Jixiang Zhang

ROS and ROS-Mediated Cellular Signaling

It has long been recognized that an increase of reactive oxygen species (ROS) can modify the cell-signaling proteins and have functional consequences, which successively mediate pathological processes such as atherosclerosis, diabetes, unchecked growth, neurodegeneration, inflammation, and aging. While numerous articles have demonstrated the impacts of ROS on various signaling pathways and clarify the mechanism of action of cell-signaling proteins, their influence on the level of intracellular ROS, and their complex interactions among multiple ROS associated signaling pathways, the systemic summary is necessary. In this review paper, we particularly focus on the pattern of the generation and homeostasis of intracellular ROS, the mechanisms and targets of ROS impacting on cell-signaling proteins (NF-κB, MAPKs, Keap1-Nrf2-ARE, and PI3K-Akt), ion channels and transporters (Ca2+ and mPTP), and modifying protein kinase and Ubiquitination/Proteasome System.

Meta-analysis of the effects of endoscopy with narrow band imaging in detecting dysplasia in Barrett's esophagus

Narrow band imaging (NBI) is a real-time imaging technique. The aim of this meta-analysis was to estimate the sensitivity, specificity, and diagnostic accuracy on the role of NBI in the detection and characterization of specialized intestinal metaplasia (SIM), high-grade dysplasia (HGD) in the Barretts esophagus. We identified studies by performing a literature search of Medline, EMBASE, and the Cochrane Library databases up to May 2013. We performed data analysis using Meta-DiSc (version 1.4) software. To assess study quality and potential for bias, we used the Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2). Overall, seven eligible studies including over 3988 lesions of 502 patients were retrieved. The results showed that endoscopic diagnosis of dysplasia performed using NBI has a high diagnostic performance, with an area under the summary receiver operating characteristic (SROC) curve near 0.90 both in HGD lesions and SIM lesions. We also found that NBI has a sensitive and specificity of 0.91 (95% confidence interval [CI] = 0.86-0.94) and 0.85 (95% CI = 0.76-0.92) on a per-patient element, and 0.97 (95% CI = 0.95-0.98) and 0.64 (95% CI = 0.59-0.68) on a per-lesion element for SIM diagnosis, respectively. The pooled per-patient sensitivity and specificity for identifying HGD are 0.91 (95% CI = 0.75-0.98) and 0.95 (95% CI = 0.91-0.97). The pooled per-lesion sensitivity and specificity for identifying HGD are 0.69 (95% CI = 0.63-0.74) and 0.90 (95% CI = 0.88-0.91). In conclusion, we found that endoscopic diagnosis with NBI is an accurate test to diagnosis dysplasia of Barretts esophagus.

Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro

Noscapine, a phthalide isoquinoline alkaloid derived from opium, has been widely used as a cough suppressant for decades. Noscapine has recently been shown to potentiate the anti-cancer effects of several therapies by inducing apoptosis in various malignant cells without any detectable toxicity in cells or tissues. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear. The signaling pathways by which noscapine induces apoptosis were investigated in colon cancer cell lines treated with various noscapine concentrations for 72 h, and a dose-dependent inhibition of cell viability was observed. Noscapine effectively inhibited the proliferation of LoVo cells in vitro (IC(50)=75 μM). This cytotoxicity was reflected by cell cycle arrest at G(2)/M and subsequent apoptosis, as indicated by increased chromatin condensation and fragmentation, the upregulation of Bax and cytochrome c (Cyt-c), the downregulation of survivin and Bcl-2, and the activation of caspase-3 and caspase-9. Moreover, in a xenograft tumor model in mice, noscapine injection clearly inhibited tumor growth via the induction of apoptosis, which was demonstrated using a TUNEL assay. These results suggest that noscapine induces apoptosis in colon cancer cells via mitochondrial pathways. Noscapine may be a safe and effective chemotherapeutic agent for the treatment of human colon cancer.

Hesperetin Induces the Apoptosis of Gastric Cancer Cells via Activating Mitochondrial Pathway by Increasing Reactive Oxygen Species

AbstractBackgroundHesperetin, has been shown to exert biological activities on various types of human cancers. However, few related studies on gastric cancer are available.AimIn this study, we sought to investigate the effect of hesperetin on gastric cancer and clarify its specific mechanism.Materials and MethodsCell Counting Kit-8, 2′,7′-dichlorofluorescin diacetate, JC-1, Hoechst 33258 staining, and western bolt were used to detect cell viability, levels of intracellular reactive oxygen species (ROS), changes in mitochondrial membrane potential (△ψm), cell apoptosis, and expressions of mitochondrial pathway proteins, respectively. Meanwhile, xenograft tumor models in nude mice were made ton evaluate the effect of hesperetin on gastric cancer in vivo.ResultsCompared with the control group, the proliferation of gastric cancer cells in hesperetin groups was significantly inhibited (Pxa0<xa00.05), and dose- and time-dependent effects were observed. Pretreatment with H2O2 (1xa0mM) or N-acetyl-l-cysteine (5xa0mM) enhanced or attenuated the hesperetin-induced inhibition of cell viability (Pxa0<xa00.05). Percentages of apoptotic cells, levels of intracellular ROS, and △ψm varied with the dose and treatment time of hesperetin (Pxa0<xa00.05), and hesperetin caused an increase in the levels of AIF, Apaf-1, Cyt C, caspase-3, caspase-9, and Bax and a decrease in Bcl-2 levels (Pxa0<xa00.05). Meanwhile, hesperetin significantly inhibited the growth of xenograft tumors (Pxa0<xa00.05).ConclusionOur study suggests that hesperetin could inhibit the proliferation and induce the apoptosis of gastric cancer cells via activating the mitochondrial pathway by increasing the ROS.

Associations between STAT3 rs744166 Polymorphisms and Susceptibility to Ulcerative Colitis and Crohn's Disease: A Meta-Analysis

Background Many studies have investigated the associations between the signal transducer and activator of transcription 3 (STAT3) in the susceptibility to ulcerative colitis (UC) and Crohns disease (CD). However, the results remain inconsistent. This meta-analysis determined the risk of STAT3 rs744166 polymorphism-conferred UC and CD susceptibility. Materials and Methods Electronic databases, including PubMed, EMBASE and the Cochrane Library, were searched for all eligible studies that evaluated the association between STAT3 rs744166 polymorphisms with UC and CD risk up to August 21, 2014. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using fixed- or random-effects models. Results Twelve studies containing 10298 patients with CD, 4244 patients with UC and 11191 controls were included in this meta-analysis. The results indicated that the STAT3 rs744166 polymorphism was associated with CD and UC susceptibility (CD: GA+AA vs. GG, ORu200a=u200a1.20, 95%CI, 1.11–1.30, I 2u200a=u200a0%, P unadjusted<0.00001, P Bonferroni<0.00005, P FDR<0.00001; UC: GA+AA vs. GG, ORu200a=u200a1.21, 95%CI, 1.08–1.36, I 2u200a=u200a1%, P unadjustedu200a=u200a0.001, P Bonferroniu200a=u200a0.005, P FDRu200a=u200a0.00125). In subgroup analyses by ethnicity, the significant association was found only among Caucasians. However, when grouped by age of onset, positive associations were found both among adults and children. In addition, when stratified by study design and genotyping methods, the risk of CD was significantly associated with the STAT3 rs744166 polymorphism in hospital-based and population-based groups and in SNP Array and SNPlex groups. For UC, significant associations were also found in population-based, PCR-RFLP and SNPlex groups. Moreover, these findings were sufficiently robust to withstand the Bonferroni correction and false discovery rate (FDR). Conclusion This meta-analysis indicates that carriers of the STAT3 rs744166 ‘A’ allele have a significantly greater risk of CD and UC, especially among Caucasians.

Meta-analysis: narrow band imaging for diagnosis of gastric intestinal metaplasia.

Background Distinguishing early gastric cancer is challenging with current imaging techniques. Narrow band imaging (NBI) is effective for characterizing gastric lesions. Objectives The aim of this meta-analysis was to estimate the diagnostic accuracy of NBI in the gastric intestinal metaplasia (GIM). Methods We performed data analysis using Meta-DiSc (version 1.4) and STATA (version 11.0) software. To assess study quality and potential for bias, we used the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Results Six studies involving 347 patients were included. On a per-patient basis, the sensitivity of NBI for diagnosis of GIM was 0.65 (95% CI u200a=u200a 0.56–0.74), and the specificity was 0.93 (95% CI u200a=u200a 0.88–0.97). The area under the summary receiver operating characteristic (SROC) curve was 0.8731. However, on a per-lesion basis, the sensitivity and specificity of NBI were 0.69 (95% CI u200a=u200a 0.63–0.74) and 0.91 (95% CI u200a=u200a 0.87–0.94), respectively. The SROC was 0.9009. The pooled sensitivity and specificity of magnification endoscopy (NBI-ME) were 0.76 (95% CI u200a=u200a 0.61–0.87) and 0.89 (95% CI u200a=u200a 0.80–0.94), respectively, on per-patient analysis. On a per-lesion basis, the pooled sensitivity and specificity of NBI-ME were 0.84 (95% CI u200a=u200a 0.76–0.89) and 0.93 (95% CI u200a=u200a 0.89–0.96), respectively. Heterogeneity was observed with an I2 for diagnostic odds ratio (DOR) of 0.01% and 85.8%, respectively. There was no statistical significance for the evaluation of publication bias. Conclusions Our meta-analysis shows that NBI is a useful tool for differential diagnosis of GIM with relatively low sensitivity and high specificity.

Hesperetin induces the apoptosis of hepatocellular carcinoma cells via mitochondrial pathway mediated by the increased intracellular reactive oxygen species, ATP and calcium

Hesperetin, a flavonoid from citrus fruits, has been proved to possess biological activity on various types of human cancers. However, few related studies on hepatocellular carcinoma are available. In this study, we aimed to investigate the effect of hesperetin on hepatocellular carcinoma cells in vitro and in vivo and clarify its potentially specific mechanism. Compared with the control group, the proliferations of hepatocellular carcinoma cells in hesperetin groups were significantly inhibited (Pxa0<xa00.05), and a dose- and time-dependent inhibition of cell viability was observed. When pretreated with H2O2 (1xa0mM) or N-acetyl-l-cysteine (5xa0mM), the inhibition of cell viability by hesperetin was enhanced or reduced, respectively (Pxa0<xa00.05). Similarly, the levels of intracellular ROS, ATP and Ca2+ changed in different groups (Pxa0<xa00.05). The results of Hoechst 33258 staining showed that the percentages of apoptotic cells in hesperetin groups are remarkably higher than that in control group (Pxa0<xa00.05). And the results of Western blot showed that hesperetin caused an increase in the levels of cytosolic AIF, cytosolic Apaf-1, cytosolic Cyt C, caspase-3, caspase-9 and Bax and a decrease in that of Bcl-2, mitochondrial AIF, mitochondrial Apaf-1 and mitochondrial Cyt C (Pxa0<xa00.05). Meanwhile, hesperetin significantly inhibited the growth of xenograft tumors. Our study suggests that hesperetin could inhibit the proliferation and induce the apoptosis of hepatocellular carcinoma via triggering the activation of the mitochondrial pathway by increasing the levels of intracellular ROS, ATP and Ca2+.

TNF-α-308 polymorphism and risk of digestive system cancers: a meta-analysis.

AIMnTo evaluate the association between the tumour necrosis factor alpha-308 (TNF-α-308) gene polymorphism and the risk of digestive system cancers.nnnMETHODSnAll eligible case-control studies published up to December 2012 were identified by searching PubMed, Web of Science, Embase and China National Knowledge Internet without language restrictions. The risk of digestive system cancers associated with the TNF-α-308 polymorphism was estimated for each study using odds ratio (OR) together with its 95%CI, respectively. Cochrane Collaboration RevMan 5.1 was used to perform the analysis. A χ²-test-based Q statistic test and an I² test were performed to assess the between-study heterogeneity. When the Q test was significant (P < 0.05) or I² > 50%, the random effects model was used, otherwise the fixed effects model was used.nnnRESULTSnFifty-eight studies from fifty-five publications with a total of 9986 cancer patients and 15511 healthy controls were included. Overall, a significant association was found between the TNF-α-308 polymorphism and the risk of digestive system cancers [dominant model: OR = 1.23, 95%CI: 1.09-1.39, (G/A) vs (G/G): OR = 1.15, 95%CI: 1.02-1.28, (A/A) vs (G/G): OR = 1.44, 95%CI: 1.19-1.73, recessive model: OR = 1.38, 95%CI: 1.15-1.66]. Furthermore, when the analysis was stratified by ethnicity, similar results were observed in both the Asian and Caucasian populations, except for the dominant model and heterozygote comparisons in the Asian population [dominant model: OR = 1.24, 95%CI: 0.99-1.56, (G/A) vs (G/G): OR = 1.09, 95%CI: 0.96-1.24]. When the cancer type subgroups were examined, similar results were detected in gastric and hepatocellular carcinomas; however, no significant association was observed among other digestive system cancers.nnnCONCLUSIONnThe TNF-α-308 gene polymorphism may be significantly associated with the risk of gastric and hepatocellular carcinomas, but not colorectal, pancreatic, or oesophageal cancer, in the Asian population.

Association between the Pro12Ala polymorphism of PPAR-γ gene and the non-alcoholic fatty liver disease: a meta-analysis.

Several studies have been conducted to examine the association between PPAR-γ2 Pro12Ala polymorphism and non-alcoholic fatty liver disease (NAFLD), but the results remain inconsistent. In this study, a meta-analysis was performed to assess the association of PPAR-γ Pro12Ala polymorphism with NAFLD risk. A total of 8 case-control studies, including 1697 cases and 2427 controls, were selected. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Overall, no evidence has indicated that the Pro12Ala polymorphism was associated with the susceptibility to NAFLD. Besides, stratified analysis with ethnicity also indicated that no significant association between PPAR-γ Pro12Ala and the risk of NAFLD under all for genetic model in both Asian and Caucasian populations was observed. This meta-analysis indicated that the Pro12Ala polymorphism is not associated with NAFLD risk. Large and well-designed studies are warranted to validate our findings.

Associations between PTPN2 polymorphisms and susceptibility to ulcerative colitis and Crohn’s disease: a meta-analysis

AbstractObjectivenUlcerative colitis (UC) and Crohn’s disease (CD) result from an interaction between genetic and environmental factors. Though several polymorphisms have been identified in PTPN2, their roles in the incidence of UC and CD are conflicting. This meta-analysis was aimed to clarify the impact of these polymorphisms on UC and CD risk.MethodPubMed, EMBASE, Cochrane Library and CBM were searched until 23 July 2013 for eligible studies on three PTPN2 polymorphisms: rs2542151, rs1893217 and rs7234029. Data were extracted, and pooled odd ratios (ORs) as well as 95xa0% confidence intervals (95xa0% CIs) were calculated.ConclusionThe meta-analysis indicated that rs2542151, rs1893217 and rs1893217 were associated with increased CD risk, while the former was associated with increased UC risk. The differences in age of onset and ethnic groups may influence the associations. Gene–gene and gene–environment interactions should be investigated in the future.ResultsSeventeen studies with 18,308 cases and 20,406 controls were included. Significant associations were found between rs2542151 polymorphism and CD susceptibility (ORxa0=xa01.22, 95xa0% CI, 1.15–1.30, I2xa0=xa032xa0%), as well as between rs2542151 and UC susceptibility (ORxa0=xa01.16, 95xa0% CI, 1.07–1.25, I2xa0=xa039xa0%). A similar result was found in Caucasians, but not in Asians. Moreover, a significant increase in CD risk for all carriers of the minor allele of rs1893217 (ORxa0=xa01.45, 95xa0% CI, 1.23–1.70, I2xa0=xa00xa0%) and rs7234029 (ORxa0=xa01.36, 95xa0% CI, 1.16–1.59, I2xa0=xa00xa0%) were found. For children, the rs1893217 polymorphism appeared to confer susceptibility to CD (ORxa0=xa01.56, 95xa0% CI, 1.28–1.89, I2xa0=xa00xa0%).