These data suggest that escin, via inactivation of NF-κB, could potentiate the efficacy of gemcitabine in combating pancreatic cancer, which could be a novel and potentially important therapeutic approach for the treatment for pancreatic cancer.
Despite rapid advances in chemotherapy and surgical resection strategies, pancreatic cancer remains the fourth leading cause of cancer related deaths in the United States with a 5-year survival rate of less than 5%. Therefore, novel therapeutic agents for the prevention and treatment of pancreatic cancer are urgently needed. The aim of this study was to investigate the effect of pristimerin, a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae, on inhibition of cell proliferation and induction of apoptosis in three pancreatic cancer cells, BxPC-3, PANC-1 and AsPC-1, in both monotherapy and in combination with gemcitabine. Treatment with pristimerin decreased the cell proliferation of all three pancreatic cancer cells in a dose- and time-dependent manner. Treatment of pancreatic cancer cells with pristimerin also resulted in G1-phase arrest which was strongly associated with a marked decrease in the level of cyclins (D1 and E) and cyclin-dependent kinases (cdk2, cdk4 and cdk6 ) with concomitant induction of WAF1/p21 and KIP1/p27. Pristimerin treatment also resulted in apoptotic cell death, cleavage of caspase-3, modulation in the expressions of Bcl-2 family proteins, inhibition of the translocation and DNA-binding activity of NF-κB. In addition, pristimerin potentiated the growth inhibition and apoptosis inducing effects of gemcitabine in all three pancreatic cancer cells, at least in part, by inhibiting constitutive as well as gemcitabine-induced activation of NF-κB in both its DNA-binding activity and transcriptional activity. Taken together, these data provide the first evidence that pristimerin has strong potential for development as a novel agent against pancreatic cancer.
Pancreatic cancer is an aggressive malignancy, which generally respond poorly to chemotherapy. Hence, novel agents that are safe and effective are highly needed. The aim of this study was to investigate whether piperlongumine, a natural product isolated from the fruit of the pepper Piper longum, has any efficacy against human pancreatic cancer when used either alone or in combination with gemcitabine in vitro and in a xenograft mouse model. In vitro, piperlongumine inhibited the proliferation of pancreatic cancer cell lines, potentiated the apoptotic effects of gemcitabine, inhibited the constitutive and inducible activation of NF-kB, and suppressed the NF-kB-regulated expression of c-Myc, cyclin D1, Bcl-2, Bcl-xL, Survivin, XIAP, VEGF, and matrix metalloproteinase-9 (MMP-9). Furthermore, in an in vivo xenograft model, we found piperlongumine alone significantly suppressed tumor growth and enhanced the antitumor properties of gemcitabine. These results were consistent with the downregulation of NF-kB activity and its target genes, decreased proliferation (PCNA and Ki-67), decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that piperlongumine alone exhibits significant antitumor effects against human pancreatic cancer and it further enhances the therapeutic effects of gemcitabine, possibly through the modulation of NF-kB-and NF-kB-regulated gene products.Cancer Prev Res; 9(3); 234-44. Ó2015 AACR.
This study aimed to assess whether repetitive intravitreal injections (IVI) of anti-vascular endothelial growth factor (anti-VEGF) cause sustained elevation of intraocular pressure (SE-IOP). We conducted a systematic review and meta-analysis based on five randomized controlled trials (RCTs) assessing 1428 subjects and 17 non-RCTs evaluating 8358 cases. In the RCTs, an increased risk of SE-IOP was found in the anti-VEGF group (summary risk ratio [RR] = 3.00, 95% confidence interval [CI]: 1.63–5.53) compared with the sham injection or laser group. The increased risk of SE-IOP was correlated with follow-up duration (RR = 2.14, 95% CI 0.69–6.57 at 6 months; RR = 3.15, 95% CI 0.99–10.09 at 12 months; RR = 3.48, 95% CI 1.38–8.78 at 23 months). The risk of SE-IOP after non-exclusion of pre-existing glaucoma patients (RR = 3.48, 95% CI 1.38–8.78) was higher than that obtained after excluding pre-existing glaucoma patients (RR = 2.6, 95% CI 1.16–5.81). In non-RCTs, the pooled prevalence of SE-IOP was 4.7% (95% CI 3.7–5.8) regardless of diagnosis criteria. In conclusion, repeated intravitreal injections of anti-VEGF agents cause a 2-fold elevation in SE-IOP risk.
The purpose of this research was to evaluate whether maltol could protect from hepatic injury induced by carbon tetrachloride (CCl4) in vivo by inhibition of apoptosis and inflammatory responses. In this work, maltol was administered at a level of 100 mg/kg for 15 days prior to exposure to a single injection of CCl4 (0.25%, i.p.). The results clearly indicated that the intrapulmonary injection of CCl4 resulted in a sharp increase in serum aspartate transaminase (AST) and alanine transaminase (ALT) activities, tumor necrosis factor-α (TNF-α), irreducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB) and interleukin-1β (IL-1β) levels. Histopathological examination demonstrated severe hepatocyte necrosis and the destruction of architecture in liver lesions. Immunohistochemical staining and western blot analysis suggested an accumulation of iNOS, NF-κB, IL-1β and TNF-α expression. Maltol, when administered to mice for 15 days, can significantly improve these deleterious changes. In addition, TUNEL and Hoechst 33258 staining showed that a liver cell nucleus of a model group diffused uniform fluorescence following CCl4 injection. Maltol pretreatment groups did not show significant cell nuclear condensation and fragmentation, indicating that maltol inhibited CCl4-induced cell apoptosis. By evaluating the liver catalase (CAT), glutathione (GSH), superoxide dismutase (SOD) activity, and further using a single agent to evaluate the oxidative stress in CCl4-induced hepatotoxicity by immunofluorescence staining, maltol dramatically attenuated the reduction levels of hepatic CAT, GSH and SOD, and the over-expression levels of CYP2E1 and HO-1. In the mouse model of CCl4-induced liver injury, we have demonstrated that the inflammatory responses were inhibited, the serum levels of ALT and AST were reduced, cell apoptosis was suppressed, and liver injury caused by CCl4 was alleviated by maltol, demonstrating that maltol may be an efficient hepatoprotective agent.
Purpose: To perform a quantitative analysis of retinal and choroid capillary ischaemia in diabetic patients by using optical coherence tomography angiography (OCTA). Methods: A total of 97 type 2 diabetic patients and 48 controls were included in this cross-sectional study. Diabetic patients without diabetic retinopathy (DR) were categorized as no DR (NDR) group; DR was classified into mild nonproliferative diabetic retinopathy (NPDR), moderate NPDR, severe NPDR and proliferative diabetic retinopathy (PDR). Quantitative parameters included foveal and parafoveal vascular density (VD) in superficial, deep and choroid capillary plexus (SCP, DCP and CCP), and foveal flow area in CCP. Stepwise comparisons between groups were performed in the adjacent stages. Results: Diabetic patients had significantly lower flow area in CCP and VD in all three layers compared with controls. In NDR group, foveal flow area in CCP significantly decreased compared with controls. In mild NPDR, parafoveal VD significantly decreased in all three layers compared with NDR, especially in temporal and nasal areas. In moderate NPDR, VD reduction extended to the inferior area in SCP and DCP compared with mild NPDR. In severe NPDR, progressive losses of VD were presented in all layers compared with moderate NDPR. In PDR, the superior VD in SCP significantly increased compared with severe NPDR. Conclusion: In diabetic patients, the microvascular ischaemia originated in choroid layer and extended inward affecting the deep and superficial layer. OCTA can serve as a reliable method for early detection and to monitor progressions in diabetic retinopathy.
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