IRE1α siRNA relieves endoplasmic reticulum stress-induced apoptosis and alleviates diabetic peripheral neuropathy in vivo and in vitro.

Diabetic peripheral neuropathy (DPN) is mainly characterized by demyelination resulted from the apoptosis of the Schwann cell (SCs). Although the exact mechanisms underlying DPN remain unclear, endoplasmic reticulum (ER) stress is strongly implicated in the apoptosis. Under ER stress, activated inositol-requiring kinase 1α (IRE1α) unregulated CHOP, phosphorylated JNK and Caspase-12 to aggravate apoptosis-mediated damage of DPN. Therefore, we tested the hypothesis that inhibition of IRE1α could reduce the ER stress-related apoptosis to relieve DPN. Here, we show that IRE1α siRNA improved the neurological morphology and function of DPN rats and rescued ER stress-related apoptosis in the sciatic nerve. Additionally, RSC96 cells transfected with IRE1α siRNA were used as in vitro model of DPN. It was found that IRE1α siRNA also decreased high glucose-induced apoptosis and inhibited ER stress-related apoptosis in the cells. Altogether, our results suggest that IRE1α should be considered a potential therapeutic agent for DPN.

Tang-Luo-Ning, a Traditional Chinese Medicine, Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis of Schwann Cells under High Glucose Environment.

Tang-Luo-Ning (TLN) has a definite effect in the clinical treatment of diabetic peripheral neuropathy (DPN). Schwann cells (SCs) apoptosis induced by endoplasmic reticulum stress (ER stress) is one of the main pathogeneses of DPN. This study investigates whether TLN can inhibit SCs apoptosis by inhibiting ER stress-induced apoptosis. Our previous researches have demonstrated that TLN could increase the expression of ER stress marker protein GRP78 and inhibited the expression of apoptosis marker protein CHOP in ER stress. In this study, the results showed that TLN attenuated apoptosis by decreasing Ca2+ level in SCs and maintaining ER morphology. TLN could decrease downstream proteins of CHOP including GADD34 and Ero1α, while it increased P-eIF2α and decreased the upstream proteins of CHOP including P-IRE1α/IRE1α and XBP-1, thereby reducing ER stress-induced apoptosis.

Protective effect of Yiguanjian decoction against DNA damage on concanavalin A-induced liver injury mice model.

OBJECTIVE: To investigate the inhibitory effect of Yiguanjian decoction (YD) on DNA damage in Concanavalin A (Con A)-induced liver injury mice model and to explain the possible mechanism. METHODS: METHODS: Totally 120 male BALB/c mice were randomly divided into 6 groups, 20 mice each: normal group, model group, Bifendate group, YD low dose group, YD middle dose group and YD high dose group. Except normal group, liver injury model induced by Con A was established. While modeling, each mouse in YD group was given YD (0.4 mL/20 g per day) by intragastric administration (0.13 g YD for YD low dose group; 0.26 g for YD middle dose group; 0.52 g for YD high dose group). Bifendate group was given Bifendate (0.2 g·kg-1·d-1) by gavage. Normal group and model group were fed with same volume of physiological saline daily. After 8 weeks, the serum alanine transaminase (ALT) and aspartate transaminase (AST) were tested. The hematoxylin-eosin staining was used to evaluate the grade of liver inflammation and liver fibrosis stage. Hepatocellular DNA damage was detected by single cell gel electrophoresis technology. The protein expression of tumor necrosis factor-α (TNF-α), Bax and MutT Homolog 1 (MTH1) was detected by western blotting and enzyme linked immunosorbent assay. Bax mRNA and MTH1 mRNA were detected by Real-time Polymerase Chain Reaction (PCR). RESULTS: YD can improve the degree of liver inflammation and fibrosis in the liver of chronic hepatitis mice, the dose effect relationship is remarkable (P < 0.05). YD can reduce liver cell DNA damage. The difference between YD middle dose group and model group was statistically significant (P < 0.05). YD middle dose group had decreased the protein expression of TNF-α in the mice liver of immunological liver injury (P < 0.05). YD can increase the protein expression of Bax (P < 0.05). Compared with normal group, the protein expression of MTH1 was decreased (P < 0.05), but there was no statistical significance between YD group and model group (P > 0.05). YD can increase the mRNA expression of Bax and MTH1 (both P < 0.05). CONCLUSION: YD can effectively inhibit the DNA damage in immunological liver injury mice, the mechanism may be that it can decrease the TNF-α and increase the Bax and MTH1 expression.