GOLPH2 protein in NSCLC tissue was higher than that of normal lung tissue. We found that positive GOLPH2 expression was closely associated with unfavorable features of patients with NSCLC. The GOLPH2 expression was an independent predictor of the prognosis of patients with NSCLC. That GOLPH2 can promote the proliferation and invasion of NSCLC cells. Conclusion: The GOLPH2 is a novel marker for NSCLC.

Our study compared the Ivor-Lewis and Sweet procedures used for treating middle and lower thoracic esophageal squamous cell carcinoma and assessed the associated perioperative complications and long-term survival rates of the patients.This retrospective study involved 624 middle and lower thoracic esophageal squamous carcinoma patients who received either Ivor-Lewis (n = 325) or Sweet (n = 299) procedures at our hospital. Further, the perioperative conditions and long-term survival rates were analyzed for both groups.Relative to the Sweet group, the Ivor-Lewis group showed lower volume of drainage within 24 hours after operation (400 (300-500) ml vs 550 (400-658) ml, P = .031). Although we found no significant differences in major postoperative complications between the groups (72 (22.2) vs 65 (21.7), P = .90), there were significant differences observed in minor postoperative complications between the Ivor-Lewis and Sweet groups (59 (18.2) vs 32 (10.7), P = .008). Perioperative death rates remained comparable for the 2 groups (2 (0.6) vs 2 (0.7), P > .99). Further, comparison of the 2 groups revealed that the Ivor-Lewis group had increased number of dissected lymph nodes, (20 (4-42) vs 16 (3-31), P < .001), especially in the upper mediastinum (4 (0-5) vs 2 (0-2), P < .001). The long-term survival rates did not differ significantly between the 2 groups (Kaplan-Meier method, P = .95; Cox regression, P = .20).These findings suggest that perioperative complications and long-term survival rates were comparable for both patients groups. Patients receiving the Sweet procedure had reduced minor postoperative complications compared to those receiving the Ivor-Lewis procedure. Due to improved quality of lymph node dissection in the upper mediastinum, the Ivor-Lewis procedure may have advantages over the Sweet procedure for treating patients with esophageal cancer with enlarged lymph nodes in the upper mediastinum.

Currently, 5-fluorouracil (5-FU) resistance became a major obstacle to its clinical use for patients with hepatocellular carcinoma (HCC). It’s urgent to develop a novel strategy for enhancing the therapeutic efficacy of 5-FU. Herein, we found that H1 (a derivative of Tetrandrine) exerted a potent anti-MDR effect on growth of 5-FU resistant HCC cells (Bel7402/5FU). The resistant fold (RF) of 5-FU is over 160-fold, while the RF of H1 is only 4.8-fold in Bel7402/5-FU cells. Further studies demonstrated that blockage of STAT3/MCL-1 signaling and induction of PUMA is responsible to anti-MDR activity of H1. Moreover, combination of H1 and 5-FU (Ratio = 1:2) could synergistically induce apoptosis of Bel7402/5-FU cells. Co-treatment of H1 enhances the suppression of p-STAT3 and MCL-1, and significantly increases PUMA expression. Finally, the combination of H1 and 5-FU results in an increase of cleaved PARP. Taken together, H1 effectively improve the cytotoxic effect of 5-FU against Bel7402/5-FU cells via blocking STAT3/MCL-1 pathway and inducing PUMA. Our findings suggested that combination 5-FU with anti-MDR agents might present a novel strategy to enhance the therapeutic efficacy of 5-FU in resistant HCC.

Water hyacinth (Eichhornia crassipes) is one of the most productive plants, but is also a troublesome weed in the world. In order to protect the public water system from chemical herbicides pollution, biological method has been suggested to control the growth and the reproduction of this weed. Lantana (Lantana camara L.) is an important weed of the family Verbenaceae and its leaf extract is highly toxic to water hyacinth. The results of this study showed that the extract of lantana leaves suppressed the emergence of leaf buds of water hyacinth plant, and caused the decay of its leaves by foliar spraying. In addition, the increase of SOD activity in water hyacinth leaves was in accordance with the accumulation of H(2)O(2) and the increase in degree of membrane peroxidation, while the activity of catalase, which might remove the excessive H(2)O(2) in water hyacinth leaves, was inhibited by treatment with lantana extract. At tissue level, high H(2)O(2) histochemical labeling was detected in guard cells after treatment with lantana extract. This overproduction of H(2)O(2) could kill the leaf cells and cause leaf necrosis in the treated plant. Therefore, the high toxicity of lantana leaf extract to water hyacinth might be due to oxidative stress.

Molecular subtypes of colorectal tumors are associated with prognosis and prediction for treatment benefit from chemotherapy. The purpose of this study was two-fold: 1) to determine the association of colorectal (CRC) molecular subtypes with response to targeted therapies in pre-clinical models and 2) to identify treatments for CRC stem-like subtype because these tumors are associated with a very poor patient prognosis. Eleven CRC cell lines were classified into molecular subtypes and tested for their response to pan-ERBB, MEK, and ERK inhibitors as single agents and in combination. All six inflammatory or TA cell lines were exquisitely sensitive to the combination of MEK and neratinib whereas all five stem-like cell lines were resistant. Growth inhibition in sensitive cell lines was greater with the combination than with either drug alone even in cell lines with KRAS mutations. The combination inhibited pERK in inflammatory cell lines but not in four out of five stem-like cell lines. MEK162 plus neratinib were synergistic in cell culture and xenograft models in inflammatory cell lines. The ERK inhibitor, SCH772984, down-regulated pERK, decreased cell viability, and was synergistic with neratinib in both inflammatory and stem-like subtypes. These results suggest that inhibition of pERK is a critical node in decreasing cell viability of stem-like CRC tumors. Our results also suggest that CRC molecular subtypes may yield predictive information and may help to identify patients who may respond to targeted inhibitors.

We studied feeding intake and food selection of nine captive forest musk deer (Moschus berezovskii) offered 17 species of plants in China. We also determined nutrient characteristics related to plant quality to assess their effect on food selection. Results indicated that forest musk deer exhibited positive selectivity for four species of plants (M. azedarach, M. baccata, K. japonica and C. orbiculatus) and negative selectivity for the remainder. Two plant species with the highest selectivity values accounted for 47.39 % of total food intake; thus, forest musk deer exhibited the strongest preference for these species. Food intake was positively correlated with feeding frequency and duration (r = 0.764, p < 0.005; r = 0.843, p < 0.005) but was not correlated with sniffing frequency or duration. However, olfaction did play an important role in food recognition by the deer. Pearson correlation analysis (data were log10 transformed) indicated that leaf intake was positively correlated with crude protein content (r = 0.708, p = 0.001) and negatively correlated with crude fiber content (r = -0.811, p < 0.001) and ash content (r = -0.496, p = 0.043). In addition, forest musk deer preferred tannin-rich plants with high protein and low fiber. Food intake was also positively correlated with potassium content (r = 0.672, p < 0.005). Our results suggest that forest musk deer is able to positively select high quality food (high protein content) and avoid low quality food (high fiber content). However, the fact that musk deer also prefer tannin-rich food requires further research to gain deeper insight into the underlying mechanisms in the food selection of forest musk deer.

Hyaluronic acid (HA) is widely used to treat various ocular diseases like dry eye syndrome, keratoconus, and other corneal epithelial injuries. The currently available eye drop solutions need frequent doses affecting the routine life style of patients. In this work, the silicone contact lens was designed to entrap HA and Pluronic®F127 to improve the wettability of the contact lens to treat various ocular diseases. The soaking method (HA-SM) was compared with the direct entrapment (DL-HA-PI) technique. The HA-Pluronic®F127-laden contact lenses (DL-HA-PI) showed acceptable optical transmittance with improved swelling (water content) properties. The in vitro release data showed high burst release with HA-SM contact lenses (12-36 h), while DL-HA-PI contact lenses showed prolong release up to 96 h. The in vivo release in the rabbit tear fluid showed high HA concentration (tear fluid) with DL-HA-PI contact lenses in comparison to the HA-SM contact lenses. The DL-HA-PI-3 batch with Pluronic®F127 showed more promising results in schirmer strip study in comparison to DL-HA-3 batch (without Pluronic®F127). The presence of Pluronic®F127 with HA showed high potential to improve hydration property of the contact lens. The corneal healing model showed reduction in the ocular inflammatory symptoms with DL-HA-PI-3 batch, thus demonstrating the potential of HA and Pluronic®F127 to be used in various ocular diseases.

m6A, the main form of mRNA modification, participates in regulating multiple normal and pathological biological events, especially in tumorigenesis. However, there is little known about the association of m6A-related genes with prognosis of clear cell renal cell cancer (ccRCC). Therefore, the prognostic value of m6A-related genes was investigated using Kaplan-Meier curves of overall survival (OS) with the log-rank test and Cox regression analysis. The differential expression of YTHDF2 mRNA in ccRCC and tumor-adjacent normal tissues and associated with clinicopathological characteristics was also analyzed. The alteration of cancer signaling pathways was screened by Gene Set Enrichment Analysis (GSEA). Univariate analysis showed that 15 m6A-related genes (including YTHDF2) were closely related to prognosis. Multivariate analysis further confirmed that YTHDF2 could serve as an independent prognostic factor for the OS of ccRCC patients (P < 0.001). Low-level expression of YTHDF2 had poor prognosis in ccRCC patients with lower tumor-node-metastasis (TNM) stage, age > 61, non-distant metastasis, non-lymph node metastasis, female gender, and higher histological grade (P < 0.05). Moreover, YTHDF2 expression in ccRCC tissues (N = 529) is significantly lower than that of tumor-adjacent normal tissues (N = 72, P = 0.0086). Furthermore, GSEA demonstrated that AKT/mTOR/GSK3 pathway, EIF4 pathway, CHREBP2 pathway, MET pathway, NFAT pathway, FAS pathway, EDG1 pathway, and CTCF pathway are altered in tumors with high YTHDF2 expression. Taken together, our results demonstrated that YTHDF2 (an m6A-related gene) could serve as a potential prognostic biomarker of ccRCC, and targeting epigenetic modification may be a novel therapeutic strategy for the treatment of ccRCC.

Vascular injury initiates rapid platelet activation, which is critical for haemostasis, while it also causes fatal thrombotic diseases, such as myocardial infarction or ischemic stroke.To study the inhibitory effects and underlying mechanisms of XJ-8, a natural compound isolated from Sanguis draxonis, on platelet activation and thrombosis.The regulatory effects of XJ-8 on the dense granule release, thromboxane A2 (TxA2 ) synthesis, α-granule release, activation of integrin αIIbβ3, and aggregation of platelets induced by multiple agonists were investigated in in vitro experiments. The effects of XJ-8 on bleeding time and FeCl3 -induced carotid artery thrombosis were also evaluated in in vivo experiments. Furthermore, we investigated the underlying mechanisms by which XJ-8 exerted its pharmacological effects.XJ-8 not only significantly inhibited the dense granule release, TxA2 synthesis, and aggregation of platelets induced by multiple agonists, but also exerted extending effects on bleeding time and therapeutic effects on thrombotic disease. In addition, XJ-8 selectively and moderately inhibited the activity of mitogen-activated protein kinase kinase kinase 3 (MAP3K3) and the activation of signalling pathways downstream MAP3K3, which play important roles in platelet activation.XJ-8 can inhibit platelet function and thrombosis by targeting MAP3K3 and has potential to be developed into a novel therapeutic agent for the treatment of thrombotic diseases.

Tacrolimus (Tac) is a common immunosuppressant that used in organ transplantation. However, its therapeutic index is narrow, and it is prone to adverse side effects, along with an increased risk of toxicity, namely, cardio-, nephro-, hepato-, and neurotoxicity. Prior metabolomic investigations involving Tac-driven toxicity primarily focused on changes in individual organs. However, extensive research on multiple matrices is uncommon. Hence, in this research, the authors systemically evaluated Tac-mediated toxicity in major organs, namely, serum, brain, heart, liver, lung, kidney, and intestines, using gas chromatography-mass spectrometry (GC-MS). The authors also employed multivariate analyses, including orthogonal projections to the latent structure (OPLS) and t-test, to screen 8 serum metabolites, namely, D-proline, glycerol, D-fructose, D-glucitol, sulfurous acid, 1-monopalmitin (MG (16:0/0:0/0:0)), glycerol monostearate (MG (0:0/18:0/0:0)), and cholesterol. Metabolic changes within the brain involved alterations in the levels of butanamide, tartronic acid, aminomalonic acid, scyllo-inositol, dihydromorphine, myo-inositol, and 11-octadecenoic acid. Within the heart, the acetone and D-fructose metabolites were altered. In the liver, D-glucitol, L-sorbose, palmitic acid, myo-inositol, and uridine were altered. In the lung, L-lactic acid, L-5-oxoproline, L-threonine, phosphoric acid, phosphorylethanolamine, D-allose, and cholesterol were altered. Lastly, in the kidney, L-valine and D-glucose were altered. Our findings will provide a systematic evaluation of the metabolic alterations in target organs within a Tac-driven toxicity mouse model.

Triple-negative breast cancer (TNBC), a subset of breast cancers, have poorer survival than other breast cancer types. Recent studies have demonstrated that the abnormal Hedgehog (Hh) pathway is activated in TNBC and that these treatment-resistant cancers are sensitive to inhibition of the Hh pathway. Smoothened (Smo) protein is a vital constituent in Hh signaling and an attractive drug target. Vismodegib (VIS) is one of the most widely studied Smo inhibitors. But the clinical application of Smo inhibitors is limited to adult patients with BCC and AML, with many side effects. Therefore, it’s necessary to develop novel Smo inhibitor with better profiles. Twenty [1,2,4]triazolo[4,3-a]pyridines were designed, synthesized and screened as Smo inhibitors. Four of these novel compounds showed directly bound to Smo protein with stronger binding affinity than VIS. The new compounds showed broad anti-proliferative activity against cancer cell lines in vitro, especially triple-negative breast cancer cells. Mechanistic studies demonstrated that TPB15 markedly induced cell cycle arrest and apoptosis in MDA-MB-468 cells. TPB15 blocked Smo translocation into the cilia and reduced Smo protein and mRNA expression. Furthermore, the expression of the downstream regulatory factor glioma-associated oncogene 1 (Gli1) was significantly inhibited. Finally, TPB15 demonstrated greater anti-tumor activity in our animal models than VIS with lower toxicity. Hence, these results support further optimization of this novel scaffold to develop improved Smo antagonists.

ATP-binding cassette (ABC) transporters are a family of proteins that mediate multi-drug resistance (MDR) via ATP-dependent drug efflux pumps. Abnormally expression and function would result in tumor MDR. That is the most important mechanism of MDR. The inhibition of ABC transporters as a strategy to reverse MDR in cancer has been studied extensively. In this review, we reviewed the structure and function of ABC transporters, and focused on the research advances in the mechanism of tumors MDR mediated by ABC transporters and the development of their modulators and reversal strategies.

To assess the effect and safety of Shengxuening (SXN), extract from excrement of bombyxin, in the treatment of renal anemia, compared to ferrous succinate and ferrous sulfate. According to the participant, intervention, comparison, outcomes, study design (PICOS) principles, we searched the Chinese Biomedical Literature Database, China National Knowledge Infrastructure Database, Chinese Evidence-Based Medicine Database, Wanfang Database (From establishment to December 2014). Two reviewers selected articles independently according to the inclusion and exclusion criteria. The quality of included studies was assessed by using the Cochrane Handbook. All statistical analyses were conducted by using Revman (vision 5.2) software. A total of 14 randomized controlled trials (RCTs) were enrolled in the review. The results revealed that, when compared with blank group, SXN significantly improved the hemoglobin (HB) levels [MD = 6.29, 95% CI (1.65–10.94), P < 0.0008] and albumin (ALB) [MD = 10.98, 95% CI (6.97–14.99), P < 0.00001]. In addition, SXN could significantly increase the HB levels [MD = 10.98, 95% CI (6.97, 14.99), P < 0.00001]. Compared with other oral medicine SXN could improve the HB levels effectively [MD = 8.49, 95% CI (2.40, 14.58), P = 0.006]. And the subgroups analysis shown that compared with ferrous-sulfate there were significant differences [MD = 17.4, 95% CI (15.06, 19.73), P < 0.000 01] and the result of ferrous-succinate had significant differences [MD = 5.34, 95% CI (2.12, 8.56), P = 0.001] too. Compared with Intravenous iron groups, there were statistical differences [MD = −5.04, 95% CI (−9.59, −0.50), P = 0.03]. In the safety analysis, the rate of adverse reactions in SXN groups and control groups were 19.3% and 3.7%, respectively (P < 0.000 01). Due to our studies were of poor methodological quality, and the sample size were small, the results were influenced by bias. Our findings suggest that the SXN had better effect and was safer in the treatment of RA than ferrous succinate and ferrous sulfate.

ABSTRACT The present study demonstrates that Icariside II (10, 20, and 40 µM) reduced Leydig cell testosterone production and cell viability in a concentration‐ and time‐dependent manner. Hoechst 33342/propidium iodide staining indicated that no morphological changes in Leydig cell nuclear chromatin occurred, caspase‐3 expression also showed no significant change, but cell death was caused by the 10‐µM Icariside II treatment. Furthermore, a significant reduction in NAD + levels was observed following Icariside II exposure (10, 20, and 40 µM). Cell death was avoided when Icariside II treated cells were incubated with extracellular NAD + (5 and 10 mM). Moreover, the addition of NAD + (5 and 10 mM) could restore ATP production and prevent cell death. The results suggest that Icariside II can reduce testosterone production by inducing necrosis, but not apoptosis, in rat Leydig cells. This mechanism may also account for the Icariside II induced depletion of NAD + and ATP levels. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:243‐250, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21481

Even if total joint arthroplasty (TJA) patients have received conventional antithrombotic therapy, the incidence of thrombosis remains high. Clinical pharmacists have been involved in the multidisciplinary team of orthopaedics, but their roles and functions are not yet defined. The objective of this study was to assess the impact of clinical pharmacist services on the use of anticoagulant drugs, the rationality of medication and the incidence of thrombosis in patients with TJA.This retrospective, observational cohort study was conducted for patients undergoing TJA procedures. Study variables were collected for a baseline period of 1 January 2016 to 30 June 2017 and an intervention period of 1 January 2018 to 30 June 2019, allowing for a 6-month run-in period. For demographic characteristics, the use of anticoagulant drugs and the incidence of thrombosis between the baseline and intervention periods, the data were statistically analysed.During the 36-month study timeframe, a total of 591 TJA procedures were performed. A total of 577 participants were included in the study (240 in the baseline group and 377 in the intervention group). After clinical pharmacist participation, the prevention rate of anticoagulant drugs (p < 0.05), the proportion of oral anticoagulants (p = 0.000) and the course of preventive treatment (p = 0.004) increased significantly. The time of administration was shortened from after 24 h to within 24 h post-surgery (p = 0.000). Although the incidence of symptomatic DVT reduced in the intervention period, there was no statistical difference in either the hospital, 1-month follow-up, or 3-month follow-up after surgery (all p > 0.05).Within the limitations of a retrospective study, clinical pharmacist intervention was associated with improvements in anticoagulation management of TJA procedures, likely conferring beneficial effects.

The previous study using Sertoli cells cultured in vitro has shown that the protective effects of astragaloside IV (AsIV) on cadmium (Cd)-induced damage to Sertoli cells and its membrane proteins. Yet, it is not known if AsIV has an equivalent effect on Cd-induced damage to the spermatogenesis microenvironment in rats. Using an in vivo model, Cd-induced damage to the spermatogenesis microenvironment and the protective effects of AsIV were studied. Eighteen male Sprague Dawley (SD) rats were randomly divided into three groups (n = 6/group): Cd group, Cd&AsIV group, and control group. Cd was administered to the rats in the Cd group via i.p. at 1 mg/kg body weight once daily, Cd and AsIV was administered to the rats in the Cd&AsIV group via i.p. at 1 mg/kg body weight and 10 mg/kg body weight respectively once daily, and the same volume of saline was administered to the rats in control group via i.p. once daily. The rats in the three groups were injected continuously for 5 days. Vesicular formation in the seminiferous tubules was observed in the Cd treatment group. The average optical density of claudin-11, zonal occludin-1 (ZO-1), and connexin 43 (Cx43) decreased significantly in the Cd treatment group. The ultrastructural damage of the Sertoli cells and tight junctions were also observed by electron microscopy. AsIV treatment rescued the morphologic changes of the seminiferous tubules of the testis and the ultrastructural damage of the Sertoli cells and tight junctions. The average optical density of claudin-11, ZO-1, and Cx43 also increased significantly after AsIV treatment. Cd damages the spermatogenesis microenvironment in rats, which can be rescued by AsIV treatment. These results illustrate that AsIV may also have a protective effect on Cd-induced damage to the spermatogenesis microenvironment in rats.Abbreviations: AsIV: astragaloside IV; Cd: cadmium; SD: Sprague Dawley; ZO-1: zonal occludin-1; Cx43: connexin 43; BTB: blood-testis barrier; MAPKs: mitogen-activated protein kinases; OSP: oligodendrocyte-specific protein; Cxs: connexins; GJIC: gap junctional intercellular communication; ROS: reactive oxygen species; MDA: malondialdehyde; TGF: tumor growth factor; PBS: phosphate buffer saline; BSA: bovine serum albumin.

To investigate the clinical characteristics and pathogenic genetic mutations of a Chinese family with anterior segment mesenchymal dysgenesis and congenital posterior polar cataract.Through family investigation, the family members were examined via slit lamp anterior segment imaging and screened for eye and other diseases by eye B-ultrasound. Genetic test was performed on the blood samples of the fourth family generation (23 people) via whole exome sequencing (trio-WES) and Sanger sequencing.Among the 36 members in four family generations, there were 11 living cases with different degrees of ocular abnormalities, such as cataracts, leukoplakia, and small cornea. All patients who received the genetic test had the heterozygous frameshift mutation c.640_656dup (p.G220Pfs∗95) on exon 4 of the PITX3 gene. This mutation was cosegregated with the clinical phenotypes in the family and thus might be one of the genetic factors that cause the corresponding ocular abnormalities in this family.The congenital posterior polar cataract with or without anterior interstitial dysplasia (ASMD) of this family was inherited in an autosomal dominant manner, and the frameshift mutation (c.640_656dup) in the PITX3 gene was the cause of ocular abnormalities observed in this family. This study is of great significance for guiding prenatal diagnosis and disease treatment.

e16146 Background: TACE is well-recognized as the mainstay treatment for intermediate-stage HCC; however, the efficacy of TACE monotherapy has been unsatisfactory in advanced-stage HCC. Donafenib is a novel multi-kinase inhibitor approved for first-line treatment of advanced-stage HCC. Herein, we evaluated the efficacy and safety of donafenib combined with TACE for treating intermediate/advanced-stage HCC. Methods: We collected clinical data of patients (pts) with unresectable HCC who had a Child-Pugh class A/B and were admitted for donafenib and TACE combination therapy at The First Affiliated Hospital of USTC between October 2021 to October 2022. Pts had at least one measurable lesion determined using mRECIST criteria. Pts with complete baseline information and at least one follow-up evaluation were incorporated in the final analysis, including the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) by CTCAE 5.0. The last follow-up time was January 1, 2023. Results: In total, 109 pts were enrolled (80.3% males, mean age 60.5 years, 86.2% ECOG of 1, 92.7% HBV positive, 53.2% BCLC stage B, 46.8% BCLC stage C, 31.2% baseline AFP≥400 μg/L, 39.5% with portal vein tumor thrombus). Among them, 54 pts (49.5%) received donafenib combined with TACE as first-line treatment, 8 (7.3%) as second-line treatment, and 47 (43.2%) with concurrent immunotherapy. At the time of data cut-off, the median follow-up time was 6.2 months, and 67 pts (61.5%) had ongoing donafenib treatment. The mean duration of treatment (DOT) with donafenib was 6.0 months, and the longest DOT was 12 months. Considering efficacy, 30 pts (27.5%) achieved complete response, 54 (49.5%) achieved partial response, 17 (15.6%) had stable disease, and 8 (7.4%) had progressive disease. The ORR and DCR were 77.1% and 92.7%, respectively. The ORRs of the first-, second-, and combination immunotherapy groups were 77.8% (42/54), 50.0% (4/8), and 80.9% (38/47), respectively. The DCRs were 92.6% (50/54), 100% (8/8), and 91.5% (43/47), respectively. Median progression-free survival was not reached. In terms of safety, 89 pts (81.7%) had AEs. The incidence of ≥grade 3 AEs was 17.4% (19/109), and the incidence of drug withdrawal due to AEs was 4.6% (5/109). The most common AEs were diarrhea (31.2%), hand-foot syndrome (29.4%), fatigue (25.7%), rash (15.6%), nausea (10.1%), and xerostomia (4.6%). The incidences of ≥grade 3 AEs in the first-, second-, and combination immunotherapy groups were 14.8% (8/54), 12.5% (1/8), and 17.0% (8/47), respectively. The combination immunotherapy group exhibited a high incidence of AEs. Conclusions: Satisfactory disease control was achieved in pts with different treatment durations after receiving donafenib combined with TACE, along with favorable safety and tolerability.

Background Docetaxel combined with prednisone plus androgen deprivation therapy (ADT) is the preferred treatment option for metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC). With the development of next-generation hormonal agents (NHAs) and poly (ADP-ribose) polymerase (PARP) inhibitors, more aggressive first-line or later-line treatment strategies have been added to the treatment of mHSPC and mCRPC. However, docetaxel rechallenge (DR) has special clinical significance in patients with “docetaxel-sensitive” prostate cancer. There are no reports on the efficacy and safety of the second DR in mCRPC patients. Case presentation We report one patient diagnosed with mCRPC who showed progression-free survival (PFS) and overall survival (OS) benefits and safety and good lower urinary tract function after the second DR. Conclusion The second DR as a potential alternative later-line treatment strategy should be considered for patients with mCRPC who worry about the high economic burden of multigene molecular testing and PARP inhibitors as well as repeated prostate needle biopsy.

OBJECTIVE To investigate the association of gastric emptying with ghrelin, obestatin and GHSR, GPR-39 in hypothalamus of diabetic rats. METHODS Sixty Wistar rats were randomly divided into three groups: a normal control group (NC, n = 20), a diabetes mellitus group (DM, n = 20) induced by intraperitoneal injection of streptozotocin (STZ) and an insulin treated group (INS, n = 20). After two and six weeks of STZ injection, gastric emptying was measured by intragastric administration of phenol red, ghrelin and obestatin in hypothalamus measured by ELISA (enzyme-linked immunosorbent assay) and GHSR and GPR-39 by RT-PCR (reverse transcription-polymerase chain reaction). RESULTS After two weeks of STZ injection, gastric emptying (%) (74 +/- 8, 40 +/- 5), ghrelin level(ng/g) (52 +/- 9, 51 +/- 7) and ratio of ghrelin/obestatin (3.8 +/- 1.0, 2.8 +/- 1.0) increased significantly in DM and INS groups compared to those in NC group [32% +/- 7%, (39 +/- 11) ng/g, 2.1 +/- 0.8, all P < 0.05]. Obestatin level(ng/g) (14.2 +/- 2.0) of hypothesis decreased significantly in DM group as compared to those in NC group (21.7 +/- 4.7) while GHSR/beta-actin increased significantly (1.26 +/- 0.46 vs 0.77 +/- 0.21, P < 0.05). Gastric emptying was positively correlated with ghrelin, ghrelin/obestatin and GHSR/beta-actin of hypothalamus (r = 0.49; r = 0.63; r = 0.73; P < 0.01). But there was a negative correlation with obestatin of hypothalamus (r = -0.74, P < 0.01). After six weeks of STZ injection, gastric emptying (78.97% +/- 8.13% vs 44.06% +/- 5.06%) increased significantly in DM and INS groups as compared to those in NC group (35.06% +/- 3.91%, P < 0.01). Gastric emptying was positively correlated with ghrelin/obestatin of hypothalamus (r = 0.40, P < 0.05). There was no detection of GPR-39 in hypothalamus. CONCLUSION The rapid gastric emptying may be due to the rising levels of ghrelin and GHSR in hypothalamus during early hyperglycemia. And the duration of hyperglycemia is affected by the rising ratio of ghrelin/obestatin.

Highly cross-linked poly(ε-caprolactone) (PCL) was fabricated via the ring-opening (co)polymerization of ε-caprolactone with/without 30 mol% trimethylene carbonate (TMC), using 4~6mol% bis-CL or bis-TMC as the cross-linker. The in vivo degradation behavior of the obtained cross-linked PCL implants was investigated via the subcutaneous implantation into the back of rats to evaluate the possibility of the cross-linked PCL as the carrier material of the biodegradable implants. The results showed that the obtained cross-linked PCL implants had a slow degradation rate with mass loss of less than 13% after 48 weeks of degradation in vivo. The introduction of 30 mol% TMC endowed a faster degradation rate to the cross-linked PCL with a mass loss of 19.69% after 48 weeks. Furthermore, the cross-linked PCL implants presented good form-stability with no observation of deformation was found during the in vivo degradation. The SEM observation indicated that the degradation of cross-linked PCL in vivo occurred via the surface erosion mechanism. The cross-linked PCL had great potential application as the carrier material for the long-term biodegradable implants.

Background: Selenoproteins, many of which protect against oxidative injury, have been postulated to affect the development of GI inflammation and cancer. Glutathione peroxidase3 (Gpx3) is an extracellular selenoprotein that is elevated in the plasma of patients with inflammatory bowel disease. Also, mice treated with Dextran Sodium Sulfate (DSS), a model of murine colitis, have increased plasma Gpx3. Based on these observations we hypothesized that Gpx3 could modify inflammatory carcinogenesis (CAC) in the colon. Methods: We selected the azoxymethane (AOM)/cyclic DSS rodent model for our studies as this is a robust model for interrogating genetic modifiers of CAC. 11 Gpx3-/and 12 WT mice were injected with 12 mg/kg AOM followed by four cycles of 3% DSS ad lib. An additional cohort of 18 Gpx3-/and 13 WT mice were subjected to cyclic DSS therapy without AOM initiation. At necropsy, colons were isolated and tumor burden and distribution were scored. TUNEL staining to evaluate apoptosis and IHC for BrdU and β-catenin was performed on colon sections. Results: When treated with AOM and cyclic DSS ad lib, both Gpx3-/and WT mice developed polyps and had mucosal injury localized to the distal colon. However, Gpx3-/mice had increased polyposis (21.1 ± 1.6 vs 10.8 ± 1.5 polyps per colon, P<0.0001), without a difference in polyp size (7.9 ± 1.1 vs 6.4 ± 0.3, P=0.20). There appeared to be an increase in polyp burden in DSS only treated Gpx3-/mice, although this did not reach statistical significance (1.0 ± 0.3 vs 0.4 ± 0.2, P=0.15). Polyp sizes were similar between both groups of mice. Histologic injury was more severe in the Gpx3-/mice (16.2 ± 2.5 vs 7.8 ±0.64, P<0.01, combined histologic injury score). Overall, there was no difference in grade of lesions, with high-grade dysplasia present in both groups of mice. While there was no difference in intra-tumoral apoptosis observed, there was significantly higher proliferation in Gpx3-/tumors (164.0 ± 46.7 vs 73.9 ±54.4 Ki67+ cells/HPF, P<0.01). Consistent with this we observed increased cytoplasmic and nuclear β-catenin staining in Gpx3-/tumors (P<0.001). Conclusions: These studies demonstrate that Gpx3 modifies tumor initiation in inflammatory carcinogenesis. This suggests that Gpx3may serve a protective role in inflammation associated colitis perhaps via decreasing levels of H2O2 and hydroperoxides in the colonic mucosa, thus reducing oxidative DNA damage.

Abstract Although epidemiologic and experimental evidence strongly indicates chronic inflammation as a risk factor for cancer, it remains unclear how chronic inflammation contributes carcinogenesis. Here we show that deletion of PPARδ diminishes colonic inflammation by reducing infiltration of immune cells via downregulation of pro-inflammatory chemokines and cytokine in a mouse model of colon inflammation. These chemokines are responsible for recruitment of leukocytes from the circulation to local inflammatory sites. Our results further reveal that COX-2 is a downstream target of PPARδ and COX-2-derived PGE2 stimulates macrophages to produce pro-inflammatory chemokines and cytokine. PGE2 is a crucial mediator of colorectal carcinogenesis. More importantly, loss of PPARδ attenuated colonic inflammation-associated adenoma growth in two mouse models of inflammation-associated colorectal cancer. Our results demonstrate that PPARδ promotes chronic colonic inflammation and colitis-associated tumorigenesis. Collectively, these findings indicate that PPARδ plays a pivotal role in connecting colonic inflammation to cancer progression and may represent a potential therapeutic target for prevention or treatment of colorectal cancer. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A43.

The aim of this work was to investigate the expression of transcription activating protein 4 (AP-4) in gastric cancer (GC) and its impacts on prognosis.The cancer tissues and normal tissues of 54 GC patients were sampled for the expression detection of AP-4, and the patients were followed up.The positive expression rate of AP-4 in the cancer tissues (68.5%) was higher than the normal tissues (22.2%; p < 0.01). The lower the tumor differentiation degree and the deeper the invasion depth, the higher the expression rate of AP-4. The median survival time of the patients with positive AP-4 expression was significantly shorter than of those without AP-4 expression (26.3/41.3 months), and the accumulative survival rate of the former was also lower than the latter (χ2 = 4.736, p = 0.03). AP-4 was expressed in GC tissues and normal gastric tissues, with the expression in the former being higher.The expression of AP-4 was positively related with the tumor differentiation degree, invasion depth, lymph node metastasis, and pTNM stage, while it was not related with patient gender, age, tumor size, location, or distant metastasis. AP-4 might be used as an indicator for the prognosis prediction of GC.

Bruceantinol (BOL), a quassinoid compound isolated from the fruits of Brucea javanica, has been reported to have cytotoxic and antibacterial effects. In this study, a rapid, sensitive, and specific ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was developed for the quantitative determination of BOL in rat plasma. The samples were treated by simple liquid-liquid extraction with ethyl acetate and separated on an UPLC BEH C18 column (2.1 mm × 50 mm) using a 3-min gradient elution scheme, which consists of water (0.1% v/v, formic acid) and methanol (0.1%, v/v, formic acid) to achieve the separation of BOL and sinomenine (IS) with high selectivity. The electrospray ionization source was used in positive ion mode; the multiple reaction monitoring quantified the target fragment ions m/z 629.6 → 569.5 for BOL and m/z 330.5 → 207.3 for IS. This work was evaluated with regards to the specificity, extraction recovery, matrix effect, linearity, accuracy, precision, stability, and dilution integrity. This approach was used to examine the pharmacokinetics of BOL in rats after oral (0.3 mg/kg) and intravenous (0.15 mg/kg) administration. BOL presented fast excretion and very low oral bioavailability.

As one of the most components of fungal cell walls, Oligo GlcNAc could induce hypersensitive cell death in rice suspension cells and seedling leaves, and H 2O 2 accumulation simultaneously. In incubation with 1 μg·mL -1 of Oligo GlcNAc, detectable cell death appeared after 12 h in rice suspension cells, which appeared on rice seedling leaves induced by 5 μg·mL -1 of Oligo GlcNAc. And the disease resistance in rice to Magnaporthe grisea was enhanced strongly.

Objective To evaluate the length of hospital stay and the incidences of complications after omentoplasty with non-omentoplasty for the patients with esophageal cancer. Methods The databases including Pubmed, Embase, The Cochrane Library, Web of Science, CBM, CNKI, VIP and Wanfang data were searched for collecting randomized controlled trials on the omentoplasty. According to the inclusive and exclusive criteria, the datas were extracted. Two reviewers independently screened literatures and assessed the qualities of the included studies and extracted data. Meta-analysis was performed by using of RevMan 5.2 software. Results A total of 6 RCTs including 2 167 patients from 206 original articles were included in this analysis. In terms of the anastomotic leakage after esophagectomy and the hospital stays, the incidence of anastomotic leakage (OR=0.19, 95%CI: 0.09~0.39, Z=4.55, P<0.000 01) and hospital stays (MD=-1.91, 95%CI: -2.26--1.57, Z=10.87, P<0.000 01) with omentoplasty was significantly lower than those of the non-omentoplasty, with significant differences. However, in terms of anastomotic stricture (OR=0.76, 95%CI: 0.29-2.01, Z=0.55, P=0.58) and mortality rate (OR=0.72, 95%CI: 0.24-2.21, Z=0.57, P=0.57), there wrer no significant differences. Conclusion Comparing with non-omentoplasty, the use of omentoplasty has beneficial effects for the postoperative complication such as anastomotic leakage and hospital stays, and does not increase the incidence of anastomotic stricture and mortality rate. Key words: Esophageal neoplasms; Meta-analysis; Omentoplasty

Background The complex mechanisms of aortic arch aneurysm have not been well studied. An animal model of aortic arch aneurysm would be beneficial to study this fatal disease. In this study, we tried to establish a rat model of aortic arch aneurysm by constricting the aortic isthmus. Methods Forty-eight male Sprague-Dawley rats were randomly divided into three groups. Rats with no aortic isthmus constriction were assigned to group A (control group). The aortic isthmus was constricted to 1.5 mm in group B and to 0.8 mm in group C. The blood pressure of the rats was measured at 0, 1, 3 and 6 months after the operation. The diameter and wall thickness of aortic arch were measured at 3 and 6 months after surgery. Results Compared to group A, group B showed no significant increase in blood pressure or aortic diameter after the operation. Compared to the control group, group B showed a marked increase in wall thickness at 3 and 6 months after surgery ( p &lt; 0.05). Compared to group A, group C showed significant increases in both blood pressure ( p &lt; 0.05) and aortic diameter ( p &lt; 0.05) after the operation. Group C also showed a more than 50% increase in wall thickness at 3 and 6 months after surgery ( P &lt; 0.05). Conclusions By constricting the aortic isthmus to 0.8 mm, a rat model of aortic arch aneurysm could be induced at 3 and 6 months after surgery.

inhibition of Vav1 does not elevate the risk of colitis associated colon cancer. Subsequently, azathioprine induced blockade of Vav1 mediated Rac1 activation in activated T cells exclusively blocks the overwhelming immune reaction in the context of IBD without supporting colorectal tumorigenesis. Innovative immunosuppressive strategies for optimized IBD therapy might therefore concentrate on an even more specific blockade of the Vav1-Rac1 signaling pathway.

tumor-initiating cells or cancer stem cells.In vivo experiments including orthotopic transplantation and conditional knockout of Etv1 in Pdx1Cre;KrasG12D/+-as well as Pdx1Cre;K-rasG12D/+;p53R175H/+-mice are ongoing to further elucidate the role of Etv1 in PanIN and PDAC initiation and progression.

CRC patients were not more likely to have UC or CD than control patients.(OR of CRC + UC = 0.84 [95%CI 0.61-1.14],p=0.259;OR of CRC + CD = 0.85 [95%CI 0.67-1.06],p= 0.145).There was no difference in age between CRC patients with IBD (UC and CD averaged) and non-IBD patients.In UC patients, we noted increased frequency of stages I-II CRC and decreased frequency of stages III-IV compared to non-IBD cancer patients (p-value=0.038).There were no differences in cancer stage in CD patients (p-value = 0.282). Conclusion:This study provides new information about IBD-CRC in elderly Americans and suggests that UC and CD may not be significant risk factors for CRC.These findings are similar to findings from the Danish population, and may reflect the impact of cancer prevention programs or reveal additional biologic factors related to disease severity and risks.Further analysis of temporal trends in this unique population is ongoing.

Abstract Although epidemiologic and experimental evidence strongly indicates chronic inflammation as a risk factor for cancer, it remains unclear how chronic inflammation contributes carcinogenesis. Peroxisome proliferator-activated receptor ≤ (PPARδ) is one member of PPAR family that belongs to the nuclear hormone receptor superfamily and is also ligand-dependent transcription factor. Although PPARδ has been shown to be involved in chronic inflammation and the progression of hereditary and sporadic CRC, its role in inflammation-induced carcinogenesis is not defined. The aim of our present study was to determine whether PPARδ contributes to the pathogenesis of colonic inflammation and inflammation-associated carcinogenesis. Here we present genetic evidence demonstrating that deletion of PPARδ diminishes colonic inflammation accompanied with reducing infiltration of immune cells and the expression of pro-inflammatory chemokines and cytokines in a mouse model of colitis. These PPARδ-dependent chemokines are responsible for recruitment of leukocytes from the circulation to local inflammatory sites and the tumor microenvironment. Our results further reveal that activation of PPARδ induces COX-2 expression in colonic epithelial cells. Importantly, COX-2-derived PGE2 stimulates macrophages to produce pro-inflammatory chemokines and cytokines. More intriguingly, loss of PPARδ attenuated colonic chronic inflammation and colitis-associated adenoma growth via PGE2 signaling in two mouse models of colitis-associated tumorigenesis. Collectively, our results demonstrate that PPARδ promotes colonic chronic inflammation and colitis-associated tumor growth via a PGE2 signaling which mediates the crosstalk between tumor epithelial cells and macrophages. Our data further supports the notion that the existence of crosstalk between PPARδ and COX-2 signaling in CRC progression. These findings indicate that PPARδ plays a pivotal role in connecting colonic inflammation to cancer progression and may represent a potential therapeutic target for prevention or treatment of colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1519. doi:1538-7445.AM2012-1519

Objective To explore the influencing factors of hypertensive cerebral hemorrhage in 68 patients with supratentorial prognosis of recovery of neurological function.Methods Clinical data of 68 patients with high blood pressure treatment supratentorial intracerebral hemorrhage,and brain CT,laboratory data were retrospectively analyzed.Neurological functions and related indicators change of were daalyzed by univariate and multivariate Logistic regression analysis.Results Gender,systolic blood pressure,diastolic blood pressure,red blood cell count,such as the impact on the prognosis was not statistically significant(all P ＞ 0.05) ; median line offset,nosocomial infections,surgery,gastrointestinal bleeding,heart failure,treatment Barthel index(BI) were a significant influence on the prognosis (all P ＜ 0.01).The median line offset,nosocomial infections,bleeding,gastrointestinal bleeding,heart failure,BI integration were the main factors affecting the prognosis of neurological function recovery.Conclusion The factors which affects nerve function recovery is an important part of improving neurological outcomes.We should emphasize them. Key words: Cerebral hemorrhage, hypertensive;  Influencing factors;  Prognosis

Objective To evaluate the efficiency and safety of esophageal stents combined with radiotherapy compared with esophageal stents alone in the treatment of advanced esophageal cancer.Methods CBM,VIP,CNKI,Cochrane Library,Pubmed and Embase etc were searched by computer begining from the establishment of these datebases to December 2012.The related references as well as communicated with other researchers were also traced to obtain certain informations.Randomized and quasi-randomized controlled trials compared esophageal stents plus radiotherapy with esophageal stents alone in the treatment of advanced esophageal cancer were included.The statistical software RevMan 5.0 was used.Results Seven published articals were included (443 patients),and all trails methodological quality were grade C.The results of Metaanalysis showed that compared with esophageal stents along,esophageal stents combined with radiotherapy improve 1-year survival rates and reduce the local recurrence rates.Gastrointestinal bleeding rates,chest pain rates,gastro-esophageal reflux rates remained similarily.Conclusion Compared with esophageal stents along,esophageal stents combined with radiotherapy can improve 1-year survival rates and reduce the local recurrence rates. Key words: Esophageal neoplasms;  Esophageal stents;  Radiotherapy;  Systematic review

<h3>Objective</h3> To Explore the feasibility of establishing the reperfusion model on AMI rabbit by the method of obstructing and releasing the Left Anterior Ventricular Branch (LAVB) of left circumflex coronary artery (LCX). <h3>Methods</h3> A total of 24 healthy Japanese albino rabbits of both sex were used in this study. Rabbits were randomly divided into 3 groups: ischaemia-reperfusion group (IR group, 8), ischaemia-noperfusion group (AMI group, 8), sham group (sham, 8). After preconditioning the myocardium twice by obstructing the blood flow for 5 min, we obstructed the flow of LAVB in IR group for 60 min, and then released it to be reperfusion. In AMI group we obstructed the flow permanently by ligating LAVB. And in sham group we only threaded but did not obstruct the flow. Then we killed them 3 days later. Venous blood was gathered. The levels of cTNI, CK and CK-MB were assayed at pre-reperfusion (baseline) and post-reperfusion period (4-h, 8-h, 12-h, 24-h, 48-h and 72-h after being reperfusion). The summation changes of ST segment elevation were observed in leads П, Ш, avF by ECG. Histopathology of myocardia, Evan9s Blue and TTC dyeing were taken into notice. STATA8.0 software pack was used for data analysis. <h3>Results</h3> The results come out that the ST segment all elevated in each group after LAVB was obstructed. In IR group the ST segment lowered more than 50% within 120 min after releasing the artery. This phenomenon had not appeared in other two groups. Compared to baseline, the cTNI, CK and CK-MB were all raised in IR group, and the peak value antedisplaced to 8 h, 12 h and 10 h. These three factors were all raised but no antedisplacement of the enzyme peak in AMI group. In sham group the raising of the three factors was slight, and no antedisplacement of the enzyme peak either. The experiment of rabbits in IR and AMI groups were consistent with the AMI diagnostic criteria in AMI Guideline of diagnosis and therapy established by Cardiac Disease branch of Chinese Medical Association in 2004. The histopathology examination and TTC staining agree with the AMI diagnosis too. The experiment of rabbits in IR group was in accordance with the recanalisation criteria of IRCA recommended by the <i>Chinese J Cardiol</i> editorial committee in 1991. The injection of Evan9s Blue was in coincidence with the recanalisation of IRCA too. <h3>Conclusions</h3> AMI-reperfusion rabbit models can be successfully established by the application of this method. It has proved to be very effective.

Abstract Background: We have recently shown an association of colorectal tumor subtypes with differential response to chemotherapy in patients (pts), and to targeted therapy in cell lines. Pts enrolled in NSABP/NRG C-07 with stem-like tumors had a poor prognosis regardless of stage or treatment, highlighting the importance of finding new treatments for stem-like tumors. Our in-vitro data showed that KRAS mutant (mt) cell lines of the intrinsic inflammatory subtype were sensitive to the combination of MEK-162 and neratinib, but stem-like subtype cell lines were resistant regardless of KRAS mt status. The purpose of this study was to extend our observations to xenograft models and to identify new agents that target the stem-like subtype. Methods: KRAS mt cell lines of the inflammatory (NCI-H747) or stem-like (SW-480) subtype were used in xenograft models to test inhibition of tumor growth by MEK-162 and neratinib, alone or in combination. Five stem-like cell lines with KRAS wt (C2BBE1, HS675T) or KRAS mt (SW480, SW620, HCT116), and two KRAS mt inflammatory cell lines (NCI-H747, SW837) were tested for cell viability after treatment with SCH772984 alone or in combination with neratinib. Results: In vivo analysis showed that treatment of NCI-H747 xenografts with a combination of MEK-162 (3mg/kg) and neratinib (10mg/kg) led to significant tumor regression compared to treatment with either drug alone (p ≥0.0001 v neratinib alone; p ≥0.002 v MEK-162 alone). In contrast, MEK-162 alone was able to inhibit tumor growth of stem-like cell line (SW480) xenografts (p ≥0.0061 v control) but neratinib was ineffective (p ≥0.145 v control) as a single agent and did not add to MEK-162. Our in-vitro and in-vivo data showed that inhibition of p-ERK directly correlated with sensitivity to the MEK and neratinib combination in inflammatory subtype. SCH772984 significantly inhibited cell viability of both inflammatory (IC50 1-2 μM) and stem-like subtype (IC50 1-2 μM) cell lines. The combination of neratinib (0.125 μM) and SCH772984 (1 μM) was effective at decreasing cell viability by 60-70% in both inflammatory and stem-like cell lines. Inhibition of ERK phosphorylation was correlated with loss of cell viability. Conclusion: The combination of MEK-162 and neratinib work synergistically to decrease tumor growth in inflammatory but not stem-like colorectal cancer subtypes. We demonstrate that SCH772984 decreases the viability of stem-like colon cancer cell lines, and works synergistically with neratinib. The use of SCH772984 alone, but more potently in combination with neratinib, may represent a therapeutic approach for pts with stem-like tumors, a finding that underscores the potential importance of employing subtype analysis in the diagnosis of colon cancer and potentially as to a guide to new therapies. Support: PA DoH, which disclaims certain responsibility. Citation Format: Rekha Pal, Ning Wei, Nan Song, Shao-yu Wu, S. Rim Kim, Patrick G. Gavin, Peter C. Lucas, Ashok Srinivasan, Samuel A. Jacobs, Soonmyung Paik, John C. Schmitz, Kay Pogue-Geile. Stem-like colorectal cancer cell lines show response to the ERK1/2 inhibitor, SCH772984, alone and in combination with neratinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5167. doi:10.1158/1538-7445.AM2017-5167

Objective To investigate the effects of plasma ghrelin,obestatin and ghrelin/obestatin(G/O) on the gastric emptying in early stage of diabetes mellitus.Methods Sixty male Wistar rats were randomly divided into normal control group(NC group),diabetes mellitus group(DM group),insulin-treated group(INS group) with 20 in each.The intraperitoneal injection of streptozotocin(STZ) was used to induce diabetic models in the later two groups.INS group was given intermediate-acting insulin by hypodermic injection every day,and the other two groups were given normal saline.Two and six weeks after the injection,half of each group was taken out for experimentation.The gastric emptying was measured by intragastric administration of phenol red,the plasma ghrelin and obestatin were detected by enzyme immunoassay.Results Two weeks later,the gastric emptying and level of plasma ghrelin and obestatin in DM group increased compared with those in NC group(P0.001,0.01,0.01),and G/O was a little higher than that in NC group.The gastric emptying and G/O in INS group decreased compared with those in DM group(P0.01).Six weeks later,the gastric emptying and level of plasma ghrelin and obestatin in DM group increased compared with those in NC group(P0.001,0.01,0.01),and G/O was higher than that in NC group(P0.05).The gastric emptying in INS group decreased compared with that in DM group(P0.01),the level of plasma obestatin increased(P0.05).Conclusions In early stage of diabetes mellitus,the increase of plasma G/O may be one of the important factors for the promotion of gastric emptying.The effect of extrinsic insulin on plasma obestatin may be related to the regulation of gastric emptying.

Objective To explore the relationship between carotid plaque microcalcifcation and ischemic stroke (including transient ischemic attack) and the value of carotid microcalcification in predicting ischemic stroke. Methods Twenty-six patients in accordance with atherothrombosis models classified by Korean modified TOAST classification were enrolled in this study from November 2016 to March 2017. The microcalcification of the bilateral carotid was detected by Micropure imaging and the severity of intracranial ischemic focal lesions was evaluated by Alberta stroke programme early CT scale (ASPECT). The relation of ASPECT scores with microcalcification of the bilateral carotid was analyzed, and the value of carotid microcalcification in predicting ischemic stroke was analyzed by receiver operating characteristic curve method. Results Microcalcifition was detected in 27 of the total 52 carotids (51.92%) in 19 patients, which localized in the fibrous cap in 23 carotids (85.19%) and the basilar part of the plaque in 4 carotids (14.81%). The microcalcification surrounded the macrocalcifiation in 14 carotids (51.85%). The ASPECT scores were 10.85±1.43 in the microcalcifition side, which were significantly higher than those in the side without microcalcifition (11.80±1.19, t=2.584, P=0.013). The area under the curve was 0.673, with sensitivity of 0.667 and specificity of 0.680. Conclusion Micropure imaging maybe a new approach to detect the carotid microcalcification, and plaques with microcalcifition may easily cause ipsilateral ischemic stroke. Key words: Carotid; Microcalcification; Ultrsound; Stroke; Micropure imaging

Objective To investigate the level of LP(a) and serum lipids indices in the functiionaries in Futian District of Shenzhen.Methods There 2 196 functionaries and 965 healthy persons were surveyed.Results The rate of high LP(a) was as high as 18.4%,being 22.1%, 13.1% and 8.3% in the senile, middle and young age group and healthy control group .There 45.8%, 41.9% and 38.8% of them with higher levels of LP(a) and CHOL.18.8%, 6.8% and 3.7% of them was with high levels of LP(a) .Conclusion The level of LP(a) in functionaries is high, especially the senile grou and the rates of LP(a) and LDL-C in the senile persons are also higher.Thus effective measures be taken.

Objective To investigate the value of ultrasound bio-microscopy(UBM) before and after angle-closure glaucoma surgeries.Methods The clinical data of 740 cases(963 eyes)of angle closure glaucoma which were performed UBM from 2004 to 2007 were retrospectively analyzed.Results All patients were clearly diagnosed and rationally operated on.The intraocular pressure was decreased in all patients.Also the post-operative evaluation is timely and reasonable.Conclusion UBM plays an important role in angle-closure glaucoma surgery.

The study investigates current situation of aesthetic appreciation quality of 300 at-school graduate students from Tianjin University of Finance Economics and Tianjin University of Science Technology by questionnaire.Compared with previous relevant investigation result of 320 at-school undergraduate students from Tianjin University of Finance Economics,it analyzes the graduate student recognition of significance of aesthetic appreciation quality,the basic situation of aesthetic appreciation activity,the principal character of aesthetic appreciation temperament and interest,basic conditions of aesthetic appreciation cultivation,and make some suggestions and countermeasures for improving aesthetic appreciation quality of graduate students from 3 aspects: to clear ideological understanding,to reinforce theory accomplishment,to enrich aesthetic appreciation practice.

4190 Dysregulation of certain bioactive lipid signaling pathways is known to contribute to progression of cancer. Endocannabinoids, a class of bioactive lipids, activate G-protein-coupled cannabinoid receptors, CB1 and CB2. Although endocannabinoid signaling is important for certain aspects of gastrointestinal homoeostasis, the role of the cannabinoid receptors in colorectal cancer has not been defined. Here we show that CB1 expression was silenced in human colorectal cancer due to methylation of the CB1 promoter. Our genetic and pharmacologic studies reveal that loss or inhibition of CB1 accelerated the intestinal adenoma growth in ApcMin/+ mice whereas activation of CB1 attenuated the intestinal tumor growth by inducing cell death via downregulation of the anti-apoptotic factor survivin. This downregulation of survivin by CB1 is mediated by a cAMP-dependent PKA signaling pathway. These results indicate that the endogenous cannabinoid system represent a potential therapeutic target for the prevention or treatment of colorectal cancer.

The cytoskeleton is considered as an important organelle in mediating early sensing and signal transduction events in plant gravitropism.There are a lot of evidences indicating that the role of actin cytoskeleton in regulating auxin polar transport,which in- duces a lateral gradient of auxin and results in plant organ curva- ture.The reorientation of microtubules in plant cells during grav- itropic response was also reported,but the role of this reorgani- zation of microtubules in controlling the differential gravitropic growth has not been clear.The advances in cellular,molecular and biochemical techniques have provided several possibilities for fur- ther research into this fascinating area.The new findings in charac- terization of cytoskeleton binding proteins have provided us a lot of useful information on various kinds of candidate regulators that could be targets of the gravity signal transduction chain.In this pa- per,the functions of cytoskeleton in gravitropism are discussed and the update progress in plant space biology is also introduced.

Aim To study the pharmacokinetics and relative bioavailability of finasteride tablets in Chinese healthy volunteers.Methods:Twenty male healthy volunteers received 2mg finasteride tablet orally in a random crossover design.Drug concentrations in plasma were determined by LC-MS.Results:The main pharmacokinetic parameters of tested and reference tablets were as follows:AUC0-24(123.95±25.47)μg·h·L-1 vs (126.35±28.16)μg·h·L-1,AUC0-∞(126.12±27.48)μg·h·L-1 vs (129.85±29.12)μg·h·L-1,Cmax(22.17±3.83)μg·L-1 vs (22.48±4.69)μg·L-1,Tmax(3.1±0.6)h vs (2.9±0.8)h,T1/2(4.2±0.3)h vs(4.3±0.5)h.respectively.The relative bioavailability of the test tablet was(99.4±9.2 )%;Conclusions:The results demonstrated that the two tablets were bioequivalent.

To measure mobility of dendritic filopodia, complexity of dendritic arborization using method of live imaging in cultured rat hippocampal neurons and to analyze their morphological characters quantitatively.Vectors expressing Green Fluorescent Protein- Fibrous Actin (GFP-F-Actin) and F-GFP were co-transfected into cultured rat hippocampal neurons at 5 d in vitro (DIV 5). Neurons expressing GFP were photographed and analyzed with Metamorph software.Dendritic filopodia was observed to move actively from DIV 7 to DIV 9. The mean density of filopodia was (10.78 +/-3.78)/100 microm, (10.68 +/-2.96)/100 microm and (9.99 +/-3.67)/100 microm (P >0.05), and there were (30.18 +/-14.03)% to (87.36 +/-20.88)% filopodia were mobile (P <0.001). During DIV 7-DIV 14, the total length of dendritic branches grew from (410.74 +/-185.98) microm to (1238.21 +/-418.32)microm (P <0.001) and the number of dendritic branches increased from 18.93 +/-7.23 to 33.60 +/-10.46 (P<0.001). The density of spine was (37.17 +/-6.46)/100 microm at DIV 14.The combination of live imaging with quantitative analysis is a useful method to study dendritic morphological development in vitro, including indicators of dendritic filopodia, dendritic arborization and spines.