Resveratrol prevents interleukin-1 β-induced dysfunction of pancreatic β-cells

Objective：Interleukin-1β（IL-1β）plays an important role in the development of type 1 and type 2 diabetes mellitus.Resveratrol,a polyphenol,is known to have a wide range of pharmacological properties in vitro.In this research,we examined the effects of resveratrol on IL-1β-inducedβ-cell dysfunction.Methods：We first evaluated the effect of resveratrol on nitric oxide（NO）formation in RINm5F cells stimulated with IL-1βusing the Griess method.Next,we performed transient transfection and reporter assays to measure the transcriptional activity of peroxisome proliferator-activated receptor-γ（PPAR-γ）.We also used Western blotting analysis to assess the effect of resveratrol on inducible nitric oxide synthase（iNOS）expression and nuclear factor-κB（NF-κB）translocation to the nuclei in cells treated with IL-1β.In addition,we assessed the transcriptional activity of NF-κB using an electrophoretic mobility shift assay（EMSA）.Finally,we evaluated the effect of resveratrol on IL-1β-induced inhibition of glucose-stimulated insulin secretion in freshly isolated rat pancreatic islets.Results：Resveratrol significantly suppressed IL-1β-induced NO production,a finding that correlated well with reduced levels of iNOS mRNA and protein.The molecular mechanism by which resveratrol inhibited iNOS gene expression appeared to involve increased PPAR-γactivity,which resulted in the inhibition of NF-κB activation.Further analysis showed that resveratrol could prevent IL-1β-induced inhibition of glucose-stimulated insulin secretion in rat islets.Conclusion：In this study,we demonstrated that resveratrol could protect against pancreaticβ-cell dysfunction caused by IL-1β.

Prognostic significance of PD-L1 expression in patients with colorectal cancer: a meta-analysis

Background The association between the expression of programmed cell death 1(PD-1) or its ligand [programmed cell death ligand-1(PD-L1)] and colorectal cancer(CRC) survival rates remains unclear. Thus, we conducted a meta-analysis to investigate the prognostic value of PD-L1 expression in CRC patients.Methods All eligible studies related to evaluation of PD-L1 expression and survival of CRC patients were searched in PubMed, Medline, Cochrane library, and the EMBASE database. Hazard ratios(HRs) and 95% confidence intervals(CI) of overall survival(OS) were examined to assess the effect of PD-L1 expression on the survival of CRC patients. The outcomes of this meta-analysis were synthesized based on randomeffects model. Subgroup analyses were also performed. Results Seven studies, wherein OS data were stratified according to the expression status of PD-L1, were analyzed. CRC patients showing positive PD-L1 expression were associated with significantly poorer prognoses in terms of overall survival, compared with those displaying negative PD-L1 expression(HR = 1.43, 95% CI: 1.07–1.92; P = 0.02). In the subgroup analyses, H-scores as well as the percentage of stained cells indicated that PD-L1 expression was significantly associated with poor prognosis(HR = 1.90, 95% CI: 1.38–2.62, P < 0.01; HR = 1.81, 95% CI: 1.08–3.03, P = 0.02). Immunohistochemical staining, utilizing a rabbit anti-PD-L1 antibody, revealed significantly superior survival in the PD-L1 negative group compared with the PD-L1 positive expression group(HR = 1.92; 95% CI, 1.40-2.63; P < 0.01). Moreover, PD-L1 expression was significantly associated with poor prognosis when polyclonal antibodies were used(HR = 1.84; 95% CI, 1.30–2.61; P < 0.01). Conclusion Our meta-analysis indicated that PD-L1 expression status is a significant prognostic factor for CRC patients. Positive PD-L1 expression was associated with worse CRC survival. Evaluation via different immunohistochemistry based techniques may partly account for the contradictory results. Therefore, further investigative studies using larger sample sizes are felt to be needed to elucidate the prognostic value of PD-L1 expression in CRC patients.

Safety and efficacy of EFGR and VEGF signaling pathway inhibition therapy in patients with colorectal cancer: a meta-analysis

Objective Epidermal growth factor receptor(EGFR) and vascular endothelial growth factor(VEGF) inhibitors are two targeted therapies for metastatic colorectal cancer(mCRC). However, few studies have focused on the safety and efficacy of combined targeted therapy against those of a single inhibition therapy of EFGR or VEGF. This meta-analysis aimed to compare the anti-tumor activity of the combined inhibition therapy and single inhibition therapy in patients with mCRC. Methods We searched PubMed, Medline, the Cochrane library, Embase, and annual meeting proceedings for relevant clinical trials. Objective response rate(ORR), progression-free survival(PFS), overall survival(OS), and adverse events were extracted and calculated.Results Nine trials comprising 3977 patients were selected for the analysis. The combined inhibition therapy showed a 3.7% improvement in ORR compared with single inhibition, and this difference was statistically significant [hazard ratio(HR) = 1.33; 95% confidence interval(CI), 1.01–1.74; P = 0.04]. Subgroup analysis showed that the combined EGFR and VEGF inhibitor therapy had an 11.65% improvement in ORR compared with VEGF inhibitor therapy(OR = 2.14; 95% CI, 1.34–3.40; P = 0.001). EGFR and VEGF inhibitor therapy and chemotherapy had an 18.08% improvement in ORR compared with chemotherapy(OR = 2.21; 95% CI, 1.05–4.64; P = 0.04). Moreover, EGFR and VEGF inhibitor therapy significantly improved PFS compared with VEGF inhibitor therapy(OR = 0.82; 95% CI, 0.69–0.97; P = 0.02). VEGF inhibitor therapy and chemotherapy significantly improved PFS compared with EGFR and VEGF inhibitor therapy and chemotherapy(OR = 1.20; 95% CI, 1.11–1.30; P = 0.00). In addition, EGFR and VEGF inhibitor therapy showed improved OS compared with VEGF inhibitor therapy(HR = 0.78, 95% CI: 0.65–0.94; P = 0.008). Finally, the combined inhibition therapy showed an obviously increased risk of cutaneous and mucosal effects(RR = 6.45; 95% CI: 2.71–15.36; P < 0.01), diarrhea/abdominal pain(RR = 1.97; 95% CI: 1.45–2.68; P < 0.01), fatigue/asthenia(RR = 1.60; 95% CI: 1.10–2.32; P = 0.01), dehydration or electrolyte disturbance(RR = 2.78; 95% CI: 1.48–5.21; P < 0.01), nail disorder(RR = 8.23; 95% CI: 1.52–44.57; P = 0.01), and dizziness/headache(RR = 3.43; 95% CI: 1.89–6.23; P < 0.01) compared with single inhibition therapy.Conclusion Compared with single inhibition therapy, the combined inhibition therapy significantly improved ORR, PFS, and OS in the treatment of mCRC patients. Compared with a single-targeted agent, the combined therapy of anti-EGFR and anti-VEGF drug provided an efficacy advantage, although it led to greater toxicity.