Nonalcoholic steatohepatitis (NASH) is a critical stage in the progression of nonalcoholic fatty liver disease (NAFLD). Tanshinone IIA (TIIA) is a tanshinone extracted from Salvia miltiorrhiza; due to its powerful anti-inflammatory and antioxidant biological activities, it is commonly used for treating cardiovascular and hepatic diseases. A NASH model was established by feeding mice a methionine and choline-deficient (MCD) diet. Liver surface microblood flow scanning, biochemical examination, histopathological examination, cytokine analysis through ELISA, lipidomic analysis, transcriptomic analysis, and Western blot analysis were used to evaluate the therapeutic effect and mechanism of TIIA on NASH. The results showed that TIIA effectively reduced lipid accumulation, fibrosis, and inflammation and alleviated endoplasmic reticulum (ER) stress. Lipidomic analysis revealed that TIIA normalized liver phospholipid metabolism in NASH mice. A KEGG analysis of the transcriptome revealed that TIIA exerted its effect by regulating the PPAR signalling pathway, protein processing in the ER, and the NOD-like receptor signalling pathway. These results suggest that TIIA alleviates NASH by activating the PPARα/FGF21 axis to negatively regulate the ER stress-induced unfolded protein response (UPR).

Leonurine is a natural product unique to the Lamiaceae plant Leonurus japonicus Houtt., and it has attracted attention due to its anti-oxidative stress, anti-apoptosis, anti-fibrosis, and metabolic regulation properties. Also, it plays an important role in the prevention and treatment of nonalcoholic fatty liver disease (NAFLD) through a variety of biological mechanisms, but its mechanism of action remains to be elucidated. Therefore, this study aims to preliminarily explore the mechanisms of action of leonurine in NAFLD. Mice were randomly divided into four groups: the normal control (NC) group, the Model (M) group, the leonurine treatment (LH) group, and the fenofibrate treatment (FB) group. The NAFLD model was induced by a high-fat high-sugar diet (HFHSD) for 12 weeks, and liver pathological changes and biochemical indices were observed after 12 weeks. Transcriptomic analysis results indicated that leonurine intervention reversed the high-fat high-sugar diet-induced changes in lipid metabolism-related genes such as stearoyl-CoA desaturase 1 (Scd1), Spermine Synthase (Sms), AP-1 Transcription Factor Subunit (Fos), Oxysterol Binding Protein Like 5 (Osbpl5), and FK506 binding protein 5 (Fkbp5) in liver tissues. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results suggest that leonurine may exert its lipid-lowering effects through the AMP-activated protein kinase (AMPK) signaling pathway. Liver lipidomic analysis showed that leonurine could alter the abundance of lipid molecules related to fatty acyl (FAs) and glycerophospholipids (GPs) such as TxB3, carnitine C12-OH, carnitine C18:1-OH, and LPC (20:3/0:0). Molecular biology experiments and molecular docking techniques verified that leonurine might improve hepatic lipid metabolism through the alpha-1A adrenergic receptor (ADRA1a)/AMPK/SCD1 axis. In summary, the present study explored the mechanism by which leonurine ameliorated NAFLD by inhibiting hepatic lipid synthesis via the ADRA1a/AMPK/SCD1 axis.

Nonalcoholic steatohepatitis (NASH) is a form of chronic liver disease that is characterized by liver inflammation and steatosis, with possible progression to fibrosis. Currently, no drugs have been approved for the treatment of NASH. In this study, we isolated a polysaccharide from Atractylodes lancea rhizome (AP) and established a methionine- and choline-deficient (MCD) diet -induced NASH mouse model to investigate the preventive effect and potential mechanism of AP on NASH. The results showed that AP effectively reduced liver lipid accumulation and inflammation and reduced autophagy and ferroptosis in hepatocytes, thereby preventing the development of NASH. These findings suggest that AP may be a promising natural candidate for the treatment of NASH.

Background: Postmenopausal osteoporosis is a common metabolic bone disease that leads to reduced bone formation and increased fracture risk. Nuciferine, an aporphine alkaloid from the lotus leaf, can regulate the TFEB-mediated autophagy-lysosomal pathway. This pathway is critical for osteogenic differentiation. However, it remains unclear whether nuciferine promotes bone formation and alleviates bone loss through this pathway. We therefore hypothesized that nuciferine activates the TFEB-mediated autophagy-lysosomal pathway to promote osteogenic differentiation, thereby counteracting estrogen deficiency-induced bone loss. Methods: We established an OVX rat model (6-month-old females, 24.0 ± 1.0 weeks, n = 10/group), treated the rats with nuciferine via oral gavage for 12 weeks, and used rat BMSCs for mechanistic studies in vitro. Results: Nuciferine significantly increased bone mineral density (BMD) and improved bone microarchitecture in OVX rats; upregulated serum levels of the bone turnover markers bone-specific alkaline phosphatase (BALP), procollagen type I N-terminal propeptide (PINP) and osteocalcin (BGP); and downregulated serum tartrate-resistant acid phosphatase (TRAP), as measured via ELISA. Nuciferine also restored the expression of osterix (OSX) and transcription factor EB (TFEB) in bone tissue, as detected via TSA staining. Furthermore, it increased the microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio and decreased p62 expression, as determined through Western blotting, indicating the activation of autophagy. In vitro, nuciferine promoted osteogenic differentiation and TFEB nuclear translocation in BMSCs, whereas TFEB silencing suppressed both, an effect partially reversed by nuciferine, as shown via ALP/ARS staining, Western blotting, RT-qPCR, and immunofluorescence. Conclusions: In conclusion, nuciferine ameliorates bone loss in OVX rats and promotes the osteogenic differentiation of BMSCs. Activation of the TFEB-mediated autophagy-lysosomal pathway is a key mechanism underlying its improvement of bone metabolism.