From zinc homeostasis to disease progression: Unveiling the neurodegenerative puzzle.

Zinc is a crucial trace element in the human body, playing a role in various physiological processes such as oxidative stress, neurotransmission, protein synthesis, and DNA repair. The zinc transporters (ZnTs) family members are responsible for exporting intracellular zinc, while Zrt- and Irt-like proteins (ZIPs) are involved in importing extracellular zinc. These processes are essential for maintaining cellular zinc homeostasis. Imbalances in zinc metabolism have been linked to the development of neurodegenerative diseases. Disruptions in zinc levels can impact the survival and activity of neurons, thereby contributing to the progression of neurodegenerative diseases through mechanisms like cell apoptosis regulation, protein phase separation, ferroptosis, oxidative stress, and neuroinflammation. Therefore, conducting a systematic review of the regulatory network of zinc and investigating the relationship between zinc dysmetabolism and neurodegenerative diseases can enhance our understanding of the pathogenesis of these diseases. Additionally, it may offer new insights and approaches for the treatment of neurodegenerative diseases.

Ferroportin-dependent ferroptosis induced by ellagic acid retards liver fibrosis by impairing the SNARE complexes formation.

Chronic liver injury causing liver fibrosis is a major cause of morbidity and mortality worldwide. Targeting the suppression of hepatic stellate cell (HSC) activation is recognized as an effective strategy for the treatment of liver fibrosis. Ellagic acid (EA), a natural polyphenol product isolated from fruits and vegetables, possesses many biological functions. Here, EA exerts its antifibrotic activity by inducing ferroptotic cell death of activated HSCs, which is accompanied by redox-active iron accumulation, lipid peroxidation, and GSH depletion in CCl4 mice and human LX-2 cells. The specific ferroptosis inhibitor ferrostatin-1 prevented EA-induced ferroptotic cell death. Mechanistically, EA impairs the formation of vesicle-associated membrane protein 2 (VAMP2)/syntaxin 4 and VAMP2/synaptosome-associated protein 23 complexes by suppressing VAMP2 expression by enhancing its degradation in a proteasome-dependent pathway. This leads to the impairment of ferroportin (FPN, an iron exporter) translocation and intracellular iron extrusion. Interestingly, VAMP2 overexpression inhibits the role of EA in blocking FPN translocation and increasing intracellular ferritin content (an iron storage marker). In contrast, VAMP2 knockdown shows a synergistic effect on EA-mediated ferroptotic events in both HSCs. Additionally, HSC-specific overexpression of VAMP2 impaired EA-induced HSC ferroptosis in mouse liver fibrosis, and HSC-specific VAMP2 knockdown increased the inhibitory effect of EA on fibrosis. Taken together, our data suggest that the natural product EA exerts its antifibrotic effects by inducing FPN-dependent ferroptosis of HSCs by disrupting the formation of SNARE complexes, and EA will hopefully serve as a prospective compound for liver fibrosis treatment.

Yes-associated protein regulates the hepatoprotective effect of vitamin D receptor activation through promoting adaptive bile duct remodeling in cholestatic mice.

Mounting clinical evidence has revealed that the vitamin D receptor (VDR) is associated with cholestatic liver injury, although the functions of VDR in this condition remain largely unexplored. Here, we investigated the effects of VDR activation on bile duct ligation (BDL) mice, and the underlying mechanisms were further investigated. A low-calcemic VDR agonist, paricalcitol (PAL, 200 ng/kg), was intraperitoneally injected into BDL mice every other day for 5 days or 28 days. Liver histology, liver function indicators, cholangiocyte proliferation, fibrosis scores, and inflammation were evaluated. Mice treated with PAL were rescued from the decreased survival rate induced by BDL and liver damage was reduced. Mechanistically, PAL promoted cholangiocyte proliferation, which was likely conducive to proliferating bile duct maturation and increased branching of bile ducts. PAL treatment also increased the expression of Yes-associated protein (YAP) and its target protein epithelial cell adhesion molecule (EpCam) and decreased the level of inactive cytoplasmic phosphorylated YAP. YAP knockdown abrogated PAL-induced primary bile duct epithelial cell proliferation, confirmed with YAP inhibitor administration. In addition, BDL-induced liver fibrosis and inflammatory cell infiltration were reduced by PAL treatment at both day 5 and day 28 post-BDL. In conclusion, VDR activation mitigates cholestatic liver injury by promoting adaptive bile duct remodeling through cholangiocytic YAP upregulation. Because PAL is an approved clinical drug, it may be useful for treatment of cholestatic liver disease. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Paricalcitol inhibits oxidative stress-induced cell senescence of the bile duct epithelium dependent on modulating Sirt1 pathway in cholestatic mice.

BACKGROUND: Clinical studies indicate that vitamin D receptor (VDR) expression is reduced in primary biliary cirrhosis patient livers. However, the mechanism by which activated VDR effect cholestatic liver injury remains unclear. METHODS: Mice were injected intraperitoneally with the VDR agonist paricalcitol or a vehicle 3 days prior to bile duct ligation (BDL) and for 5 or 28 days after surgery. The analyses of liver morphology and necrotic areas were based on H&E staining. Serum biochemical indicators of liver damage were analyzed by commercial kits. The mechanisms of paricalcitol on cholestatic liver injury were determined by Western blot analysis. RESULTS: Paricalcitol ameliorated the BDL-induced liver damage in mice. Paricalcitol increased the proliferation of BECs to promote the repair of the bile duct. Paricalcitol also reduced the BDL-induced oxidative stress level in the mice. Mechanistic analysis revealed that paricalcitol decreased the number of SA-ß-gal-positive cells and downregulated the expression of p53, p21 and p16 proteins which was associated with reducing oxidative stress. Additionally, paricalcitol exerted the inhibitory effect of cell senescence was through reducing DNA damage and promoting DNA repair. Interesting, we found that paricalcitol prevented the downregulation of oxidative stress-induced Sirt1 expression in the BDL mice and t-BHP-induced BECs models. Moreover, paricalcitol suppressed cell senescence through a Sirt1-dependent pathway. These results were confirmed by antioxidant ALCAR and the Sirt1 inhibitor EX-527. CONCLUSION: Paricalcitol alleviated cholestatic liver injury through promoting the repair of damaged bile ducts and reducing oxidative stress-induced cell senescence of the bile duct via modulating Sirt1 pathway.

Velvet antler polypeptide prevents the disruption of hepatic tight junctions via inhibiting oxidative stress in cholestatic mice and liver cell lines.

The present study aims to examine the protective effects and mechanism of a velvet antler polypeptide (VAP) against lithocholic acid (LCA)-induced cholestatic liver injury in mice. A 7.0 kDa VAP was orally administered at doses of 10 and 20 mg kg-1 day-1. Hematoxylin and eosin (H&E) staining of the liver showed that VAP7.0 reduced LCA-induced infiltration of inflammatory cells and areas of necrotic hepatocytes. In addition, VAP7.0 greatly reduced the levels of alanine aminotransferase (ALT), total bile acid (TBA) and total bilirubin (TBIL) in LCA mouse serum and prolonged the survival time of mice with LCA. VAP7.0 reduced the production of reactive oxygen species (ROS), decreased malondialdehyde (MDA) and increased the superoxide dismutase (SOD) levels in LCA mice. VAP7.0 also reduced OGG1 expression, which is a biochemical indicator of oxidative stress. Mechanistic analysis revealed that VAP7.0 significantly inhibited LCA-induced disruption of tight junction integrity, as determined by observing the morphology of the bile canaliculus, and this finding was confirmed by observation of the bile canalicular structure and tight junction proteins Occludin and ZO-1 expression. Moreover, we also found that VAP7.0 maintained the stability of hepatic paracellular permeability, as determined by Evans blue dye assays and horseradish peroxidase (HRP) tracer distribution through inhibiting the activation of the PI3K pathway in LCA mouse livers. In addition, VAP7.0 ameliorated H2O2-induced barrier dysfunction and tight junction disruption via inhibiting the PI3K activity in human HepG2 and SMMC7721 cells, which was confirmed by the PI3K activator 740Y-P. H2O2 disturbed the localization of the tight junction proteins ZO-1 and Occludin, resulting in the transfer of these proteins from the membrane to the cytoplasm of cells, whereas pretreatment of cells with VAP7.0 prevented the disruption of the localization of these proteins, as determined by immunofluorescence staining and western blot analysis. These results demonstrate that VAP7.0 reduces liver injury by inhibiting oxidative stress and maintains the stability of hepatic tight junctions via suppressing the activation of the intracellular signaling molecule PI3K in LCA mice and hepatocellular carcinoma cells.