Cardiolipin Synthase 1 Ameliorates NASH Through Activating Transcription Factor 3 Transcriptional Inactivation.

BACKGROUND AND AIMS: NASH is an increasingly prevalent disease that is the major cause of liver dysfunction. Previous research has indicated that adipose cardiolipin synthase 1 (CRLS1) levels are associated with insulin sensitivity; however, the precise roles of CRLS1 and underlying mechanisms involving CRLS1 in the pathological process of NASH have not been elucidated. APPROACH AND RESULTS: Here, we discovered that CRLS1 was significantly down-regulated in genetically obese and diet-induced mice models. In vitro studies demonstrated that overexpression of CRLS1 markedly attenuated hepatic steatosis and inflammation in hepatocytes, whereas short hairpin RNA-mediated CRLS1 knockdown aggravated these abnormalities. Moreover, high-fat diet-induced insulin resistance and hepatic steatosis were significantly exacerbated in hepatocyte-specific Crls1-knockout (Crls1-HKO) mice. It is worth noting that Crls1 depletion significantly aggravated high-fat and high-cholesterol diet-induced inflammatory response and fibrosis during NASH development. RNA-sequencing analysis systematically demonstrated a prominently aggravated lipid metabolism disorder in which inflammation and fibrosis resulted from Crls1 deficiency. Mechanically, activating transcription factor 3 (ATF3) was identified as the key differentially expressed gene in Crls1-HKO mice through transcriptomic analysis, and our investigation further showed that CRLS1 suppresses ATF3 expression and inhibits its activity in palmitic acid-stimulated hepatocytes, whereas ATF3 partially reverses lipid accumulation and inflammation inhibited by CRLS1 overexpression under metabolic stress. CONCLUSIONS: In conclusion, CRLS1 ameliorates insulin resistance, hepatic steatosis, inflammation, and fibrosis during the pathological process of NASH by inhibiting the expression and activity of ATF3.

Anti-inflammatory and osteoprotective effects of Shi-Wei-Ru-Xiang pills on collagen-induced arthritis in rats via inhibiting MAPK and STAT3 pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Shi-Wei-Ru-Xiang pills (SW) as a tradition Tibetan medicine has been clinically proved effective in rheumatoid arthritis (RA) treatment. However, the underlying mechanism of SW remains unclear. AIM OF THE STUDY: This study aimed to investigate the anti-arthritic effect of SW and its possible mechanisms of action. MATERIALS AND METHODS: A CIA rat model in vivo, and IL-1ß-stimulated synoviocytes or chondrocytes and a co-culture system (IL-1ß-stimulated synoviocytes/chondrocytes) in vitro were used to evaluate the effects of SW on the treatment of RA. Arthritic score, paw swelling rate, hematoxylin-eosin (HE) staining, and Safranin-O-Fast green (S-O) staining were used to evaluate the anti-arthritic activity of SW in CIA rats. TUNEL assay or flow cytometry were performed to measure chondrocytes apoptosis in vivo and invitro. The effects of SW on the expression and production of pro-inflammatory cytokines were assessed by qRT-PCR and Elisa. The inhibitory effects of SW on the phosphorylation of p38, Erk1/2, and STAT3 were analyzed by Western blot. RESULTS: SW treatment significantly alleviated paw swelling, severity of arthritic and cartilage destruction in CIA rats. Moreover, SW decreased the expression of mRNAs of proinflammatory cytokines including TNF-α, IL-1ß and IL-6 in the synovium, suppressed the production of these pro-inflammatory cytokines in serum and hind paws, downregulated the protein expression of p-p38, p-Erk1/2 and p-STAT3, and protected the chondrocytes apoptosis in CIA rats. Consistent with the results in vivo, SW also inhibited the activation of MAPK and STAT3 pathways, suppressed the expression of pro-inflammatory cytokines in IL-1ß-stimulated synoviocytes, and attenuated chondrocytes apoptosis in IL-1ß-stimulated chondrocytes. In the co-culture system, SW pre-treatment in IL-1ß-stimulated synoviocytes exhibited inhibition of chondrocytes apoptosis, which was associated with attenuation of inflammation in synoviocytes. CONCLUSION: These results suggested that the underlying mechanisms by which SW exerts its anti-arthritis effect may be related to the reduction of proinflammatory cytokine levels, inhibition of p38, Erk1/2 and STAT3 phosphorylation, and attenuating of chondrocyte apoptosis.

Analgesic and neuroprotective effects of Baimai Ointment on diabetic peripheral neuropathy.

ETHNOPHARMACOLOGY RELEVANCE: Baimai (BM) ointment, a traditional Tibetan medicine, has been widely used to treat "white vein" disease, paralysis, hemiplegia and claudication caused by trauma, because of its great effects on muscle stretching and collateral activation. As one of the most terrible complications in diabetes patients, diabetes peripheral neuropathy (DPN) is mainly manifested as abnormal pain or numbness in extremities. However, whether BM ointment is a potential drug for DPN treatment is unclear. AIMS OF THE STUDY: The aim of this study was to investigate the therapeutic effects of BM on DPN in a high-fat diet/low-dose of streptozotocin induced type 2 diabetes rat model and explore underlying mechanisms. METHODS: The chemical components of BM were determined by high performance liquid chromatography (HPLC), and the possible targets and related pathways candidates involved in the effects of BM on DPN were predicted using network pharmacology methods. Next, the effects of different doses (1.5, 3.0 and 6.0 g/kg) of BM on physiological changes, pain behaviors, motor nerve conduction velocity (MNCV) in DPN rats were assessed and compared with placebo- and mecobalamine (Meco)-treated DPN controls. Then, the effects of BM on the expression of pain associated genes as well as the phosphorylation of PI3K/AKT and MAPKs pathways in DRG of DPN rats were examined. RESULTS: Through HPLC analysis, curcumin was identified as one of the primary contents of BM. The information from network pharmacology indicated a series of target candidates for BM including IL6, IL10, TNF, CCL2, CXCL12, EGF, VEGFA, BDNF, TGFß1 and TNF, as well as PI3K-AKT and MAPK signaling pathways. Topical treatment of BM significantly improved the hypersensitivity of mechanical and thermal pain, MNCV and the morphological changes and demyelination of sciatic nerve fibers, without affecting the body weight, serum metabolism or blood glucose. The up-regulated levels of neuropeptides Cgrp, Sst, Sp and chemokines Ccl2 and Ccl3 along with the abnormal expression of p-P38, p-ERK and p-AKT in the DRG of DPN rats were alleviated by BM application. CONCLUSION: BM ointment has great activities in relieving pain hypersensitivity, neuroprotecting peripheral nerves damage caused by DPN, which may be related to the inhibition of related neuropeptide (Cgrp, Sst, Sp) and chemokine (Ccl2, Ccl3) expression and the regulation of PI3K/AKT and MAPKs signaling pathways in DRG.