Nuclear factor-erythroid 2 related factor 2 (Nrf2)-mediated signaling plays a central role in maintaining cellular redox homeostasis of hepatic cells. Carbon monoxide releasing molecule-A1 (CORM-A1) has been reported to stimulate up-regulation and nuclear translocation of Nrf2 in hepatocytes. However, the role of CORM-A1 in improving lipid metabolism, antioxidant signaling and mitochondrial functions in nonalcoholic steatohepatitis (NASH) is unknown. In this study, we report that CORM-A1 prevents hepatic steatosis in high fat high fructose (HFHF) diet fed C57BL/6J mice, used as model of NASH. The beneficial effects of CORM-A1 in HFHF fed mice was associated with improved lipid homeostasis, Nrf2 activation, upregulation of antioxidant responsive (ARE) genes and increased ATP production. As, mitochondria are intracellular source of reactive oxygen species (ROS) and important sites of lipid metabolism, we further investigated the mechanisms of action of CORM-A1-mediated improvement in mitochondrial function in palmitic acid (PA) treated HepG2 cells. Cellular oxidative stress and cell viability were found to be improved in PA + CORM-A1 treated cells via Nrf2 translocation and activation of cytoprotective genes. Furthermore, in PA treated cells, CORM-A1 improved mitochondrial oxidative stress, membrane potential and rescued mitochondrial biogenesis thru upregulation of Drp1, TFAM, PGC-1α and NRF-1 genes. CORM-A1 treatment improved cellular status by lowering glycolytic respiration and maximizing OCR. Improvement in mitochondrial respiration and increment in ATP production in PA + CORM-A1 treated cells further corroborate our findings. In summary, our data demonstrate for the first time that CORM-A1 ameliorates tissue damage in steatotic liver via Nrf2 activation and improved mitochondrial function, thus, suggesting the anti-NASH potential of CORM-A1.
A new set of curcumin
analogues with a Schiff base moiety
were
synthesized from a bis-aldehyde derivative of hydroxybenzylidene cyclohexanone
and various alicyclic and aromatic amines. The single crystals of
compound 2 (bis-aldehyde), compound 3b (bis-cyclohexylimino
derivative), and compound 3c (bis-1-imino piperidyl derivative)
were developed. The said bis-imino and bis-amino curcuminoids were
tested for anticancer activity against MCF-7 utilizing the conventional
MTT assay. These Schiff bases had significantly higher anticancer
efficacy than curcumin and methotrexate against MCF-7 cell lines.
Compounds 3k, 3b, and 3l have the highest
efficacy among all synthesized curcuminoids. The MTT results are in
accordance with the binding affinities found by docking the said molecules
with HER2 Tyrosine Kinase (HER2-TK). Compound 3b is identified
as a promising HER2-TK inhibitor and also shows effective inhibition
against Gram-positive bacteria Staphylococcus aureus.
Background
Stem cells are widely used for therapy including treatment of liver damage. Adipose-derived mesenchymal stem cells (ADMSCs) administered to treat fatty liver are known to improve liver function but their use is restricted due to a poor success rate. This study investigates efficacy of melatonin-primed ADMSCs (Mel. MSCs) in experimentally induced non-alcoholic fatty liver disease (NAFLD).
Results
MSCs treated with LPS showed prominent DCFDA fluorescence as compared to the untreated cells. Also, the JC-1 staining had accounted for higher intensity of green monomer and a weak fluorescence of red dimer indicating weaker mitochondrial membrane potential. But melatonin co-treatment could make necessary corrective changes as evidenced by reverse set of results. The overall cell survival was also found to be improved following melatonin treatment as evidenced by the MTT assay. Also, the antioxidant (Nrf2 and Ho-1) and anti-inflammatory genes (Il-4 and Il-10) showed a decrement in their mRNA levels following LPS treatment whereas the pro-inflammatory genes (Tnf-α, Il-6, Tlr-4, and Lbp) showed a reciprocal increment in the said group. Melatonin co-treatment accounted for an improved status of antioxidant and anti-inflammatory genes as evidenced by their mRNA levels. High-fat high-fructose diet (HFFD) fed C57BL/6J mice recorded higher serum AST and ALT levels and fatty manifestation in histology of liver along with lowered mRNA levels of antioxidant (Nrf2, Catalase, and Gss) genes and Hgf. These set of parameters showed a significant improvement in HFFD + Mel.MSC group.
Conclusion
A significant improvement in viability of MSCs was recorded due to lowered intracellular oxidative stress and improves mitochondrial membrane potential. Further, melatonin-primed MSCs accounted for a significant decrement in fatty manifestations in liver and an improved physiological status of NAFLD in HFFD fed C57BL/6J mice. Taken together, it is hypothesized that melatonin priming to MSCs prior to its use can significantly augment the success of stem cell therapy.
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