Attenuation of kainic acid-induced epilepsy by butyrate is associated with inhibition of glial activation

Purpose: To investigate the function and potential therapeutic relevance of butyrate in epilepsy using rat models of kainic acid (KA)-induced epilepsy.Methods: The neurotoxin KA was applied to rats and rat astrocytes to establish models of epilepsy in vivo and in vitro. Multiple parameters, including behavioural seizure scores, were evaluated in rats and rat astrocytes treated with KA alone or in combination with butyrate. Western blot was performed to examine the levels of phosphorylated extracellular signal-related kinase (p-ERK), proinflammatory cytokine (IL-1ß), and glial fibrillary acidic protein (GFAP).Results: Significant increases were observed in the seizure-related proteins p-ERK and GFAP and in the proinflammatory cytokine IL-1ß in KA-treated rats and rat astrocytes (p < 0.05). Butyrate treatment attenuated KA-induced epileptic behaviour in rats and significantly reduced the expression of p-ERK, GFAP, and IL-1ß in a dose-dependent manner (p < 0.05).Conclusion: Butyrate has potential as a treatment for epilepsy by inhibiting the activation of p-ERK, astrogliosis, and inflammation, which were induced by KA in rats and rat astrocytes.Keywords: Kainic acid, Epilepsy, Butyrate, Glial activation, Astrogliosi

The degradation of TGR5 mediated by Smurf1 contributes to diabetic nephropathy

Summary: The multiple roles of TGR5 in the regulation of glucose metabolism, inflammation, and oxidative stress have drawn attention as therapeutic candidates for diabetes-related kidney disease. However, diabetes induces downregulation of renal TGR5 protein expression, and the regulatory mechanisms have not been clarified. Here, we identify that Smurf1, an E3 ubiquitin ligase, is a critical interactor of TGR5 and mediates the ubiquitination and proteasomal degradation of TGR5 under high glucose stimulation in glomerular mesangial cells. Genetic deficiency of Smurf1 restores TGR5 protein expression and attenuates renal injuries in diabetic mice. Mechanistically, Smurf1 interacts with the TGR5 ICL2 region by its HECT domain and induces K11/K48-linked polyubiquitination of TGR5 at K306 residue. Moreover, restoration of TGR5 protects db/db mice from diabetic nephropathy. These observations elucidate the critical role of Smurf1 in regulating TGR5 stability, suggesting that pharmacological targeting of the interaction between Smurf1 and TGR5 could serve as a promising therapeutic strategy against diabetic nephropathy