Gan Shen

Melatonin protects against alcoholic liver injury by attenuating oxidative stress, inflammatory response, and apoptosis

Melatonin is reported to exhibit a wide variety of biological effects, including antioxidant and anti-inflammatory. Previous studies show that melatonin has a protective role in different types of liver injury and fibrosis. But its role in the pathogenesis of alcoholic liver injury remains obscure. The present investigation was designed to determine the effects of melatonin on alcohol-induced hepatic injury in mice. The degree of alcoholic liver injury was evaluated by measuring serum markers and pathological examination. Treatment with melatonin significantly attenuated the increased level of serum aminotransferase, reduced the severe extent of hepatic cell damage, steatosis and the immigration of inflammatory cells, but had no effects on hepatic expression of lipogenic genes. Furthermore, melatonin decreased serum and tissue inflammatory cytokines levels, tissue lipid peroxidation, neutrophil infiltration and inhibited the apoptosis of hepatocytes. Kupffer cells isolated from ethanol-fed mice produced high amounts of reactive oxygen species and tumor necrosis factor alpha, whereas Kupffer cells from melatonin treatment mice produced less reactive oxygen species and tumor necrosis factor alpha compared with model alcohol-feeding mice. These findings suggest that melatonin may represent a novel, protective strategy against alcoholic liver injury by attenuating oxidative stress, inflammatory response and apoptosis.

Paeonol, the main active principles of Paeonia moutan, ameliorates alcoholic steatohepatitis in mice.

AIM OF STUDY Paeonol, a major phenolic component of Moutan Cortex, is traditionally used as a Chinese herbal medicine in various diseases including hepatitis. Evidence shows that paeonol has anti-inflammatory, anti-tumor, and anti-atherosclerosis effects. However, the effect of paeonol on alcoholic liver injury remains obscure. The present investigation was designed to determine the effects of paeonol on alcohol-induced hepatic injury in mice. MATERIALS AND METHODS The degree of alcoholic liver injury was evaluated biochemically by measuring serum markers and pathological examination. Real-time PCR and ELISA methods were used to check the expression of cytokines. Western blotting was used to check CYP 450 expression. RESULTS Treatment with paeonol significantly attenuated the level of serum aminotransferase, reduced the severe extent of hepatic cell damage, steatosis, and the infiltration of inflammatory cells in a model of alcoholic liver injury (P<0.05). Interestingly, paeonol markedly decreased hepatic mRNA expression of lipogenic genes (P<0.05) while had no effect on protein expression of hepatic CYP2E1. Furthermore, paeonol significantly decreased serum and tissue inflammatory cytokine levels, tissue lipid peroxidation, neutrophil infiltration and inhibited the apoptosis of hepatocytes (P<0.05). Kupffer cells isolated from ethanol-fed mice produced high amounts of tumor necrosis factor alpha, whereas Kupffer cells from paeonol treatment ethanol-fed mice produced less tumor necrosis factor alpha (P<0.05). CONCLUSIONS These findings suggest that paeonol may represent a novel, protective strategy against alcoholic liver injury by attenuating hepatic steatosis, inflammatory response and apoptosis.

Microbiota modulate tumoral immune surveillance in lung through a γδT17 immune cell-dependent mechanism

Commensal bacteria are crucial to maintain immune homeostasis in mucosal tissues and disturbances in their ecology can affect disease susceptibility. Here, we report evidence that commensal bacteria shape the efficiency of immune surveillance in mucosal tissues. Antibiotic-treated (Abt) mice were more susceptible to development of engrafted B16/F10 melanoma and Lewis lung carcinoma, exhibiting a shortened mean survival time with more numerous and larger tumor foci in the lungs. The defective antitumor response of Abt mice was independent of dehydration caused by antibiotics. Host defenses relied upon intact commensal bacteria with no class specificity. Mechanistic investigations revealed a defective induction of the γδT17 cell response in lungs of Abt mice; here, more aggressive tumor development was observed, possibly related to a reduction in IL6 and IL23 expression there. Adding normal γδT cells or supplementing IL17 restored the impaired immune surveillance phenotype in Abt mice. Overall, our results demonstrated the importance of commensal bacteria in supporting the host immune response against cancer, defined an important role for γδT17 responses in the mechanism, and suggested deleterious effects of antibiotic treatment on cancer susceptibility and progression.

Promoter methylation of p16, Runx3, DAPK and CHFR genes is frequent in gastric carcinoma.

AIMS AND BACKGROUND Transcriptional silencing induced by hypermethylation of CpG islands in the promoter regions of genes is believed to be an important mechanism of carcinogenesis in human cancers including gastric cancer. A number of reports on methylation of various genes in gastric cancer have been published, but most of these studies focused on cancer tissues or only a single gene. In this study, we determined the promoter hypermethylation status and mRNA expression of 4 genes: p16, Runx3, DAPK and CHFR. METHODS Methylation-specific polymerase chain reaction (MSP) was used to determine the methylation status of p16, Runx3, DAPK and CHFR gene promoters in cancer and adjacent normal gastric mucosa specimens from 70 patients with gastric cancer, as well as normal gastric biopsy samples from 30 people without cancer serving as controls. In addition, the mRNA expression of p16, Runx3, DAPK and CHFR was investigated in 34 gastric cancer patients by RT-PCR. Bisulfite DNA sequence analysis was applied to check the positive samples detected by MSP. RESULTS When carcinoma specimens were compared with adjacent normal gastric mucosa samples, a significant increase in promoter methylation of p16, Runx3, DAPK and CHFR was observed, while all 30 histologically normal gastric specimens were methylation free for all 4 genes. The methylation rate of the 4 genes increased from normal stomach tissue to tumor-adjacent gastric mucosa to gastric cancer tissue. Concurrent methylation in 2 or more genes was found in 22.9% of tumor-adjacent normal gastric mucosa and 75.7% of cancer tissues. No correlation was found between hypermethylation and other clinicopathological parameters such as sex, age, and tumor location. However, the frequency of DAPK and CHFR methylation in cancer tissues was significantly associated with the extent of differentiation and lymph node metastasis (P < 0.05) and the frequency of Runx3 methylation was significantly associated with tumor size (P < 0.05). Weak expression and loss of expression of the 4 genes was observed in cancer tissues and was significantly associated with promoter hypermethylation (P < 0.05). CONCLUSIONS Promoter hypermethylation of p16, Runx3, DAPK and CHFR is frequent in gastric cancer. DAPK and CHFR promoter hypermethylation may be an important help in evaluating the differentiation grade and lymph node status of gastric cancer. Weak gene expression and loss of gene expression due to promoter hypermethylation may be a cancer-specific event.

Melatonin and Tryptophan Circadian Profiles in Patients with Advanced Non-Small Cell Lung Cancer

IntroductionAccumulating studies indicate that melatonin is a natural oncostatic agent capable of mediating the influence of the psychoneuroendocrine system on cancer growth. Although there is increasing evidence to show that the pineal gland may play a role in human non-small cell lung cancer (NSCLC), there is uncertainty about circadian profiles of melatonin, its precursor tryptophan, and its major metabolite, 6-sulfatoxymelatonin (6-OH-MLT) in NSCLC patients before and after treatment with standard chemotherapy (cisplatin plus vinorelbine). The aim of this study was to investigate the concentration changes of melatonin, tryptophan, and 6-OH-MLT in NSCLC patients treated with standard chemotherapy.MethodsWe examined the circadian melatonin, tryptophan, and 6-OH-MLT rhythms in 30 patients suffering from advanced-stage NSCLC and compared them with those of 63 healthy volunteers free from neoplastic disease. Blood samples were collected at 12 noon and 12 midnight. Urine samples were collected at 7 am and 4 pm. The levels of melatonin in serum and of 6-OH-MLT in urine were measured by high-performance liquid chromatography. The concentration of amino acids including tryptophan in serum was measured by amino acid analyzer.ResultsMelatonin, tryptophan, and 6-OH-MLT concentrations were significantly lower in cancer patients, in comparison with healthy subjects. A significant inverse correlation between melatonin and tryptophan was observed. Additionally, after three cycles of standard chemotherapy, there was a tendency of melatonin, tryptophan, and 6-OH-MLT concentrations to progressively decrease in NSCLC patients.ConclusionThe results of the present study indicate that the presence of NSCLC influences the metabolism of melatonin, and chemotherapy in NSCLC patients may progressively decrease the production of melatonin.

Pathobiologic implications of methylation and expression status of Runx3 and CHFR genes in gastric cancer.

Runx3 and CHFR genes were defined as tumor suppressor genes in gastric cancer (GC) recently. This paper was to investigate the roles of methylation and expression status of Runx3 and CHFR genes in GC patients. Methylation-specific polymerase chain reaction (MSP) and bisulfite DNA sequencing (BSP) were used to detect methylation status of Runx3 and CHFR genes in GC patients. The expression of Runx3 and CHFR in GC patients was analyzed by reverse transcription polymerase chain reaction (RT–PCR) and immunohistochemical analysis. The expression of the protein and mRNA decreased remarkably in the patients with aberrant promoter methylation of Runx3 and CHFR genes. The methylation status of Runx3 and CHFR were inversely related to the tumor size, tumor invasion depth and tumor differentiation in GC patients. Moreover, the protein expression of Runx3 and CHFR were significantly correlated with tumor invasion depth and tumor differentiation, respectively. Aberrant promoter methylation of Runx3 and CHFR genes may be involved in the carcinogenesis and development of GC and may provide useful clues for the prediction of the malignant behaviors of GC.

Tumor suppressor genes and their underlying interactions in paclitaxel resistance in cancer therapy

ObjectivesPaclitaxel (PTX) is frequently used in the clinical treatment of solid tumors. But the PTX-resistance is a great obstacle in cancer treatment. Exploration of the mechanisms of drug resistance suggests that tumor suppressor genes (TSGs) play a key role in the response of chemotherapeutic drugs. TSGs, a set of genes that are often inactivated in cancers, can regulate various biological processes. In this study, an overview of the contribution of TSGs to PTX resistance and their underlying relationship in cancers are reported by using GeneMANIA, a web-based tool for gene/protein function prediction.MethodsUsing PubMed online database and Google web site, the terms “paclitaxel resistance” or “taxol resistance” or “drug resistance” or “chemotherapy resistance”, and “cancer” or “carcinoma”, and “tumor suppressor genes” or “TSGs” or “negative regulated protein” or “antioncogenes” were searched and analyzed. GeneMANIA data base was used to predict gene/protein interactions and functions.ResultsWe identified 22 TSGs involved in PTX resistance, including BRCA1, TP53, PTEN, APC, CDKN1A, CDKN2A, HIN-1, RASSF1, YAP, ING4, PLK2, FBW7, BLU, LZTS1, REST, FADD, PDCD4, TGFBI, ING1, Bax, PinX1 and hEx. The TSGs were found to have direct and indirect relationships with each other, and thus they could contribute to PTX resistance as a group. The varied expression status and regulation function of the TSGs on cell cycle in different cancers might play an important role in PTX resistance.ConclusionA further understanding of the roles of tumor suppressor genes in drug resistance is an important step to overcome chemotherapy tolerance. Tumor suppressor gene therapy targets the altered genes and signaling pathways and can be a new strategy to reverse chemotherapy resistance.

Clinical practice guidelines for hypertension in China: a systematic review of the methodological quality

Objective Clinical practice guidelines (CPGs) provide clinicians with specific recommendations for practice, but due to the increasing number of CPGs developed by diverse organisations over the past few years, there are concerns about the quality of some CPGs. This paper proposes a systematic review of the methodological quality of the CPGs for hypertension that were developed in China. Design A systematic review of CPGs for the management of hypertension in adult patients in China. Data resources Chinese electronic databases, Chinese guideline websites and Google Scholar were searched, and the reference lists of relevant publications were also screened for additional information. CPGs for the management of hypertension in adult patients were identified. The main characteristics of the CPGs were extracted, and the scaled Appraisal of Guidelines, REsearch and Evaluation II (AGREE II) domain percentages were independently evaluated by two reviewers. Results A total of 17 CPGs, with publication dates ranging from 2001 to 2011, were identified. There was considerable variation in the quality of the CPGs across the AGREE II domains. Overall, the domains of ‘rigor of development’ and ‘editorial independence’ were poorly addressed, with an average score of 18% and 16%, respectively. Also less well addressed were the ‘stakeholder involvement’ and ‘applicability’ domains, for which the average domain scores were 28% and 20%, respectively. The CPGs performance was less problematic in the domains of ‘scope and purpose’ and ‘clarity and presentation’, with a median of 41% for both. After considering the domain scores, 8 CPGs could be recommended with modification for use. Conclusions There is considerable room for improvement of the methodological quality of CPGs for hypertension in China. Greater efforts should to be devoted to ensure the explicit and transparent reporting of potential conflicts of interest of stakeholders, and to consider the quality of the evidence and grade recommendations in the CPG development process.

Relationship between epithelial cell adhesion molecule (EpCAM) overexpression and gastric cancer patients: A systematic review and meta-analysis

Objectives The epithelial cell adhesion molecule (EpCAM) is one of the most commonly used markers of cancer stem cells (CSCs), but the clinical and prognostic significance of EpCAM in gastric cancer (GC) remains disputable. Motivated by heterogeneous and inconclusive results, we conducted a systematic review and meta-analysis to systematically summarize and elucidate the association between EpCAM overexpression and GC patients. Methods The PubMed, Cochrane Library, Medline, Web of Knowledge and the China National Knowledge Infrastructure (CNKI) databases were searched to identify relevant studies. The RevMan 5.3 software was used for the meta-analysis. Fixed-effects or random-effects models were applied depending on the presence of heterogeneity. The pooled odds ratio (ORs) and 95% confidence intervals (CIs) were applied to estimate the associations between EpCAM and gastric cancer. For the significant heterogeneity studies, sensitivity analyses were applied based on the population to test the robustness of the pooled results and identify possible sources of heterogeneity. Results A total of 11 studies including 1960 GC patients met our inclusion criteria. The results of the meta-analyses revealed that there were significant differences in EpCAM overexpression and tumour size (OR = 2.97, 95% CI: 2.13~4.13, P < 0.00001), the nature of the tissue (OR = 80.30, 95% CI: 29.21~220.81, P < 0.00001), lymph node metastasis (OR = 2.78, 95% CI: 1.23~6.27, P = 0.01), and the cumulative 5-year overall survival rate (OR = 0.54, 95% CI:0.29~0.99, P = 0.05). No significant associations were identified between EpCAM overexpression and gender (OR = 0.89, 95% CI: 0.66~1.19, P = 0.43), age (OR = 1.13, 95% CI: 0.58~2.20, P = 0.73), tumour stage (OR = 2.26, 95% CI: 0.79~6.45, P = 0.13), distant metastasis (OR = 2.15, 95% CI: 0.20~22.69, P = 0.52), TNM stage (OR = 5.14, 95% CI: 0.77~34.37, P = 0.09), Lauren type (OR = 1.18, 95% CI: 0.08~16.45, P = 0.9), differentiation (OR = 1.88, 95% CI: 0.65~5.41, P = 0.24). However, due to significant heterogeneity in tumor stage, lymph node metastasis, TNM stage, differentiation and Lauren type, these results should be taken carefully. Conclusions The meta-analysis demonstrated that the expression of EpCAM in the gastric cancer group was greater than that in the control group. Moreover, EpCAM overexpression was associated with larger tumour size, lymphnode metastasis and worse prognosis in gastric cancer. Due to significant heterogeneity, the sensitivity analysis suggests that population factor may be an important source of heterogeneity, and these results should be treated with caution. EpCAM may be useful as a novel prognostic factor, and large-scale and well-designed studies are needed to validate our results in the future.

Systematic review of hypertension clinical practice guidelines based on the burden of disease: a global perspective.

To perform a systematic review for the development, geographical distribution, and subject classification of clinical practice guidelines (CPGs) for hypertension worldwide.