Browsing by Subject "SIRT1"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Decreased SIRT1 Activity Is Involved in the Acute Injury Response of Chondrocytes to Ex Vivo Injurious Mechanical Overload
    (MDPI, 2023-03-30) Karnik, Sonali; Noori-Dokht, Hessam; Williams, Taylor; Joukar, Amin; Trippel, Stephen B.; Sankar, Uma; Wagner, Diane R; Mechanical and Energy Engineering, School of Engineering and Technology
    A better understanding of molecular events following cartilage injury is required to develop treatments that prevent or delay the onset of trauma-induced osteoarthritis. In this study, alterations to SIRT1 activity in bovine articular cartilage explants were evaluated in the 24 h following a mechanical overload, and the effect of pharmacological SIRT1 activator SRT1720 on acute chondrocyte injury was assessed. SIRT1 enzymatic activity decreased as early as 5 min following the mechanical overload, and remained suppressed for at least 24 h. The chondrocyte injury response, including apoptosis, oxidative stress, secretion of inflammatory mediators, and alterations in cartilage matrix expression, was prevented with pharmacological activation of SIRT1 in a dose-dependent manner. Overall, the results implicate SIRT1 deactivation as a key molecular event in chondrocyte injury following a mechanical impact overload. As decreased SIRT1 signaling is associated with advanced age, these findings suggest that downregulated SIRT1 activity may be common to both age-related and injury-induced osteoarthritis.
  • Thumbnail Image
    Item
    Irradiated riboflavin over nonradiated one: Potent antimigratory, antiproliferative and cytotoxic effects on glioblastoma cells
    (Wiley, 2024) Kacar, Sedat; Hacioglu, Ceyhan; Kar, Fatih; Surgery, School of Medicine
    Riboflavin is a water-soluble yellowish vitamin and is controversial regarding its effect on tumour cells. Riboflavin is a powerful photosensitizer that upon exposure to radiation, undergoes an intersystem conversion with molecular oxygen, leading to the production of ROS. In the current study, we sought to ascertain the impact of irradiated riboflavin on C6 glioblastoma cells regarding proliferation, cell death, oxidative stress and migration. First, we compared the proliferative behaviour of cells following nonradiated and radiated riboflavin. Next, we performed apoptotic assays including Annexin V and caspase 3, 7 and 9 assays. Then we checked on oxidative stress and status by flow cytometry and ELISA kits. Finally, we examined inflammatory change and levels of MMP2 and SIRT1 proteins. We caught a clear antiproliferative and cytotoxic effect of irradiated riboflavin compared to nonradiated one. Therefore, we proceeded with our experiments using radiated riboflavin. In all apoptotic assays, we observed a dose-dependent increase. Additionally, the levels of oxidants were found to increase, while antioxidant levels decreased following riboflavin treatment. In the inflammation analysis, we observed elevated levels of both pro-inflammatory and anti-inflammatory cytokines. Additionally, after treatment, we observed reduced levels of MMP2 and SIRT. In conclusion, radiated riboflavin clearly demonstrates superior antiproliferative and apoptotic effects on C6 cells at lower doses compared to nonradiated riboflavin.
  • Thumbnail Image
    Item
    Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage
    (Oxford University Press, 2016-06) Ding, Ning; Bonham, Emily M.; Hannon, Brooke E.; Amick, Thomas R.; Baylin, Stephen B.; O'Hagan, Heather M.; Medical and Molecular Genetics, School of Medicine
    At sites of chronic inflammation, epithelial cells are exposed to high levels of reactive oxygen species and undergo cancer-associated DNA methylation changes, suggesting that inflammation may initiate epigenetic alterations. Previously, we demonstrated that oxidative damage causes epigenetic silencing proteins to become part of a large complex that is localized to GC-rich regions of the genome, including promoter CpG islands that are epigenetically silenced in cancer. However, whether these proteins were recruited directly to damaged DNA or during the DNA repair process was unknown. Here we demonstrate that the mismatch repair protein heterodimer MSH2-MSH6 participates in the oxidative damage-induced recruitment of DNA methyltransferase 1 (DNMT1) to chromatin. Hydrogen peroxide treatment induces the interaction of MSH2-MSH6 with DNMT1, suggesting that the recruitment is through a protein–protein interaction. Importantly, the reduction in transcription for genes with CpG island-containing promoters caused by oxidative damage is abrogated by knockdown of MSH6 and/or DNMT1. Our findings provide evidence that the role of DNMT1 at sites of oxidative damage is to reduce transcription, potentially preventing transcription from interfering with the repair process. This study uniquely brings together several factors that are known to contribute to colon cancer, namely inflammation, mismatch repair proteins, and epigenetic changes.
  • Thumbnail Image
    Item
    Protective role of remogliflozin against experimental liver fibrosis by activating AMPK/SIRT1/Nrf2 and suppressing NF-κB pathways
    (Frontiers Media, 2025-06-09) ALSuhaymi, Naif; Alsugoor, Mahdi H.; Shokry, Aya A.; Fayed, Hany M.; Mohamed, Bassim M. S. A.; Afifi, Sherif M.; Esatbeyoglu, Tuba; Korany, Reda M. S.; Elbaset, Marawan A.; Neurology, School of Medicine
    Liver fibrosis is considered an epidemic health problem since it can lead to several insults that can be fatal. Remogliflozin (Remo), an inhibitor of the sodium-glucose cotransporter 2 (SGLT2) protein, is one of the most recently developed antidiabetic drugs for treating type 2 diabetes mellitus (T2DM). The antidiabetic and antioxidant impacts of Remo have been demonstrated in numerous animal models; however, its antifibrotic activity remains unclear. Therefore, we planned this study to clarify the preventive activity of Remo against thioacetamide (TAA)-induced liver fibrosis in male rats, along with its anticipated pathways. Four groups of rats (n = 6) were used in our investigation: the control group; the TAA group, which received 100 mg/kg b.wt IP twice a week for 6 weeks; and the TAA + Remo groups, which were given two doses of Remo at 25 and 50 mg/kg b.wt orally, respectively, for 4 weeks in addition to TAA injections. The TAA group showed a marked increase in liver enzymes, lipid peroxidation, and proinflammatory cytokines, along with a marked decrease in albumin and cellular antioxidant status. Additionally, the TAA group showed a marked increase in nuclear factor-κB (NF-κB) and a marked decrease in AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and nuclear factor erythroid 2-related factor 2 (Nrf2) levels and expressions. The harmful effects of TAA were significantly mitigated by Remo therapy, which improved the aforementioned parameters. Histopathological findings corroborated the biochemical results. The results of our study suggest that Remo has anti-inflammatory and antioxidant properties that protect against TAA-induced liver fibrosis by inhibiting the NF-κB pathway and activating the AMPK/SIRT1/Nrf2 pathway.
  • Thumbnail Image
    Item
    SIRT1 DEFICIENCY COMPROMISES MOUSE EMBRYONIC STEM CELL DIFFERENTIATION, AND EMBRYONIC AND ADULT HEMATOPOIESIS IN THE MOUSE
    (2011-03-16) Ou, Xuan; Broxmeyer, Hal E.; Pelus, Louis; Roman, Ann; Yoder, Mervin C.
    SIRT1 (Sirtuin 1) is a founding member of a family of seven proteins and histone deacetylases. It is involved in cellular resistance to stress, metabolism, differentiation, aging, and tumor suppression. SIRT1-/- mice demonstrate embryonic and postnatal development defects. We examined hematopoietic and endothelial cell differentiation of SIRT1-/- mouse embryonic stem (mES) cells in vitro, and hematopoietic progenitors in SIRT1+/+, SIRT1+/-, and SIRT1-/- mice. SIRT1-/- ES cells exhibited markedly delayed/immature formation of blast colony-forming cells (BL-CFCs). When individual blast colonies were analyzed for hematopoietic and endothelial potential, replated SIRT1-/- BL-CFC possessed limited hematopoietic potential, whereas endothelial potential was essentially unaltered. The ability of SIRT1-/- ES cells to form primitive erythroid progenitors was not only delayed but greatly decreased. Moreover, after differentiation of SIRT1-/- mES cells, there were also significant decreases in granulocyte-macrophage (CFU-GM) and multipotential (CFU-GEMM) progenitor cells. Differentiation delay/defects were associated with delayed capacity to switch off Oct4, Nanog and Fgf5, decreased β-H1 globin, β-major globin, and Scl gene expression and reduced activation of the Erk1/2 pathway upon SIRT1-/- ES cell commitment. Reintroduction of WT SIRT1 into SIRT1-/- cells partially rescued the primitive erythroid progenitor formation of SIRT1-/- cells and the expression of hemoglobin genes, Hbb-bh1 and Hbb-b1, suggesting that the defect of hematopoietic commitment is due to deletion of SIRT1, and not to genetic drifting of SIRT1-/- cells. To confirm the requirement for SIRT1 for normal development of hematopoietic progenitor cells, we assessed embryonic and adult hematopoiesis in SIRT1+/+, SIRT1+/- and SIRT1-/- mice. Yolk sacs from SIRT1 mutant embryos generated fewer primitive erythroid precursors compared to wild-type (WT) and heterozygous mice. Moreover, knockout of SIRT1 decreased primary bone marrow hematopoietic progenitor cells (HPCs) in 5 week and 12 month old mice, which was especially notable at lower (5%) O2 tension. In addition these progenitors survived less well in vitro under conditions of delayed growth factor addition. Taken together, these results demonstrate that SIRT1 plays a role in ES cell hematopoietic differentiation and mouse hematopoiesis.
  • Thumbnail Image
    Item
    Sirtuin biology and relevance to diabetes treatment
    (Taylor & Francis, 2012) Dong, X. Charlie; Biochemistry and Molecular Biology, School of Medicine
    Sirtuins are a group of NAD(+)-dependent enzymes that post-translationally modify histones and other proteins. Among seven mammalian sirtuins, SIRT1 has been the most extensively studied and has been demonstrated to play a critical role in all major metabolic organs and tissues. SIRT1 regulates glucose and lipid homeostasis in the liver, modulates insulin secretion in pancreatic islets, controls insulin sensitivity and glucose uptake in skeletal muscle, increases adiponectin expression in white adipose tissue and controls food intake and energy expenditure in the brain. Recently, SIRT3 has been demonstrated to modulate insulin sensitivity in skeletal muscle and systemic metabolism, and Sirt3-null mice manifest characteristics of metabolic syndrome on a high-fat diet. Thus, it is reasonable to believe that enhancing the activities of SIRT1 and SIRT3 may be beneficial for Type 2 diabetes. Although it is controversial, the SIRT1 activator SRT1720 has been reported to be effective in improving glucose metabolism and insulin sensitivity in animal models. More research needs to be conducted so that we can better understand the physiological functions and molecular mechanisms of sirtuins in order to therapeutically target these enzymes for diabetes treatment.