demethyleneberberine and Disease-Models--Animal

Demethyleneberberine (DMB) is a natural product from traditional Chinese medicinal herb the rhizome of Coptis chinensis Franch., which has been reported to possess multiple pharmacological activities, especially anti-inflammation and immunoregulation. However, the potential mechanism of DMB in inflammation is still a mystery. In this study, a mouse model of ulcerative colitis (UC) was induced by Dextran sulfate sodium salt (DSS), and in vitro experiments were performed in RAW264.7 macrophages and the primary intestinal macrophages which obtained from Toll-Like receptor 4 (TLR4) and NOD-Like receptor protein 3 (NLRP3) knockout fetal mouse. Mitochondrial was increased by overexpression of peroxlsome proliferator-activated receptor-γ coactlvator-1α (PGC-1α) and exhausted by adding Ethidium Bromide (EtBr) in RAW264.7 to evaluate the function of mitochondria in the maturation of IL-1β. Additionally, the safety of DMB (50 mg/kg/d) in mice was assessed by orally administrating for 98 days. DMB siginificantly improved colon atrophy, colonic tissue mass score, neutrophil infiltration and histological damage, which was mainly attributed to the anti-inflammatory effect of DMB. Further in vitro analysis showed that DMB blocked the excessive mitochondrial biosynthesis and maintained the homeostasis of mitochondria in inflammatory response. Moreover, the maturation of IL-1β was suppressed by DMB in a mitochondria dependent manner. Crucially, DMB was a candidate agent for UC with free of toxicity and side effects. These findings demonstrated that DMB ameliorated inflammatory response by inhibiting TLR4-mitochondria signaling, and revealed the effectiveness and mechanism of DMB for alleviation of UC and provided an additional strategy for UC intervention.

Topics: Animals; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Inflammation; Mice; Mice, Inbred C57BL; Mitochondria; NF-kappa B; Toll-Like Receptor 4

Demethyleneberberine (DMB) is an essential metabolite of Berberine (BBR) in vivo. Recent reports have revealed multiple novel therapeutic applications of BBR. However, the pharmacological activities of DMB remain to be elucidated. This study aimed to demonstrate the hepatoprotective and anti-fibrotic effects of DMB both in vitro and in vivo. Here we showed that DMB protects against thioacetamide (TAA)-induced hepatic fibrosis in mice and exhibits a higher safety profile as compared to BBR. Flow cytometry and Western blotting analysis showed that DMB is able to suppress the activation of hepatic stellate cells (HSCs) and induce cell apoptosis through the nuclear factor-κB (NF-κB) cascade. Immunohistochemical (IHC) and quantitative polymerase chain reaction (qPCR) analysis indicated that DMB also has inhibitory effects on collagen synthesis and is able to increase collagen degradation by blocking the transforming growth factor β 1 (TGF-β1)-Smad signaling and reducing the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs). These findings indicate that DMB has the potential to attenuate hepatic fibrosis via suppressing HSC activation.

Topics: Actins; Animals; Apoptosis; Berberine; Cell Line; Collagen; Disease Models, Animal; Hepatic Stellate Cells; Liver Cirrhosis; Male; Matrix Metalloproteinases; Mice; Mice, Inbred ICR; NF-kappa B; Protective Agents; Rats; Signal Transduction; Smad Proteins; Thioacetamide; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta1

Excessive alcohol consumption induces oxidative stress and lipid accumulation in the liver. Mitochondria have long been recognized as the key target for alcoholic liver disease (ALD). Recently, the artificial mitochondria-targeted antioxidant MitoQ has been used to treat ALD effectively in mice. Here, we introduce the natural mitochondria-targeted antioxidant demethyleneberberine (DMB), which has been found in Chinese herb Cortex Phellodendri chinensis. The protective effect of DMB on ALD was evaluated with HepG2 cells and acutely/chronically ethanol-fed mice, mimicking two common patterns of drinking in human. The results showed that DMB, which is composed of a potential antioxidant structure, could penetrate the membrane of mitochondria and accumulate in mitochondria either in vitro or in vivo. Consequently, the acute drinking-caused oxidative stress and mitochondrial dysfunction were significantly ameliorated by DMB. Moreover, we also found that DMB suppressed CYP2E1, hypoxia inducible factor α, and inducible nitric oxide synthase, which contributed to oxidative stress and restored sirtuin 1/AMP-activated protein kinase/peroxisome proliferator-activated receptor-γ coactivator-1α pathway-associated fatty acid oxidation in chronic ethanol-fed mice, which in turn ameliorated lipid peroxidation and macrosteatosis in the liver. Taking these findings together, DMB could serve as a novel and potential therapy for ALD in human beings.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Berberine; Cytochrome P-450 CYP2E1; Disease Models, Animal; Ethanol; Fatty Acids; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Diseases, Alcoholic; Male; Mice; Mitochondria; Nitric Oxide Synthase Type II; Oxidation-Reduction; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Signal Transduction; Sirtuin 1; Transcription Factors