RESUMEN

Myocardial ischemia-reperfusion injury (MIRI) is a significant complication following reperfusion therapy after myocardial infarction. Mitochondrial oxidative stress is a critical factor in MIRI, and Sirtuin 3 (SIRT3), as a major mitochondrial deacetylase, plays a key protective role, with its activity potentially regulated by O-GlcNAcylation. This study used the H9C2 cell line to establish a simulated ischemia/reperfusion (SI/R) model, we utilized co-immunoprecipitated to validate the relationship between O-GlcNAc transferase (OGT) and SIRT3, demonstrated SIRT3 O-GlcNAcylation sites through LC-MS/MS, and performed site mutations using CRISPR/Cas9 technology. The results were validated using immunoblotting. SIRT3 and superoxide dismutase 2 (SOD2) activities were detected using a fluorometric assay, while mitochondrial reactive oxygen species (MROS) levels and cellular apoptosis were assessed using immunofluorescence. We have identified an interaction between SIRT3 and OGT, where SIRT3 undergoes dynamic O-GlcNAcylation at the S190 site, facilitating SIRT3 deacetylase activity. During SI/R, elevated levels of O-GlcNAcylation activate SOD2 by promoting SIRT3 enzyme activity, thereby inhibiting excessive MROS production. This significantly mitigates the occurrence of malignant autophagy in myocardial cells during reperfusion, promoting their survival. Conversely, blocking SIRT3 O-GlcNAcylation at the S190 site exacerbates SI/R injury. We demonstrate that O-GlcNAcylation is a crucial post-translational modification (PTM) of SIRT3 during SI/R, shedding light on a promising mechanism for future therapeutic approaches.

Asunto(s)

Daño por Reperfusión Miocárdica , Estrés Oxidativo , Sirtuina 3 , Superóxido Dismutasa , Sirtuina 3/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Animales , Superóxido Dismutasa/metabolismo , Línea Celular , Ratas , Especies Reactivas de Oxígeno/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Mitocondrias/metabolismo , Apoptosis , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Humanos , Sirtuinas

RESUMEN

Abnormal SUMOylation is implicated in non-alcoholic fatty liver disease (NAFLD) progression. Forkhead box protein A1 (FoxA1) has been shown to protect liver from steatosis, which was down-regulated in NAFLD. This study elucidated the role of FoxA1 deSUMOylation in NAFLD. NAFLD models were established in high-fat diet (HFD)-induced mice and palmitate acid (PAL)-treated hepatocytes. Hepatic steatosis was evaluated by biochemical and histological methods. Lipid droplet formation was determined by BODIPY and Oil red O staining. Target molecule levels were analyzed by RT-qPCR, Western blotting, and immunohistochemistry staining. SUMOylation of FoxA1 was determined by Ni-NTA pull-down assay and SUMOylation assay Ultra Kit. Protein interaction and ubiquitination were detected by Co-IP. Gene transcription was assessed by ChIP and dual luciferase reporter assays. Liver FoxA1 knockout mice developed severe liver steatosis, which could be ameliorated by sirtuin 6 (Sirt6) overexpression. Nutritional stresses reduced Sumo2/3-mediated FoxA1 SUMOylation at lysine residue K6, which promoted lipid droplet formation by repressing fatty acid ß-oxidation. Moreover, Sirt6 was a target gene of FoxA1, and Sirt6 transcription activity was restrained by deSUMOylation of FoxA1 at site K6. Furthermore, nutritional stresses-induced deSUMOylation of FoxA1 promoted the ubiquitination and degradation of FoxA1 with assistance of murine double minute 2 (Mdm2). Finally, activating FoxA1 SUMOylation delayed the progression of NAFLD in mice. DeSUMOylation of FoxA1 at K6 promotes FoxA1 degradation and then inhibits Sirt6 transcription, thereby suppressing fatty acid ß-oxidation and facilitating NAFLD development. Our findings suggest that FoxA1 SUMOylation activation might be a promising therapeutic strategy for NAFLD.

Asunto(s)

Regulación hacia Abajo , Factor Nuclear 3-alfa del Hepatocito , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico , Sirtuinas , Sumoilación , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Factor Nuclear 3-alfa del Hepatocito/genética , Ratones , Humanos , Sirtuinas/metabolismo , Sirtuinas/genética , Masculino , Ratones Endogámicos C57BL , Dieta Alta en Grasa , Modelos Animales de Enfermedad

RESUMEN

Several metabolites have been shown to have independent and at times unexpected biological effects outside of their metabolic pathways. These include succinate, lactate, fumarate, and 2-hydroxyglutarate. 2-Hydroxybutyrate (2HB) is a byproduct of endogenous cysteine synthesis, produced during periods of cellular stress. 2HB rises acutely after exercise; it also rises during infection and is also chronically increased in a number of metabolic disorders. We show here that 2HB inhibits branched-chain aminotransferase enzymes, which in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBPß-mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity in vitro. We found that repeated injection with 2HB can replicate the improvement to oxidative capacity that occurs following exercise training. Together, we show that 2-HB regulates fundamental aspects of skeletal muscle metabolism.

Asunto(s)

Fatiga Muscular , Animales , Ratones , Músculo Esquelético/metabolismo , Retroalimentación Fisiológica , ADP-Ribosilación , Transaminasas/metabolismo , Transaminasas/genética , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Proteína beta Potenciadora de Unión a CCAAT/genética , Sirtuinas/metabolismo , Sirtuinas/genética , Hidroxibutiratos/metabolismo

RESUMEN

MitoAMPK was proved to inhibit the Warburg effect, but the specific mechanisms on non-small-cell lung cancer remain unclear. Here, we selected SIRT6 and MZF1 to clarify the mechanism. By western blotting, quantitative polymerase chain reaction, the CCK-8 assay, and immunohistochemistry assays, we found SIRT6 expression was lower in NSCLC tissues and cell lines than normal tissues and cells. Moreover, SIRT6 could inhibit the Warburg effect by regulating glycolysis-related genes of SLC2A2, SLC2A4 and PKM2. Finally, we demonstrated the interaction between SIRT6 and MZF1 using ChIP-qPCR. In conclusion, mitoAMPK inhibits the Warburg effect by regulating the expression of the MZF1-SIRT6 complex.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción de Tipo Kruppel , Neoplasias Pulmonares , Sirtuinas , Efecto Warburg en Oncología , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Sirtuinas/metabolismo , Sirtuinas/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Línea Celular Tumoral , Glucólisis/genética , Femenino , Masculino

RESUMEN

OBJECTIVE: Bidirectional influences between senescence and inflammation are newly discovered. This study aimed to clarify the roles and mechanism of Porphyromonas gingivalis (P. gingivalis) in exacerbating senescence in human gingival fibroblasts (HGFs). DESIGN: Subgingival plaque and gingivae were collected from twenty-four periodontitis patients and eighteen periodontally healthy subjects. Quantities of P. gingivalis in subgingival plaque were explored using real-time PCR and the expressions of p53, p21 and SIRT6 in gingivae were detected by IHC. Moreover, senescence in HGFs was induced by P. gingivalis lipopolysaccharide (LPS) and the expressions of senescence-related ß-galactosidase (SA-ß-gal), p53, p21 and senescence-associated secretory phenotype (IL-6 and IL-8) with or without treatment by SIRT6 activator UBCS039 were explored by IHC, western blot and ELISA, respectively. In addition, the levels of SIRT6, Nrf2, HO-1 and reactive oxygen species (ROS) were examined by western blot and flow cytometry. RESULTS: Quantities of P. gingivalis in subgingival plaque and semi-quantitative scores of p53 and p21 in gingivae of periodontitis patients were increased compared with healthy controls (p < 0.05), while SIRT6 score in periodontitis patients was decreased (p < 0.001). Quantities of P. gingivalis were positively correlated with p53 and p21 scores (0.6 < r < 0.9, p < 0.01), and negatively correlated with SIRT6 score (-0.9 < r<-0.6, p < 0.01). Moreover, P. gingivalis LPS increased the levels of SA-ß-gal, p53, p21, IL-6, IL-8 and ROS and decreased the levels of SIRT6, Nrf2 and HO-1 in HGFs, which was rescued by UBCS039 (p < 0.05). CONCLUSIONS: P. gingivalis LPS could induce senescence of HGFs, which could be reversed by SIRT6 via Nrf2-HO-1 signaling pathway.

Asunto(s)

Senescencia Celular , Fibroblastos , Encía , Factor 2 Relacionado con NF-E2 , Porphyromonas gingivalis , Especies Reactivas de Oxígeno , Sirtuinas , Humanos , Porphyromonas gingivalis/patogenicidad , Encía/microbiología , Encía/metabolismo , Fibroblastos/metabolismo , Sirtuinas/metabolismo , Sirtuinas/genética , Masculino , Femenino , Adulto , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Especies Reactivas de Oxígeno/metabolismo , Lipopolisacáridos/farmacología , Periodontitis/microbiología , Periodontitis/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Persona de Mediana Edad , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética

RESUMEN

The accumulation of SIRT4 in the nuclei of kidney cells drives kidney fibrosis, so blocking the movement of this protein could be a potential therapeutic strategy against fibrosis.

Asunto(s)

Fibrosis , Sirtuinas , Sirtuinas/metabolismo , Animales , Humanos , Riñón/patología , Riñón/metabolismo , Ratones , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Proteínas Mitocondriales

RESUMEN

Introduction: Group 3 innate lymphoid cells (ILC3s) are enriched in the intestinal mucosa and play important roles in host defense against infection and inflammatory diseases. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)- dependent deacetylase and has been shown to control intestinal epithelial cell differentiation and survival. However, the role of SIRT6 in ILC3s remains unknown. Methods: To investigate the role of SIRT6 in gut ILC3s, we generated SIRT6 conditional knockout mice by crossing Rorccre and Sirt6flox/flox mice. Cell number and cytokine production was examined using flow cytometry. Citrobacter rodentium infection and dextran sodium sulfate-induced colitis models were used to determine the role of SIRT6 in gut defense. RT-qPCR, flow cytometry and immunohistochemistry were used to assess the intestinal inflammatory responses. Results: Here we show that SIRT6 inhibits IL-22 expression in intestinal ILC3s in a cell-intrinsic manner. Deletion of SIRT6 in ILC3s does not affect the cell numbers of total ILC3s and subsets, but results in increased IL-22 production. Furthermore, ablation of SIRT6 in ILC3s protects mice against Citrobacter rodentium infection and dextran sodium sulfate-induced colitis. Our results suggest that SIRT6 may play a role in ILC3 function by regulating gut immune responses against bacterial infection and inflammation. Discussion: Our finding provided insight into the relation of epigenetic regulators with IL-22 production and supplied a new perspective for a potential strategy against inflammatory bowel disease.

Asunto(s)

Citrobacter rodentium , Colitis , Infecciones por Enterobacteriaceae , Inmunidad Innata , Interleucina-22 , Interleucinas , Linfocitos , Ratones Noqueados , Sirtuinas , Animales , Ratones , Linfocitos/inmunología , Linfocitos/metabolismo , Interleucinas/metabolismo , Interleucinas/inmunología , Interleucinas/genética , Sirtuinas/genética , Sirtuinas/metabolismo , Colitis/inmunología , Colitis/inducido químicamente , Citrobacter rodentium/inmunología , Infecciones por Enterobacteriaceae/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Ratones Endogámicos C57BL , Sulfato de Dextran , Modelos Animales de Enfermedad

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Ligustrum lucidum W.T. Aiton is a traditional Chinese medicine that has long been used with high hepatoprotective therapeutic and condition value. Specnuezhenide (SP), the standard prominent secoiridoid compound of Fructus Ligustri Lucidi may ameliorate hepatic inflammation in chronic liver diseases. AIM OF THE STUDY: Regulating inflammation through SIRT6-P2X7R axis has caused the emergence of novel molecular mechanism strategies for reversing hepatic fibrosis. This study focused on the mechanism of SP in modulating the liver inflammatory microenvironment in hepatic fibrosis. MATERIALS AND METHODS: C57BL/6 mice with hepatic fibrosis were stimulated with thioacetamide (TAA) prior to administration of SP. Hepatic stellate cells (HSCs) or normal mouse primary hepatocytes were exposed to transforming growth factor-ß (TGF-ß) treatment. Meanwhile, normal mouse bone marrow-derived macrophages (BMDMs) were treated with lipopolysaccharide/adenosine triphosphate (LPS/ATP), aiming to obtain the conditioned medium. HSCs and hepatocytes were transfected with SIRT6 knockdown vector (siRNA-SIRT6) to estimate the impact of SP on the SIRT6-P2X7R/NLRP3 signaling pathway. RESULTS: SP suppressed the HSCs extracellular matrix (ECM) deposition as well as pro-inflammatory cytokine levels induced by the medium of BMDMs or TGF-ß. In addition, SP also significantly up-regulated SIRT6, inhibited P2X7R-NLRP3 inflammasome in HSCs and hepatocytes, and functioned as MDL-800 (a SIRT6 agonist). SP reduced the hepatocytes pyroptosis and further prevented the occurrence of inflammatory response in the liver. SP could inhibit the activation of BMDMs and impede IL-1ß and IL-18 from entering extracellular regions. Moreover, deficiency of SIRT6 in HSCs or hepatocytes reduced SP's regulation of P2X7R suppression. For TAA-treated mice, SP mitigated histopathological changes, ECM accumulation, EMT process, and NETs formation in hepatic fibrosis. CONCLUSIONS: Therefore, SP decreased inflammatory response via SIRT6-P2X7R/NLRP3 pathway and suppressed fibrillogenesis. These findings supported SP as the novel candidate to treat hepatic fibrosis.

Asunto(s)

Cirrosis Hepática , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de Señal , Sirtuinas , Animales , Sirtuinas/metabolismo , Sirtuinas/genética , Transducción de Señal/efectos de los fármacos , Ratones , Masculino , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Tioacetamida/toxicidad , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Antiinflamatorios/farmacología

RESUMEN

Sirtuin 5 (SIRT5) is increasingly recognized as a key regulator of cellular metabolism, which is commonly dysregulated in cancer cells, resulting in enhanced proliferation and tumor progression. To investigate the clinicopathologic implications of SIRT5 dysregulation in glioblastoma, we performed comprehensive analyses of transcriptomic data and functional verifications using in vitro and in vivo glioblastoma models. We found that higher SIRT5 expression levels were associated with a favorable prognosis in glioma patients. Knockdown of SIRT5 significantly enhanced glioblastoma cell growth. Our data suggest its potential role in regulating mitochondrial metabolism in gliomas. Furthermore, SIRT5 is also significantly correlated with synaptic remodeling pathways. Our findings indicate a tumor-suppressive role for SIRT5 that extends beyond regulating cancer metabolism, by which it may function through modulating neuroplasticity. Understanding these cellular interactions provides nuanced insights into the multifaceted role of SIRT5 and the broader therapeutic implications of this for the development of novel treatment strategies.

Asunto(s)

Proliferación Celular , Glioma , Mitocondrias , Sirtuinas , Sirtuinas/metabolismo , Sirtuinas/genética , Humanos , Mitocondrias/metabolismo , Mitocondrias/genética , Animales , Glioma/metabolismo , Glioma/patología , Glioma/genética , Línea Celular Tumoral , Ratones , Regulación Neoplásica de la Expresión Génica , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , Pronóstico , Ratones Desnudos , Sinapsis/metabolismo , Sinapsis/patología , Plasticidad Neuronal

RESUMEN

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.

Asunto(s)

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/genética

RESUMEN

Vascular dementia (VaD) is a prevalent form of dementia resulting from chronic cerebral hypoperfusion (CCH). However, the pathogenic mechanisms of VaD and corresponding therapeutic strategies are not well understood. Sirtuin 6 (SIRT6) has been implicated in various biological processes, including cellular metabolism, DNA repair, redox homeostasis, and aging. Nevertheless, its functional relevance in VaD remains unexplored. In this study, we utilized a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate the role of SIRT6. We detected a significant decrease in neuronal SIRT6 protein expression following CCH. Intriguingly, neuron-specific ablation of Sirt6 in mice exacerbated neuronal damage and cognitive deficits after CCH. Conversely, treatment with MDL-800, an agonist of SIRT6, effectively mitigated neuronal loss and facilitated neurological recovery. Mechanistically, SIRT6 inhibited excessive mitochondrial fission by suppressing the CCH-induced STAT5-PGAM5-Drp1 signaling cascade. Additionally, the gene expression of monocyte SIRT6 in patients with asymptomatic carotid stenosis showed a correlation with cognitive outcomes, suggesting translational implications in human subjects. Our findings provide the first evidence that SIRT6 prevents cognitive impairment induced by CCH, and mechanistically, this protection is achieved through the remodeling of mitochondrial dynamics in a STAT5-PGAM5-Drp1-dependent manner.

Asunto(s)

Disfunción Cognitiva , Dinaminas , Dinámicas Mitocondriales , Factor de Transcripción STAT5 , Sirtuinas , Anciano , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Isquemia Encefálica/complicaciones , Isquemia Encefálica/patología , Isquemia Encefálica/metabolismo , Estenosis Carotídea/complicaciones , Estenosis Carotídea/metabolismo , Enfermedad Crónica , Disfunción Cognitiva/patología , Dinaminas/metabolismo , Dinaminas/genética , Ratones Endogámicos C57BL , Dinámicas Mitocondriales/efectos de los fármacos , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Transducción de Señal/efectos de los fármacos , Sirtuinas/metabolismo , Sirtuinas/genética , Factor de Transcripción STAT5/metabolismo

RESUMEN

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have a variety of cardiovascular and renoprotective effects and have been developed as novel agents for the treatment of heart failure. However, the beneficial mechanisms of SGLT2i on cardiac tissue need to be investigated further. In this study, we established a mouse model of acute myocardial infarction (AMI) using coronary artery constriction surgery and investigated the role of dapagliflozin (DAPA) in protecting cardiomyocytes from hypoxic injury induced by AMI. In vitro experiments were done using hypoxic cultured H9c2 ventricular cells to verify this potential mechanism. Expression of the SIRT family and related genes and proteins was verified by qPCR, Western blotting and immunofluorescence staining, and the intrinsic potential mechanism of cardiomyocyte death due to AMI and hypoxia was comprehensively investigated by RNA sequencing. The RNA sequencing results of cardiomyocytes from AMI mice showed that the SIRT family may be mainly involved in the mechanisms of hypoxia-induced cardiomyocyte death. In vitro hypoxia-induced ventricular cells showed the role of dapagliflozin in conferring resistance to hypoxic injury in cardiomyocytes. It showed that SIRT1/3/6 were downregulated in H9c2 cells in a hypoxic environment, and the addition of dapagliflozin significantly increased the gene and protein expression of SIRT1, 3 and 6. We then verified the underlying mechanisms induced by dapagliflozin in hypoxic cardiomyocytes using RNA-seq, and found that dapagliflozin upregulated the hypoxia-induced gene downregulation, which includes ESRRA, EPAS1, AGTRAP, etc., that associated with SIRTs-related and apoptosis-related signaling to prevent H9c2 cell death. This study provides laboratory data for SGLT2i dapagliflozin treatment of AMI and confirms that dapagliflozin can be used to treat hypoxia-induced cellular necrosis in cardiomyocytes, in which SIRT1 and SIRT3 may play an important role. This opens up further opportunities for SGLT2i in the treatment of heart disease.

Asunto(s)

Compuestos de Bencidrilo , Glucósidos , Infarto del Miocardio , Miocitos Cardíacos , Transducción de Señal , Sirtuina 1 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Glucósidos/farmacología , Glucósidos/uso terapéutico , Animales , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Ratones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Sirtuina 1/metabolismo , Sirtuina 1/genética , Transducción de Señal/efectos de los fármacos , Masculino , Sirtuina 3/metabolismo , Sirtuina 3/genética , Sirtuinas/metabolismo , Sirtuinas/genética , Línea Celular , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Hipoxia de la Célula/efectos de los fármacos , Ratas , Apoptosis/efectos de los fármacos

RESUMEN

Segmental bone defects and nonunion of fractures caused by trauma, infection, tumor or systemic diseases with limited osteogenesis and prolonged bone healing cycles are challenging issues in orthopedic clinical practice. Therefore, identifying regulatory factors for bone tissue regeneration and metabolism is crucial for accelerating bone repair and reconstructing defective areas. Silence information regulator 6 (SIRT6), functioning as a deacetylase and nucleotide transferase, is extensively involved in the regulation of differentiation, apoptosis, metabolism, and inflammation in bone cells including osteoblasts and osteoclasts, and is considered to be an important factor in regulating bone metabolism. SIRT6 forms a complex with B lymphocyte-induced maturation protein 1 (Blimp1), down-regulates the expression of the nuclear factor κB (NF-κB) pathway, and promotes the expression of the ERα-FasL axis signal to inhibit osteoclast formation and maturation differentiation, thereby hindering bone resorption and increasing bone mass. In addition, SIRT6 activates the Akt-mTOR pathway to regulate the autophagy level and osteogenesis of bone marrow mesenchymal stem cells, inhibits glycolysis and reactive oxygen production in osteoblasts, promotes osteoblast differentiation through the CREB/CCN1/COX2 pathway and the bone morphogenetic protein (BMP) signaling pathway, enhances bone formation, and accelerates bone regeneration and repair of skeletal tissue. This article provides an overview of the research progress on SIRT6 in the pathophysiology of bone regeneration, revealing its potential as a novel therapeutic target for bone tissue repair to alleviate the progression of skeletal pathological diseases.

Asunto(s)

Regeneración Ósea , Osteogénesis , Sirtuinas , Humanos , Sirtuinas/metabolismo , Osteoblastos , Animales , Diferenciación Celular , Transducción de Señal , Osteoclastos , FN-kappa B/metabolismo

RESUMEN

Cuproptosis is characterized by lipoylated protein aggregation and loss of iron-sulfur (Fe-S) proteins, which are crucial for a wide range of important cellular functions, including DNA replication and damage repair. Sirt2 and sirt4 are lipoamidases that remove the lipoyl moiety from lipoylated proteins using nicotinamide adenine dinucleotide (NAD+) as a cofactor. However, to date, it is not clear whether nicotinamide mononucleotide (NMN), a precursor of NAD+, affects cellular sensitivity to cuproptosis. Therefore, in the current study, cuproptosis was induced by the copper (Cu) ionophore elesclomol (Es) in HeLa cells. It was also found that Es/Cu treatment increased cellular DNA damage level. On the other hand, NMN treatment partially rescued cuproptosis in a dose-dependent manner, as well as reduced cellular DNA damage level. In addition, NMN upregulated the expression of Fe-S protein POLD1, without affecting the aggregation of lipoylated proteins. Mechanistic study revealed that NMN increased the expression of sirt2 and cellular reduced nicotinamide adenine dinucleotide phosphate (NADPH) level. Overexpression of sirt2 and sirt4 did not change the aggregation of lipoylated proteins, however, sirt2, but not sirt4, increased cellular NADPH levels and partially rescued cuproptosis. Inhibition of NAD+ kinase (NADK), which is responsible for generating NADPH, abolished the rescuing function of NMN and sirt2 for Es/Cu induced cell death. Taken together, our results suggested that DNA damage is a characteristic feature of cuproptosis. NMN can partially rescue cuproptosis by upregulating sirt2, increase intracellular NADPH content and maintain the level of Fe-S proteins, independent of the lipoamidase activity of sirt2.

Asunto(s)

Daño del ADN , NADP , Mononucleótido de Nicotinamida , Sirtuina 2 , Regulación hacia Arriba , Humanos , Sirtuina 2/metabolismo , Sirtuina 2/genética , Células HeLa , NADP/metabolismo , Daño del ADN/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Mononucleótido de Nicotinamida/farmacología , Mononucleótido de Nicotinamida/metabolismo , Cobre/farmacología , Cobre/metabolismo , Sirtuinas/metabolismo

RESUMEN

OBJECTIVE: Colorectal cancer progression involves complex cellular mechanisms. This study examines the effects of Lactobacillus plantarum-derived extracellular vesicles (LEVs) on the SIRT5/p53 axis, focusing on glycolytic metabolic reprogramming and abnormal proliferation in intestinal epithelial cells. METHODS: LEVs were isolated from Lactobacillus plantarum and incubated with Caco-2 cells. Differential gene expression was analyzed through RNA sequencing and compared with TCGA-COAD data. Key target genes and pathways were identified using PPI network and pathway enrichment analysis. Various assays, including RT-qPCR, EdU staining, colony formation, flow cytometry, and Western blotting, were used to assess gene expression, cell proliferation, and metabolic changes. Co-immunoprecipitation confirmed the interaction between SIRT5 and p53, and animal models were employed to validate in vivo effects. RESULTS: Bioinformatics analysis indicated the SIRT5/p53 axis as a critical pathway in LEVs' modulation of colorectal cancer. LEVs were found to inhibit colorectal cancer cell proliferation and glycolytic metabolism by downregulating SIRT5, influencing p53 desuccinylation. In vivo, LEVs regulated this axis, reducing tumor formation in mice. Clinical sample analysis showed that SIRT5 and p53 succinylation levels correlated with patient prognosis. CONCLUSION: Lactobacillus-derived extracellular vesicles play a pivotal role in suppressing colonic tumor formation by modulating the SIRT5/p53 axis. This results in decreased glycolytic metabolic reprogramming and reduced proliferation in intestinal epithelial cells.

Asunto(s)

Proliferación Celular , Neoplasias Colorrectales , Vesículas Extracelulares , Glucólisis , Sirtuinas , Proteína p53 Supresora de Tumor , Sirtuinas/metabolismo , Sirtuinas/genética , Proteína p53 Supresora de Tumor/metabolismo , Humanos , Vesículas Extracelulares/metabolismo , Animales , Células CACO-2 , Ratones , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Células Epiteliales/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Lactobacillus plantarum/metabolismo , Ratones Desnudos , Ratones Endogámicos BALB C

RESUMEN

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.

Asunto(s)

Insuficiencia Multiorgánica , Sepsis , Sirtuinas , Sirtuinas/metabolismo , Sepsis/metabolismo , Sepsis/complicaciones , Humanos , Animales , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/metabolismo , Estrés Oxidativo , Transducción de Señal

RESUMEN

The accumulating evidence has made it clear that iron overload is a crucial mechanism in bone loss. Protocatechualdehyde (PCA) has also been used to prevent osteoporosis in recent years. Whether PCA can reverse the harmful effects of iron overload on bone mass in aged rats is still unknown. Therefore, this study aimed to assess the role of PCA in iron overload-induced bone loss in senile rats. In the aged rat model, we observed that iron overload affects bone metabolism and bone remodeling, manifested by bone loss and decreased bone mineral density. The administration of PCA effectively mitigated the detrimental effects caused by iron overload, and concomitant reduction in MDA serum levels and elevation of SOD were noted. In addition, PCA-treated rats were observed to have significantly increased bone mass and elevated expression of SIRT3，BMP2，SOD2 and reduced expression of TNF-α in bone tissue. We also observed that PCA was able to reduce oxidative stress and inflammation and restore the imbalance in bone metabolism. When MC3T3-E1 and RAW264.7 cells induced osteoblast and osteoclasts differentiation, PCA intervention could significantly recover the restriction of osteogenic differentiation and up-regulation of osteoclast differentiation treated by iron overload. Further, by detecting changes in ROS, SOD, MDA, expression of SIRT3 and mitochondrial membrane potentials, we confirm that the damage caused to cells by iron overload is associated with decreased SIRT3 activity, and that 3-TYP have similar effects on oxidative stress caused by FAC. In conclusion, PCA can resist iron overload-induced bone damage by improving SIRT3 activity, anti-inflammatory and anti-oxidative stress.

Asunto(s)

Sobrecarga de Hierro , Estrés Oxidativo , Animales , Estrés Oxidativo/efectos de los fármacos , Sobrecarga de Hierro/metabolismo , Ratones , Ratas , Masculino , Células RAW 264.7 , Ratas Sprague-Dawley , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Sirtuina 3/metabolismo , Sirtuina 3/genética , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteoporosis/metabolismo , Osteoporosis/etiología , Osteoporosis/tratamiento farmacológico , Benzaldehídos/farmacología , Benzaldehídos/uso terapéutico , Inflamación , Osteogénesis/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Densidad Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Envejecimiento , Modelos Animales de Enfermedad , Superóxido Dismutasa/metabolismo , Sirtuinas

RESUMEN

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.

Asunto(s)

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 Droga

RESUMEN

Diffuse large B-cell lymphoma (DLBCL) is the most common diagnosed subtype of lymphoma with high invasiveness and heterogeneity. Glycolysis is involved in regulating DLBCL progression. We aimed to explore the role of forkhead box protein A1 (FOXA1) in DLBCL and the mechanisms related to sirtuine5 (SIRT5) and glycolysis. FOXA1 expression in DLBCL cells was analyzed. Then, the proliferation and apoptosis of DLBCL cells were detected using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EDU) staining and flow cytometry analysis following FOXA1 or SIRT5 knockdown. The glycolysis was assessed by measuring extracellular acidification rate (ECAR), glucose consumption and lactate secretion. Immunoblotting was employed to examine the expression of apoptosis- and glycolysis-related proteins. Additionally, luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were conducted to test the combination of FOXA1 to SIRT5 promotor region. Subsequently, SIRT5 expression was upregulated to conduct rescue assays. Finally, the effects of FOXA1 downregulation on the growth and glycolysis in OCI-ly7 tumor-bearing mice were examined. As a result, FOXA1 was upregulated in DLBCL cells and FOXA1 or SIRT5 knockdown inhibited the proliferation, accelerated the apoptosis and suppressed glycolysis reprograming in DLBCL cells. Importantly, FOXA1 could transcriptionally activate SIRT5 expression in DLBCL cells. Besides, SIRT5 overexpression counteracted the effects of FOXA1 deficiency on the proliferation, apoptosis and glycolysis reprogramming in DLBCL cells. Furthermore, FOXA1 knockdown inhibited the tumor growth, suppressed the glycolysis reprogramming and downregulated SIRT5 expression in vivo. In summary, FOXA1 could transcriptionally activate SIRT5 to reprogram glycolysis, thereby facilitating the malignant progression of DLBCL.

Asunto(s)

Glucólisis , Factor Nuclear 3-alfa del Hepatocito , Linfoma de Células B Grandes Difuso , Sirtuinas , Activación Transcripcional , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/genética , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Factor Nuclear 3-alfa del Hepatocito/genética , Humanos , Animales , Sirtuinas/metabolismo , Sirtuinas/genética , Ratones , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Apoptosis , Progresión de la Enfermedad

RESUMEN

Nicotinamide adenine dinucleotide provides the critical redox pair, NAD+ and NADH, for cellular energy metabolism. In addition, NAD+ is the precursor for de novo NADP+ synthesis as well as the co-substrates for CD38, poly(ADP-ribose) polymerase and sirtuins, thus, playing a central role in the regulation of oxidative stress and cell signaling. Declines of the NAD+ level and altered NAD+/NADH redox states have been observed in cardiometabolic diseases of various etiologies. NAD based therapies have emerged as a promising strategy to treat cardiovascular disease. Strategies that reduce NAD+ consumption or promote NAD+ production have repleted intracellular NAD+ or normalized NAD+/NADH redox in preclinical studies. These interventions have shown cardioprotective effects in multiple models suggesting a great promise of the NAD+ elevating therapy. Mechanisms for the benefit of boosting NAD+ level, however, remain incompletely understood. Moreover, despite the robust pre-clinical studies there are still challenges to translate the therapy to clinic. Here, we review the most up to date literature on mechanisms underlying the NAD+ elevating interventions and discuss the progress of human studies. We also aim to provide a better understanding of how NAD metabolism is changed in failing hearts with a particular emphasis on types of strategies employed and methods to target these pathways. Finally, we conclude with a comprehensive assessment of the challenges in developing NAD-based therapies for heart diseases, and to provide a perspective on the future of the targeting strategies.

Asunto(s)

Insuficiencia Cardíaca , NAD , Humanos , NAD/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/terapia , Animales , Oxidación-Reducción , Estrés Oxidativo , Sirtuinas/metabolismo , Transducción de Señal , Metabolismo Energético