Jatrorrhizine ameliorates Schwann cell myelination via inhibiting HDAC3 ability to recruit Atxn2l for regulating the NRG1-ErbB2-PI3K-AKT pathway in diabetic peripheral neuropathy mice.

Diabetic peripheral neuropathy (DPN) is a chronic complication associated with nerve dysfunction and uncontrolled hyperglycemia. Unfortunately, due to its complicated etiology, there has been no successful therapy for DPN. Our research recently revealed that jatrorrhizine (JAT), one of the active constituents of Rhizoma Coptidis, remarkably ameliorated DPN. This work highlighted the potential mechanism through which JAT relieves DPN using db/db mice. The results indicated that JAT treatment significantly decreased the threshold for thermal and mechanical stimuli and increased nerve conduction velocity. Histopathological analysis revealed that JAT significantly increased the number of sciatic nerve fibers and axons, myelin thickness, and axonal diameters. Additionally, JAT markedly elevated the expression of myelination-associated proteins (MBP, MPZ, and Pmp22). The screening of histone deacetylases (HDAC) determined that histone deacetylase 3 (HDAC3) is an excellent target for JAT-induced myelination enhancement. Liquid chromatography-mass spectrometry-(MS)/MS and coimmunoprecipitation analyses further confirmed that HDAC3 antagonizes the NRG1-ErbB2-PI3K-AKT signaling axis by interacting with Atxn2l to augment SCs myelination. Thus, JAT ameliorates SCs myelination in DPN mice via inhibiting the recruitment of Atxn2l by HDAC3 to regulate the NRG1-ErbB2-PI3K-AKT pathway.

Epiberberine ameliorated diabetic nephropathy by inactivating the angiotensinogen (Agt) to repress TGFß/Smad2 pathway.

BACKGROUND: Diabetic nephropathy (DN) is a severe microvascular complication of diabetes with prominent morbidity and mortality. At present, there are hardly any effective drugs to treat DN. Epiberberine (EPI), an isoquinoline alkaloid, has attracted considerable attention due to its anti-hyperglycemic, anti-hyperlipidemic, and anti-inflammatory functions. However, whether there is a protective effect of EPI on DN has not been reported. PURPOSE: The research was aimed to investigate the activities of EPI alleviating kidney damage in db/db mice and to explore its possible mechanisms. STUDY DESIGN: The db/db mice and high-glucose (HG) induced glomerular mesangial cells (GMCs) were used to explore the protective effect of EPI on DN in vivo and in vitro. METHODS: The changes in fasting blood glucose, metabolic index, renal function, and histopathological morphology in db/db mice were detected to evaluate the therapeutic effect of EPI. Then, renal transcriptome and molecular docking were used to screen the key targets. Subsequently, HG-induced GMCs through mimicing the pathological changes in DN were utilized to study the renal protective effects of EPI and its potential mechanism. RESULTS: The results in vivo showed that EPI administration for 8 weeks significantly alleviated diabetes-related metabolic disorders, improved renal functions, and relieved the histopathological abnormalities of renal tissue, especially renal fibrosis in db/db mice. The results in vitro showed that EPI inhibited the proliferation and induced the G2/M phase arrest of HG-induced GMCs. Moreover, a key gene Angiotensinogen (Agt) was screen out by the RNA-seq of kidney and molecular docking, and EPI reduced Agt, TGFß1, and Smad2 expression in vitro and in vivo. Noteworthy, Agt knockdown by siRNA significantly attenuated these beneficial efficacies exerted by EPI, indicating that Agt played a crucial role in the process of EPI improving DN. CONCLUSION: These findings suggested that EPI might be a potential drug for the treatment of DN dependent on the Agt-TGFß/Smad2 pathway.