SCH772984 ameliorates lipopolysaccharide-induced hypoglycemia in mice through reversing MEK/ERK/Foxo1-mediated gluconeogenesis suppression.

Lipopolysaccharide (LPS) results in a lethal hypoglycemic response. However, the main molecular mechanism involved in LPS-induced glucose metabolism disorder is poorly understood. This study intends to investigate the signaling pathways involved in LPS-induced hypoglycemia and potential efficacy of extracellular signal-regulated kinase (ERK) inhibitor SCH772984. The effects of LPS and SCH772984 on gluconeogenesis, glucose absorption, and glycogenolysis were evaluated by pyruvate tolerance test, oral glucose tolerance test, and glucagon test, respectively. After a single intraperitoneal injection of 0.5 mg/kg LPS, the mice's blood glucose levels and gluconeogenesis ability were significantly lower than that of control group. Besides, mRNA and protein expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) decreased significantly after LPS treatment. LPS induced the phosphorylation of ERK1/2, MEK1/2 (mitogen-activated protein kinase), and Foxo1 while inhibited Foxo1 expression in the nucleus, indicating an important role of the MEK/ERK/Foxo1 signaling in the inhibition of gluconeogenesis by LPS. Furthermore, SCH772984 elevated blood glucose, increased the G6Pase and PEPCK expression, and inhibited pERK1/2 and pFoxo1 expression in LPS-induced mice. In summary, LPS inhibited gluconeogenesis and induced hypoglycemia through the MEK/ERK/Foxo1 signal pathway, and ERK inhibitor could effectively reverse decreased blood glucose in mice with LPS treatment. These findings provide a novel therapeutic target for LPS-induced hypoglycemia.

Risk of infection with different immunosuppressive drugs combined with glucocorticoids for the treatment of idiopathic membranous nephropathy: A pairwise and network meta-analysis.

INTRODUCTION: Idiopathic membranous nephropathy (IMN) is a common cause of nephrotic syndrome in adults and one of the leading causes of end-stage renal disease (ESRD). During recent years, the incidence of IMN has been increasing. The main treatment option for IMN is the use of immunosuppressive (IS) drugs combined with glucocorticoids (GC). However, the infection risk with different IS drug treatments has not been systematically compared. Therefore, a network meta-analysis was performed to compare the risk of infection of different IS drug treatments for IMN. METHODS: Randomized controlled trials (RCTs) that assessed the risk of infection in patients with IMN treated with different IS drugs combined with GC were included in the network meta-analysis. Risk ratios for dichotomous data with 95% confidence intervals (CI) were calculated and the data were pooled with a random-effects model. The surface under the cumulative ranking area (SUCRA) was calculated to rank the risk of infection with different interventions. RESULTS: A total of 38 RCTs with 2066 participants were included for comparison of nine interventions. Tacrolimus combined with GC (TAC + GC) was associated with a significantly lower risk of infection than that with intravenous cyclophosphamide (IVCTX) + GC with a risk ratio (95% CI) of 0.52 (0.34-0.79). IVCTX + GC was associated with a significantly higher risk of infection than that with TAC + GC, cyclosporin (CSA) + GC, and oral cyclophosphamide (POCTX) + GC. A sensitivity analysis, excluding studies with a very long follow-up period, revealed minimal differences in the estimates. The SUCRA showed that CSA + GC had the lowest risk of infection (SUCRA 86.0%), and the second best treatment was POCTX + GC (SUCRA 78.6%). Conversely, IVCTX + GC (SUCRA 16.2%) had a higher risk of infection than that with the other IS drugs. CONCLUSIONS: CSA + GC and POCTX+ GC were associated with a lower risk of infection than that with other IS drugs combined with GC for IMN. Combined with comparative efficacy data, these results can help patients make informed decisions about treatment options for IMN. PROSPERO registration: CRD42018104849.