3,423 research outputs found

    Sirtuin functions and modulation: from chemistry to the clinic

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    Sirtuins are NAD+ -dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity. Here, we review the role, mechanism of action, and biological function of the seven sirtuins, as well as their inhibitors and activators

    Pharmacological activation of endogenous protective pathways against oxidative stress under conditions of sepsis

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    Funding The study was funded entirely by institutional funds.Peer reviewedPostprin

    RIP1-HAT1-SirT complex identification and targeting in treatment and prevention of cancer

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    Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.Experimental Design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and in vivo studies with different mice models.Results: Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene-induced mammary gland hyperproliferation in vivoConclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention

    Inactivation of endoplasmic reticulum stress and the prevention of neurodegenerative diseases

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    Biotherapeutics and nutritional therapy are essential for the treatment of endoplasmic reticulum (ER) stress in diabetes and neurodegenerative diseases. Oxidative stress and nutrient excess may induce ER stress associated with activation of the unfolded protein response and connected to cell death. The heat shock gene Sirtuin 1 (Sirt 1) is important to the heat shock response with amyloid beta aggregation associated with the induction of mitophagy and ER stress in neuron cells. Genomic medicine that activates nuclear Sirt 1 is essential for the prevention of mitochondrial apoptosis and ER stress. Inhibitors such as drugs, alcohol, excess caffeine and palmitic acid may override the therapeutic effects of Sirt 1 activators with relevance to ER stress associated cell life and death decisions

    Identification of a novel polyprenylated acylphloroglucinol‑derived SIRT1 inhibitor with cancer‑specific anti-proliferative and invasion-suppressing activities

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    SIRT1, a class III histone deacetylase, plays a critical role in regulating cancer cell growth, migration and invasion, which makes it a potential target for cancer therapeutics. In this study, we screened derivatives of several groups of natural products and identified a novel SIRT1 inhibitor JQ-101, a synthetic derivative of the polyprenylated acylphloroglucinol (PPAP) natural products, with an IC(50) for SIRT1 of 30 µM in vitro, with 5-fold higher activity for SIRT1 vs. SIRT2. Exposure of tumor cells to JQ-101 significantly enhanced acetylation of p53 and histone H4K16 at known sites of SIRT1 deacetylation, validating SIRT1 as its cellular target. JQ-101 suppressed cancer cell growth and survival by targeting SIRT1, and also exhibited selective cytotoxicity towards a panel of human tumor cell lines, while producing no toxicity in two normal human cell types at comparable concentrations. JQ-101 induced both apoptosis and cell senescence, and suppressed cancer cell invasion in vitro. In summary, we have identified JQ-101 as a new SIRT1 inhibitor which may have potential application in cancer treatment through its ability to induce tumor cell apoptosis and senescence and suppress cancer cell invasion.CA164245 - NCI NIH HHS; R01 CA101992 - NCI NIH HHS; R21 CA129046 - NCI NIH HHS; R21 CA141036 - NCI NIH HHS; P50 GM067041 - NIGMS NIH HHS; UL1RR025771 - NCRR NIH HHS; CA101992 - NCI NIH HHS; UL1 RR025771 - NCRR NIH HHS; GM-073855 - NIGMS NIH HHS; CA129046 - NCI NIH HHS; R21 CA164245 - NCI NIH HHS; GM-067041 - NIGMS NIH HHS; CA141036 - NCI NIH HHS; R01 GM073855 - NIGMS NIH HH

    Effects of niacin restriction on sirtuin and PARP responses to photodamage in human skin.

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    Sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs), NAD(+)-dependent enzymes, link cellular energy status with responses to environmental stresses. Skin is frequently exposed to the DNA damaging effects of UV irradiation, a known etiology in skin cancer. Thus, understanding the defense mechanisms in response to UV, including the role of SIRTs and PARPs, may be important in developing skin cancer prevention strategies. Here, we report expression of the seven SIRT family members in human skin. SIRTs gene expressions are progressively upregulated in A431 epidermoid carcinoma cells (SIRTs1 and 3), actinic keratoses (SIRTs 2, 3, 5, 6, and 7) and squamous cell carcinoma (SIRTs 1-7). Photodamage induces dynamic changes in SIRT expression with upregulation of both SIRT1 and SIRT4 mRNAs. Specific losses of SIRT proteins occur early after photodamage followed by accumulation later, especially for SIRT4. Niacin restriction, which decreases NAD(+), the sirtuin substrate, results in an increase in acetylated proteins, upregulation of SIRTs 2 and 4, increased inherent DNA damage, alterations in SIRT responses to photodamage, abrogation of PARP activation following photodamage, and increased sensitivity to photodamage that is completely reversed by repleting niacin. These data support the hypothesis that SIRTs and PARPs play important roles in resistance to photodamage and identify specific SIRTs that respond to photodamage and may be targets for skin cancer prevention

    The light and shadow of senescence and inflammation in cardiovascular pathology and regenerative medicine

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    Recent epidemiologic studies evidence a dramatic increase of cardiovascular diseases, especially associated with the aging of the world population. During aging, the progressive impairment of the cardiovascular functions results from the compromised tissue abilities to protect the heart against stress. At the molecular level, in fact, a gradual weakening of the cellular processes regulating cardiovascular homeostasis occurs in aging cells. Atherosclerosis and heart failure are particularly correlated with aging-related cardiovascular senescence, that is, the inability of cells to progress in the mitotic program until completion of cytokinesis. In this review, we explore the intrinsic and extrinsic causes of cellular senescence and their role in the onset of these cardiovascular pathologies. Additionally, we dissect the effects of aging on the cardiac endogenous and exogenous reservoirs of stem cells. Finally, we offer an overview on the strategies of regenerative medicine that have been advanced in the quest for heart rejuvenation

    Getting old through the blood. Circulating molecules in aging and senescence of cardiovascular regenerative cells

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    Global aging is a hallmark of our century. The natural multifactorial process resulting in aging involves structural and functional changes, affecting molecules, cells, and tissues. As the western population is getting older, we are witnessing an increase in the burden of cardiovascular events, some of which are known to be directly linked to cellular senescence and dysfunction. In this review, we will focus on the description of a few circulating molecules, which have been correlated to life span, aging, and cardiovascular homeostasis. We will review the current literature concerning the circulating levels and related signaling pathways of selected proteins (insulin-like growth factor 1, growth and differentiation factor-11, and PAI-1) and microRNAs of interest (miR-34a, miR-146a, miR-21), whose bloodstream levels have been associated to aging in different organisms. In particular, we will also discuss their potential role in the biology and senescence of cardiovascular regenerative cell types, such as endothelial progenitor cells, mesenchymal stromal cells, and cardiac progenitor cells

    Role of Sirtuin-1 in the pathogenesis of hypertension in spontaneously hypertensive rats : molecular mechanisms

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    Il a été démontré que la sirtuine 1 (Sirt-1), une histone désacétylase de classe III, est surexprimée dans le coeur des rats spontanément hypertendus (SHR). Nous avons récemment montré que les cellules musculaires lisses vasculaires (CMLV) des SHR présentent une expression accrue de Sirt-1 par rapport aux rats Wistar Kyoto (WKY) de même âge qui contribue à l’augmentation de la régulation de la protéine Giα impliquée dans la pathogenèse de l'hypertension. La présente étude a été effectuée pour étudier le rôle de l'augmentation de l'expression de la Sirt-1 dans la pathogenèse de l'hypertension chez les SHR et pour explorer les mécanismes moléculaires impliqués dans cette réponse. Dans cette étude, un inhibiteur sélectif de la Sirt-1, EX-527 (5 mg/kg de poids corporel), a été injecté par voie intrapéritonéale chez des rats SHR adultes de 8 semaines et des rats WKY de même âge, deux fois par semaine pendant 3 semaines. La pression artérielle (PA) et la fréquence cardiaque ont été mesurées deux fois par semaine par la méthode non invasive du brassard autour de la queue. Le traitement avec l’inhibiteur spécifique de la Sirt-1, l'EX-527, a atténué les augmentations de PA (de 76 mmHg) et de fréquence cardiaque chez les rats SHR. La surexpression de Sirt-1 et des protéines Giα dans le coeur, les CMLV et l'aorte a été atténuée au niveau des contrôles par l'inhibiteur de la Sirt-1. L'inhibition de la Sirt-1 a également atténué les niveaux accrus des anions superoxydes, l’activité de la NADPH oxydase et la surexpression des sous-unités de la NADPH oxydase ; les protéines Nox2, Nox4 et P47phox dans les CMLV isolées des SHR traités par l’EX-527. De plus, les niveaux réduits du monoxyde d'azote synthase endothélial (eNOS) et du monoxyde d'azote (NO) et les niveaux accrus de la peroxynitrite (ONOO-) dans les CMLV des SHR ont également été rétablis à des niveaux contrôles par l'inhibiteur de la Sirt-1. Ces résultats suggèrent que l'inhibition de la surexpression de la Sirt-1, en diminuant les niveaux accrus des protéines Giα et du stress nitro-oxydant, atténue la PA élevée chez les rats SHR. Il est donc possible de suggérer que les inhibiteurs de la Sirt-1 puissent être utilisés comme des agents thérapeutiques dans le traitement des complications cardiovasculaires associées à l'hypertension.Sirtuin-1 (Sirt-1), class III histone deacetylase, has been shown to be overexpressed in hearts from spontaneously hypertensive rats (SHR). We recently showed that vascular smooth muscle cells (VSMC) from SHR exhibit enhanced expression of Sirt-1 as compared to age-matched Wistar Kyoto (WKY) rats, which contributes to the upregulation of Giα protein implicated in the pathogenesis of hypertension. The present study was undertaken to investigate the role of upregulated Sirt-1 expression in the pathogenesis of hypertension in SHR and to explore the underlying molecular mechanisms involved in this response. For this study, a selective inhibitor of Sirt-1, EX-527 (5mg/kg of body weight), was injected intraperitoneally into 8-week-old adult SHR and age-matched WKY rats twice per week for 3 weeks. The blood pressure (BP) and heart rate was measured twice a week by the CODA™ non-invasive tail cuff method. Treatment of SHR with Sirt-1-specific inhibitor, EX-527, attenuated high BP by 76 mmHg and inhibited the augmented heart rate. The overexpression of Sirt-1 and Giα proteins in heart, VSMC and aorta was attenuated to the control levels by Sirt-1 inhibitor. Inhibition of Sirt-1 also attenuated the enhanced levels of superoxide anion, NADPH oxidase activity and the overexpression of NADPH oxidase subunits; Nox2, Nox4 and P47phox proteins in VSMC isolated from EX-527-treated SHR. Furthermore, the decreased levels of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) and increased levels of peroxynitrite (ONOO-) in VSMC from SHR were also restored to control levels by Sirt-1 inhibitor. These results suggest that the inhibition of overexpression of Sirt-1 through decreasing the enhanced levels of Giα proteins and nitro-oxidative stress attenuates the high BP in SHR. It may thus be suggested that inhibitors of Sirt-1 may have the potential to be used as therapeutic agents in the treatment of cardiovascular complications associated with hypertension

    Application of Small Epigenetic Modulators in Pediatric Medulloblastoma

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    Medulloblastoma is one of the most frequent among pediatric brain tumors, and it has been classified in various subgroups. Some of them already benefit from quite good therapeutic options, whereas others urgently need novel therapeutic approaches. Epigenetic modulators have long been studied in various types of cancer. Within this review, we summarize the main preclinical studies regarding epigenetic targets (such as HDAC, SIRT, BET, EZH2, G9a, LSD1, and DNMT) inhibitors in medulloblastoma. Furthermore, we shed light on the increasing number of applications of drug combinations as well as hybrid compounds involving epigenetic mechanisms. Nevertheless, in the studies published so far, mainly un-specific or old modulators have been used, and the PKs (brain permeability) have not been well-evaluated. Thus, these findings should be considered as a starting point for further improvement and not as a final result
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