RESUMO
In this editorial, we comment on the article by Zhou et al. The study reveals the connection between ferroptosis and pyroptosis and the effect of silent information regulator sirtuin 1 (SIRT1) activation in acute liver failure (ALF). ALF is characterized by a sudden and severe liver injury resulting in significant hepatocyte damage, often posing a high risk of mortality. The predominant form of hepatic cell death in ALF involves apoptosis, ferroptosis, autophagy, pyroptosis, and necroptosis. Glutathione peroxidase 4 (GPX4) inhibition sensitizes the cell to ferroptosis and triggers cell death, while Gasdermin D (GSDMD) is a mediator of pyroptosis. The study showed that ferroptosis and pyroptosis in ALF are regulated by blocking the p53/GPX4/GSDMD pathway, bridging the gap between the two processes. The inhibition of p53 elevates the levels of GPX4, reducing the levels of inflammatory and liver injury markers, ferroptotic events, and GSDMD-N protein levels. Reduced p53 expression and increased GPX4 on deletion of GSDMD indicated ferroptosis and pyroptosis interaction. SIRT1 is a NAD-dependent deacetylase, and its activation attenuates liver injury and inflammation, accompanied by reduced ferroptosis and pyroptosis-related proteins in ALF. SIRT1 activation also inhibits the p53/GPX4/GSDMD axis by inducing p53 acetylation, attenuating LPS/D-GalN-induced ALF.
Assuntos
Ferroptose , Peptídeos e Proteínas de Sinalização Intracelular , Falência Hepática Aguda , Proteínas de Ligação a Fosfato , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Sirtuína 1 , Proteína Supressora de Tumor p53 , Sirtuína 1/metabolismo , Sirtuína 1/genética , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Proteína Supressora de Tumor p53/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Ferroptose/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Animais , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/genética , Transdução de Sinais , Piroptose/efeitos dos fármacos , Hepatócitos/metabolismo , Fígado/patologia , Fígado/metabolismo , Camundongos , GasderminasRESUMO
In this editorial, we comment on the article published in the recent issue of the World Journal of Gastroenterology. Acute liver failure (ALF) is a fatal disease that causes uncontrolled massive hepatocyte death and rapid loss of liver function. Ferroptosis and pyroptosis, cell death forms that can be initiated or blocked concurrently, can play significant roles in developing inflammation and various malignancies. However, their roles in ALF remain unclear. The article discovered the positive feedback between ferroptosis and pyroptosis in the progression of ALF, and revealed that the silent information regulator sirtuin 1 (SIRT1) inhibits both pathways through p53, dramatically reducing inflammation and protecting hepatocytes. This suggests the potential use of SIRT1 and its downstream molecules as therapeutics for ALF. Thus, we will discuss the role of ferroptosis and pyroptosis in ALF and the crosstalk between these cell death mechanisms. Additionally, we address potential treatments that could alleviate ALF by simultaneously inhibiting both cell death pathways, as well as examples of SIRT1 activators being used as disease treatment strategies, providing new insights into the therapy of ALF.
Assuntos
Ferroptose , Hepatócitos , Falência Hepática Aguda , Piroptose , Sirtuína 1 , Humanos , Piroptose/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Sirtuína 1/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatócitos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Fígado/patologia , Fígado/metabolismo , Fígado/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Proteína Supressora de Tumor p53/metabolismoRESUMO
Intestinal barrier dysfunction with high serum endotoxin is common in patients with liver fibrosis, but the mechanisms underlying liver fibrosis remain unclear. Melatonin is a well-recognized antioxidant and an anti-inflammatory agent that benefits multiple organs. However, the beneficial effects of melatonin on gut leakiness-associated liver fibrosis have not been systemically studied. Here, we investigated the protective mechanisms of melatonin against thioacetamide (TAA)-induced gut barrier dysfunction and hepatic fibrosis by focusing on posttranslational protein modifications through the gut-liver axis. Our results showed that gut leakiness markers, including decreased gut tight/adherens junction proteins (TJ/AJs) with increased intestinal deformation, apoptosis, and serum endotoxin, were observed early at 1 week after TAA exposure. Liver injury, apoptosis, and fibrosis were prominent at 2 and 4 weeks. Mechanistically, we found that gut TJ/AJs were hyper-acetylated, followed by ubiquitin-dependent proteolysis, leading to their degradation and gut leakiness. Gut dysbiosis, hepatic protein hyper-acetylation, and SIRT1 downregulation were also observed. Consistently, intestinal Sirt1 deficiency greatly enhanced protein hyper-acetylation, gut leakiness, endotoxemia, and liver fibrosis. Pretreatment with melatonin prevented or improved all these changes in both the gut and liver. Furthermore, melatonin blunted protein acetylation and injury in TAA-exposed T84 human intestinal and AML12 mouse liver cells. Overall, this study demonstrated novel mechanisms by which melatonin prevents gut leakiness and liver fibrosis through the gut-liver axis by attenuating the acetylation of intestinal and hepatic proteins. Thus, melatonin consumption can become a potentially safe supplement for liver fibrosis patients by preventing protein hyper-acetylation and gut leakiness.
Assuntos
Cirrose Hepática , Melatonina , Sirtuína 1 , Tioacetamida , Tioacetamida/toxicidade , Sirtuína 1/metabolismo , Melatonina/farmacologia , Animais , Cirrose Hepática/metabolismo , Cirrose Hepática/induzido quimicamente , Camundongos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Acetilação/efeitos dos fármacos , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologiaRESUMO
The likelihood of survival for cancer patients has greatly improved due to chemotherapy medicines. However, these antitumor agents might also have unfavorable effects on the cardiovascular system, which could result in sudden or gradual cardiac failure. The production of free radicals that result in oxidative stress appears to be the key mechanism by which chemotherapy-induced cardiotoxicity (CIC) happens. Reports suggest that the Sirtuin-1 (Sirt1)/Nuclear factor E2-associated factor 2 (Nrf2) signaling pathway has been considered an alternative path for counteracting cardiotoxicity by suppressing oxidative stress, inflammation, and apoptosis. This review concludes recent knowledge about CIC with a special focus on the anti-oxidative regulation properties of the Sirt1/Nrf2 pathway.
Assuntos
Antineoplásicos , Cardiotoxicidade , Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Sirtuína 1 , Humanos , Sirtuína 1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Cardiotoxicidade/etiologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Animais , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Cerebrovascular disease, one of the high-risk diseases worldwide, is high in morbidity, disability, mortality, and recurrence rates, which brings many harms to human beings such as physical and mental harm, economic losses, and impairment of social relations. Cerebral ischemia-reperfusion injury (CIRI) is one of the most common pathological manifestations, with mild hypothermia therapy being the most commonly used treatment in clinical practice. In this study, the research team established a CIRI animal model and found that the neuronal apoptosis rate was significantly increased, accompanied by significant ferroptosis, increased inflammation and oxidative stress damage in brain tissue, and obviously inhibited SIRT1/AMPK pathway. However, after mild hypothermia treatment, the pathological changes of CIRI rats were significantly reversed, and the SIRT1/AMPK pathway was reactivated. Therefore, mild hypothermia may achieve the purpose of CIRI repair by activating the SIRT1/AMPK signaling pathway, and targeted regulation of the SIRT1/AMPK signaling pathway may be a research direction for optimizing mild hypothermia therapy or developing new treatment plans for CIRI.
Assuntos
Proteínas Quinases Ativadas por AMP , Apoptose , Hipotermia Induzida , Neurônios , Estresse Oxidativo , Traumatismo por Reperfusão , Transdução de Sinais , Sirtuína 1 , Sirtuína 1/metabolismo , Traumatismo por Reperfusão/terapia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Animais , Hipotermia Induzida/métodos , Neurônios/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Masculino , Isquemia Encefálica/terapia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Ratos Sprague-Dawley , Ratos , Modelos Animais de DoençasRESUMO
Despite recent advances in systemic therapy for hepatocellular carcinoma (HCC), the prognosis of hepatitis B virus (HBV)-induced HCC patients remains poor. By screening a sgRNA library targeting human deubiquitinases, we find that ubiquitin-specific peptidase 26 (USP26) deficiency impairs HBV-positive HCC cell proliferation. Genetically engineered murine models with Usp26 knockout confirm that Usp26 drives HCC tumorigenesis. Mechanistically, we find that the HBV-encoded protein HBx binds to the promoter and induces the production of USP26, which is an X-linked gene exclusively expressed in the testis. HBx consequently promotes the association of USP26 with SIRT1 to synergistically stabilize SIRT1 by deubiquitination, which promotes cell proliferation and impedes cell apoptosis to accelerate HCC tumorigenesis. In patients with HBV-positive HCC, USP26 is robustly induced, and its levels correlate with SIRT1 levels and poor prognosis. Collectively, our study highlights a causative link between HBV infection, deubiquitinase induction and development of HCC, identifying a druggable target, USP26.
Assuntos
Carcinoma Hepatocelular , Proliferação de Células , Epigênese Genética , Vírus da Hepatite B , Neoplasias Hepáticas , Sirtuína 1 , Transativadores , Proteínas Virais Reguladoras e Acessórias , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Humanos , Animais , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Vírus da Hepatite B/genética , Camundongos , Sirtuína 1/metabolismo , Sirtuína 1/genética , Transativadores/metabolismo , Transativadores/genética , Masculino , Proliferação de Células/genética , Proteínas Virais Reguladoras e Acessórias/metabolismo , Carcinogênese/genética , Hepatite B/virologia , Hepatite B/complicações , Hepatite B/genética , Hepatite B/metabolismo , Linhagem Celular Tumoral , Camundongos Knockout , Regulação Neoplásica da Expressão Gênica , Enzimas Desubiquitinantes/metabolismo , Enzimas Desubiquitinantes/genética , Apoptose/genética , Cisteína Endopeptidases/metabolismo , Cisteína Endopeptidases/genética , Regiões Promotoras Genéticas/genéticaRESUMO
Gene therapy using a protein-based CRISPR system in the brain has practical limitations due to current delivery systems, especially in the presence of arterial occlusion. To overcome these obstacles and improve stability, we designed a system for intranasal administration of gene therapy for the treatment of ischemic stroke. Methods: Nanoparticles containing the protein-based CRISPR/dCas9 system targeting Sirt1 were delivered intranasally to the brain in a mouse model of ischemic stroke. The CRISPR/dCas9 system was encapsulated with calcium phosphate (CaP) nanoparticles to prevent them from being degraded. They were then conjugated with ß-hydroxybutyrates (bHb) to target monocarboxylic acid transporter 1 (MCT1) in nasal epithelial cells to facilitate their transfer into the brain. Results: Human nasal epithelial cells were shown to uptake and transfer nanoparticles to human brain endothelial cells with high efficiency in vitro. The intranasal administration of the dCas9/CaP/PEI-PEG-bHb nanoparticles in mice effectively upregulated the target gene, Sirt1, in the brain, decreased cerebral edema and increased survival after permanent middle cerebral artery occlusion. Additionally, we observed no significant in vivo toxicity associated with intranasal administration of the nanoparticles, highlighting the safety of this approach. Conclusion: This study demonstrates that the proposed protein-based CRISPR-dCas9 system targeting neuroprotective genes in general, and SIRT1 in particular, can be a potential novel therapy for acute ischemic stroke.
Assuntos
Administração Intranasal , Encéfalo , Modelos Animais de Doenças , Terapia Genética , AVC Isquêmico , Nanopartículas , Sirtuína 1 , Animais , Camundongos , Humanos , AVC Isquêmico/terapia , AVC Isquêmico/genética , Nanopartículas/administração & dosagem , Terapia Genética/métodos , Sirtuína 1/genética , Sirtuína 1/metabolismo , Encéfalo/metabolismo , Masculino , Fosfatos de Cálcio , Sistemas CRISPR-Cas , Camundongos Endogâmicos C57BL , Células Endoteliais/metabolismo , Isquemia Encefálica/terapia , Isquemia Encefálica/genética , Infarto da Artéria Cerebral Média/terapia , Infarto da Artéria Cerebral Média/genética , Células Epiteliais/metabolismoRESUMO
BACKGROUND: The complex interplay between Sirtuin 1 (SIRT1) and FOXO3 in endometrial cancer (EC) remains understudied. This research aims to unravel the interactions of deacetylase SIRT1 and transcription factor FOXO3 in EC, focusing on their impact on mitophagy and hormone resistance. METHODS: High-throughput sequencing, cell experiments, and bioinformatics tools were employed to investigate the roles and interactions of SIRT1 and FOXO3 in EC. Co-immunoprecipitation (Co-IP) assay was used to assess the interaction between SIRT1 and FOXO3 in RL95-2 cells. Functional assays were used to assess cell viability, proliferation, migration, invasion, apoptosis, and the expression of related genes and proteins. A mouse model of EC was established to evaluate tumor growth and hormone resistance under different interventions. Immunohistochemistry and TUNEL assays were used to assess protein expression and apoptosis in tumor tissues. RESULTS: High-throughput transcriptome sequencing revealed a close association between SIRT1, FOXO3, and EC development. Co-IP showed a protein-protein interaction between SIRT1 and FOXO3. Overexpression of SIRT1 enhanced FOXO3 deacetylation and activity, promoting BNIP3 transcription and PINK1/Parkin-mediated mitophagy, which in turn promoted cell proliferation, migration, invasion, and inhibited apoptosis in vitro, as well as increased tumor growth and hormone resistance in vivo. These findings highlighted SIRT1 as an upstream regulator and potential therapeutic target in EC. CONCLUSION: This study reveals a novel molecular mechanism underlying the functional relevance of SIRT1 in regulating mitophagy and hormone resistance through the deacetylation of FOXO3 in EC, thereby providing valuable insights for new therapeutic strategies.
Assuntos
Neoplasias do Endométrio , Proteína Forkhead Box O3 , Mitofagia , Sirtuína 1 , Feminino , Proteína Forkhead Box O3/metabolismo , Proteína Forkhead Box O3/genética , Humanos , Mitofagia/genética , Sirtuína 1/metabolismo , Sirtuína 1/genética , Animais , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Linhagem Celular Tumoral , Camundongos , Acetilação , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Apoptose/genética , Movimento Celular , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
BACKGROUND AND AIMS: Acetaminophen (APAP) is the main cause of acute liver injury (ALI) in the Western. Our previous study has shown that fenofibrate activated hepatic expression of fibroblast growth factor 21 (FGF21) can protect the liver form APAP injuries by promoting autophagy. However, the underlying mechanism involved in FGF21-mediated autophagy remains unsolved. METHODS: The ALI mice model was established by intraperitoneal injection of APAP. To investigate the influence of FGF21 on autophagy and Sirt1 expression in APAP-induced ALI, FGF21 knockout (FGF21KO) mice and exogenously supplemented mouse recombinant FGF21 protein were used. In addition, primary isolated hepatocytes and the Sirt1 inhibitor EX527 were used to observe whether FGF21 activated autophagy in APAP injury is regulated by Sirt1 at the cellular level. RESULTS: FGF21, Sirt1, and autophagy levels increased in mice with acute liver injury (ALI) and in primary cultured hepatocytes. Deletion of the FGF21 gene exacerbated APAP-induced liver necrosis and oxidative stress, and decreased mitochondrial potential. It also reduced the mRNA and protein levels of autophagy-related proteins such as Sirt1, LC3-II, and p62, as well as the number of autophagosomes. Replenishment of FGF21 reversed these processes. In addition, EX527 partially counteracted the protective effect of FGF21 by worsening oxidative damage, mitochondrial damage, and reducing autophagy in primary liver cells treated with APAP. CONCLUSION: FGF21 increases autophagy by upregulating Sirt1 to alleviate APAP-induced injuries.
Assuntos
Acetaminofen , Autofagia , Doença Hepática Induzida por Substâncias e Drogas , Fatores de Crescimento de Fibroblastos , Hepatócitos , Camundongos Endogâmicos C57BL , Sirtuína 1 , Animais , Acetaminofen/efeitos adversos , Sirtuína 1/metabolismo , Sirtuína 1/genética , Autofagia/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Camundongos , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Masculino , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/efeitos dos fármacosRESUMO
Mitochondrial damage is an early and key marker of neuronal damage in prion diseases. As a process involved in mitochondrial quality control, mitochondrial biogenesis regulates mitochondrial homeostasis in neurons and promotes neuron health by increasing the number of effective mitochondria in the cytoplasm. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that regulates neuronal mitochondrial biogenesis and quality control in neurodegenerative diseases via deacetylation of a variety of substrates. In a cellular model of prion diseases, we found that both SIRT1 protein levels and deacetylase activity decreased, and SIRT1 overexpression and activation significantly ameliorated mitochondrial morphological damage and dysfunction caused by the neurotoxic peptide PrP106-126. Moreover, we found that mitochondrial biogenesis was impaired, and SIRT1 overexpression and activation alleviated PrP106-126-induced impairment of mitochondrial biogenesis in N2a cells. Further studies in PrP106-126-treated N2a cells revealed that SIRT1 regulates mitochondrial biogenesis through the PGC-1α-TFAM pathway. Finally, we showed that resveratrol resolved PrP106-126-induced mitochondrial dysfunction and cell apoptosis by promoting mitochondrial biogenesis through activation of the SIRT1-dependent PGC-1α/TFAM signaling pathway in N2a cells. Taken together, our findings further describe SIRT1 regulation of mitochondrial biogenesis and improve our understanding of mitochondria-related pathogenesis in prion diseases. Our findings support further investigation of SIRT1 as a potential target for therapeutic intervention of prion diseases.
Assuntos
Mitocôndrias , Biogênese de Organelas , Fragmentos de Peptídeos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Príons , Sirtuína 1 , Sirtuína 1/metabolismo , Sirtuína 1/genética , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Príons/metabolismo , Animais , Camundongos , Fragmentos de Peptídeos/metabolismo , Resveratrol/farmacologia , Fatores de Transcrição/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genéticaRESUMO
BACKGROUND: Previous studies have indicated that occlusal disharmony (OD) can promote anxiety-like behaviours. However, the specific molecules involved in the development of anxiety-like behaviours and their underlying mechanisms remain unknown. METHODS: OD was produced by anterior crossbite of female mice. We measured the anxiety levels of mice in each group and screened the hippocampal mRNA expression profiles of mice in the control group and OD group. The role of target mRNA in OD-induced anxiety-like behaviours was evaluated and we preliminarily explored the possible downstream pathways. RESULTS: The results suggested that OD can induce and promote anxiety-like behaviours with/without chronic unpredictable mild stress. We found that Sirt1 was significantly downregulated within the hippocampus in OD mice. In addition, the downregulation of Sirt1 within the hippocampus in OD and control mice promoted anxiety-like behaviours, increased acetylated histone H3 expression and decreased Dnah12 transcription levels. In contrast, in OD mice subjected to an injection of resveratrol, there was a remission of anxiety-like behaviours and an upregulation of Sirt1 in the hippocampus, the effects of which were accompanied by decreased acetylated histone H3 expression and increased Dnah12 transcription levels. CONCLUSIONS: OD leads to increased sensitivity to chronic stress in mice, resulting in anxiety-like behaviours. During this process, Sirt1 acts as an effective factor in the regulation of OD-induced anxiety-like behaviours. CLINICAL RELEVANCE: OD, as a stressor, could induce anxiety-like behaviours. It investigates the impact of OD (a stressor) on the molecular genetic of the pathophysiology of major neuropsychiatric disorders.
Assuntos
Ansiedade , Comportamento Animal , Modelos Animais de Doenças , Sirtuína 1 , Animais , Sirtuína 1/metabolismo , Camundongos , Feminino , Má Oclusão , Hipocampo/metabolismo , Resveratrol/farmacologia , Regulação para Baixo , RNA Mensageiro/metabolismoRESUMO
Heart failure (HF) represents the terminal stage of cardiovascular diseases, with limited therapeutic options currently available. Calotropin (CAL), a cardenolide isolated from Calotropis gigantea, exhibits a similar chemical structure and inhibitory effect on Na+/K+-ATPase to digoxin, a positive inotropic drugs used in heart failure treatment. However, the specific effect of calotropin in ischemic HF (IHF) remains unknown. The objective of this study is to assess the anti-HF effect and clarify its underlying mechanisms. The left anterior descending (LAD) artery ligation on Male Sprague-Dawley (SD) rats was used to construct ischemic HF model. Daily administration of CAL at 0.05â¯mg/kg significantly enhanced ejection fraction (EF) and fractional shortening (FS), while inhibiting cardiac fibrosis in IHF rats. CAL reduced the OGD/R-induced H9c2 cell injury. Furthermore, CAL upregulated the expression of SERCA2a and SIRT1. The cardioprotective effect of CAL against IHF was abrogated in the presence of the SIRT1 inhibitor EX527. Notably, we identified FOXD3 as a pivotal transcription factor mediating CAL-induced SERCA2a regulation. CAL promoted the deacetylation and nuclear translocation of FOXD3 in a SIRT1-dependent manner. In conclusion, our study explores a novel mechanism of calotropin for improving cardiac dysfunction in ischemic heart failure by regulating SIRT1/FOXD3/SERCA2a pathway.
Assuntos
Fatores de Transcrição Forkhead , Insuficiência Cardíaca , Infarto do Miocárdio , Ratos Sprague-Dawley , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Transdução de Sinais , Sirtuína 1 , Animais , Masculino , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Sirtuína 1/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Ratos , Fatores de Transcrição Forkhead/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cardenolídeos/farmacologia , Linhagem Celular , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Modelos Animais de Doenças , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/complicaçõesRESUMO
Dynamic changes in maternalâzygotic transition (MZT) require complex regulation of zygote formation, maternal transcript decay, embryonic genome activation (EGA), and cell cycle progression. Although these changes are well described, some key regulatory factors are still elusive. Sirtuin-1 (SIRT1), an NAD+-dependent histone deacetylase, is a versatile driver of MZT via its epigenetic and nonepigenetic substrates. This study focused on the dynamics of SIRT1 in early embryos and its contribution to MZT. A conditional SIRT1-deficient knockout mouse model was used, accompanied by porcine and human embryos. Embryos across mammalian species showed the prominent localization of SIRT1 in the nucleus throughout early embryonic development. Accordingly, SIRT1 interacts with histone H4 on lysine K16 (H4K16) in both mouse and human blastocysts. While maternal SIRT1 is dispensable for MZT, at least one allele of embryonic Sirt1 is required for early embryonic development around the time of EGA. This role of SIRT1 is surprisingly mediated via a transcription-independent mode of action.
Assuntos
Desenvolvimento Embrionário , Camundongos Knockout , Sirtuína 1 , Zigoto , Animais , Feminino , Humanos , Camundongos , Blastocisto/metabolismo , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Histonas/metabolismo , Sirtuína 1/metabolismo , Sirtuína 1/genética , Suínos , Zigoto/metabolismo , MasculinoRESUMO
Sirtuin 1 (SIRT1) is a key upstream regulator of lipid metabolism; however, the molecular mechanisms by which SIRT1 regulates milk fat synthesis in dairy goats remain unclear. This study aimed to investigate the regulatory roles of SIRT1 in modulating lipid metabolism in goat mammary epithelial cells (GMECs) and its impact on the adipose triglyceride lipase (ATGL) promoter activity using RNA interference (RNAi) and gene overexpression techniques. The results showed that SIRT1 is significantly upregulated during lactation compared to the dry period. Additionally, SIRT1 knockdown notably increased the expressions of genes related to fatty acid synthesis (SREBP1, SCD1, FASN, ELOVL6), triacylglycerol (TAG) production (DGAT2, AGPAT6), and lipid droplet formation (PLIN2). Consistent with the transcriptional changes, SIRT1 knockdown significantly increased the intracellular contents of TAG and cholesterol and the lipid droplet abundance in the GMECs, while SIRT1 overexpression had the opposite effects. Furthermore, the co-overexpression of SIRT1 and Forkhead box protein O1 (FOXO1) led to a more pronounced increase in ATGL promoter activity, and the ability of SIRT1 to enhance ATGL promoter activity was nearly abolished when the FOXO1 binding sites (FKH1 and FKH2) were mutated, indicating that SIRT1 enhances the transcriptional activity of ATGL via the FKH element in the ATGL promoter. Collectively, our data reveal that SIRT1 enhances the transcriptional activity of ATGL through the FOXO1 binding sites located in the ATGL promoter, thereby regulating lipid metabolism. These findings provide novel insights into the role of SIRT1 in fatty acid metabolism in dairy goats.
Assuntos
Células Epiteliais , Ácidos Graxos , Proteína Forkhead Box O1 , Cabras , Lipase , Glândulas Mamárias Animais , Regiões Promotoras Genéticas , Sirtuína 1 , Animais , Sirtuína 1/metabolismo , Sirtuína 1/genética , Lipase/metabolismo , Lipase/genética , Células Epiteliais/metabolismo , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/citologia , Feminino , Ácidos Graxos/metabolismo , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Metabolismo dos Lipídeos , Lactação , Triglicerídeos/metabolismo , Triglicerídeos/biossíntese , Regulação da Expressão GênicaRESUMO
OBJECTIVE: To study the effect of dexmedetomidine (Dex) on myocardial injury induced by acute kidney injury (AKI) in diabetes mellitus rats and explore the potential mechanisms. METHODS: The Type 2 diabetes mellitus (T2DM) model was prepared in 40 adult male Wistar rats. These rats were randomly divided into four groups (n=10/group), including the control (Con) group, AKI group, Dex preconditioning (DPreC) group, and resveratrol (Res) combined with Dex preconditioning (Res+DPreC) group. The AKI model was prepared in the AKI, DPreC, and Res+DPreC group. The DPreC group received Dex, while the Con and AKI group received normal saline. The Res+DPreC group received Res in addition to Dex preconditioning. Histopathologic, apoptotic, enzymatic, and inflammatory changes in myocardial tissue were observed or detected. RESULTS: Histopathologic, apoptotic, and enzymatic changes in myocardial tissue demonstrated that AKI induced myocardial injury in T2DM rats; Dex preconditioning could mitigate this injury; and RES enhanced this effect. Inflammatory changes suggested that Dex alleviated the inflammatory response induced by AKI in T2DM rats via regulating the expressions of SIRT1, TNF-α, IL-17A, and IL-10. CONCLUSIONS: Dex could alleviate myocardial injury induced by AKI in DM rats via regulating the inflammatory response associated with SIRT1, TNF-α, IL-17A, and IL-10, and Res could enhance this protective effect.
Assuntos
Injúria Renal Aguda , Dexmedetomidina , Diabetes Mellitus Experimental , Inflamação , Ratos Wistar , Animais , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/metabolismo , Masculino , Ratos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Inflamação/patologia , Inflamação/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Miocárdio/patologia , Miocárdio/metabolismo , Resveratrol/farmacologia , Sirtuína 1/metabolismo , Apoptose/efeitos dos fármacosRESUMO
Long noncoding RNAs (lncRNAs) are crucial regulators of biological processes such as transcription interference and activation, chromatin remodeling, and mRNA translation. Uncontrolled gene expression could result from various epigenetic modifiers, like lncRNAs. So, this study aimed to evaluate the expression profiles of lncRNA GIAT4RA, lncRNA AATBC, lncRNA Sirt1-AS, and SMARCB1 in lung cancer. The current study included lung cancer patients (n = 50), patients with chronic inflammatory diseases (n = 30), and healthy volunteers (n = 20). The expression of blood genes and the concentration of serum neuron-specific enolase were determined by real-time PCR and electrochemiluminescence immunoassay, respectively. The receiver operating characteristic and Kaplan-Meier analyses assess the sensitivity of genes as diagnostic and prognostic biomarkers, respectively. LncRNA GIAT4RA and lncRNA AATBC were upregulated, while lncRNA Sirt1-AS was significantly downregulated in all patients compared to the control group. SMARCB1 expression was significantly downregulated in chronic inflammatory patients, while in those with lung cancer, it showed an insignificant difference. The expression of lncRNA GIAT4RA and lncRNA AATBC was significantly related to the stage of lung cancer. The survival analyses showed that lower lncRNA Sirt1-AS was linked to lung cancer patients' poorer disease-free survival and overall survival. Differences in lncRNA GIAT4RA, lncRNA AATBC, and lncRNA Sirt1-AS expression were detected in all patients. The consequent abnormal expression of lncRNAs could be crucial in lung cancer development. LncRNA GIAT4RA, lncRNA AATBC, and lncRNA Sirt1-AS may be utilized as promising diagnostic biomarkers. LncRNA AATBC, lncRNA Sirt1-AS, and SMARCB1 may be valuable prognostic biomarkers for lung cancer.
Assuntos
Biomarcadores Tumorais , Neoplasias Pulmonares , RNA Longo não Codificante , Proteína SMARCB1 , Humanos , RNA Longo não Codificante/sangue , RNA Longo não Codificante/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Proteína SMARCB1/genética , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Prognóstico , Regulação Neoplásica da Expressão Gênica , Idoso , Perfilação da Expressão Gênica , Sirtuína 1/genética , Sirtuína 1/sangue , Adulto , Estimativa de Kaplan-MeierRESUMO
Purpose: Resveratrol (RSV) is a nutraceutical compound known for its therapeutic potential in neurodegenerative and metabolic diseases. RSV promotes survival signals in retinal ganglion cells (RGCs) through activation of SIRT1, an NAD+-dependent deacetylase. RSV and SIRT1 reduce RGC loss induced by direct optic nerve injury, but effects in indirect models of traumatic optic neuropathy remain unknown and are examined in this study. Methods: An electromagnetic stereotaxic impactor device was used to impart five traumatic skull impacts with an inter-concussion interval of 48 hours to wild type (WT) and SIRT1 knock in (KI) C57BL/6J mice overexpressing the SIRT1 gene. A cohort of WT mice also received intranasal administration of RSV (16 mg/kg) throughout the experimental period. Loss of righting reflex (RR), optokinetic response (OKR) scores, and immunolabeled RGC count are determined to assess optic neuropathy in this model of traumatic brain injury (TBI). Results: TBI significantly decreases RGC survival and decreases OKR scores compared with control uninjured mice. Either RSV administration in WT mice, or SIRT1 overexpression in SIRT1 KI mice, significantly increases RGC survival and improves OKR scores. RR time increases after the first few impacts in all groups of mice subjected to TBI, demonstrating that RSV and SIRT1 overexpression are able to attenuate optic neuropathy following similar degrees of TBI. Conclusions: Intranasal RSV is effective in preserving visual function in WT mice following TBI. Constitutive overexpression of SIRT1 recapitulates the neuroprotective effect of RSV. Translational Relevance: Results support future exploration of RSV as a potential therapy for indirect traumatic optic neuropathy.
Assuntos
Modelos Animais de Doenças , Traumatismos Cranianos Fechados , Camundongos Endogâmicos C57BL , Traumatismos do Nervo Óptico , Resveratrol , Células Ganglionares da Retina , Sirtuína 1 , Animais , Sirtuína 1/genética , Sirtuína 1/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/metabolismo , Traumatismos do Nervo Óptico/tratamento farmacológico , Traumatismos do Nervo Óptico/genética , Traumatismos do Nervo Óptico/patologia , Camundongos , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Resveratrol/administração & dosagem , Traumatismos Cranianos Fechados/genética , Traumatismos Cranianos Fechados/patologia , Traumatismos Cranianos Fechados/tratamento farmacológico , Masculino , Administração Intranasal , Sobrevivência Celular/efeitos dos fármacos , Camundongos Transgênicos , Reflexo de Endireitamento/efeitos dos fármacos , Nistagmo Optocinético/efeitos dos fármacosRESUMO
Acute lung injury (ALI) is closely related to high mortality in severe acute pancreatitis (SAP). This study unveils the therapeutic effect and mechanism of miR-217-5p on SAP-associated ALI. The miR-217-5p RNA expression was significantly up-regulated in lipopolysaccharide (LPS)-stimulated primary rat alveolar epithelial type II cells (AEC II) and sodium taurocholate-treated pancreas and lung in SAP rats. miR-217 inhibition protected AEC II from LPS-induced damage by inhibiting apoptosis and reducing the TNF-α, IL-6, and ROS levels. miR-217 inhibition suppressed apoptosis and alleviated mitochondrial damage through mitochondria-mediated apoptotic pathway in vitro. Sirt1 is a direct target of miR-217-5p. Dual-luciferase reporter assay confirmed the binding of miR-217-5p to Sirt1 mRNA 3'-UTR. The rescue experiment identified that the anti-apoptotic, anti-inflammatory, and anti-oxidative effects of miR-217 inhibition were mediated by Sirt1 in vitro. Emodin (EMO) protected AEC II from LPS-induced damage and alleviated pancreatic and lung tissue injuries. EMO exerted similar effects as miR-217 inhibition in vitro and in vivo. The effects of EMO were abolished by miR-217 overexpression. In conclusion, miR-217-5p inhibition exerts protective effects on SAP-ALI in vitro and in vivo by repressing apoptosis, inflammation, and oxidative stress through Sirt1 activation. EMO protects against lung injuries in SAP-associated ALI rats through miR-217-5p/Sirt1 axis.
Assuntos
Lesão Pulmonar Aguda , Apoptose , Emodina , MicroRNAs , Pancreatite , Ratos Sprague-Dawley , Sirtuína 1 , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Sirtuína 1/metabolismo , Sirtuína 1/genética , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Emodina/farmacologia , Emodina/uso terapêutico , Masculino , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Pancreatite/genética , Pancreatite/induzido quimicamente , Apoptose/efeitos dos fármacos , Apoptose/genética , Lipopolissacarídeos/efeitos adversos , Ratos , Células Cultivadas , Doença Aguda , Modelos Animais de DoençasRESUMO
Diabetes mellitus is known as the "epidemic of the century" due to its global prevalence. Several pre-clinical and clinical studies have shown that male germ cell toxicity is one of the major consequences of diabetes mellitus. Although ß-aminoisobutyric acid (BAIBA) has been shown to be advantageous in the diabetic nephropathy and cardiomyopathy, its specific role in the diabetes-induced testicular toxicity remains unknown. In this study, an attempt was made to elucidate the molecular mechanisms of BAIBA-mediated germ cell protection in diabetic rats. Adult male Sprague-dawley rats were subjected to either no treatment (control) or BAIBA (100â¯mg/kg; BAIBA control) or Streptozotocin (50â¯mg/kg; diabetic control) or low (25â¯mg/kg), medium (50â¯mg/kg) and high (100â¯mg/kg) doses of BAIBA in diabetic conditions. Significant alterations in sperm related parameters, oxidative stress and apoptotic biomarkers, pancreatic and testicular histology, DNA damage and changes in expression of proteins in testes were found in the diabetic rats. 100â¯mg/kg of BAIBA significantly reduced the elevated blood glucose levels (P ≤ 0.05), increased body weight (P ≤ 0.01 in the 4th week), lowered malondialdehyde (P ≤ 0.05) and nitrite levels (P ≤ 0.01), elevated testosterone (P ≤ 0.05) and FSH levels (P ≤ 0.05), increased sperm count and motility (P ≤ 0.01), decreased testicular DNA damage (P ≤ 0.001), improved histological features of pancreas and testes, decreased TUNEL positive cells (P ≤ 0.01), decreased RAGE (P ≤ 0.01) and Bax (P ≤ 0.05) expressions and increased SIRT1 (P ≤ 0.05) and Atg 12 (P ≤ 0.05) expressions in the testes. 50â¯mg/kg of BAIBA partially restored the above-mentioned parameters whereas 25â¯mg/kg of BAIBA was found to be insignificant in counteracting the toxicity. It is interesting to note that BAIBA protects male germ cell damage in diabetic rats by regulating the IGF-1/AMPK/SIRT-1 signaling pathway.
Assuntos
Ácidos Aminoisobutíricos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Fator de Crescimento Insulin-Like I , Estresse Oxidativo , Ratos Sprague-Dawley , Transdução de Sinais , Sirtuína 1 , Testículo , Animais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Sirtuína 1/genética , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Ácidos Aminoisobutíricos/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Dano ao DNA/efeitos dos fármacosRESUMO
BACKGROUND: The increasing incidence of diabetes mellitus has established diabetic cataracts (DC) as a significant worldwide public health issue. The mechanisms underlying DC remain unknown, and effective prevention and treatment strategies are lacking. Accordingly, we aimed to explore the role and mechanism behind N6-methyladenosine (m6A) in DC progression. METHODS: Methyltransferase-like 3 (METTL3), p21, Beclin1, LC3, and p62 expression levels were measured in human tissues. This study assessed total m6A levels and common m6A-regulated biomarkers in both in vitro and in vivo DC models. Autophagy flux was detected in vitro through Ad-mCherry-GFP-LC3B and Monodansylcadaverine (MDC) staining. Cellular senescence was assessed utilizing the senescence-associated ß-galactosidase (SA-ß-Gal) assay. Furthermore, the effect of METTL3 on SIRT1 mRNA modification was demonstrated, and its mechanism was elucidated using RT-qPCR, western blot, RNA stability assays, and RIP analysis. RESULTS: METTL3, p21, and p62 expression levels were elevated in lens epithelial cells (LECs) from DC patients, while Beclin1 and LC3 levels were reduced. Silencing METTL3-mediated m6A modifications restored high-glucose-induced autophagy inhibition and prevented premature senescence in LECs. Notably, SIRT1720 and Metformin significantly enhanced autophagosome generation and delayed cellular senescence. The m6A-reading protein YTHDF2 bound to m6A modifications, and YTHDF2 silencing significantly reduced METTL3-mediated SIRT1 inactivation. CONCLUSIONS: METTL3 induces senescence in DC by destabilizing SIRT1 mRNA in an m6A-YTHDF2-dependent manner. The METTL3-YTHDF2-SIRT1 axis is a key target and potential pathogenic mechanism in DC.