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In preparation for a potential pregnancy, the endometrium of the uterus changes into a temporary structure called the decidua. Senescent decidual stromal cells (DSCs) are enriched in the decidua during decidualization, but the underlying mechanisms of this process remain unclear. Here, we performed single-cell RNA transcriptomics on ESCs and DSCs and found that cell senescence during decidualization is accompanied by increased levels of the branched-chain amino acid (BCAA) transporter SLC3A2. Depletion of leucine, one of the branched-chain amino acids, from cultured media decreased senescence, while high leucine diet resulted in increased senescence and high rates of embryo loss in mice. BCAAs induced senescence in DSCs via the p38 MAPK pathway. In contrast, TNFSF14+ decidual natural killer (dNK) cells were found to inhibit DSC senescence by interacting with its ligand TNFRSF14. As in mice fed high-leucine diets, both mice with NK cell depletion and Tnfrsf14-deficient mice with excessive uterine senescence experienced adverse pregnancy outcomes. Further, we found excessive uterine senescence, SLC3A2-mediated BCAA intake, and insufficient TNFRSF14 expression in the decidua of patients with recurrent spontaneous abortion. In summary, this study suggests that dNK cells maintain senescence homeostasis of DSCs via TNFSF14/TNFRSF14, providing a potential therapeutic strategy to prevent DSC senescence-associated spontaneous abortion.
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BACKGROUND: N6-methyladenosine (m6A) modification of messenger RNA (mRNA) is crucial for liquid-liquid phase separation in mammals. Increasing evidence indicates that liquid-liquid phase separation in proteins and RNAs affects diabetic cardiomyopathy. However, the molecular mechanism by which m6A-mediated phase separation regulates diabetic cardiac fibrosis remains elusive. METHODS: Leptin receptor-deficient mice (db/db), cardiac fibroblast-specific Notch1 conditional knockout (POSTN-Cre × Notch1flox/flox) mice, and Cre mice were used to induce diabetic cardiac fibrosis. Adeno-associated virus 9 carrying cardiac fibroblast-specific periostin (Postn) promoter-driven small hairpin RNA targeting Alkbh5, Ythdf2, or Notch1, and the phase separation inhibitor 1,6-hexanediol were administered to investigate their roles in diabetic cardiac fibrosis. Histological and biochemical analyses were performed to determine how Alkbh5 and Ythdf2 regulate Notch1 expression in diabetic cardiac fibrosis. NOTCH1 was reconstituted in ALKBH5- and YTHDF2-deficient cardiac fibroblasts and mouse hearts to study its effects on mitochondrial fission and diabetic cardiac fibrosis. Heart tissue samples from patients with diabetic cardiomyopathy were used to validate our findings. RESULTS: In mice with diabetic cardiac fibrosis, decreased Notch1 expression was accompanied by high m6A mRNA levels and mitochondrial fission. Fibroblast-specific deletion of Notch1 enhanced mitochondrial fission and cardiac fibroblast proliferation and induced diabetic cardiac fibrosis in mice. Notch1 downregulation was associated with Alkbh5-mediated m6A demethylation in the 3'UTR of Notch1 mRNA and elevated m6A mRNA levels. These elevated m6A levels in Notch1 mRNA markedly enhanced YTHDF2 phase separation, increased the recognition of m6A residues in Notch1 mRNA by YTHDF2, and induced Notch1 degradation. Conversely, epitranscriptomic downregulation rescues Notch1 expression, resulting in the opposite effects. Human heart tissues from patients with diabetic cardiomyopathy were used to validate the findings in mice with diabetic cardiac fibrosis. CONCLUSIONS: We identified a novel epitranscriptomic mechanism by which m6A-mediated phase separation suppresses Notch1 expression, thereby promoting mitochondrial fission in diabetic cardiac fibrosis. Our findings provide new insights for the development of novel treatment approaches for patients with diabetic cardiac fibrosis.
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Adenosina , Homólogo AlkB 5 da RNA Desmetilase , Cardiomiopatias Diabéticas , Fibrose , Camundongos Knockout , Dinâmica Mitocondrial , Proteínas de Ligação a RNA , Receptor Notch1 , Transdução de Sinais , Animais , Receptor Notch1/metabolismo , Receptor Notch1/genética , Humanos , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/etiologia , Adenosina/análogos & derivados , Adenosina/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Masculino , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Células Cultivadas , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Fibroblastos/metabolismo , Fibroblastos/patologia , Camundongos , Processamento Pós-Transcricional do RNA , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Separação de Fases , Moléculas de Adesão Celular , Receptores para LeptinaRESUMO
BACKGROUND: Folic acid (FA) supplementation during pregnancy aims to protect foetal development. However, maternal over-supplementation of FA has been demonstrated to cause metabolic dysfunction and increase the risk of autism, retinoblastoma, and respiratory illness in the offspring. Moreover, FA supplementation reduces the risk of congenital heart disease. However, little is known about its possible adverse effects on cardiac health resulting from maternal over-supplementation. In this study, we assessed the detrimental effects of maternal FA over-supplementation on the cardiac health of the offspring. METHODS AND RESULTS: Eight-week-old C57BL/6J pregnant mice were randomly divided into control and over-supplemented groups. The offspring cardiac function was assessed using echocardiography. Cardiac fibrosis was assessed in the left ventricular myocardium by histological analysis. Proteomic, protein, RNA, and DNA methylation analyses were performed by liquid chromatography-tandem mass spectrometry, western blotting, real-time quantitative PCR, and bisulfite sequencing, respectively. We found that maternal periconceptional FA over-supplementation impaired cardiac function with the decreased left ventricular ejection fraction in the offspring. Biochemical indices and tissue staining further confirmed impaired cardiac function in offspring caused by maternal FA over-supplementation. The combined proteomic, RNA expression, and DNA methylation analyses suggested that key genes involved in cardiac function were inhibited at the transcriptional level possibly due to increased DNA methylation. Among these, superoxide dismutase 1 was downregulated, and reactive oxygen species (ROS) levels increased in the mouse heart. Inhibition of ROS generation using the antioxidant N-acetylcysteine rescued the impaired cardiac function resulting from maternal FA over-supplementation. CONCLUSIONS: Our study revealed that over-supplementation with FA during mouse pregnancy is detrimental to cardiac function with the decreased left ventricular ejection fraction in the offspring and provides insights into the mechanisms underlying the association between maternal FA status and health outcomes in the offspring.
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Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.
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Diabetic neuropathic pain (DNP), one of the most common complications of diabetes, is characterized by bilateral symmetrical distal limb pain and substantial morbidity. To compare the differences is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched-chain amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high-fat diet/low-dose streptozotocin (HFD/STZ)-induced T2DM and leptin receptor-deficient diabetic (db/db) mouse models, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated DNP symptoms. Mechanistically, using a combination of RNA sequencing of mouse dorsal root ganglion (DRG) tissues and label-free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L-type amino acid transporter 1 (LAT1) through ATF4, which is reversed by BCAA supplementation. Abnormally upregulated LAT1 reduced Kv1.2 localization to the cell membrane, and inhibited Kv1.2 channels, thereby increasing neuronal excitability and causing neuropathy. Furthermore, intraperitoneal injection of the LAT1 inhibitor, BCH, alleviated DNP symptoms in mice, confirming that BCAA-deficiency-induced LAT1 activation contributes to the onset of DNP. These findings provide fresh insights into the metabolic differences between DNP and T2DM, and the development of approaches for the management of DNP.
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Aminoácidos de Cadeia Ramificada , Diabetes Mellitus Experimental , Neuropatias Diabéticas , Canal de Potássio Kv1.2 , Transportador 1 de Aminoácidos Neutros Grandes , Regulação para Cima , Animais , Aminoácidos de Cadeia Ramificada/metabolismo , Camundongos , Humanos , Masculino , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/genética , Transportador 1 de Aminoácidos Neutros Grandes/genética , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Canal de Potássio Kv1.2/genética , Canal de Potássio Kv1.2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Modelos Animais de Doenças , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Neuralgia/metabolismo , Neuralgia/genética , Feminino , Camundongos Endogâmicos C57BL , Pessoa de Meia-IdadeRESUMO
Cardiovascular disease is currently the number one cause of death endangering human health. There is currently a large body of research showing that the development of cardiovascular disease and its complications is often accompanied by inflammatory processes. In recent years, epitranscriptional modifications have been shown to be involved in regulating the pathophysiological development of inflammation in cardiovascular diseases, with 6-methyladenine being one of the most common RNA transcriptional modifications. In this review, we link different cardiovascular diseases, including atherosclerosis, heart failure, myocardial infarction, and myocardial ischemia-reperfusion, with inflammation and describe the regulatory processes involved in RNA methylation. Advances in RNA methylation research have revealed the close relationship between the regulation of transcriptome modifications and inflammation in cardiovascular diseases and brought potential therapeutic targets for disease diagnosis and treatment. At the same time, we also discussed different cell aspects. In addition, in the article we also describe the different application aspects and clinical pathways of RNA methylation therapy. In summary, this article reviews the mechanism, regulation and disease treatment effects of m6A modification on inflammation and inflammatory cells in cardiovascular diseases in recent years. We will discuss issues facing the field and new opportunities that may be the focus of future research.
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Doenças Cardiovasculares , Epigênese Genética , Inflamação , Humanos , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Inflamação/genética , Animais , Adenina/análogos & derivados , Transcriptoma , MetilaçãoRESUMO
Cardiac fibrosis is a major public health problem worldwide, with high morbidity and mortality, affecting almost all patients with heart disease worldwide. It is characterized by fibroblast activation, abnormal proliferation, excessive deposition, and abnormal distribution of extracellular matrix (ECM) proteins. The maladaptive process of cardiac fibrosis is complex and often involves multiple mechanisms. With the increasing research on cardiac fibrosis, redox has been recognized as an important part of cardiac remodeling, and an imbalance in redox homeostasis can adversely affect the function and structure of the heart. The metabolism of metal ions is essential for life, and abnormal metabolism of metal ions in cells can impair a variety of biochemical processes, especially redox. However, current research on metal ion metabolism is still very limited. This review comprehensively examines the effects of metal ion (iron, copper, calcium, and zinc) metabolism-mediated redox homeostasis on cardiac fibrosis, outlines possible therapeutic interventions, and addresses ongoing challenges in this rapidly evolving field.
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Proteínas da Matriz Extracelular , Humanos , Fibrose , Proteínas da Matriz Extracelular/metabolismo , Homeostase , Oxirredução , ÍonsRESUMO
Maternal hyperhomocysteinemia is widely considered as an independent risk of congenital heart disease (CHD). However, whether high paternal homocysteine causes CHD remains unknown. Here, we showed that increased homocysteine levels of male mice caused decreased sperm count, sperm motility defect and ventricular septal defect of the offspring. Moreover, high levels of paternal homocysteine decrease sperm DNMT3A/3B, accompanied with changes in DNA methylation levels in the promoter regions of CHD-related genes. Folic acid supplement could decrease the occurrence of VSD in high homocysteine male mice. This study reveals that increased paternal homocysteine level increases VSD risk in the offspring, indicating that decreasing paternal homocysteine may be an intervening target of CHD.
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Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced ß-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.
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Cardiac fibroblasts play a pivotal role in cardiac fibrosis by transformation of fibroblasts into myofibroblasts, which synthesis and secrete a large number of extracellular matrix proteins. Ultimately, this will lead to cardiac wall stiffness and impaired cardiac performance. The epigenetic regulation and fate reprogramming of cardiac fibroblasts has been advanced considerably in recent decades. Non coding RNAs (microRNAs, lncRNAs, circRNAs) regulate the functions and behaviors of cardiac fibroblasts, including proliferation, migration, phenotypic transformation, inflammation, pyroptosis, apoptosis, autophagy, which can provide the basis for novel targeted therapeutic treatments that abrogate activation and inflammation of cardiac fibroblasts, induce different death pathways in cardiac fibroblasts, or make it sensitive to established pathogenic cells targeted cytotoxic agents and biotherapy. This review summarizes our current knowledge in this field of ncRNAs function in epigenetic regulation and fate determination of cardiac fibroblasts as well as the details of signaling pathways contribute to cardiac fibrosis. Moreover, we will comment on the emerging landscape of lncRNAs and circRNAs function in regulating signal transduction pathways, gene translation processes and post-translational regulation of gene expression in cardiac fibroblast. In the end, the prospect of cardiac fibroblasts targeted therapy for cardiac fibrosis based on ncRNAs is discussed.
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MicroRNAs , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Epigênese Genética , RNA Circular/metabolismo , RNA não Traduzido/genética , Fibrose , MicroRNAs/genética , MicroRNAs/metabolismo , Fibroblastos/metabolismo , Cardiotônicos/metabolismo , Inflamação/patologiaRESUMO
Cardiac fibrosis is a critical pathophysiological process that occurs with diverse types of cardiac injury. Lipids are the most important bioenergy substrates for maintaining optimal heart performance and act as second messengers to transduce signals within cardiac cells. However, lipid metabolism reprogramming is a double-edged sword in the regulation of cardiomyocyte homeostasis and heart function. Moreover, lipids can exert diverse effects on cardiac fibrosis through different signaling pathways. In this review, we provide a brief overview of aberrant cardiac lipid metabolism and recent progress in pharmacological research targeting lipid metabolism alterations in cardiac fibrosis.
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Cardiomiopatias , Miocárdio , Humanos , Miocárdio/metabolismo , Metabolismo dos Lipídeos , Reprogramação Metabólica , Miócitos Cardíacos/metabolismo , Cardiomiopatias/metabolismo , Fibrose , LipídeosRESUMO
Objective: To summarize the clinical and genetic characteristics of children with β-ketothiolase deficiency (BKTD). Methods: The clinical characteristics, biochemical, markers detected by tandem mass spectrometry (MS/MS) and gas chromatography-mass spectrometry (GC/MS), as well as the variants in ACAT1 gene among 5 children with BKTD in Children's Hospital of Chongqing Medical University between October 2018 and December 2022 were retrospectively analyzed. Results: The onset age of the disease in 5 patients (4 males and 1 female) ranged from 9.7 to 28.0 months. During the acute phase, severe metabolic acidosis was observed with a pH of 6.9-7.1, as well as hypoglycaemia (2.3-3.4 mmol/L) and positive urinary ketone bodies (+-++++). Blood levels of methylcrotonyl carnitine, methylmalonyl carnitine and malonyl carnitine were 0.03-0.42, 0.34-1.43 and 0.83-3.53 μmol/L respectively and were significantly elevated. Urinary 2-methyl-3-hydroxybutyric acid was 22-202 and 3-hydroxybutyric acid was 4-6 066, both were higher than the normal levels. Methylcrotonylglycine was mild elevated (0-29). The metabolites detected by MS/MS and GC/MS were significantly reduced after treatment. Analysis of ACAT1 gene mutation was performed in 5 children. Most variants were missense (8/9). Four previously unreported variants were identified: c.678G>T (p.Trp226Cys), c.302A>G (p.Gln101Arg), c.627_629dupTGA (p.Asn209_Glu210insAsp) and c.316C>T (p.Gln106Ter), the first 2 variants were predicted to be damaging by SIFT, PolyPhen-2 and Mutation Taster software. c.316C>T (p.Gln106Ter) is a nonsense variant. Conclusions: β-ketothiolase deficiency is relatively rare, lacks specific clinical manifestations, however severe metabolic acidosis, hypoglycemia, and ketosis during the acute onset were consistent findings. Missense mutations in the ACAT1 gene are common genetic causes of β-ketothiolase deficiency.
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Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Acidose , Carnitina , Estudos Retrospectivos , Espectrometria de Massas em TandemRESUMO
Background: As one of the most frequent complications of type 2 diabetes mellitus (T2DM), diabetic peripheral neuropathy (DPN) shows a profound impact on 50% of patients with symptoms of neuropathic pain, numbness and other paresthesia. No valid serum biomarkers for the prediction of DPN have been identified in the clinic so far. This study is to investigate the potential serum biomarkers for DPN firstly based on 1H-Nuclear Magnetic Resonance (1H-NMR)-based metabolomics technique. Methods: Thirty-six patients enrolled in this study were divided into two groups: 18 T2DM patients without DPN (T2DM group) and 18 T2DM patients with DPN (DPN group). Serum metabolites were measured via 1H-NMR spectroscopy. Bioinformatic approaches including principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), independent sample t-test, Fisher's test, Pearson and Spearman correlation analysis, Stepwise multiple linear regression analysis and receiver operating characteristic (ROC) curve analysis were used to identify the potential altered serum biomarkers. Results: A total of 20 metabolites were obtained and further analyzed. Formate was identified as the only potential biomarker that decreased in the DPN group with statistical significance after multiple comparisons (p<0.05). Formate also displayed a negative relationship with some elevated clinical markers in DPN. ROC curve analysis showed a good discriminative ability for formate in DPN with an area under the curve (AUC) value of 0.981. Conclusion: Formate could be considered a potential serum metabolic biomarker for DPN. The reduced level of formate in DPN may be associated with mitochondrial dysfunction and gut microbiota alteration. Monitoring the level of serum formate would be an important strategy for the early diagnosis of DPN and a supplement of formate may be a promising treatment for DPN in the future.
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Dysregulated lipid metabolism occurs in pathological processes characterized by cell proliferation and migration. Nonetheless, the mechanism of increased mitochondrial lipid oxidation is poorly appreciated in diabetic cardiac fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. Herein, increased WTAP expression promotes cardiac fibroblast proliferation and migration, contributing to diabetic cardiac fibrosis. Knockdown of WTAP suppresses mitochondrial lipid oxidation, fibroblast proliferation and migration to ameliorate diabetic cardiac fibrosis. Mechanistically, WTAP-mediated m6A methylation of AR induced its degradation, dependent on YTHDF2. Additionally, AR directly interacts with mitochondrial lipid oxidation enzyme Decr1; overexpression of AR-suppressed Decr1-mediates mitochondrial lipid oxidation, inhibiting cardiac fibroblast proliferation and migration. Knockdown of AR produced the opposite effect. Clinically, increased WTAP and YTHDF2 levels correlate with decreased AR expression in human DCM heart tissue. We describe a mechanism wherein WTAP boosts higher mitochondrial lipid oxidation, cardiac fibroblast proliferation, and migration by enhancing AR methylation in a YTHDF2-dependent manner.
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Prenatal diagnosis of congenital heart disease (CHD) relies primarily on fetal echocardiography conducted at mid-gestational age-the sensitivity of which varies among centers and practitioners. An objective method for early diagnosis is needed. Here, we conducted a case-control study recruiting 103 pregnant women with healthy offspring and 104 cases with CHD offspring, including VSD (42/104), ASD (20/104), and other CHD phenotypes. Plasma was collected during the first trimester and proteomic analysis was performed. Principal component analysis revealed considerable differences between the controls and the CHDs. Among the significantly altered proteins, 25 upregulated proteins in CHDs were enriched in amino acid metabolism, extracellular matrix receptor, and actin skeleton regulation, whereas 49 downregulated proteins were enriched in carbohydrate metabolism, cardiac muscle contraction, and cardiomyopathy. The machine learning model reached an area under the curve of 0.964 and was highly accurate in recognizing CHDs. This study provides a highly valuable proteomics resource to better recognize the cause of CHD and has developed a reliable objective method for the early recognition of CHD, facilitating early intervention and better prognosis.
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Cardiopatias Congênitas , Proteoma , Gravidez , Humanos , Feminino , Estudos de Casos e Controles , Proteômica , Cardiopatias Congênitas/diagnóstico , Biomarcadores , Cisplatino , CiclofosfamidaRESUMO
The tyrosine kinase inhibitor (TKI) Sunitinib is one the therapies approved for advanced renal cell carcinoma. Here, we undertake proteogenomic profiling of 115 tumors from patients with clear cell renal cell carcinoma (ccRCC) undergoing Sunitinib treatment and reveal the molecular basis of differential clinical outcomes with TKI therapy. We find that chromosome 7q gain-induced mTOR signaling activation is associated with poor therapeutic outcomes with Sunitinib treatment, whereas the aristolochic acid signature and VHL mutation synergistically caused enhanced glycolysis is correlated with better prognosis. The proteomic and phosphoproteomic analysis further highlights the responsibility of mTOR signaling for non-response to Sunitinib. Immune landscape characterization reveals diverse tumor microenvironment subsets in ccRCC. Finally, we construct a multi-omics classifier that can detect responder and non-responder patients (receiver operating characteristic-area under the curve, 0.98). Our study highlights associations between ccRCC molecular characteristics and the response to TKI, which can facilitate future improvement of therapeutic responses.
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Carcinoma de Células Renais , Neoplasias Renais , Proteogenômica , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Sunitinibe/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Proteômica , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR/genética , Microambiente TumoralRESUMO
With the in-depth investigation of cardiac fibrosis, oxidative stress (OS) has been recognized as a significant pathophysiological pathway involved in cardiac remodeling and progression. OS is a condition characterized by the disruption of equilibrium between reactive oxygen species (ROS) produced by the organism and the antioxidant defense system, resulting in adverse effects on the structure and function of the heart. The accumulation of reactive substances beyond cellular thresholds disrupts the normal physiology of both cardiomyocytes and non-cardiomyocytes, leading to OS, inflammation, hypertrophy, and cardiac fibrosis. Furthermore, cardiac OS also modulates several crucial genes involved in maintaining cellular homeostasis, including those associated with mitochondrial biogenesis, injury, and antioxidant defense, which are inevitably associated with concurrent epigenetic changes. Multiple studies have demonstrated the crucial role of epigenetic modifications in regulating cardiac OS. Consequently, modulating OS through targeted epigenetic modifications emerges as a potentially promising therapeutic strategy for managing cardiac fibrosis. This article provides a new review of current research on this subject and proposes that epigenetics may improve OS-induced cardiac fibrosis.
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Antioxidantes , Cardiomiopatias , Humanos , Antioxidantes/metabolismo , Estresse Oxidativo , Cardiomiopatias/metabolismo , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fibrose , Epigênese GenéticaRESUMO
Accumulating evidence has shown that aerobic glycolysis is essential for the establishment and maintenance of the fibrotic phenotype, so treatments targeting glycolytic reprogramming may become an important strategy to reduce fibrosis. Here, we reviewed current evidence on the glycolytic reprogramming in organ fibrosis, new dynamics of the epigenetic landscape. Epigenetic regulation of the expression of specific genes involved mediates glycolytic reprogramming, thereby affecting fibrosis progression. A comprehensive understanding of the interplay between aerobic glycolysis and epigenetics holds great promise for the treatment and intervention of fibrotic diseases. This article aims to comprehensively review the effect of aerobic glycolysis on organ fibrosis, and to elucidate the relevant epigenetic mechanisms of glycolytic reprogramming in different organs.
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Epigênese Genética , Glicólise , Humanos , Glicólise/genética , FibroseRESUMO
Cardiac fibrosis (CF) is considered an ultimate common pathway of a wide variety of heart diseases in response to diverse pathological and pathophysiological stimuli. Mitochondria are characterized as isolated organelles with a double-membrane structure, and they primarily contribute to and maintain highly dynamic energy and metabolic networks whose distribution and structure exert potent support for cellular properties and performance. Because the myocardium is a highly oxidative tissue with high energy demands to continuously pump blood, mitochondria are the most abundant organelles within mature cardiomyocytes, accounting for up to one-third of the total cell volume, and play an essential role in maintaining optimal performance of the heart. Mitochondrial quality control (MQC), including mitochondrial fusion, fission, mitophagy, mitochondrial biogenesis, and mitochondrial metabolism and biosynthesis, is crucial machinery that modulates cardiac cells and heart function by maintaining and regulating the morphological structure, function and lifespan of mitochondria. Certain investigations have focused on mitochondrial dynamics, including manipulating and maintaining the dynamic balance of energy demand and nutrient supply, and the resultant findings suggest that changes in mitochondrial morphology and function may contribute to bioenergetic adaptation during cardiac fibrosis and pathological remodeling. In this review, we discuss the function of epigenetic regulation and molecular mechanisms of MQC in the pathogenesis of CF and provide evidence for targeting MQC for CF. Finally, we discuss how these findings can be applied to improve the treatment and prevention of CF.