Association between processed and unprocessed red meat consumption and risk of nonalcoholic fatty liver disease: A systematic review and dose-response meta-analysis.

Background: The nature of the relationship between red meat consumption and nonalcoholic fatty liver disease (NAFLD) remains unclear. Through this meta-analysis, we aimed to determine the association and dose-response relationship between red meat consumption (both processed and unprocessed) and the risk of NAFLD. Methods: We systematically searched CENTRAL, PubMed, Embase, Web of Science and Scopus from inception to February 2022 for observational studies in which the exposure of interest was red meat consumption; the outcome of interest was the risk of NAFLD; and where odds ratios (ORs) or risk ratios were provided or could be calculated. We used random-effects meta-analyses to pool the effect sizes and performed analyses to estimate the linearity of the dose-response relationships between red meat intake and NAFLD risk. Results: We included 10 studies in this review. The meta-analysis showed a significant association between the intake of red meat (OR = 1.27; 95% confidence interval (CI) = 1.07-1.50, P = 0.000, I2 = 81%), processed red meat (OR = 1.20; 95% CI = 1.04-1.3, P = 0.162, I2 = 34.9%) or unprocessed red meat (OR = 1.28; 95% CI = 1.05-1.55, P = 0.001, I2 = 76.2%) and the risk of NAFLD. We also found a significant linear dose-response association between processed red meat intake and NAFLD, with each 25-g increment of processed red meat intake per day was associated with an 11.1% higher risk of NAFLD (OR = 1.11; 95% CI = 1.01-1.22, P = 0.029), and a nonlinear association between unprocessed meat intake and NAFLD (P = 0.003 for nonlinearity). Conclusions: Our findings indicate a potential positive association between red meat consumption (both processed and unprocessed) and NAFLD risk, especially in relation to increased intake of processed red meat compared to unprocessed red meat. However, caution is advised in interpreting these results; further research could establish a clearer understanding of the relationship between red meat consumption and NAFLD risk. Registration: PROSPERO: CRD42022332839.

Effect of soy isoflavone supplementation on blood pressure: a meta-analysis of randomized controlled trials.

BACKGROUND: Previous experimental studies have suggested that the consumption of soy isoflavones may have a potential impact on lowering blood pressure. Nevertheless, epidemiological studies have presented conflicting outcomes concerning the correlation between soy isoflavone consumption and blood pressure levels. Consequently, a comprehensive meta-analysis of all eligible randomized controlled trials (RCTs) was conducted to explore the influence of soy isoflavones on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in adults. METHODS: A thorough search of PubMed, Embase, and the Cochrane Library for relevant literature up to April 30, 2023 was conducted. RCTs involving adults that compared soy isoflavone supplementation with a placebo (the same matrix devoid of soy isoflavone) were included. The combined effect size was presented as the weighted mean difference (WMD) along with 95% confidence interval (CI), employing a fixed-effects model. RESULTS: Our meta-analysis included a total of 24 studies involving 1945 participants. The results revealed a significant reduction in both SBP and DBP with soy isoflavone supplementation. Subgroup analyses suggested more pronounced reductions in SBP and DBP for interventions lasting ≥6 months, in individuals receiving mixed-type soy isoflavone, and among patients with metabolic syndrome or prehypertension. However, we did not detect significant nonlinear associations between supplementation dosage and intervention duration concerning both SBP and DBP. The overall quality of evidence was deemed moderate. CONCLUSIONS: The current meta-analysis revealed that supplementation with soy isoflavones alone effectively reduces blood pressure. Additional high-quality studies are required to investigate the efficacy of blood pressure reduction through supplementation with an optimal quantity and proportion of soy isoflavone.

Impact of sarcopenia and sarcopenic obesity on survival in patients with primary liver cancer: a systematic review and meta-analysis.

Background: Sarcopenia and sarcopenic obesity are associated with an increased possibility of adverse clinical outcomes; however, the effects of sarcopenia and sarcopenic obesity on patients with primary liver cancer remain controversial. Therefore, the present study aimed to determine the impact of sarcopenia and sarcopenic obesity on survival in patients with primary liver cancer. Methods: We searched studies published in English in PubMed, Embase, Web of Science, and Cochrane Library databases up to 13 November 2022. Cohort studies that reported the association among sarcopenia, sarcopenic obesity, and patient survival were included. Results: A total of 64 cohort studies with data on 11,970 patients with primary liver cancer were included in the meta-analysis. Sarcopenia was associated with poor overall survival in patients with primary liver cancer [adjusted hazard ratio (HR) 2.11, 95% confidence interval (CI): 1.89-2.36, P < 0.0001], with similar findings for sarcopenic obesity (adjusted HR: 2.87, 95% CI: 2.23-3.70, P < 0.0001). Sarcopenia was also associated with poor overall survival across the subgroups analyzed by ethnicity, type of liver cancer, treatment modalities, method used to define sarcopenia, and etiology of liver cancer. We also found a negative correlation among sarcopenia, sarcopenic obesity, and recurrence-free/disease-free survival (adjusted HR: 1.73, 95% CI: 1.50-1.99, P < 0.001; adjusted HR: 2.28, 95% CI: 1.54-3.35, P < 0.001, respectively). Conclusion: Sarcopenia and sarcopenic obesity were significantly associated with poor overall survival and recurrence-free/disease-free survival in patients with primary liver cancer. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=378433, PROSPERO [42022378433].

Correlation of Nonalcoholic Fatty Liver Disease with Dietary Folate and Serum Folate in U.S. Adults: Cross-Sectional Analyses from National Health and Nutrition Examination Survey 2009-2018.

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a global health problem, and dietary intervention is still considered one of the primary interventions. This study aimed to examine cross-sectional associations between dietary and serum levels of folate and NAFLD. Methods: We conducted a study of 7543 adults who participated in the National Health and Nutrition Examination Survey, 2009-2018. NAFLD status was determined by a fatty liver index (FLI) value ≥60. Multivariable logistic regression models were used to estimate associations between folate and NAFLD. Results: Almost half (45%) of the patients were classified as having NAFLD based on the FLI. In the fully adjusted model, participants in the highest quartile of dietary total folate and food folate were found to have a lower prevalence of NAFLD than those in the lowest quartile [odds ratio (OR)quartile 4 versus 1 = 0.582; 95% confidence interval (CI) = 0.350-0.968; and ORquartile 4 versus 1 = 0.737; 95% CI = 0.611-0.888, respectively], and the fourth quartile values of serum total folate and 5-methyl-tetrahydrofolate were significantly negatively associated with NAFLD prevalence (ORquartile 4 versus 1 = 0.664; 95% CI = 0.495-0.891; and ORquartile 4 versus 1 = 0.712; 95% CI = 0.532-0.954, respectively). Subgroup analyses revealed that this beneficial association was more significant in women (ORquartile 4 versus 1 = 0.526; 95% CI = 0.329-0.843; pinteraction < 0.001) than in men (ORquartile 4 versus 1 = 0.805; 95% CI = 0.546-1.186). Conclusions: Higher dietary folate intake and serum folate levels are associated with a lower NAFLD prevalence among U.S. adults and the trend is more pronounced among women, indicating opportunities for dietary NAFLD interventions.

Sesamin Protects against APAP-Induced Acute Liver Injury by Inhibiting Oxidative Stress and Inflammatory Response via Deactivation of HMGB1/TLR4/NFκB Signal in Mice.

Acetaminophen (APAP) overdose would lead to liver toxicity and even acute liver failure in severe cases by triggering an inflammatory response and oxidative stress. Sesamin has been reported to possess anti-inflammatory and antioxidant actions in several animal disease models. In the present study, the effects and mechanisms of sesamin on APAP-induced acute liver injury (ALI) were explored. The results showed that pretreatment with sesamin significantly alleviated APAP-induced ALI, as indicated by decreased serum aminotransferase activities, hepatic pathological damages, and hepatic cellular apoptosis. But sesamin has no significant effects on the expression of cytochrome P450 2E1 (CYP2E1), APAP-cysteine adducts (APAP-CYS) production, and glutathione content in the liver of APAP-administered mice. Moreover, APAP-induced liver oxidative stress and inflammatory response also were remarkedly attenuated by sesamin, including reducing hepatic reactive oxygen species levels, promoting antioxidant generation, and inhibiting the expression of TNF-α and IL-1ß, as well as decreasing inflammatory cell recruitment. Notably, sesamin inhibited serum high-mobility group box 1 (HMGB1) releases and blocked hepatic activation of Toll-like receptor 4 (TLR4)-interleukin 1 receptor-associated kinase 3-nuclear factor kappa B (NF-κB) signaling pathway in APAP-administered mice. These findings indicated that sesamin could mitigate APAP-induced ALI through suppression of oxidative stress and inflammatory response, which might be mediated by the deactivation of HMGB1/TLR4/NF-κB signaling in mice.

Increased ILT2 expression contributes to dysfunction of CD56dimCD16+NK cells in chronic hepatitis B virus infection.

Natural killer (NK) cells play a crucial role in the control of human viral infections but their activity is significantly impaired in patients infected with chronic hepatitis B (CHB). The mechanism that contributes to NK cell dysfunction in CHB needs further elucidation. In this study, we analyzed the expression and function of the novel inhibitory receptor immunoglobulin-like transcript-2 (ILT2) on NK cells from 131 CHB patients and 36 healthy controls. We observed that ILT2 expression on circulating CD56dimCD16+NK cells was increased in immune-tolerant, immune-active and HBeAg-negative hepatitis patients compared with inactive carriers and controls. The frequency of ILT2+CD56dimNK cells was positively correlated with serum viral load in immune-tolerant patients. The percentage of ILT2+CD56dimNK cells decreased along with HBV load in CHB patients who received antiviral therapy. Functional analysis showed that ILT2+CD56dimNK cells in CHB patients had significantly reduced degranulation and IFN-γ production. Upregulation of ILT2 was associated with high levels of apoptosis in CD56dimCD16+NK cells from CHB patients. ILT2 blockade was shown to increase the cytotoxicity and IFN-γ production of CD56dimNK cells in some CHB patients. Finally, ILT2 was found to be moderately upregulated by TGF-ß1, which was increased in immune-tolerant, immune-active and HBeAg-negative hepatitis patients. Our results show that chronic HBV infection increases the levels of the inhibitory receptor ILT2 on CD56dimNK cells and inhibits their functions, providing a new mechanism of NK-cell disability in CHB patients.

NOD1 Agonist Protects Against Lipopolysaccharide and D-Galactosamine-Induced Fatal Hepatitis Through the Upregulation of A20 Expression in Hepatocytes.

Increasing evidence suggests that NODs are involved in liver diseases; however, the underlying mechanisms remain obscure. In the present study, we analyzed the effect of NOD1 agonist pretreatment on acute liver failure induced by lipopolysaccharide (LPS) in D-galactosamine (D-GalN)-sensitized mice. We found that pretreatment with the NOD1 agonist markedly reduced LPS/D-GalN-induced mortality, elevation of serum ALT levels, and hepatocyte apoptosis. The protective effect of NOD1 agonist was independent of tumor necrosis factor (TNF)-α inhibition. NOD1 agonist pretreatment also attenuated TNF-α/D-GalN-induced apoptotic liver damage. The anti-apoptotic protein A20 expression was more pronounced in NOD1 agonist pretreated mice than in controls, and knockdown of A20 abrogated the protective effect of NOD1 agonist on LPS/D-GalN-induced liver injury and hepatocyte apoptosis. Further experiments showed that NOD1 agonist-induced A20 upregulation required the presence of kupffer cells and TNF-α. Taken together, our data strongly indicate that NOD1 is involved in the regulation of liver injury and could be a potential therapeutic target for liver diseases.

Efficacy of oral antiviral drugs to prevent mother-to-child transmission of hepatitis B virus: a network meta-analysis.

BACKGROUND: Hepatitis B is a serious global health problem. Mother-to-child transmission (MTCT) of hepatitis B virus (HBV) is a major risk factor in the endemicity of HBV infection. Oral antiviral drugs are recommended to highly viremic mothers to decrease MTCT of HBV. The present network analysis compared the efficacy of available treatments to prevent the MTCT of HBV. METHODS: The electronic databases of PubMed, Embase, Web of Science, Scopus, and Wanfang data were searched for eligible studies. Pair-wise meta-analysis and Bayesian network analysis were applied to compare the efficacy of antiviral drugs. RESULTS: Seventy-five studies involving 12,740 pregnant females were eligible for analysis. On pair-wise analysis, lamivudine (OR 0.15, 95% CI 0.09-0.25, I-squared = 0%), telbivudine (OR 0.07, 95% CI 0.05-0.10, I-squared = 0%) and tenofovir (OR 0.07, 95% CI 0.04-0.13, I-squared = 0%) significantly decreased the MTCT rate. Results of multiple comparisons with ranking probability based on Bayesian analysis showed that tenofovir (SUCRA = 96.83%) appeared more effective than the two other drugs. CONCLUSION: In addition to active and passive immunoprophylaxis, lamivudine, telbivudine and tenofovir in highly viremic mothers can further decrease MTCT of HBV. Based on direct and indirect evidence, tenofovir appears to be more effective than the two other drugs in the prevention of HBV MTCT.

Natural killer cell activation contributes to hepatitis B viral control in a mouse model.

The roles of CD4 + T cells and CD8 + T cells in hepatitis B virus (HBV) infection have been well documented. However, the role of innate immunity in HBV infection remains obscure. Here we examined the effect of activation of innate immunity by polyinosinic: polycytidylic acid (PolyI:C) on HBV infection. A chronic HBV replication mouse model was established by hydrodynamical injection of pAAV/HBV1.2 plasmid into C57BL/6 mice. We found that HBV did not seem to induce an active NK-cell response in the mouse model. Early PolyI:C treatment markedly decreased serum HBV levels and led to HBV clearance. Following PolyI:C injection, NK cells were activated and accumulated in the liver. Depletion of NK cells markedly attenuated the anti-HBV activity of PolyI:C. Moreover, we found that IFN-γ production from NK cells was essential for the antiviral effect of PolyI:C in the model. Importantly, activation of NK cells by PolyI:C could also lead to HBV suppression in HBV-tolerant mice and HBV-transgenic mice. These results suggest that activated NK cells might suppress HBV and contribute to HBV clearance during natural HBV infection. In addition, therapeutic activation of NK cells may represent a new strategy for the treatment of chronic HBV infection.

Functional dichotomy of Vδ2 γδ T cells in chronic hepatitis C virus infections: role in cytotoxicity but not for IFN-γ production.

Vδ2 γδ (Vδ2) T cells, a major human γδ T cell subset, exhibit broad anti-tumor and anti-infective activity; however, their precise role in chronic hepatitis C virus (HCV) infections remains unclear. In this study, we analyzed the phenotype and function of Vδ2 T cells in 43 HCV-infected patients compared to 39 healthy controls (HCs). Vδ2 T cells from HCV-infected patients were activated and differentiated into effector cells. Vδ2 T cells in patients expressed significantly higher levels of natural killer (NK) cell markers CD56 and CD16 than in HCs, acquiring cytotoxic NK-like phenotype. The Vδ2 T cell phenotype was associated with increased cytolytic effector molecules expression in HCV-infected patients with elevated serum ALT levels. Surprisingly, Vδ2 T cells in patients had a markedly impaired capacity to produce IFN-γ. Further in vitro and in vivo analysis showed that interferon-α, which was induced during HCV infection, caused Vδ2 T cell function bias toward cytotoxicity. These results suggest a functional dichotomy for Vδ2 T cells in chronic HCV infections: a role in cytotoxicity but not for IFN-γ production, which may contribute to both the liver inflammation and HCV persistence.

The efficacy of lamivudine prophylaxis against hepatitis B reactivation in breast cancer patients undergoing chemotherapy: a meta-analysis.

BACKGROUND/PURPOSE: Lamivudine has been recommended as prophylaxis for the reactivation of hepatitis B virus (HBV) infection in patients undergoing chemotherapy. However, information on breast cancer patients in particular has been lacking. The purpose of this meta-analysis was to assess the overall efficacy of lamivudine prophylaxis compared to untreated patients with hepatitis B S-antigen (HBsAg) seropositive breast cancer who had undergone chemotherapy. METHODS: Studies that compared the efficacy of treatment with lamivudine prophylaxis versus no prophylaxis in HBsAg seropositive breast cancer patients were identified through Medline, Cochrane, and Embase databases. RESULTS: Six studies involving 499 patients were analyzed. The rates of HBV reactivation in patients with lamivudine prophylaxis were significantly lower than those with no prophylaxis (risk ratio [RR] = 0.23, 95% confidence interval [CI]: 0.13-0.39, p < 0.00001). Patients given lamivudine prophylaxis had significant reductions in the rates of hepatitis attributable to HBV compared with those not given treatment (RR = 0.20, 95% CI: 0.08-0.47, p = 0.002). The rates of moderate and severe hepatitis in patients with lamivudine prophylaxis were significantly lower compared with those patients who had not received prophylaxis (RR = 0.25, 95% CI: 0.10-0.62, p < 0.003; RR = 0.25, 95% CI: 0.10-0.59, p = 0.002). Patients given lamivudine prophylaxis had significantly fewer disruptions of chemotherapy (RR = 0.36, 95% CI: 0.21-0.64, p = 0.0004). There was no significant heterogeneity in the comparisons. CONCLUSION: Lamivudine prophylaxis in HBsAg seropositive breast cancer patients undergoing chemotherapy is effective in reducing HBV reactivation and HBV-associated morbidity and mortality.

Changes in glucose-6-phosphate dehydrogenase expression results in altered behavior of HBV-associated liver cancer cells.

Hepatocellular carcinoma (HCC) is regarded as a major global health care issue, and chronic hepatitis B virus (HBV) infection is considered to be involved in pathogenesis of HCC. To increase knowledge of HCC pathogenesis, as well as discover potential novel molecules for anti-cancer therapy, mass spectrometry and isobaric tag for relative and absolute quantitation (iTARQ) were employed. The differences between nine HBV-related HCC and adjacent non-HCC tissue specimens were studied. In total, 222 proteins were analyzed for differential expression in the two types of samples. Among these proteins, several were further confirmed by immunohistochemical, immunoblotting, and real-time RT-PCR analysis. RNA interference induced downregulation of glucose-6-phosphate dehydrogenase (G6PD) and decreased HBV replication by fivefold by the IFN pathway. Decreased G6PD expression resulted in decreased hepatoma cell migration and invasion in cell culture. In summary, the investigation provides new information on pathogenesis of HBV infection and suggests G6PD as a novel anti-HCC target. G6PD suppression may contribute to treatment strategies for inhibiting tumor progression.

Efficacy of lamivudine combined with adefovir dipivoxil versus entecavir monotherapy in patients with hepatitis B-associated decompensated cirrhosis: A meta-analysis.

Whether the combination of lamivudine (LAM) plus adefovir (ADV) de novo is more effective than entecavir (ETV) monotherapy in patients with HBV-associated decompensated cirrhosis is still controversial. We searched seven randomized controlled trials that included 411 patients in this meta-analysis. There are 205 and 206 patients in these two groups separately. The pooled risk ratio (RR) and mean difference (MD) were used to assess the treatment effects. ETV monotherapy significantly improved Child-Turcotte-Pugh (CTP) scores (MD = 0.33, 95%CI [0.21-0.44], P < .00001), and was associated with lower rates of serum creatinine increase compared LAM + ADV combination therapy (RR = 4.76, 95%CI [1.11-20.33], P = .04) at 48 weeks. The reduction of alanine aminotransferase (ALT) levels, HBV DNA levels, the rate of ALT normalization, undetectable HBV DNA, HBV e antigen (HBeAg) loss, HBeAg seroconversion and mortality were similar between the two groups. ETV is more effective than LAM + ADV in improving CTP scores at 48 weeks. Both of the LAM + ADV and ETV had similar efficacy in improving virological and biochemical parameters at 48 weeks of follow-up. Furthermore, use of these agents in decompensated HBV patients was generally safe and well tolerated at 48 weeks. However, the nephrotoxicity of ADV, and the potential adverse effects of ETV should be considered and monitored during prolonged therapy.

HSPB1 is an intracellular antiviral factor against hepatitis B virus.

Hepatitis B virus (HBV) is the most common of the hepatitis viruses that cause chronic liver infections in humans and it is considered a major global health problem. However, the mechanisms of HBV replication are complex and not yet fully understood. In this study, the HBV DNA-transfected HepG2.2.15 cell line and its parental HepG2 cell line were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ)-coupled two-dimensional liquid chromatography tandem mass-spectrophotometry (2D LC-MS/MS), a successfully exploited high-throughput proteomic technology. In total, 2,028 unique proteins were identified and 170 proteins were differentially expressed in HepG2.2.15 cells as compared with that in HepG2. Several differentially expressed proteins were further validated by Western blot and real-time quantitative reverse transcription-PCR. Furthermore, the association of HBV replication with heat shock protein B1, one of the highly expressed proteins in HepG2.2.15 cells, was verified. HSPB1 functions as a anti-viral protein during HBV infection by specifically inducing type interferon and some downstream antiviral effectors. This study is the first to report the application of iTRAQ technology to analyze the underlying mechanisms of HBV replication. Many of the differentially expressed proteins identified have not been linked to HBV replication before, and may provide valuable novel insights into HBV replication.

The influence of hepatitis B virus on antiviral treatment with interferon and ribavirin in Asian patients with hepatitis C virus/hepatitis B virus coinfection: a meta-analysis.

BACKGROUND: Clinical and laboratory studies have indicated that coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV) can suppress one another, eliciting a dominant disease phenotype. To assess whether HBV can influence the antiviral effect of treatment on HCV, we performed a meta-analysis to comparatively analyze the response to interferon plus ribavirin treatment in patients with HBV/HCV coinfection and HCV mono-infection. METHODS: Published studies in the English-language medical literature that involved cohorts of HBV/HCV coinfection and HCV mono-infection were obtained by searching Medline, Cochrane and Embase databases. Studies that compared the efficacy of treatment with interferon plus ribavirin in HBV/HCV coinfection and HCV mono-infection were assessed. End-of-treatment virological response (ETVR), sustained virological response (SVR), HCV relapse rate, and alanine aminotransferase (ALT) normalization rate were compared between HBV/HCV coinfection and HCV mono-infection patients. RESULTS: Five trials involving 705 patients were analyzed. At the end of follow-up serum ALT normalization rates in patients with HCV mono-infection were significantly higher than in patients with HBV/HCV coinfection (odds ratio (OR) = 0.56, 95% confidence interval (CI): 0.40-0.80, P = 0.001). The ETVR and SVR achieved in HBV/HCV coinfection patients were comparable to those in HCV mono-infection patients (OR = 1.03, 95% CI: 0.37-2.82, P = 0.96 and OR = 0.87, 95% CI: 0.62-1.21, P = 0.38, respectively). The rate of relapse for HCV or HCV genotype 1 was not significantly different between HBV/HCV coinfection patients and HCV mono-infection patients (OR = 1.55, 95% CI: 0.98-2.47, P = 0.06; HCV genotype 1: OR = 2.4, 95% CI: 1.17-4.91, P = 0.19). CONCLUSIONS: Treatment with interferon and ribavirin achieves similar ETVR and SVR in HBV/HCV coinfection and HCV mono-infection. HBV/HCV coinfection patients had distinctively lower end of follow-up serum ALT normalization.

Quantitative proteome analysis of ovarian cancer tissues using a iTRAQ approach.

Quantitative proteomics can be used as a screening tool for identification of differentially expressed proteins as potential biomarkers for cancers. Here, we comparatively analyzed the proteome profiles of ovarian cancer tissues and normal ovarian epithelial tissues. Using the high-throughput proteomic technology of isobaric tags for relative and absolute quantitation (iTRAQ)-coupled with two-dimensional-liquid chromatography-tandem mass spectrometry, 1,259 unique proteins were identified. Of those, 205 were potentially differentially expressed between ovarian cancer and normal ovarian tissues. Several of the potentially differentially expressed proteins were validated by Western blotting and real-time quantitative RT-PCR analyses. Furthermore, up-regulation of KRT8, PPA1, IDH2, and S100A11 were validated in ovarian tissue microarrays by immunohistochemistry. Silencing of S100A11 expression suppressed the migration and invasion properties of ovarian cancer cells in vitro. Our study represents the successful application of iTRAQ technology to an investigation of ovarian cancer. Many of the potentially differentially expressed proteins identified had not been linked to ovarian cancer before, and provide valuable novel insights into the underlying mechanisms of carcinogenesis in human ovarian cancer.

Proteomic investigation of 5-fluorouracil resistance in a human hepatocellular carcinoma cell line.

Multi-drug resistance (MDR) is a major obstacle towards a successful treatment of hepatocellular carcinoma (HCC). The mechanisms of MDR are intricate and have not been fully understood. Therefore, we employed a cell-line model consisting of the 5-fluorouracil (5-FU) resistant BEL7402/5-FU cell line and its parental BEL7402 cell line. Using relative and absolute quantification (iTRAQ)-coupled 2D LC-MS/MS, a successfully exploited high-throughput proteomic technology, in total, 660 unique proteins were identified and 52 proteins showed to be differentially expressed in BEL7402/5-FU compared with BEL7402. Several differentially expressed proteins were further validated by Western blot and real-time quantitative RT-PCR analysis. Furthermore, the association of MDR with ANXA3, one of the highly expressed proteins in BEL7402/5-FU, was verified. Our study represents the first successful application of iTRAQ technology for MDR mechanisms analysis in HCC. Many of the differentially expressed proteins identified had not been linked to MDR in HCC before, which provide valuable information for further understanding of MDR.

Lamivudine plus adefovir combination therapy versus entecavir monotherapy for lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis.

BACKGROUND: Chronic hepatitis B virus (HBV) infection represents a serious global health problem and resistance to lamivudine (LAM) has become a serious clinical challenge. Previous rescue therapy for the treatment of chronic LAM-resistant hepatitis B infected patients included switching to entecavir (ETV) and adding adefovir (ADV) or tenofovir (TFV). At present, switching to ETV is not recommended for rescue therapy for LAM-resistant chronic hepatitis B (CHB). The aim of this report was to determine whether add-on ADV was a superior rescue strategy in the treatment of CHB patients with LAM resistance. METHODS: We searched Medline/PubMed, EMBASE, Web of Knowledge, and the Cochrane Library. Relative risks (RRs) of virologic response, virologic breakthrough, normalization of serum alanine aminotransferase (ALT) levels and HBeAg seroconversion rates were studied. Factors predicting virologic response, standardized mean differences (SMD) in HBV DNA levels and safety were reviewed. RESULTS: Six eligible trials (451 patients in total) were included in the analysis. The rate of virologic breakthrough in the ETV group was higher than that in the LAM plus ADV group. There were no statistical differences in virologic response, ALT normalization and HBeAg seroconversion in either group 48 weeks post treatment. LAM plus ADV combination therapy produced faster and greater HBV DNA reduction rates 24 weeks post therapy compared to ETV monotherapy. HBV DNA baseline levels and the initial virologic response (IVR) were predictive of the virologic response. Additionally, combination therapy or monotherapy were both well tolerated. CONCLUSIONS: LAM plus ADV combination therapy was more effective and produced longer-lasting effects than switching to ETV monotherapy in treating CHB patients with LAM resistance. However, considering the practical benefits and limitations of ADV, individualized therapy will be needed in patients with prior history of LAM resistant infections.