Background and Purpose: Mitochondrial fission-fusion dynamics and bioenergy dysfunctions are participated in cerebral ischemia/reperfusion (I/R) injury. Our study aims to investigate the role of Mul1-dependent Mfn2 ubiquitination and its mediated mitochondrial dysfunctions and explain the molecular mechanism of ginsenoside compound K (CK) targeting Mul1 against cerebral I/R injury. Experimental Approach: We used a combination of in vitro and in vivo models, including oxygen and glucose deprivation/reperfusion-induced PC12 cell model and middle cerebral artery occlusion/reperfusion-induced rat model, to mimic I/R injury. The potential mechanisms and pharmacological effects of ginsenoside CK on mitochondrial dynamics and bioenergy were evaluated by Mul1 knockdown and pharmacological antagonism study using a series of experiments. Key Results: I/R injury stimuli upregulated the binding of Mul1 with Mfn2 to regulate Mfn2 ubiquitination and degradation, which resulted in increased mitochondrial fission, bioenergy dysfunction, neuronal apoptosis, and neurological impairment. Knockdown of Mul1 exerted beneficial effect on cerebral I/R-induced neuronal death by abolishing mitochondrial fission, mitophagy, and bioenergy dysfunction. More importantly, ginsenoside CK mainly inhibited Mul1 expression to reduce Mfn2 ubiquitination and mitochondrial translocation of DRP1, thereby inhibiting mitochondrial fission, mitophagy and mitochondrial apoptosis against cerebral I/R injury in both in vitro and in vivo models. Conclusions and Implications: These data for the first time explain molecular basis of the Mul-dependent mitochondrial dysfunctions during I/R damages and provide the evidence that ginsenoside CK may be a promising therapeutic agent against cerebral I/R injury by targeting Mul1/Mfn2-mediated mitochondrial dynamics and bioenergy.

Background and Purpose: Polysaccharides from Panax ginseng C. A. Meyer (P. ginseng) are the main active component and exhibit significant intestinal anti-inflammatory activity. However, the unclear therapeutic mechanism of ginseng polysaccharide hinders the application for medicine or functional food. Experimental Approach: In this study, a polysaccharide was isolated from P. ginseng (GP). The primary structure and morphology of GP were studied by HPLC, FT-IR spectra, and scanning electron microscopy (SEM). Further, its intestinal anti-inflammatory activity and its mechanism of function were evaluated in experimental systems using DSS-induced rats, fecal microbiota transplantation (FMT), and LPS-stimulated HT-29 cells. Key Results: Results showed that GP restored mTOR-dependent autophagic dysfunction via modulating the structure of gut microbiota and blocking the TLR4-MyD88 pathway. Consequently, active autophagy suppressed inflammation through the inhibition of NF-κB, oxidative stress, and the release of cytokines. Conclusion and Implications: Therefore, our research provided a rationale for future investigations into the relationship between microbiota and autophagy via TLR4 and revealed the therapeutic potential of GP for inflammatory bowel disease.

Aerobic cellular respiration provides chemical energy, adenosine triphosphate (ATP), to maintain multiple cellular functions. Sirtuin 1 (SIRT1) can deacetylate peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) to promote mitochondrial biosynthesis. Targeting energy metabolism is a potential strategy for the prevention and treatment of various diseases, such as cardiac and neurological disorders. Ginsenosides, one of the major bioactive constituents of Panax ginseng, have been extensively used due to their diverse beneficial effects on healthy subjects and patients with different diseases. However, the underlying molecular mechanisms of total ginsenosides (GS) on energy metabolism remain unclear. In this study, oxygen consumption rate, ATP production, mitochondrial biosynthesis, glucose metabolism, and SIRT1-PGC-1α pathways in untreated and GS-treated different cells, fly, and mouse models were investigated. GS pretreatment enhanced mitochondrial respiration capacity and ATP production in aerobic respiration-dominated cardiomyocytes and neurons, and promoted tricarboxylic acid metabolism in cardiomyocytes. Moreover, GS clearly enhanced NAD+-dependent SIRT1 activation to increase mitochondrial biosynthesis in cardiomyocytes and neurons, which was completely abrogated by nicotinamide. In addition, GS had protective effects against hypoxia- or oxygen-glucose deprivation-induced cardiomyocyte damage through activation of the SIRT1-PGC-1α pathway. Importantly, ginsenoside monomers, such as Rg1, Re, Rf, Rb1, Rc, Rh1, Rb2, and Rb3, were found to activate SIRT1 and promote energy metabolism. This study may provide new insights into the extensive application of ginseng for cardiac and neurological protection in healthy subjects and patients with ischemic disorders.