Research Progress of BAP1 in Structure, Function, and Cancer.

Cancer is an important chronic non-communicable disease that endangers human health and has become the main cause of death of residents around the world in the 21st century. At present, most of the mature treatment methods stay at the level of cell and tissue, which is difficult to fundamentally solve the problem of cancer. Therefore, explaining the pathogenesis of cancer at the molecular level becomes the answer to the key problem of cancer regulation. BRCA-associated protein 1 (brca1- associated protein 1) is a kind of ubiquitination enzyme encoded by the BAP1 gene and composed of 729 amino acids. As a carcinogenic protein, BAP1 can affect the cancer cell cycle and proliferation capacity, mutation, and deletion. For example, depending on catalytic activity, it participates in the regulation of intracellular function through transcription, epigenetic, and DNA damage repair. This article mainly reviews the basic structure and function of BAP1 in cells, its role in cancer development, and cancer-related mutants.

Ivermectin inhibits tumor metastasis by regulating the Wnt/ß-catenin/integrin ß1/FAK signaling pathway.

Tumor metastasis is the major cause of cancer mortality; therefore, it is imperative to discover effective therapeutic drugs for anti-metastasis therapy. In the current study, we investigated whether ivermectin (IVM), an FDA-approved antiparasitic drug, could prevent cancer metastasis. Colorectal and breast cancer cell lines and a cancer cell-derived xenograft tumor metastasis model were used to investigate the anti-metastasis effect of IVM. Our results showed that IVM significantly inhibited the motility of cancer cells in vitro and tumor metastasis in vivo. Mechanistically, IVM suppressed the expressions of the migration-related proteins via inhibiting the activation of Wnt/ß-catenin/integrin ß1/FAK and the downstream signaling cascades. Our findings indicated that IVM was capable of suppressing tumor metastasis, which provided the rationale on exploring the potential clinical application of IVM in the prevention and treatment of cancer metastasis.

Comparison of the supraglottic airway device BlockBusterTM and laryngeal mask airway Supreme in anaesthetised, paralyzed adult patients: a multicenter randomized controlled trial.

BACKGROUND: This multicenter prospective, randomized controlled clinical trial compared the clinical performance of supraglottic airway device (SAD) BlockBusterTM and laryngeal mask airway (LMA) Supreme for airway maintenance in anesthetized, paralyzed adult patients. METHODS: A total of 651 adult patients scheduled for elective surgery in 13 hospitals were randomly allocated into BlockBuster group (n = 351) or Supreme group (n = 300). The primary outcome was oropharyngeal leak pressure (OLP). Duration and ease of insertion, fiberscopic view of positioning, airway manipulations, and complications were also assessed. RESULTS: The OLP was significantly higher in BlockBuster group compared with Supreme group (29.9 ± 4.2 cmH2O vs 27.4 ± 4.3 cmH2O, p < 0.001). Success rate of insertion at the first attempt (90.2% vs 85.1%, p = 0.027), rate of optimal fiberscopic view (p = 0.002) and satisfactory positioning of SAD (p < 0.001) were significantly increased in BlockBuster group. CONCLUSIONS: Both SAD BlockBusterTM and LMA Supreme are safe, effective, and easy-to-use devices for airway maintenance in anesthetized, paralyzed adult patients, but the SAD BlockBusterTM is superior to LMA Supreme in terms of OLP, success rate at the first attempt, and fiber-optic view of positioning. TRIAL REGISTRATION: The trial is registered at www.chictr.org.cn (ChiCTR-ONC-16009105).

Tri-ortho-cresyl phosphate induces axonal degeneration in chicken DRG neurons by the NAD+ pathway.

Wallerian degeneration (WD) is a well-known process by which degenerating axons and myelin are cleared after nerve injury. Although organophosphate-induced delayed neuropathy (OPIDN) is characterized by Wallerian-like degeneration of long axons in human and sensitive animals, the precise pathological mechanism remains unclear. In this study, we cultured embryonic chicken dorsal root ganglia (DRG) neurons, the model of OPIDN in vitro, to investigate the underlying mechanism of axon degeneration induced by tri-ortho-cresyl phosphate (TOCP), an OPIDN inducer. The results showed that TOCP exposure time- and concentration-dependently induced a serious degeneration and fragmentation of the axons from the DRG neurons. A collapse of mitochondrial membrane potential and a dramatic depletion of ATP levels were found in the DRG neurons after TOCP treatment. In addition, nicotinamide nucleotide adenylyl transferase 2 (NMNAT2) expression and nicotinamide adenine dinucleotide (NAD+) level was also found to be decreased in the DRG neurons exposed to TOCP. However, the TOCP-induced Wallerian degeneration in the DRG neurons could be inhibited by ATP supplementation. And exogenous NAD+ or NAD+ processor nicotinamide riboside can rescue TOCP-induced ATP deficiency and prevent TOCP-induced axon degeneration of the DRG neurons. These findings may shed light on the pathophysiological mechanism of TOCP-induced axonal damages, and implicate the potential application of NAD+ to treat OPIDN.

Efficacy of thunder-fire moxibustion in treating ankylosing spondylitis of kidney deficiency and governor meridian cold and its influence on TNF-α and RANKL: study protocol for a prospective, nonblinded, single-center, randomized controlled trial.

BACKGROUND: Ankylosing spondylitis (AS) is a common chronic inflammatory spondyloarthropathy. It is considered in traditional Chinese medicine (TCM) that the pathogenesis of AS is mainly due to Yang deficiency of kidney governor meridian and internal prosperity of cold evil. Thunder-fire moxibustion is a kind of moxibustion that is characterized in abundance in drug composition, high heat radiation, and strong penetration. Thunder-fire moxibustion on the spinal segment of the governor meridian in treating AS seems compatible with the main pathogenesis of kidney deficiency and governor meridian cold. The trial aims to explore the efficacy of thunder-fire moxibustion in patients with AS of kidney deficiency and governor meridian cold and its influence on bone metabolism, through a prospective randomized trial. METHODS: Sixty patients with AS of kidney deficiency and governor meridian cold will be recruited and randomly assigned to the treatment group (thunder-fire moxibustion three times a week plus basic treatment) and the control group (basic treatment) at the Center of TCM of Beijing Luhe Hospital Affiliated to Capital Medical University (Beijing, China). Each patient will be treated for 4 weeks. The primary outcome is the efficacy of TCM syndrome, and the secondary outcome indexes will include the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Short-Form-36 Questionnaire (SF-36), tumor necrosis factor-α (TNF-α), and receptor activator of nuclear factor-κB ligand (RANKL). TNF-α and RANKL with observation will be determined once respectively before and after treatment, while the other indexes will be observed once prior to the treatment, 2 weeks post-treatment, and at the end of the treatment. Side effects will be recorded and analyzed as well. Inter-group comparison and analysis will be performed based on the intention-to-treat set and per-protocol set. DISCUSSION: This prospective randomized trial will help verify the efficacy of thunder-fire moxibustion in treating AS of kidney deficiency and governor meridian cold, discuss preliminarily its mechanism in treating this disease, and provide high-quality evidences for scientific researches on clinical treatment with thunder-fire moxibustion against AS. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100044227 . Registered on 12 March 2021.

Lapatinib alleviates TOCP-induced axonal damage in the spinal cord of mouse.

Neuregulin-1 (NRG1), a family of EGF-like factors that activates ErbB receptors, can regulate the proliferation, migration, and myelinating of Schwann cells. We previously reported that NRG1/ErbB signal is responsible for organophosphate (OP)-induced delayed neuropathy (OPIDN) in hens, a susceptive animal model to neuropathic organophosphorous compounds. Our previous study discovered that a neuropathic OP, tri-o-cresyl phosphate (TOCP) activated NRG1/ErbB signaling pathway in both spinal cord and sciatic nerves of hens during the formation of OPIDN and lapatinib, a non-selective antagonist of ErbB1 and ErbB2 receptors, alleviated the toxicity. In this study, we intended to further look into the potential role of NRG1 in the pathogenesis of TOCP-induced axon damage in spinal cord and sciatic nerves and whether lapatinib could also rescue this damage in mice, an OPIDN-resistant animal model. The results revealed that no obvious toxic signs were observed after single TOCP exposure. However, slight histopathological wreck in lumbar spinal cord and sciatic nerves was found following TOCP intoxication, and the damage in sciatic nerves was characterized by axon degeneration of myelin sheath but not the loss of neural skeleton. Only histopathological damage induced by TOCP in spinal cord could be prevented by lapatinib. The translational expression of NRG1/ErbB signaling molecules was analyzed by both in vivo and in vitro studies. In general, NRG1/ErbB pathway was activated by TOCP while combined treatment with lapatinib attenuated TOCP-induced NRG1/ErbB signaling cascade. The results implied that NRG1/ErbB system may predominately play functional role in spinal cord (central nervous system) but not in sciatic nerves (peripheral nervous system) of mouse subjected to neurotoxic OP, which was confirmed by the study in vitro that lapatinib was not able to attenuate TOCP-induced neurotoxicity in rodent Schwann cell line RSC 96 cells.

Comparisons of recurrence-free survival and overall survival between microwave versus radiofrequency ablation treatment for hepatocellular carcinoma: A multiple centers retrospective cohort study with propensity score matching.

Both microwave (MW) ablation and radiofrequency (RF) ablation are widely used for hepatocellular carcinoma (HCC) treatments in clinic. However, it is still unclear if ablative methods could influence the recurrence-free survival (RFS) and overall survival (OS) of HCC patients. Therefore, we carried out this multi-center retrospective cohort study to investigate the differences of recurrence-free survival (RFS) and overall survival (OS) between MW ablation and RF ablation by survival analysis. From January 2014 to December 2016, patients who received thermal ablation surgery for HCC treatment were screened. Finally, 452 patients met the eligibility criteria and finished the follow-up. Univariable and multivariable regression analyses were used to identify independent predictive factors of the RFS and OS. Also, propensity score matching (PSM) was used to balance the bias between two groups. Finally, we found that before the PSM, the univariable and multivariable regression analyses revealed that there were no significant differences on the RFS between two groups. Same results were obtained for the OS. After PSM, 115 pairs of patients were created, and both the univariable and multivariable regression analyses suggested that there were still no significant differences on the RFS between two groups. Same results were obtained for the OS. In conclusion, our present study showed that there were no significant differences between MW ablation and RF ablation for HCC patients on the RFS or OS.

Prophylactic atorvastatin prior to intra-arterial administration of iodinated contrast media for prevention of contrast-induced acute kidney injury: A meta-analysis of randomized trial data
.

BACKGROUND: The efficacy of high-dose atorvastatin pretreatment in reducing the incidence of contrast-induced nephropathy in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) has been examined in some randomized studies. However, the results across the trials remain controversial. OBJECTIVE: This study sought to perform a meta-analysis to evaluate the effect of high-dose atorvastatin in the prevention of contrast-induced nephropathy (CIN) while undergoing CAG or PCI. MATERIALS AND METHODS: Comprehensive literature searches for randomized controlled trials (RCTs) comparing high-dose atorvastatin vs. low-dose statin or placebo pretreatment for prevention of contrast-induced acute kidney injury in patients undergoing CAG were performed using PubMed, Embase, and the Cochrane library updated to June 2017. The primary outcome was the incidence of CIN. RESULTS: A total of 11 RCTs were included in this analysis. The high-dose atorvastatin treatment can significantly reduce the incidence of CIN (OR 0.46, 95% CI 0.35 - 0.62, p < 0.00001). The benefit was consistent in comparison with the low-dose group (OR 0.41, 95% CI 0.25 - 0.66, p = 0.0003) and the placebo group (OR 0.50, 95% CI 0.26 - 0.98, p = 0.04). CONCLUSION: Our study demonstrates that high-dose statin pretreatment shows a benefit specifically in reducing the incidence of contrast-induced acute kidney injury in patients undergoing CAG, especially compared with low-dose statin pretreatment.

Efficacy of atorvastatin on the prevention of contrast-induced acute kidney injury: a meta-analysis.

BACKGROUND: Results of studies on the efficacy of atorvastatin pretreatment on reducing the prevalence of contrast-induced acute kidney injury (CIAKI) in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) have been controversial. OBJECTIVE: We undertook a meta-analysis to evaluate the efficacy of atorvastatin on contrast-induced nephropathy (CIN) after CAG or PCI. MATERIALS AND METHODS: We undertook a systematic search of electronic databases (PubMed, Embase, and the Cochrane Library) up to June 2017. A meta-analysis was carried out including randomized controlled trials (RCTs) that compared atorvastatin pretreatment with pretreatment with a low-dose statin or placebo for CIAKI prevention in patients undergoing CAG. The main endpoint was CIN prevalence. RESULTS: Nine RCTs were included in our meta-analysis. Atorvastatin pretreatment reduced the prevalence of CIN significantly (odds ratio [OR] 0.46; 95% confidence interval [95% CI] 0.27-0.79; p=0.004). The benefit of high-dose atorvastatin pretreatment was consistent when compared with the control group (OR 0.45; 95% CI 0.21-0.95; p=0.04). CONCLUSION: At high doses, atorvastatin pretreatment was associated with a significant reduction in the prevalence of CIAKI in patients undergoing CAG. Pretreatment with high-dose atorvastatin could be employed to prevent CIAKI.

Empirically derived dietary patterns and ovarian cancer risk: a meta-analysis.

Dietary patterns, which reflect overall diet and possible nutrient and food interactions, have been reported to be related to ovarian cancer (OC) risk. However, studies on the relationship between dietary patterns and OC risk have been inconsistent. Thus, we carried out a systematic meta-analysis to assess the relationship between dietary patterns and the risk of OC. Relevant studies are identified by searching the Medline and Embase electronic databases up to December 2016. The Cochrane Q statistic and the I statistical were used to evaluate heterogeneity. A total of 22 studies fulfilled the inclusion criteria and were included in this meta-analysis. There was evidence of a decreased risk for OC in the highest versus the lowest categories of healthy dietary pattern [odds ratio (OR)=0.86; 95% confidence interval (CI): 0.74-0.99; P=0.04]. An increased risk of OC was shown for the highest versus the lowest category of a western-style dietary pattern (OR=1.19; 95% CI: 1.01-1.41; P=0.04). No significant association with OC risk was observed in the highest versus the lowest category of a heavy drinking pattern (OR=0.89; 95% CI: 0.67-1.19; P=0.42). The results of this meta-analysis suggest that a healthy dietary pattern is associated with reduced risk for OC and a western-style dietary pattern is associated with an increased risk of OC. Further studies are needed to confirm our results.

Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is associated with immune phases of patients with chronic hepatitis B.

Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a newly negative immune regulator but its role in different immune phases of patients with chronic hepatitis B (CHB) is unknown. We determined the mRNA levels of TIPE2, interleukin-6, interleukin-10, tumor necrosis factors-α and interferon-γ in peripheral blood mononuclear cells from 205 naïve treated CHB patients and 15 healthy controls by quantitative real time polymerase chain reaction. Intrahepatic TIPE2 protein was also determined using immunohistochemistry staining. The TIPE2 mRNA level in CHB patients was significantly higher than that in healthy controls. Moreover, the TIPE2 mRNA level in immune clearance (IC) phases was significantly higher than that in immune tolerance (IT) phase; whereas TIPE2 mRNA in HBeAg negative hepatitis (ENH) was obviously higher than low replication (LR) phase. Furthermore, the optional cut off values of 2.02 and 1.59 for TIPE2 mRNA level have strong power in identifying IC and ENH from IT and LR. In addition, intrahepatic TIPE2 protein was predominantly located in hepatocyte plasma and correlated with hepatic inflammatory and fibrosis. Multivariate analysis showed tumor necrosis factors-α, interferon-γ and HBV DNA load were independently correlated with TIPE2 level. In conclusion, TIPE2 might be associated to the immune clearance of patients with chronic hepatitis B.

Triptolide inhibits viability and induces apoptosis in liver cancer cells through activation of the tumor suppressor gene p53.

The present study investigated the effect of triptolide on viability and apoptosis along with underlying mechanism in liver cancer cells. CCK-8 assay showed that triptolide treatment for 48 h significantly reduced the viability of HepG2 and QSG7701 cells at 50 µM concentration. Annexin V-FITC and propidium iodide staining showed that triptolide treatment of HepG2 cells at 50 µM concentrations induced apoptosis in 56.45% cells compared to only 2.36% cells in the control cultures. Western blot assay showed that treatment of HepG2 cells with 50 µM concentration of triptolide significantly induced phosphorylation of p53 in a 2 h-treatment. Phosphorylation of histone H2A.X indicator of DNA damage was induced by triptolide treatment after 12 h in HepG2 cells. The level of nuclear p53 in a 6 h-treatment with 0, 10, 20, 30, 40 and 50 µM concentration of triptolide was found to be 15.3, 19.6, 28.5, 43.7, 63.8 and 91.5%, respectively. Treatment of HepG2 cells with triptolide at 50 µM concentration caused a significant increase in the binding potential of p53 to DNA. Triptolide treatment of HepG2 cells caused a significant increase in the expression of p21, Bax and DR5 genes in HepG2 cells. It also increased the expression of miR-34b and miR-34c in HepG2 cells markedly. Treatment of HepG2 cells with p53 inhibitor, pifithrin-α prior to incubation with triptolide significantly prevented induction of cell apoptosis. Suppression of p53 expression by siRNA inhibited the expression of p53 as well as its target genes along with the prevention of apoptosis induction. In conclusion, triptolide inhibits viability and induces apoptosis in liver cancer cells through activation of the tumor suppressor gene p53. Thus, triptolide can be used for the treatment of liver cancer.

Altered expression of A20 gene in peripheral blood mononuclear cells is associated with the progression of chronic hepatitis B virus infection.

A20 is an important negative immune regulator but its role in chronic hepatitis B virus (HBV) infection is still unknown. This present study was to investigate the potential role of A20 gene in the progression of chronic HBV infection. A total of 236 chronic HBV patients were included and consisted of 63 hepatocellular carcinoma (HCC), 87 liver cirrhosis (LC) and 86 chronic hepatitis B (CHB). The mRNA level of A20 gene in peripheral blood mononuclear cells was determined using quantitative real-time polymerase chain reaction. Receptor operating characteristic curve (ROC) was performed to determine the diagnostic value of A20 mRNA in different stages of chronic HBV infection. A20 mRNA levels in all HBV patients were significantly higher than healthy controls (n=30), of whom HCC and LC patients showed higher A20 mRNA level than CHB patients. In CHB patients, A20 mRNA was closely associated with alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin. In LC patients, A20 mRNA was significantly associated with ALT, AST, albumin, haemoglobin and platelet. In HCC patients, elevated A20mRNA was also observed in patients with vascular invasion, liver cirrhosis and ascites, compared with those without. ROC analysis revealed that A20 mRNA could effectively discriminate LC from CHB, decompensated LC from compensated LC, and HCC from CHB. In conclusion, A20 mRNA expression in peripheral blood mononuclear cells was associated with dynamic progression of chronic HBV infection. A20 gene might be a potential biomarker to determine the different stages of chronic HBV infection.

Genome-wide gene expression analysis of peripheral leukocytes in relation to the male predominance of Guillain-Barre syndrome: differential gene expression between male and female patients.

BACKGROUND: Guillain-Barre syndrome (GBS) fulfils most of the clinical features of an autoimmune disease except for its male predominance. No previous studies have evaluated the differential genome-wide expression between male and female GBS patients. OBJECTIVE: This study sought to identify differences between male and female GBS patients in the gene expression profiles of peripheral leukocytes. METHODS: We downloaded gene chip data-sets pertaining to peripheral leukocyte samples from GBS patients using the gene expression omnibus (submitted by Chang et al.) and applied hierarchical cluster analysis to detect whether there was a gender difference in genome-wide gene expression levels. Then, we identified the sexually differentially expressed genes using a bioinformatic approach and applied enrichment analysis to the gene ontology and Kyoto Encyclopaedia of Genes and Genomes terms to identify significant pathways related to these genes. RESULTS: We observed gender stratification among GBS patients. Twenty genes were expressed more highly in male patients and were enriched for functions, such as macrophage differentiation, leukocyte migration, bladder cancer, pathogenic Escherichia coli infection. In female patients, 62 genes were more highly expressed and were enriched for responses to viral infection and defence, retinoic acid-inducible gene I (RIG-I)-like receptors, cytoplasmic DNA sensing. Matrix metalloproteinase 9 (MMP9) seem to play an important role in the male predominance of GBS. CONCLUSIONS: This study demonstrated gender differences in the genome-wide gene expression of patients with GBS. Bioinformatic approaches offer new means for identifying candidate genes and pathways relevant to the pathophysiology of GBS.

Increased A20 mRNA Level in Peripheral Blood Mononuclear Cells is Associated With Immune Phases of Patients With Chronic Hepatitis B.

The zinc finger protein A20 is a newly identified negative regulator of immune response and mediates signal pathway of NF-κB in liver inflammation. However, the role of A20 in the natural history of patients with chronic hepatitis B (CHB) has not been demonstrated. In this present study, we aimed to investigate the dynamic expression of A20 and determine the potential association of A20 in the progression of chronic hepatitis B virus infection.This retrospective study contained 136 patients with chronic hepatitis B and 30 healthy controls (HCs). The mRNA level of A20, TNF-α, NF-κB p65 and toll-like receptor (TLR) 4 in peripheral blood mononuclear cells (PBMCs) was determined using a relative quantitative real-time polymerase chain reaction. The hepatic A20 protein expression was determined by immunohistochemistry. Clinical and laboratory parameters were obtained.In the present study, the relative expression of A20 mRNA was significantly increased in CHB patients compared with HCs and was positively associated with alanine aminotransferase, aspartate aminotransferase, and total bilirubin. In CHB patients, the levels of A20 mRNA in the immune clearance (IC) phase and hepatitis B negative (ENH) phase were significantly higher than that in immune tolerance (IT) phase and low-replicative (LR) phase (P < 0.001). Furthermore, the A20 mRNA level was significantly correlated with TNF-α/ NF-κB p65/TLR4 mRNA levels in CHB patients. Of note, we reported that cutoff values of 4.19 and 3.97 for the level of A20 mRNA have significant power in discriminating IC from IT, and ENH from LR in CHB patients respectively.In conclusion, our results suggested that increased levels of A20 mRNA and protein contribute to disease progression of chronic hepatitis B virus infection.

TIPE2 mRNA Level in PBMCs Serves as a Novel Biomarker for Predicting Short-Term Mortality of Acute-on-Chronic Hepatitis B Liver Failure: A Prospective Single-Center Study.

It remains difficult to accurately predicate short-term mortality of acute-on-chronic hepatitis B liver failure (ACHBLF). Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a novel identified negative regulator of immune response and we have previously demonstrated TIPE2 play an essential role in the pathogenesis of ACHBLF. We therefore aimed to evaluate the diagnosis value of TIPE2 mRNA in peripheral blood mononuclear cells (PBMCs) for predicting 3-month mortality of ACHBLF patients. This prospective study consisted of 108 ACHBLF patients from March 2009 to May 2013 as training cohort and 63 ACHBLF patients from June 2013 to December 2014 as validation cohort. Forty-two patients with chronic hepatitis B (CHB) and 22 healthy volunteers were also included as controls. The mRNA level of TIPE2 in PBMCs was determined using quantitative real-time polymerase chain reaction. Univariate analysis and Cox proportional hazard regression analysis were performed to identify independent risk factors to 3-month mortality. Area under the receptor operating characteristic curve (AUROC) was performed to assess diagnostic value of TIPE2 mRNA in training and validation cohort. The level of TIPE2 mRNA was significantly higher in ACHBLF patients (median (interquartile): 6.5 [3.7, 9.6]) compared with CHB (2.3 [1.6, 3.7]) and healthy controls (0.4 [0.3, 0.6]; both P < 0.05). Cox proportional hazards regression analyses showed 5 independent risk factors associated with 3-month mortality of ACHBLF: white blood cells (HR = 1.058, 95% CI: 1.023-1.095), spontaneous bacterial peritonitis (HR = 2.541, 95% CI: 1.378-4.686), hepatic encephalopathy (HR = 1.848, 95% CI: 1.028-3.321), model for end-stage liver diseases (MELD) score (HR = 1.062, 95% CI: 1.009-1.118), and TIPE2 mRNA (HR = 1.081, 95% CI: 1.009-1.159). An optimal cut-off point 6.54 of TIPE2 mRNA showed sensitivity of 74.63%, specificity of 90.24%, positive predictive value of 92.5%, and negative predictive value of 67.3% for predicting 3-month mortality in training cohort. Furthermore, TIPE2 mRNA plus MELD performed better than MELD alone for predicting 3-month mortality in training (AUROC, 0.853 vs 0.722, P < 0.05) and validation cohort (AUROC, 0.909 vs 0.717, P < 0.001). TIPE2 mRNA level might be a novel biomarker in predicting 3-month mortality of ACHBLF. Combination of TIPE2 mRNA and MELD would improve the diagnostic value of MELD alone in predicting 3-month mortality of patients with ACHBLF.

[Effects of Nourishing Yin Removing Fire Chinese Herbs on Gene Expression of Hypothalamic Ghrelin and its Receptor in Female Precocious Rats].

OBJECTIVE: To observe the effect of nourishing yin removing fire Chinese herbs (NYRF-CH) on the gene expression of hypothalamic growth hormone secretion peptide (Ghrelin) and its receptor growth hormone secretion peptide receptor 1alpha (GHSR1-alpha) at the puberty onset of danazol induced female precocious rats. METHODS: Forty female SD rats were randomly divided into 4 groups, i.e., the normal group (N), the model group (M), the normal saline intervention group (NS), and the NYRFCH intervention group (NI), 10 in each group. 300 microg danazol was subcutaneously injected to all rats except those in the N group to prepare precocious rat model. NYRFCH and normal saline was respectively administered to rats in the NI and the NS group from the 15th day old for 7-10 days. No treatment was given to rats in the N group. Time of rats' vulva opening was recorded. Ovary index and uterus index were calculated. Peripheral blood levels of estradiol (E2), follicle stimulating hormone (FSH), and luteinizing hormone (LH), and hypothalamic contents of gonadotropin releasing hormone (GnRH) as well as the gene expression of hypothalamic Ghrelin and GHSR1-alpha were determined. Results Compared with the N group, the vulva opening time was advanced in the model group; peripheral blood levels of E2 and LH, uterus index, hypothalamic contents of GnRH increased; peripheral blood FSH levels and mRNA levels of hypothalamic Ghrelin and GHSR1-alpha decreased (P < 0.05, P < 0.01). Compared with the M group and the NS group, the vulva opening time was not advanced in the NI group; peripheral blood levels of E2 and LH, uterus index and hypothalamic contents of GnRH obviously decreased (P < 0.05, P < 0.01); mRNA levels of hypothalamic Ghrelin and GHSR1-alpha increased (all P < 0.01). But there was no statistical difference in the hypothalamic contents of Ghrelin, or the number and activity of GHSR1-alpha (P > 0.05). CONCLUSION: NYRFCH had regulatory effect on regulating hypothalamic Ghrelin and GHSR1-alpha at gene transcription levels.

Arctigenin enhances swimming endurance of sedentary rats partially by regulation of antioxidant pathways.

AIM: Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan found in traditional Chinese herbs, has been determined to exhibit a variety of pharmacological activities, including anti-tumor, anti-inflammation, neuroprotection, and endurance enhancement. In the present study, we investigated the antioxidation and anti-fatigue effects of arctigenin in rats. METHODS: Rat L6 skeletal muscle cell line was exposed to H2O2 (700 µmol/L), and ROS level was assayed using DCFH-DA as a probe. Male SD rats were injected with arctigenin (15 mg·kg(-1)·d(-1), ip) for 6 weeks, and then the weight-loaded forced swimming test (WFST) was performed to evaluate their endurance. The levels of antioxidant-related genes in L6 cells and the skeletal muscles of rats were analyzed using real-time RT-PCR and Western blotting. RESULTS: Incubation of L6 cells with arctigenin (1, 5, 20 µmol/L) dose-dependently decreased the H2O2-induced ROS production. WFST results demonstrated that chronic administration of arctigenin significantly enhanced the endurance of rats. Furthermore, molecular biology studies on L6 cells and skeletal muscles of the rats showed that arctigenin effectively increased the expression of the antioxidant-related genes, including superoxide dismutase (SOD), glutathione reductase (Gsr), glutathione peroxidase (GPX1), thioredoxin (Txn) and uncoupling protein 2 (UCP2), through regulation of two potential antioxidant pathways: AMPK/PGC-1α/PPARα in mitochondria and AMPK/p53/Nrf2 in the cell nucleus. CONCLUSION: Arctigenin efficiently enhances rat swimming endurance by elevation of the antioxidant capacity of the skeletal muscles, which has thereby highlighted the potential of this natural product as an antioxidant in the treatment of fatigue and related diseases.

Nickel-catalyzed sonogashira reactions of non-activated secondary alkyl bromides and iodides.

A nicked reaction: The title reaction of terminal alkynes with non-activated secondary alkyl iodides and bromides was accomplished for the first time. This reaction provides a new and practical approach for the synthesis of substituted alkynes (see scheme; cod=cyclo-1,5-octadiene).

Activation of ß2-adrenoceptor enhances synaptic potentiation and behavioral memory via cAMP-PKA signaling in the medial prefrontal cortex of rats.

The prefrontal cortex (PFC) plays a critical role in cognitive functions, including working memory, attention regulation, behavioral inhibition, as well as memory storage. The functions of PFC are very sensitive to norepinephrine (NE), and even low levels of endogenously released NE exert a dramatic influence on the functioning of the PFC. Activation of ß-adrenoceptors (ß-ARs) facilitates synaptic potentiation and enhances memory in the hippocampus. However, little is known regarding these processes in the PFC. In the present study, we investigate the role of ß2-AR in synaptic plasticity and behavioral memory. Our results show that ß2-AR selective agonist clenbuterol facilitates spike-timing-dependent long-term potentiation (tLTP) under the physiological conditions with intact GABAergic inhibition, and such facilitation is prevented by co-application with the cAMP inhibitor Rp-cAMPS. Loading postsynaptic pyramidal cells with Rp-cAMPS, the PKA inhibitor PKI(5-24), or the G protein inhibitor GDP-ß-S significantly decreases, but does not eliminate, the effect of clenbuterol. Clenbuterol suppresses the GABAergic transmission, while blocking GABAergic transmission by the GABA(A) receptor blocker partially mimics the effect of clenbuterol. In behavioral tests, a post-training infusion of clenbuterol into mPFC enhances 24-h trace fear memory. In summary, we observed that prefrontal cortical ß2-AR activation by clenbuterol facilitates tLTP and enhances trace fear memory. The mechanism underlying tLTP facilitation involves stimulating postsynaptic cAMP-PKA signaling cascades and suppressing GABAergic circuit activities.