Adaptation to different forms of environmental stress is crucial for maintaining essential cellular functions and survival. The nucleolus plays a decisive role as a signaling hub for coordinating cellular responses to various extrinsic and intrinsic cues. p53 levels are normally kept low in unstressed cells, mainly due to E3 ubiquitin ligase MDM2-mediated degradation. Under stress, nucleophosmin (NPM) relocates from the nucleolus to the nucleoplasm and binds MDM2, thereby preventing degradation of p53 and allowing cell-cycle arrest and DNA repair. Here, we demonstrate that the mammalian sirtuin SIRT7 is an essential component for the regulation of p53 stability during stress responses induced by ultraviolet (UV) irradiation. The catalytic activity of SIRT7 is substantially increased upon UV irradiation through ataxia telangiectasia mutated and Rad3 related (ATR)-mediated phosphorylation, which promotes efficient deacetylation of the SIRT7 target NPM. Deacetylation is required for stress-dependent relocation of NPM into the nucleoplasm and MDM2 binding, thereby preventing ubiquitination and degradation of p53. In the absence of SIRT7, stress-dependent stabilization of p53 is abrogated, both in vitro and in vivo, impairing cellular stress responses. The study uncovers an essential SIRT7-dependent mechanism for stabilization of the tumor suppressor p53 in response to genotoxic stress.
Uvod: Koronarna arterijska bolest (CAD) jedno je od najrasprostranjenijih hroni~nih oboljenja. Vitamin D-vezuju}i protein (VDBP) i njegovi genetski polimorfizmi predo~eni su kao podlo`ne komponente za CAD. Cilj ove studije bio je da se ispita povezanost izme|u polimorfizama pojedina~nih nukleotida (SNPs) proteina VDBP -rs7041 i rs4588 i podlo` -nosti CAD u populaciji Iranaca. Metode: Ukupno 143 mu{karca sa CAD i 145 zdravih kontrolnih ispitanika odgovaraju}eg uzrasta i pola podvrgnuto je genotipizaciji za polimorfizme -rs7041 i rs4588 pomo}u metode lan~ane reakcije polimeraze odnosno polimorfizama du`ine restrikcionih fragmenata (PCR-RFLP). Nivo 25(OH)D u serumu odre|en je pomo}u kolorimetrijskog enzimskog imunoeseja na mikroplo~i. Rezultati: Otkrili smo zna~ajnu povezanost izme|u genotipa GG (rs7041) i CAD (p=0,02, OR=0,537 95% CI=0,306-0,944). [to se ti~e polimorfizma rs4588, uo~ena je zna~ajna razlika, pri ~emu su genotip CA (P=0,00032, OR=2,578, SummaryBackground: Coronary Artery Disease (CAD) is one of the most widespread non-communicable diseases. Vitamin Dbinding protein (VDBP) and its genetic poly morphisms have been highlighted as the susceptible components for CAD. The aim of the present study was to examine the association of VDBP single nucleotide poly morphisms (SNPs) -rs7041 and rs4588 -with CAD susceptibility among the Iranian population. Methods: A total of 143 men with CAD and 145 healthy age-sex matched controls underwent genotyping for thers7041 and rs4588 polymorphisms using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Serum level of 25(OH)D was assayed using microplate colorimetric enzyme immunoassay. Results: We found a significant association between GG genotype (rs7041) and CAD (p=0.02, OR=0.537 95% CI =0.306-0.944). Regarding rs4588 polymorphism, a significant difference was observed in which the CA genotype
Background:Differential expression profile of microRNAs (miRNAs) could be a diagnosis signature for monitoring gastric cancer (GC) progression. In this study, we focus on the comparison of expression levels of miR-21, miR-25, miR-93, miR-106b, and miR-375 during the sequential pattern of GC development, including normal gastric, gastric dysplasia, and GC sample.Methods:We used SYBR Green-based quantitative-PCR to quantify miRNAs expression.Results:Our analysis revealed the increased expression levels of miR-21 (p = 0.034), miR-25 (p = 0.0003), miR-93 (p = 0.0406), and miR-106b (p = 0.023) in GC samples. In addition, GC patients with positive lymph node metastasis showed the up-regulation of miR-25, miR-93, and miR-106b (p < 0.05).Conclusion:Our findings suggested that the expression of miR-21, miR-25, miR-93, and miR-106b altered in GC, and some of them may be further investigated as biomarkers for GC early detection and prognosis prediction.
Giant cell arteritis (GCA), medium and large vessel granulomatous vasculitis affecting the elderly, is characterized by a multitude of vascular complications, including venous thrombosis, myocardial infraction and stroke. The formation of granulomatous infiltrates and the enhanced accumulation of proinflammatory cytokines are typical features of this condition. The GCA pathogenesis remains largely unknown, but recent studies have suggested the involvement of oxidative stress, mainly sustained by an enhanced reactive oxygen species (ROS) production by immature neutrophils. On this basis, in the present study, we intended to evaluate, in GCA patients, the presence of systemic oxidative stress and possible alterations in the expression level of nuclear sirtuins, enzymes involved in the inhibition of inflammation and oxidative stress. Thirty GCA patients were included in the study and compared to 30 healthy controls in terms of leukocyte ROS production, oxidative stress and SIRT1 expression. Our results clearly indicated a significant increase (p < 0.05) both in the ROS levels in the leukocyte fractions and plasma oxidative stress markers (lipid peroxidation and total antioxidant capacity) in the GCA patients compared to the healthy controls. In PBMCs from the GCA patients, a significant decrease in SIRT1 expression (p < 0.05) but not in SIRT6 and SIRT7 expression was found. Taken together, our preliminary findings indicate that, in GCA patients, plasma oxidative stress is paralleled by a reduced SIRT1 expression in PBMC. Further studies are needed to highlight if and how these alterations contribute to GCA pathogenesis.
Sirtuins are key players for maintaining cellular homeostasis and are often deregulated in different human diseases. SIRT7 is the only member of mammalian sirtuins that principally resides in the nucleolus, a nuclear compartment involved in ribosomal biogenesis, senescence, and cellular stress responses. The ablation of SIRT7 induces global genomic instability, premature ageing, metabolic dysfunctions, and reduced stress tolerance, highlighting its critical role in counteracting ageing-associated processes. In this review, we describe the molecular mechanisms employed by SIRT7 to ensure cellular and organismal integrity with particular emphasis on SIRT7-dependent regulation of nucleolar functions.
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