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Small molecule inhibitors targeting the bromodomain and extra-terminal domain (BET) family proteins have emerged as a promising class of anti-cancer drugs. Nevertheless, the clinical advancement of these agents has been significantly hampered by challenges related to their potency, oral bioavailability, or toxicity. In this study, virtual screening approaches were employed to discover novel inhibitors of the bromodomain-containing protein 4 (BRD4) by analyzing their comparable chemical structural features to established BRD4 inhibitors. Several of these compounds exhibited inhibitory effects on BRD4 activity ranging from 60 % to 70 % at 100 µM concentrations, while one compound also exhibited an 84 % inhibition of Sirtuin 2 (SIRT2) activity. Furthermore, a subset of structurally diverse compounds from the BRD4 inhibitors was selected to investigate their anti-cancer properties in both 2D and 3D cell cultures. These compounds exhibited varying effects on cell numbers depending on the specific cell line, and some of them induced cell cycle arrest in the G0/G1 phase in breast cancer (MDA-MB-231) cells. Moreover, all the compounds studied reduced the sizes of spheroids, and the most potent compound exhibited a 90 % decrease in growth at a concentration of 10 µM in T47D cells. These compounds hold potential as epigenetic regulators for future studies.
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Antineoplásicos , Neoplasias de la Mama , Factores de Transcripción , Femenino , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Proteínas que Contienen Bromodominio , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Dominios Proteicos/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Flavonoides/química , Flavonoides/farmacologíaRESUMEN
Death receptor-mediated extrinsic apoptosis system had been developed as a promising therapeutic strategy in clinical oncology, such as TRAIL therapy. However, multiple studies have demonstrated that TRAIL resistance is the biggest problem for disappointing clinical trials despite preclinical success. Targeting cellular FLICE inhibitory protein (cFLIP) is one strategy of combinatorial therapies to overcome resistance to DR-mediated apoptosis due to its negative regulator of extrinsic apoptosis. E × 527 (Selisistat) is a specific inhibitor of SIRT1 activity with safe and well tolerance in clinical trials. Here, we show that E × 527 could strengthen significantly activation of rhFasL-mediated apoptotic signaling pathway and increased apoptotic rate of T leukemia cells with high expression of cFLIP. Mechanically, Inhibition of SIRT1 by E × 527 increased polyubiquitination level of cFLIP via increasing acetylation of Ku70, which could promote proteosomal degradation of cFLIP protein. It implied that combinatorial therapies of E × 527 plus TRAIL may have a potential as a novel clinical application for TRAIL-resistant hematologic malignancies.
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Apoptosis , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Sirtuina 1 , Ligando Inductor de Apoptosis Relacionado con TNF , Humanos , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Apoptosis/efectos de los fármacos , Sirtuina 1/metabolismo , Sirtuina 1/antagonistas & inhibidores , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Leucemia de Células T/tratamiento farmacológico , Leucemia de Células T/metabolismo , Leucemia de Células T/patología , Carbazoles/farmacología , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Autoantígeno Ku/metabolismo , Animales , Transducción de Señal/efectos de los fármacos , Ratones , Azocinas , Compuestos de BencidriloRESUMEN
The hypothalamus lies at the intersection of brain and hormonal mechanisms governing essential bodily functions, including metabolic/body weight homeostasis and reproduction. While metabolism and fertility are precisely regulated by independent neuroendocrine axes, these are tightly connected, as reflection of the bidirectional interplay between the energy status of the organisms and their capacity to reproduce; a connection with important pathophysiological implications in disorders affecting these two crucial systems. Beyond the well-characterized roles of key hormones (e.g., leptin, insulin, ghrelin) and neuropeptides (e.g., melanocortins, kisspeptins) in the integral control of metabolism and reproduction, mounting evidence has pointed out a relevant function of cell energy sensors and lipid sensing mechanisms in the hypothalamic control of metabolism, with prominent roles also for metabolic sensors, such as mTOR, AMPK and SIRT1, in the nutritional regulation of key aspects of reproduction, such as pubertal maturation. We provide herein a synoptic overview of these novel regulatory pathways, with a particular focus on their putative function in the metabolic control of puberty, and delineate new avenues for further exploration of the intricate mechanisms whereby metabolism and reproduction are tightly connected.
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Peso Corporal , Metabolismo Energético , Metabolismo de los Lípidos , Sistemas Neurosecretores , Reproducción , Humanos , Reproducción/fisiología , Animales , Peso Corporal/fisiología , Sistemas Neurosecretores/metabolismo , Sistemas Neurosecretores/fisiología , Metabolismo de los Lípidos/fisiología , Metabolismo Energético/fisiología , Hipotálamo/metabolismoRESUMEN
Aging, a complex process marked by molecular and cellular changes, inevitably influences tissue and organ homeostasis and leads to an increased onset or progression of many chronic diseases and conditions, one of which is age-related hearing loss (ARHL). ARHL, known as presbycusis, is characterized by the gradual and irreversible decline in auditory sensitivity, accompanied by the loss of auditory sensory cells and neurons, and the decline in auditory processing abilities associated with aging. The extended human lifespan achieved by modern medicine simultaneously exposes a rising prevalence of age-related conditions, with ARHL being one of the most significant. While our understanding of the molecular basis for aging has increased over the past three decades, a further understanding of the interrelationship between the key pathways controlling the aging process and the development of ARHL is needed to identify novel targets for the treatment of AHRL. The dysregulation of molecular pathways (AMPK, mTOR, insulin/IGF-1, and sirtuins) and cellular pathways (senescence, autophagy, and oxidative stress) have been shown to contribute to ARHL. However, the mechanistic basis for these pathways in the initiation and progression of ARHL needs to be clarified. Therefore, understanding how longevity pathways are associated with ARHL will directly influence the development of therapeutic strategies to treat or prevent ARHL. This review explores our current understanding of the molecular and cellular mechanisms of aging and hearing loss and their potential to provide new approaches for early diagnosis, prevention, and treatment of ARHL.
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Envejecimiento , Senescencia Celular , Presbiacusia , Humanos , Envejecimiento/metabolismo , Animales , Presbiacusia/metabolismo , Presbiacusia/genética , Presbiacusia/patología , Transducción de Señal , Estrés Oxidativo , Pérdida Auditiva/metabolismo , Pérdida Auditiva/genética , Pérdida Auditiva/patología , Autofagia , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Diabetic kidney disease, known as diabetic nephropathy (DN), is a widespread severe diabetes complication leading to kidney failure. Due to the lack of efficacious therapies, this study endeavors to enhance DN therapeutic effectiveness of ferulic acid (FRA), a natural phenolic with poor oral bioavailability, by developing a transdermal kidney-targeted spanlastic formulation. Spanlastics (SP) nanovesicles were prepared using Span 60 and Labrasol or Brij35 as edge activators (EA). Cationic guar (CG) and hyaluronic acid (HA) were employed as coatings. The formulations were assessed for entrapment efficiency (EE), particle size (PS) and zeta potential (ZP). A 21 × 31 factorial optimization of FRA spanlastic formulations revealed the desirable nanoformula was FRA-L-H-SP comprising Labrasol and hyaluronate coating. Transmission electron microscopy (TEM), Fourier-transform infrared (FT-IR), Diphenylpicrylhydrazyl (DPPH) antioxidant activity, in-vitro release, and rat skin ex-vivo permeation assessed this formula and the uncoated one (FRA-L-SP). Biochemical indicators and histopathology for diabetes and kidney injury were evaluated in the Streptozotocin (STZ)-induced DN rat model. Results showed significant improvements after treatment with FRA-L-H-SP compared to FRA-L-SP and free FRA, with decreased blood glucose, creatinine, and intercellular adhesion molecule-1 (ICAM-1) levels and increased insulin, AMP-activated protein kinase (AMPK), and sirtuins (SIRT). This enhancement can be acknowledged as passive targeting of SP and active targeting properties of hyaluronic to cluster of differentiation 44 (CD44) receptors, revealing the potential to improve DN pathophysiology.
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Due to its peculiar structure and function, the cardiovascular system is particularly vulnerable to the detrimental effects of ageing. Current knowledge about the molecular mechanisms of ageing revealed the processes actively promoting ageing, e.g. progressive telomeres shortening, and the mechanisms opposing it, e.g. endogenous production of antioxidant substances. This knowledge can be used to measure biological age at a cellular and molecular level and to interfere with it by pharmacological or non-pharmacological interventions. Biological ageing is determined by the simultaneous occurrence of independent hallmarks, which encompass a wide range of biological processes, from genomic changes to systemic inflammation and dysbiosis. This narrative review will summarize the role of ageing hallmarks in the cardiovascular system, how they can be measured and what are the possible interventions to counteract their effects.
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Patient age is critical for mesenchymal stem cell quality and differentiation capacity. We demonstrate that proliferation and adipogenic capacity of subcutaneous adipose stem cells (ASCs) from female patients declined with advanced age, associated with reduction in cell nucleus size, increase in nuclear lamina protein lamin B1/B2, and lamin A, upregulation of senescence marker p16INK4a and senescence-associated ß-galactosidase activity. Adipogenic induction resulted in differentiation of adipocytes and upregulation of adipogenic genes CCAAT enhancer binding protein alpha, fatty acid binding protein 4, lipoprotein lipase, and peroxisome proliferator-activated receptor-γ, which was not affected by the Sirt-1 activator YK-3-237 or the Sirt-1 inhibitor EX-527. Protein expression of the stem cell markers Oct4 and Sox2 was not significantly downregulated with advanced patient age. Mitochondrial reactive oxygen species were increased in ASCs from old-aged patients, whereas protein expression of NADPH oxidases NOX1 and NOX4 was downregulated, and dual oxidase isoforms remained unchanged. Generation of nitric oxide and iNOS expression was downregulated. Protein expression of Sirt-1 and Sirt-3 decreased with patient age, whereas Sirt-2 and Sirt-5 remained unchanged. Induction of adipogenesis stimulated protein expression of Sirt-1 and Sirt-3, which was not affected upon pre-incubation with the Sirt-1-activator YK-3-237 or the Sirt-1-inhibitor EX-527. The Sirt-1 inhibitor Sirtinol downregulated adiponectin protein expression and the number of adipocytes, whereas YK-3-237 exerted stimulatory effects. In summary, our data demonstrate increased oxidative stress in ASCs of aging patients, and decline of adipogenic capacity due to Sirt-1- mediated adiponectin downregulation in elderly patients.
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Adipogénesis , Estrés Oxidativo , Sirtuinas , Humanos , Femenino , Sirtuinas/metabolismo , Sirtuinas/genética , Anciano , Persona de Mediana Edad , Adipocitos/metabolismo , Adipocitos/citología , Diferenciación Celular , Especies Reactivas de Oxígeno/metabolismo , Adulto , Envejecimiento/metabolismo , Envejecimiento/fisiología , Células Madre Mesenquimatosas/metabolismo , Células Cultivadas , Células Madre/metabolismo , Células Madre/citología , Proliferación Celular , Senescencia Celular , Sirtuina 1/metabolismo , Sirtuina 1/genéticaRESUMEN
Despite progress in diagnosis and treatment strategies, breast cancer remains a primary risk to female health as indicated by second most cancer-deaths globally caused by this cancer. High risk mutation is linked to prognosis of breast cancer. Due to high resistance of breast cancer against current therapies, there is necessity of novel treatment strategies. Sirtuins are signaling proteins belonging to histone deacetylase class III family, known to control several cellular processes. Therefore, targeting sirtuins could be one of the approaches to treat breast cancer. Several plants synthesize phytoestrogens which exhibit structural and physiological similarities to estrogens and have been recognized to possess anticancer activity. In our study, we investigated several phytoestrogens for sirtuin inhibition by conducting molecular docking studies, and in-vitro studies against breast cancer cell lines. In molecular docking studies, we identified coumestrol possessing high binding energy with sirtuin proteins 1-3 as compared to other phytoestrogens. The molecular dynamic studies showed stable interaction of ligand and protein with higher affinity at sirtuin proteins 1-3 binding sites. In cell proliferation assay and colony formation assay using breast cancer cell lines (MCF-7 and MDAMB-231) coumestrol caused significant reduction in cell proliferation and number of colonies formed. Further, the flow cytometric analysis showed that coumestrol induces intracellular reactive oxygen species and the western blot analysis revealed reduction in the level of SIRT-1 expression in breast cancer cell lines. In conclusion, in-silico data and in-vitro studies suggest that the phytoestrogen coumestrol has sirtuin inhibitory activity against breast cancer.
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Neoplasias de la Mama , Proliferación Celular , Simulación del Acoplamiento Molecular , Fitoestrógenos , Humanos , Fitoestrógenos/farmacología , Fitoestrógenos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , Proliferación Celular/efectos de los fármacos , Sirtuinas/antagonistas & inhibidores , Sirtuinas/metabolismo , Sirtuinas/química , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Estructura Molecular , Relación Estructura-Actividad , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND: The Sirtuins (SIRT) family plays a key role in the diagnosis and treatment of many renal diseases, but no studies have been reported in acute rejection of kidney transplantation. The aim of this study was to explore the diagnostic value of SIRT family change characteristics in acute rejection of kidney transplantation. METHODS: We first explored the SIRT family expression profile in renal tissues using the HPA database; subsequently, we explored the potential biological functions and mechanistic changes during acute rejection of kidney transplantation by GSEA enrichment analysis. The Cibersort algorithm specifies the level of immune cell infiltration and explores the correlation between the SIRT family and immune cells using correlation analysis; Next, we constructed a diagnostic model using "Logistic regression analysis" and "Nomogram model", and evaluated the diagnostic model using calibration curves and ROC curves, and the decision curve (DCA) was used to evaluate the clinical diagnostic value of SIRT family changes; Finally, we constructed a model of acute rejection of rat kidney transplantation, and assessed rat kidney function by detecting the levels of urea nitrogen and creatinine in serum. Meanwhile, the expression level of SIRT family in kidney tissues was initially verified by transcriptome sequencing and RT-PCR. RESULTS: We found that all seven SIRT family members were located and expressed in renal tissues. The results of enrichment analysis revealed that a large number of immune-related biological functions and pathways are activated during acute rejection of kidney transplantation, the difference was statistically significant (p < 0.05). The Cibersort algorithm revealed significant changes in the level of infiltration of 10 immune cells (p < 0.05), while correlation analysis revealed a strong link between the SIRT family and immune cells (p < 0.05). We constructed a diagnostic model for acute rejection using seven SIRT families, and the ROC curves(AUC = 0.71)and calibration curves proved their good diagnostic value, and the DCA curves also proved the role of SIRT families in clinical decision-making. Next, we again demonstrated the good diagnostic performance of the SIRT family in ABMR and TCMR, respectively(ROC curves:AUC = 0.64ï¼AUC = 0.81). Finally, in a rat model of acute rejection of kidney transplantation, we found that renal function (BUN and creatinine) was significantly impaired in rats in the Allo group compared to rats in the Syn group (P < 0.05). Meanwhile, by transcriptome analysis and RT-PCR assay, we found that, except for SIRT1, the remaining SIRT family members were significantly changed in kidney tissues (P < 0.05). CONCLUSION: The SIRT family has significant changes during acute rejection in kidney transplantation, and the SIRT family may be able to serve as a potential therapeutic target for alleviating acute rejection in kidney transplantation.
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Rechazo de Injerto , Trasplante de Riñón , Sirtuinas , Transcriptoma , Animales , Sirtuinas/metabolismo , Sirtuinas/genética , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/inmunología , Ratas , Masculino , Humanos , Riñón/patología , Riñón/metabolismo , Modelos Animales de Enfermedad , Enfermedad Aguda , Perfilación de la Expresión GénicaRESUMEN
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis causes a high mortality rate and current treatment focuses on supportive therapies but lacks specific therapeutic targets. Notably, sirtuins (SIRTs) shows potential clinical application in the treatment of sepsis. It has been demonstrated that SIRTs, the nicotinamide adenine dinucleotide+(NAD+)-dependent deacetylases that regulate key signaling pathways in eukaryotes and prokaryotes, are involved in a variety of biological processes. To date, seven mammalian yeast Sir2 homologs have been identified. SIRTs can regulate inflammation, oxidative stress, apoptosis, autophagy, and other pathways that play important roles in sepsis-induced organ dysfunction. However, the existing studies on SIRTs in sepsis are too scattered, and there is no relevant literature to integrate them. This review innovatively summarizes the different mechanisms of SIRTs in sepsis organ dysfunction according to the different systems, and focuses on SIRT agonists, inhibitors, and targeted drugs that have been proved to be effective in the treatment of sepsis, so as to integrate the clinical research and basic research closely. We searched PubMed for all literature related to SIRTs and sepsis since its inception using the following medical subject headings: sirtuins, SIRTs, and sepsis. Data on the mechanisms of SIRTs in sepsis-induced organ damage and their potential as targets for disease treatment were extracted.
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Insuficiencia Multiorgánica , Sepsis , Sirtuinas , Sirtuinas/metabolismo , Sepsis/metabolismo , Sepsis/complicaciones , Humanos , Animales , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/metabolismo , Estrés Oxidativo , Transducción de SeñalRESUMEN
Aging is a process of time-associated depletion in the physiological functions, essential for the survival and reproducibility of living beings. Some age-related disorders can be successfully controlled with some biomedical techniques or pharmaceutical approaches. There are some precise remedies that demonstrate conspicuous promise in the preclinical and clinical setup of extending lifespan or enhancing health by altering natural senescence. The sirtuin family of proteins is one of the most favorable targets for antiaging strategies. Sirtuins were initially identified as transcription repressors in yeast, but today they are known to exist in bacteria and eukaryotes, as well as humans. The SIRT (1-7) family of proteins in humans is made up of seven members, each of which has either mono-ADP ribosyl transferase or deacetylase activity. Researchers suggest that sirtuins are essential for cell metabolism and play a major role in how cells react to various stimuli, such as oxidative or genotoxic stress. A healthy lifestyle, which includes exercise and a balanced diet, has been demonstrated to impact health span by adjusting the levels of sirtuins, suggesting the involvement of sirtuins in extending human longevity. The hunt for sirtuin activators is among the most extensive and comprehensive research subjects in the present scenario. Some optimism has been generated to investigate antiaging therapies by natural compounds, such as curcumin and others. This review article highlights the role of sirtuins in native senescence and their primordial roles in the progression of several life-threatening diseases. Further, it also provides recent information on the sirtuin activators and inhibitors and their therapeutic benefits.
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Envejecimiento , Sirtuinas , Humanos , Sirtuinas/metabolismo , Envejecimiento/metabolismo , Animales , Senescencia Celular , LongevidadRESUMEN
Understanding the role of iron in ethanol-derived hepatic stress could help elucidate the efficacy of dietary or clinical interventions designed to minimize liver damage from chronic alcohol consumption. We hypothesized that normal levels of iron are involved in ethanol-derived liver damage and reduced dietary iron intake would lower the damage caused by ethanol. We used a pair-fed mouse model utilizing basal Lieber-DeCarli liquid diets for 22 weeks to test this hypothesis. In our mouse model, chronic ethanol exposure led to mild hepatic stress possibly characteristic of early-stage alcoholic liver disease, seen as increases in liver-to-body weight ratios. Dietary iron restriction caused a slight decrease in non-heme iron and ferritin (FeRL) expression while it increased transferrin receptor 1 (TfR1) expression without changing ferroportin 1 (FPN1) expression. It also elevated protein lysine acetylation to a more significant level than in ethanol-fed mice under normal dietary iron conditions. Interestingly, iron restriction led to an additional reduction in nicotinamide adenine dinucleotide (NAD+) and NADH levels. Consistent with this observation, the major mitochondrial NAD+-dependent deacetylase, NAD-dependent deacetylase sirtuin-3 (SIRT3), expression was significantly reduced causing increased protein lysine acetylation in ethanol-fed mice at normal and low-iron conditions. In addition, the detection of superoxide dismutase 1 and 2 levels (SOD1 and SOD2) and oxidative phosphorylation (OXPHOS) complex activities allowed us to evaluate the changes in antioxidant and energy metabolism regulated by ethanol consumption at normal and low-iron conditions. We observed that the ethanol-fed mice had mild liver damage associated with reduced energy and antioxidant metabolism. On the other hand, iron restriction may exacerbate certain activities of ethanol further, such as increased protein lysine acetylation and reduced antioxidant metabolism. This metabolic change may prove a barrier to the effectiveness of dietary reduction of iron intake as a preventative measure in chronic alcohol consumption.
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Antioxidantes , Metabolismo Energético , Etanol , Animales , Ratones , Acetilación/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Antioxidantes/metabolismo , Masculino , Hierro/metabolismo , Superóxido Dismutasa-1/metabolismo , Superóxido Dismutasa-1/genética , Superóxido Dismutasa/metabolismo , Lisina/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Receptores de Transferrina/metabolismo , Sirtuina 3/metabolismo , Sirtuina 3/genética , NAD/metabolismo , Ferritinas/metabolismo , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Estrés Oxidativo/efectos de los fármacos , Ratones Endogámicos C57BL , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/patología , Hepatopatías Alcohólicas/etiologíaRESUMEN
The sirtuin family comprises seven NAD+-dependent enzymes which catalyze protein lysine deacylation and mono ADP-ribosylation. Sirtuins act as central regulators of genomic stability and gene expression and control key processes, including energetic metabolism, cell cycle, differentiation, apoptosis, and aging. As a result, all sirtuins play critical roles in cellular homeostasis and organism wellness, and their dysregulation has been linked to metabolic, cardiovascular, and neurological diseases. Furthermore, sirtuins have shown dichotomous roles in cancer, acting as context-dependent tumor suppressors or promoters. Given their central role in different cellular processes, sirtuins have attracted increasing research interest aimed at developing both activators and inhibitors. Indeed, sirtuin modulation may have therapeutic effects in many age-related diseases, including diabetes, cardiovascular and neurodegenerative disorders, and cancer. Moreover, isoform selective modulators may increase our knowledge of sirtuin biology and aid to develop better therapies. Through this review, we provide critical insights into sirtuin pharmacology and illustrate their enzymatic activities and biological functions. Furthermore, we outline the most relevant sirtuin modulators in terms of their modes of action, structure-activity relationships, pharmacological effects, and clinical applications.
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Nonsmall cell lung cancer (NSCLC) is a highly prevalent lung malignancy characterized by insidious onset, rapid progression and advanced stage at the time of diagnosis, making radical surgery impossible. Sirtuin (SIRT) is a histone deacetylase that relies on NAD+ for its function, regulating the aging process through modifications in protein activity and stability. It is intricately linked to various processes, including glycolipid metabolism, inflammation, lifespan regulation, tumor formation and stress response. An increasing number of studies indicate that SIRTs significantly contribute to the progression of NSCLC by regulating pathophysiological processes such as energy metabolism, autophagy and apoptosis in tumor cells through the deacetylation of histones or nonhistone proteins. The present review elaborates on the roles of different SIRTs and their mechanisms in NSCLC, while also summarizing novel therapeutic agents based on SIRTs. It aims to present new ideas and a theoretical basis for NSCLC treatment.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Sirtuinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Sirtuinas/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Autofagia , Apoptosis , Metabolismo EnergéticoRESUMEN
Autoimmune diseases (AID) have emerged as prominent contributors to disability and mortality worldwide, characterized by intricate pathogenic mechanisms involving genetic, environmental, and autoimmune factors. In response to this challenge, a growing body of research in recent years has delved into genetic modifications, yielding valuable insights into AID prevention and treatment. Sirtuins (SIRTs) constitute a class of NAD-dependent histone deacetylases that orchestrate deacetylation processes, wielding significant regulatory influence over cellular metabolism, oxidative stress, immune response, apoptosis, and aging through epigenetic modifications. Resveratrol, the pioneering activator of the SIRTs family, and its derivatives have captured global scholarly interest. In the context of AID, these compounds hold promise for therapeutic intervention by modulating the SIRTs pathway, impacting immune cell functionality, suppressing the release of inflammatory mediators, and mitigating tissue damage. This review endeavors to explore the potential of resveratrol and its derivatives in AID treatment, elucidating their mechanisms of action and providing a comprehensive analysis of current research advancements and obstacles. Through a thorough examination of existing literature, our objective is to advocate for the utilization of resveratrol and its derivatives in AID treatment while offering crucial insights for the formulation of innovative therapeutic approaches.
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Enfermedades Autoinmunes , Resveratrol , Sirtuinas , Resveratrol/uso terapéutico , Resveratrol/farmacología , Humanos , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Animales , Sirtuinas/metabolismoRESUMEN
Sirtuins are pivotal in orchestrating numerous cellular pathways, critically influencing cell metabolism, DNA repair, aging processes, and oxidative stress. In recent years, the involvement of sirtuins in tumor biology has garnered substantial attention, with a growing body of evidence underscoring their regulatory roles in various aberrant cellular processes within tumor environments. This article delves into the sirtuin family and its biological functions, shedding light on their dual roles-either as promoters or inhibitors-in various cancers including oral, breast, hepatocellular, lung, and gastric cancers. It further explores potential anti-tumor agents targeting sirtuins, unraveling the complex interplay between sirtuins, miRNAs, and chemotherapeutic drugs. The dual roles of sirtuins in cancer biology reflect the complexity of targeting these enzymes but also highlight the immense therapeutic potential. These advancements hold significant promise for enhancing clinical outcomes, marking a pivotal step forward in the ongoing battle against cancer.
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Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This dysfunction promotes the production of reactive oxygen species (ROS), which cause oxidative stress and inflammation. Angiotensin II, the main mediator of the renin-angiotensin-aldosterone system, also contributes to CVD by promoting ROS production. Reduced activity of sirtuins (SIRTs), a family of proteins that regulate cellular metabolism, also worsens oxidative stress. Reduction of energy production by mitochondria is a common feature of all metabolic disorders. High SIRT levels and 5' adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta, which promotes ketosis. Ketosis, in turn, increases autophagy and mitophagy, processes that clear cells of debris and protect against damage. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), a class of drugs used to treat type 2 diabetes, have a beneficial effect on these mechanisms. Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events. SGLT2i also increase mitochondrial efficiency, reduce oxidative stress and inflammation, and strengthen tissues. These findings suggest that SGLT2i hold great potential for the treatment of CVD. Furthermore, they are proposed as anti-aging drugs; however, rigorous research is needed to validate these preliminary findings.
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Kidney diseases, including chronic kidney disease (CKD), diabetic nephropathy, and acute kidney injury (AKI), represent a significant global health burden. The kidneys are metabolically very active organs demanding a large amount of ATP. They are composed of highly specialized cell types in the glomerulus and subsequent tubular compartments which fine-tune metabolism to meet their numerous and diverse functions. Defective renal cell metabolism, including altered fatty acid oxidation or glycolysis, has been linked to both AKI and CKD. Mitochondria play a vital role in renal metabolism, and emerging research has identified mitochondrial sirtuins (SIRT3, SIRT4 and SIRT5) as key regulators of renal cell metabolic adaptation, especially SIRT3. Sirtuins belong to an evolutionarily conserved family of mainly NAD+-dependent deacetylases, deacylases, and ADP-ribosyl transferases. Their dependence on NAD+, used as a co-substrate, directly links their enzymatic activity to the metabolic status of the cell. In the kidney, SIRT3 has been described to play crucial roles in the regulation of mitochondrial function, and the antioxidative and antifibrotic response. SIRT3 has been found to be constantly downregulated in renal diseases. Genetic or pharmacologic upregulation of SIRT3 has also been associated with beneficial renal outcomes. Importantly, experimental pieces of evidence suggest that SIRT3 may act as an important energy sensor in renal cells by regulating the activity of key enzymes involved in metabolic adaptation. Activation of SIRT3 may thus represent an interesting strategy to ameliorate renal cell energetics. In this review, we discuss the roles of SIRT3 in lipid and glucose metabolism and in mediating a metabolic switch in a physiological and pathological context. Moreover, we highlight the emerging significance of other mitochondrial sirtuins, SIRT4 and SIRT5, in renal metabolism. Understanding the role of mitochondrial sirtuins in kidney diseases may also open new avenues for innovative and efficient therapeutic interventions and ultimately improve the management of renal injuries.
Asunto(s)
Enfermedades Renales , Riñón , Mitocondrias , Sirtuina 3 , Sirtuinas , Humanos , Sirtuinas/metabolismo , Sirtuina 3/metabolismo , Sirtuina 3/genética , Mitocondrias/metabolismo , Animales , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Riñón/metabolismo , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genéticaRESUMEN
BACKGROUND: Hypertension may result in atrial fibrillation (AF) and lipid metabolism disorders. The Sirtuins3 (SIRT3) / AMP-activated protein kinase (AMPK) signaling pathway has the capacity to regulate lipid metabolism disorders and the onset of AF. We hypothesize that the SIRT3/AMPK signaling pathway suppresses lipid metabolism disorders, thereby mitigating salt-sensitive hypertension (SSHT)-induced susceptibility to AF. METHODS: The study involved 7-week-old male Dahl salt-sensitive that were fed either high-salt diet (8% NaCl; DSH group) or normal diet (0.3% NaCl; DSN group). Then DSH group were administered either oral metformin (MET, an AMPK agonist) or intraperitoneal injection of Honokiol (HK, a SIRT3 agonist). This experimental model allowed for the measurement of SBP, the expression levels of lipid metabolism-related biomarker, pathological examination of atrial fibrosis and lipid accumulation, as well as AF inducibility and AF duration. RESULTS: DSH decrease SIRT3, phosphorylation-AMPK and VLCAD expression, increased FASN and FABP4 expression and concentrations of FFA and TG, atrial fibrosis and lipid accumulation in atrial tissue, enhanced level of SBP, promoted AF induction rate and prolonged AF duration, which are blocked by MET and HK. Our results also showed that the degree of atrial fibrosis was negatively correlated with VLCAD expression, but positively correlated with the expression of FASN and FABP4. CONCLUSIONS: We have confirmed that high-salt diet can result in hypertension, associated atrial tissue lipid metabolism dysfunction. This condition is linked to the inhibition of the SIRT3/AMPK signaling pathway, which plays a significant role in the progression of susceptibility to AF in SSHT rats.
RESUMEN
Sirtuins (SIRTs) are a family of proteins with enzymatic activity. In particular, they are a family of class III NAD+-dependent histone deacetylases and ADP-ribosyltransferases. NAD+-dependent deac(et)ylase activities catalyzed by sirtuin include ac(et)ylation, propionylation, butyrylation, crotonylation, manylation, and succinylation. Specifically, human SIRT3 is a 399 amino acid protein with two functional domains: a large Rossmann folding motif and NAD+ binding, and a small complex helix and zinc-binding motif. SIRT3 is widely expressed in mitochondria-rich tissues and is involved in maintaining mitochondrial integrity, homeostasis, and function. Moreover, SIRT3 regulates related diseases, such as aging, hepatic, kidney, neurodegenerative and cardiovascular disease, metabolic diseases, and cancer development. In particular, one of the most significant and damaging post-translational modifications is irreversible protein oxidation, i.e. carbonylation. This process is induced explicitly by increased ROS production due to mitochondrial dysfunction. SIRT3 is carbonylated by 4-hydroxynonenal at the level of Cys280. The carbonylation induces conformational changes in the active site, resulting in allosteric inhibition of SIRT3 activity and loss of the ability to deacetylate and regulate antioxidant enzyme activity. Phytochemicals and, in particular, polyphenols, thanks to their strong antioxidant activity, are natural compounds with a positive regulatory action on SIRT3 in various pathologies. Indeed, the enzymatic SIRT3 activity is modulated, for example, by different natural polyphenol classes, including resveratrol and the bergamot polyphenolic fraction. Thus, this review aims to elucidate the mechanisms by which phytochemicals can interact with SIRT3, resulting in post-translational modifications that regulate cellular metabolism.