Hypoglycemic activity of puerarin through modulation of oxidative stress and mitochondrial function via AMPK.

Hyperglycemia is the dominant phenotype of diabetes and the main contributor of diabetic complications. Puerarin is widely used in cardiovascular diseases and diabetic vascular complications. However, little is known about its direct effects on diabetes. The aim of our study is to investigate its antidiabetic effect in vivo and in vitro, and explore the underlying mechanism. We used type I diabetic mice induced by streptozotocin to observe the effects of puerarin on glucose metabolism. In addition, oxidative stress and hepatic mitochondrial respiratory activity were evaluated in type I diabetic mice. In vitro, glucose consumption in HepG2 cells was assayed along with the qPCR detection of glucogenesis genes expression. Moreover, ATP production was examined and phosphorylation of AMPK was determined using Western blot. Finally, the molecular docking was performed to predict the potential interaction of puerarin with AMPK utilizing program LibDock of Discovery Studio 2018 software. The results showed that puerarin improved HepG2 glucose consumption and upregulated the glucogenesis related genes expression. Also, puerarin lowered fasting and fed blood glucose with improvement of glucose tolerance in type I diabetic mice. Further mechanism investigation showed that puerarin suppressed oxidative stress and improved hepatic mitochondrial respiratory function with enhancing ATP production and activating phosphorylation of AMPK. Docking study showed that puerarin interacted with AMPK activate site and enhancing phosphorylation. Taken together, these findings indicated that puerarin exhibited the hypoglycemic effect through attenuating oxidative stress and improving mitochondrial function via AMPK regulation, which may serve as a potential therapeutic option for diabetes treatment.

Cyclophosphamide for the treatment of acute lymphoblastic leukemia: A protocol for systematic review.

BACKGROUND: Previous clinical trials have reported that cyclophosphamide can be used for the treatment of acute lymphoblastic leukemia (ALL). However, its efficacy is still unclear. In this systematic review study, we aim to evaluate its efficacy and safety for ALL. METHODS: The following 9 databases will be searched from their inception to the present: Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), and four Chinese databases. The randomized controlled trials or case control studies of cyclophosphamide that assess the clinical efficacy and safety in patients with ALL are included. The methodological quality of all eligible included studies will be assessed by the Cochrane risk of bias tool.The primary outcome measurement will be all-cause mortality at the period of treatment and follow-up. The secondary outcome measurements will include the health-related quality of life (HRQL), postinduction complete remission (CR) rate, event-free survival (EFS), relapse rate, and adverse events. Two authors will independently select eligible studies, exact data, and assess the methodological quality of included studies. RevMan 5.3 software will be used to synthesize the data. Reporting bias will be evaluated by the funnel plots, Begg, and Egger tests. RESULTS: This systematic review will evaluate the clinical efficacy and safety of cyclophosphamide for ALL. DISSEMINATION AND ETHICS: The findings of this review will summarize the present evidence of cyclophosphamide for ALL, and may provide guidance for clinical practice of cyclophosphamide for ALL. Its results will be published through peer-reviewed journals. This study does not need ethic approval, because it will not involve the individual data. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018119333.

Salvianolic Acid A Protects Against Diabetic Nephropathy through Ameliorating Glomerular Endothelial Dysfunction via Inhibiting AGE-RAGE Signaling.

BACKGROUND/AIMS: Glomerular endothelium dysfunction leads to the progression of renal architectonic and functional abnormalities in early-stage diabetic nephropathy (DN). Advanced glycation end products (AGEs) and receptor for AGEs (RAGE) are proved to play important roles in diabetic nephropathy. This study investigated the role of Salvianolic acid A (SalA) on early-stage DN and its possible underlying mechanism. METHODS: In vitro AGEs formation and breaking rate were measured to illustrate the effect of SalA on AGEs. Type 2 diabetic nephropathy rats were induced by high-fat diet and low-dose streptozocin (STZ). After eight-week treatment with SalA 1 mg/kg/day, 24h-urine protein, creatinine clearance was tested and renal structural injury was assessed by PAS and PASM staining. Primary glomerular endothelial cell permeability was evaluated after exposed to AGEs. AGEs-induced RhoA/ROCK and subsequently activated disarrange of cytoskeleton were assessed by western blot and immunofluorescence. RESULTS: Biochemical assay and histological examination demonstrated that SalA markedly reduced endothelium loss and glomerular hyperfiltration, suppressed glomerular hypertrophy and mesangial matrix expansion, eventually reduced urinary albumin and ameliorated renal function. Further investigation suggested that SalA exerted its renoprotective effects through inhibiting AGE-RAGE signaling. It not only inhibited formation of AGEs and increased its breaking in vitro, but also reduced AGEs accumulation in vivo and downregulated RAGE expression. SalA restored glomerular endothelial permeability through suppressing AGEs-induced rearrangement of actin cytoskeleton via AGE-RAGE-RhoA/ ROCK pathway. Moreover, SalA attenuated oxidative stress induced by AGEs, subsequently alleviated inflammation and restored the disturbed autophagy in glomerular endothelial cell and diabetic rats via AGE-RAGE-Nox4 axis. CONCLUSION: Our study indicated that SalA restored glomerular endothelial function and alleviated renal structural deterioration through inhibiting AGE-RAGE, thus effectively ameliorated early-stage diabetic nephropathy. SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.