Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endogenous cannabinoid anandamide (AEA) is a lipid mediator that blocks proliferation and induces apoptosis in many cell types. Although AEA levels are elevated in liver fibrosis, its role in fibrogenesis remains unclear. This study investigated effects of AEA in primary hepatic stellate cells (HSCs). Anandamide blocked HSC proliferation at concentrations of 1 to 10 micromol/L but did not affect HSC proliferation or activation at nanomolar concentrations. At higher concentrations (25-100 micromol/L), AEA rapidly and dose-dependently induced cell death in primary culture-activated and in vivo-activated HSCs, with over 70% cell death after 4 hours at 25 micromol/L. In contrast to treatment with Fas ligand or gliotoxin, AEA-mediated death was caspase independent and showed typical features of necrosis such as rapid adenosine triphosphate depletion and propidium iodide uptake. Anandamide-induced reactive oxygen species (ROS) formation, and an increase in intracellular Ca(2+). Pretreatment with the antioxidant glutathione or Ca(2+)-chelation attenuated AEA-induced cell death. Although the putative endocannabinoid receptors CB1, CB2, and VR1 were expressed in HSCs, specific receptor blockade failed to block cell death. Depletion of membrane cholesterol by methyl-beta-cyclodextrin inhibited AEA binding, blocked ROS formation and intracellular Ca(2+)-increase, and prevented cell death. In primary hepatocytes, AEA showed significantly lower binding and failed to induce cell death even after prolonged treatment. In conclusion, AEA efficiently induces necrosis in activated HSCs, an effect that depends on membrane cholesterol and a subsequent increase in intracellular Ca(2+) and ROS. The anti-proliferative effects and the selective killing of HSCs, but not hepatocytes, indicate that AEA may be used as a potential anti-fibrogenic tool.
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PMID:Anandamide induces necrosis in primary hepatic stellate cells. 1584 44

Hepatic fibrogenesis is reduced in the absence of leptin. We hypothesized that leptin protects hepatic stellate cells (HSCs) from apoptosis and tested this in in vitro and in vivo systems. (i) Fas ligand (fas-L)-mediated apoptosis was induced in vitro in activated HSCs in the absence and presence of leptin. (ii) HSC apoptosis was also induced by UV irradiation in the absence and presence of leptin. (iii) Fas-L-mediated apoptosis was induced in vitro in HSCs from db/db mice in the absence and presence of leptin. (iv) Liver fibrosis was induced in wt and db/db mice. (v) Liver fibrosis was induced in wild-type mice with TAA, and mice received additional leptin or a control solution. HSC apoptosis was assessed by TUNEL staining. Western blot for alpha-SMA was used to determine differences in HSC activation. Results were as follows. (i) Fas-L induced significant apoptosis of HSC, and preincubation with leptin reduced this approximately threefold. (ii) Leptin provided no protection from UV-induced apoptosis. (iii) HSCs from db/db mice were not protected by leptin against fas-L-induced apoptosis. (iv) TAA-induced fibrosis was significantly less in db/db mice compared to wild type. (v) Wild-type mice receiving leptin had less apoptosis and more alpha-SMA than controls. We conclude that leptin protects HSC from in vitro and in vivo apoptosis. The antiapoptotic effect of leptin requires the long form of the leptin receptor and interacts with the apoptotic pathway proximal to mitochondrial activation.
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PMID:In vitro and in vivo protection of stellate cells from apoptosis by leptin. 1695 95

The liver is a vital organ for life and the only internal organ that is capable of natural regeneration. Although the liver has high regeneration capacity, excessive hepatocyte death can lead to liver failure. Various factors can lead to liver damage including drug abuse, some natural products, alcohol, hepatitis, and autoimmunity. Some models for studying liver injury are APAP-based model, Fas ligand (FasL), D-galactosamine/endotoxin (Gal/ET), Concanavalin A, and carbon tetrachloride-based models. The regeneration of the liver can be carried out using umbilical cord blood stem cells which have various advantages over other stem cell types used in liver transplantation. UCB-derived stem cells lack tumorigenicity, have karyotype stability and high immunomodulatory, low risk of graft versus host disease (GVHD), low risk of transmitting somatic mutations or viral infections, and low immunogenicity. They are readily available and their collection is safe and painless. This review focuses on recent development and modern trends in the use of umbilical cord stem cells for the regeneration of liver fibrosis.
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PMID:Therapeutic Potential of Umbilical Cord Stem Cells for Liver Regeneration. 3207 30