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1.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33925111

RESUMO

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.


Assuntos
Osso e Ossos/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Animais , Osso e Ossos/fisiologia , Diferenciação Celular/genética , Humanos , Camundongos , Mitocôndrias/metabolismo , Biogênese de Organelas , Osteoblastos/metabolismo , Osteócitos/metabolismo , Osteogênese , Transdução de Sinais , Sirtuína 3/metabolismo , Fatores de Transcrição/metabolismo
2.
Int Immunopharmacol ; 95: 107533, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33752080

RESUMO

Doxorubicin (DOX) is a potent chemotherapeutic drug but the clinical use was limited by its dose-dependent cardiotoxicity. Pinocembrin (PCB), a flavonoid originally isolated from honeybee propolis and rhizomes of Boesenbergia pandurate displays diverse biological activities. However, the role of PCB in DOX-induced cardiac injury and its underlying molecular mechanism are not fully elucidated. The present study was designed to evaluate the protective role of PCB in a DOX-induced cardiotoxicity in vivo and in vitro. Our results revealed that PCB administration greatly improved cardiac function and reduced cardiac fibrosis manifested by LVEF, LVFS, LVIDd, LVIDs, and myocardial fibrotic area which were impaired by DOX treatment. The cardiac injury evidenced by LDH and CK-MB activities were reduced while the levels of IL-1ß and IL-18 were decreased following PCB treatment compared to DOX-treated mice. Mechanically, our present results showed that PCB significantly inhibited DOX-induced cardiomyocyte pyroptosis via activating Nrf2/Sirt3 signal pathway. Furthermore, the inhibition of Nrf2 in H9c2 cells abolished the protective role of PCB against DOX-induced cell toxicity, which was at least partly via upregulation of NLRP3-mediated pyroptosis. In conclusion, our study clearly demonstrated that PCB reduced cardiomyocyte pyroptosis to protect hearts from DOX-induced cardiotoxicity through activation of Nrf2/Sirt3 signal pathway.


Assuntos
Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Flavanonas/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Sirtuína 3/metabolismo , Animais , Antibióticos Antineoplásicos , Cardiotônicos/farmacologia , Cardiotoxicidade/metabolismo , Linhagem Celular , Doxorrubicina , Flavanonas/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Piroptose/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Sheng Li Xue Bao ; 73(1): 17-25, 2021 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-33665656

RESUMO

This study was aimed to determine the effect of acute cerebral ischemia on the protein expression level of silent mating type information regulator 2 homolog 3 (Sirt3) in the neurons and clarify the pathological role of Sirt3 in acute cerebral ischemia. The mice with middle cerebral artery occlusion (MCAO) and primary cultured rat hippocampal neurons with oxygen glucose deprivation (OGD) were used as acute cerebral ischemia models in vivo and in vitro, respectively. Sirt3 overexpression was induced in rat hippocampal neurons by lentivirus transfection. Western blot was utilized to measure the changes in Sirt3 protein expression level. CCK8 assay was used to detect cell viability. Immunofluorescent staining was used to detect mitochondrial function. Transmission electron microscope was used to detect mitochondrial autophagy. The results showed that, compared with the normoxia group, hippocampal neurons from OGD1 h/reoxygenation 2 h (R2 h) and OGD1 h/R12 h groups exhibited down-regulated Sirt3 protein expression levels. Compared with contralateral normal brain tissue, the ipsilateral penumbra region from MCAO1 h/reperfusion 24 h (R24 h) and MCAO1 h/R72 h groups exhibited down-regulated Sirt3 protein expression levels, while there was no significant difference between the Sirt3 protein levels on both sides of sham group. OGD1 h/R12 h treatment damaged mitochondrial function, activated mitochondrial autophagy and reduced cell viability in hippocampal neurons, whereas Sirt3 over-expression attenuated the above damage effects of OGD1 h/R12 h treatment. These results suggest that acute cerebral ischemia results in a decrease in Sirt3 protein level. Sirt3 overexpression can alleviate acute cerebral ischemia-induced neural injuries by improving the mitochondrial function. The current study sheds light on a novel strategy against neural injuries caused by acute cerebral ischemia.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Sirtuína 3 , Animais , Regulação para Baixo , Infarto da Artéria Cerebral Média , Camundongos , Mitocôndrias , Neurônios/metabolismo , Ratos , Sirtuína 3/genética , Sirtuína 3/metabolismo , Sirtuínas
4.
Adv Clin Exp Med ; 30(2): 139-146, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33650328

RESUMO

BACKGROUND: Ischemic stroke, also known as cerebrovascular accident or cerebral stroke, occupies the first place in the world's top 10 causes of death, with high incidence, mortality and disability rates. OBJECTIVES: To investigate the effect of stilbene glycoside upregulated SIRT3/AMPK expression on neuronal mitochondrial autophagy and neuronal apoptosis in ischemic stroke. MATERIAL AND METHODS: The PC12 cells were cultured without serum to construct an ischemic neuron model. The cells were divided into 6 groups: normal group (untreated cells), model group (ischemic treated cells), TSG group (stilbene glycoside treatment), NC group (SIRT3 and AMPK negative control treatment), si-SIRT3 group (SIRT3 silencing treatment), TSG+si-SIRT3 group (joint treatment), and TSG+si-SIRT3+oe-AMPK group (joint treatment). Cell survival and the expression of related molecules were detected. RESULTS: Compared with normal group, the model group had significantly decreased cell survival rate, mitochondrial membrane potential, as well as the expression of Bcl-2, LC3II/I, P62, PINK1, Parkin, SIRT3, AMPK, and p-AMPK, while showing significantly increased proportion of apoptosis and the expression of caspase 3 and Bax. Compared with the model group, TSG treatment promoted cell survival rate and mitochondrial autophagy, and inhibited apoptosis, while SIRT3 silencing treatment reduced cell survival rate and mitochondrial autophagy, and increased apoptosis. The SIRT3 silencing could block the inhibitory effect of TSG on the apoptosis of ischemic PC12 cells and promote mitochondrial autophagy, and AMPK overexpression could save the apoptosis of ischemic PC12 cells caused by SIRT3 silencing, and promote mitochondrial autophagy. CONCLUSIONS: By promoting the expression of SIRT3/AMPK, TSG promotes mitochondrial autophagy in ischemic neurons and inhibits their apoptosis.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Sirtuína 3 , Estilbenos , Acidente Vascular Cerebral , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Autofagia , Isquemia Encefálica/tratamento farmacológico , Glicosídeos , Neurônios/metabolismo , Ratos , Transdução de Sinais , Sirtuína 3/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico
5.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669567

RESUMO

Sirtuins (SIRTs) are NAD+-dependent deacetylases that regulate proliferation and cell death. In the human ovary, granulosa cells express sirtuin 1 (SIRT1), which has also been detected in human tumors derived from granulosa cells, i.e., granulosa cell tumors (GCTs), and in KGN cells. KGN cells are an established cellular model for the majority of GCTs and were used to explore the role of SIRT1. The SIRT1 activator SRT2104 increased cell proliferation. By contrast, the inhibitor EX527 reduced cell numbers, without inducing apoptosis. These results were supported by the outcome of siRNA-mediated silencing studies. A tissue microarray containing 92 GCTs revealed nuclear and/or cytoplasmic SIRT1 staining in the majority of the samples, and also, SIRT2-7 were detected in most samples. The expression of SIRT1-7 was not correlated with the survival of the patients; however, SIRT3 and SIRT7 expression was significantly correlated with the proliferation marker Ki-67, implying roles in tumor cell proliferation. SIRT3 was identified by a proteomic analysis as the most abundant SIRT in KGN. The results of the siRNA-silencing experiments indicate involvement of SIRT3 in proliferation. Thus, several SIRTs are expressed by GCTs, and SIRT1 and SIRT3 are involved in the growth regulation of KGN. If transferable to GCTs, these SIRTs may represent novel drug targets.


Assuntos
Sirtuína 1/metabolismo , Sirtuína 3/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carbazóis/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Tumor de Células da Granulosa/genética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Sirtuína 1/genética , Adulto Jovem
6.
Life Sci ; 272: 119178, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33610576

RESUMO

Atherosclerosis (AS) is the most common cause of death in cardiovascular diseases and poses severe challenges to human life and safety. Epigenetics plays a vital role in every single link of AS. Whereas, how epigenetics regulates its development and regression is still unknown. Sirt3, a recognized histone deacetylase, having been reported to be involved in other acylation processes in recent years, is broadening its role in epigenetic modifications. Sirt3 is an important factor in the normal physiology of blood vessels through deacetylation of mitochondrial proteins and participates in various metabolic activities. Besides, medical research targeting Sirt3 is in full swing as well. This review combining histone deacetylase Sirt3 with AS, aims to clarify the latest progress in the significant role of Sirt3 in the development and regression of AS and to provide a novel prospect for a new regulatory factor and potential intervention target for AS.


Assuntos
Aterosclerose/metabolismo , Sirtuína 3/metabolismo , Doenças Cardiovasculares/metabolismo , Epigênese Genética/genética , Epigenômica , Histona Desacetilases/metabolismo , Humanos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Sirtuína 3/genética , Sirtuína 3/fisiologia
7.
J Food Sci ; 86(3): 1105-1113, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33580500

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a metabolic syndrome, whose main characteristics are excessive lipid accumulation and oxidative stress. Major royal jelly proteins (MRJPs) is a kind of water-soluble protein, which is abundant in royal jelly (RJ). The aim of this study was to evaluate the effect of MRJPs on lipid accumulation and oxidative stress of liver cells. Here, we first optimized the conditions for extracting MRJPs from RJ and identified the extraction effect and product by SDS-PAGE. Then, we used oleic acid (OA) of 1.0 mM to induce hepatocytes for 24 hr to establish a stable cell models of lipid accumulation, and we found that pre-administration (24 hr) of MRJPs (0.2, 0.5, and 1.0 g/L) could significantly reduce the lipid drop content and triglyceride level in the model cells, and simultaneously reduce the alanine aminotransferase and aspertate aminotransferase levels in the cell culture supernatant. In addition, pre-incubation (24 hr) with MRJPs (0.2, 0.5, and 1.0 g/L) could restore superoxide dismutase (SOD) level and mitochondrial membrane potential as compared with OA group. Furthermore, MRJPs administration significantly upregulated the expression of Silent Information Regulator 2 Associated Protein 3, mitochondrial superoxide dismutase (SOD2), and cytochrome c oxidase subunit IV in OA-treated HepG2 cells. The study for the first time provides evidences on the lipid-lowering effect of MRJPs at the cellular level, which can further provide support for the development and application of polypeptide drugs in the future, and can also provide a choice for the prevention and treatment of liver metabolic diseases represented by NAFLD. PRACTICAL APPLICATION: Our study proved that MRJPs had substantial preventing effect on OA-induced lipid accumulation and mitochondrial dysfunction in HepG2 cells. This research can further provide theoretical support for the development and application of peptide drugs in the future. Besides, it can not only further broaden our understanding of NAFLD and other diseases, but also provide ideas for research on oxidative stress and lipid accumulation in the body.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Hepatócitos/fisiologia , Proteínas de Insetos/farmacologia , Metabolismo dos Lipídeos , Mitocôndrias/fisiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Sirtuína 3/metabolismo , Animais , Abelhas/fisiologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Técnicas In Vitro , Mitocôndrias/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/efeitos dos fármacos
8.
J Biol Regul Homeost Agents ; 35(1): 85-96, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33480219

RESUMO

This study aimed at probing into the function of muscone in ameliorating myocardial ischemiareperfusion (I/R) injury and exploring the underlying mechanism. To analyze the function of muscone, H9c2 cardiomyocytes were treated with hypoxia/reoxygenation (H/R) and Sprague-Dawley (SD) rats were treated with left anterior descending (LAD) of the coronary artery ligation for 30 min and reperfusion for 2 h to induce myocardial I/R injury. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to detect the expression of SIRT3. MTT assay and TUNEL assay were performed to investigate H9c2 viability and apoptosis, respectively. ELISA was employed to determine the expressions of inflammatory cytokines TNF-α, IL-6 and IL-1ß, and myocardial injury markers CK and LDH. Oxidative stress markers MDA and SOD, and ROS expression levels were also detected. SIRT3 inhibitor 3-TYP was used to further confirm whether muscone worked via the augmentation of SIRT3. Herein, we found that muscone significantly inhibited inflammation and oxidative stress in H9c2 cardiomyocytes in a dose-dependent manner. H9c2 viability was promoted by muscone while apoptosis was inhibited. In SD rats, pre-treatment of muscone alleviated I/R injury-induced cardiac function dysregulation and left ventricle remolding. Furthermore, muscone increased SIRT3 expression at both mRNA and protein levels. With 3-TYP inhibiting SIRT3, the protective effects of muscone in H9c2 cardiomyocytes and SD rats were all significantly alleviated. In summary, muscone can attenuate inflammation, oxidative stress and cardiomyocytes injury in H9c2 cells treated with H/R and alleviate myocardial I/R injury of SD rats, which are dependent on SIRT3.


Assuntos
Traumatismo por Reperfusão Miocárdica , Animais , Apoptose , Cicloparafinas , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Sirtuína 3/metabolismo
9.
Int J Mol Sci ; 22(3)2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499277

RESUMO

Atherosclerosis remains a large health and economic burden. Even though it has been studied for more than a century, its complex pathophysiology has not been elucidated. The relatively well-established contributors include: chronic inflammation in response to oxidized cholesterol, reactive oxygen species-induced damage and apoptosis. Recently, profilin 1, a regulator of actin dynamics emerged as a potential new player in the field. Profilin is abundant in stable atherosclerotic plaques and in thrombi extracted from infarct-related arteries in patients with acute myocardial infarction. The exact role of profilin in atherosclerosis and its complications, as well as its mechanisms of action, remain unknown. Here, we summarize several pathways in which profilin may act through mitochondria in a number of processes implicated in atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Doença da Artéria Coronariana/metabolismo , Mitocôndrias/metabolismo , Infarto do Miocárdio/metabolismo , Profilinas/metabolismo , Sirtuína 3/metabolismo , Actinas/química , Doença Aguda , Animais , Apoptose , Humanos , Camundongos , Placa Aterosclerótica/patologia , Isoformas de Proteínas , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo
10.
Arterioscler Thromb Vasc Biol ; 41(2): 714-730, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33327751

RESUMO

OBJECTIVE: Infiltrated macrophages actively promote perivascular adipose tissue remodeling and represent a dominant population in the perivascular adipose tissue microenvironment of hypertensive mice. However, the role of macrophages in initiating metabolic inflammation remains uncertain. SIRT3 (sirtuin-3), a NAD-dependent deacetylase, is sensitive to metabolic status and mediates adaptation responses. In this study, we investigated the role of SIRT3-mediated metabolic shift in regulating NLRP3 (Nod-like receptor family pyrin domain-containing 3) inflammasome activation. Approach and Results: Here, we report that Ang II (angiotensin II) accelerates perivascular adipose tissue inflammation and fibrosis, accompanied by NLRP3 inflammasome activation and IL (interleukin)-1ß secretion in myeloid SIRT3 knockout (SIRT3-/-) mice. This effect is associated with adipose tissue mitochondrial dysfunction. In vitro studies indicate that the deletion of SIRT3 in bone marrow-derived macrophages induces IL-1ß production by shifting the metabolic phenotype from oxidative phosphorylation to glycolysis. Mechanistically, SIRT3 deacetylates and activates PDHA1 (pyruvate dehydrogenase E1 alpha) at lysine 83, and the loss of SIRT3 leads to PDH activity decrease and lactate accumulation. Knocking down LDHA (lactate dehydrogenase A) or using carnosine, a buffer against lactic acid, attenuates IL-1ß secretion. Furthermore, the blockade of IL-1ß from macrophages into brown adipocytes restores thermogenic markers and mitochondrial oxygen consumption. Moreover, NLRP3 knockout (NLRP3-/-) mice exhibited reduced IL-1ß production while rescuing the mitochondrial function of brown adipocytes and alleviating perivascular adipose tissue fibrosis. CONCLUSIONS: SIRT3 represents a potential therapeutic target to attenuate NLRP3-related inflammation. Pharmacological targeting of glycolytic metabolism may represent an effective therapeutic approach.


Assuntos
Tecido Adiposo Marrom/metabolismo , Plasticidade Celular , Metabolismo Energético , Hipertensão/enzimologia , Macrófagos/enzimologia , Paniculite/enzimologia , Sirtuína 3/metabolismo , Acetilação , Tecido Adiposo Marrom/patologia , Angiotensina II , Animais , Modelos Animais de Doenças , Fibrose , Células HEK293 , Humanos , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/patologia , Inflamassomos/genética , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Ácido Láctico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Paniculite/induzido quimicamente , Paniculite/genética , Paniculite/patologia , Fenótipo , Piruvato Desidrogenase (Lipoamida)/metabolismo , Transdução de Sinais , Sirtuína 3/genética
11.
PLoS One ; 15(7): e0235491, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32658908

RESUMO

Noise-induced hearing loss (NIHL) affects millions of people worldwide and presents a large social and personal burden. Pharmacological activation of SIRT3, a regulator of the mitochondrial oxidative stress response, has a protective effect on hearing thresholds after traumatic noise damage in mice. In contrast, the role of endogenously activated SIRT3 in hearing recovery has not been established. Here we tested the hypothesis that SIRT3 is required in mice for recovery of auditory thresholds after a noise exposure that confers a temporary threshold shift (TTS). SIRT3-specific immunoreactivity is present in outer hair cells, around the post-synaptic regions of inner hair cells, and faintly within inner hair cells. Prior to noise exposure, homozygous Sirt3-KO mice have slightly but significantly higher thresholds than their wild-type littermates measured by the auditory brainstem response (ABR), but not by distortion product otoacoustic emissions (DPOAE). Moreover, homozygous Sirt3-KO mice display a significant reduction in the progression of their peak 1 amplitude at higher frequencies prior to noise exposure. After exposure to a single sub-traumatic noise dose that does not permanently reduce cochlear function, compromise cell survival, or damage synaptic structures in wild-type mice, there was no difference in hearing function between the two genotypes, measured by ABR and DPOAE. The numbers of hair cells and auditory synapses were similar in both genotypes before and after noise exposure. These loss-of-function studies complement previously published gain-of-function studies and help refine our understanding of SIRT3's role in cochlear homeostasis under different damage paradigms. They suggest that SIRT3 may promote spiral ganglion neuron function. They imply that cellular mechanisms of homeostasis, in addition to the mitochondrial oxidative stress response, act to restore hearing after TTS. Finally, we present a novel application of a biomedical statistical analysis for identifying changes between peak 1 amplitude progressions in ABR waveforms after damage.


Assuntos
Percepção Auditiva , Audição/fisiologia , Ruído , Sirtuína 3/metabolismo , Animais , Técnicas de Inativação de Genes , Masculino , Camundongos , Sirtuína 3/deficiência , Sirtuína 3/genética
12.
Arch Biochem Biophys ; 689: 108415, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32562663

RESUMO

Regorafenib, a multiple kinase inhibitor, is recently approved for treatment of patients with advanced hepatocellular carcinoma (HCC). Previous studies demonstrated that regorafenib was a mitochondrial toxicant, which associated with the impairment of mitochondria. Sirt3 is involved in the regulation of mitochondrial function in cancers. This study aimed to investigate the mechanism of Sirt3 involved in the mitochondrial dysfunction which associated with regorafenib treatment in liver cancer cells. We found regorafenib inhibited Sirt3 and p-ERK expression in HCC cells in a dose-dependent manner. Bioinformatics analysis showed that Sirt3 expression was down-regulated in liver cancer tissues and its low expression was correlated with worse overall survival (OS) in liver cancer patients. After transfected with Sirt3 overexpression plasmid, we found that Sirt3 sensitized liver cancer cells to regorafenib and resulted in much more apoptosis with a significant increase of ROS level. However, exogenous antioxidant could not weaken the apoptosis. Mitochondrial membrane potential assay indicated that Sirt3 overexpression accelerated the mitochondrial depolarization process induced by regorafenib and aggravated mitochondrial injury. Cellular oxygen consumption assay showed that mitochondrial dysfunction was caused by the damage of the electron transport chain. The results demonstrated that Sirt3 overexpression promoted the increase of ROS and apoptosis induced by regorafenib through the acceleration of mitochondrial dysfunction by impairing function of the electron transport chain in liver cancer cells. Our studies verified the functional role of Sirt3 in regorafenib treatment and suggested that regorafenib accompanied with Sirt3 activator as a novel treatment strategy for HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Sirtuína 3/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo
13.
Mol Med Rep ; 22(1): 257-264, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32468046

RESUMO

The incidence of peri-implant bone loss is high, and is a difficult condition to treat. Previous studies have shown that titanium (Ti) ions released from implants can lead to osteoblast cell damage, but the specific mechanisms have not been elucidated. The present study established a Ti ion damage osteoblast cell model. The levels of mitochondrion­derived reactive oxygen species (mROS) and autophagy, cell viability and the sirtuin 3 (SIRT3)/superoxide dismutase 2 (SOD2) pathway were examined in this model. It was found that Ti ions decreased osteoblast viability. Moreover, with increased Ti ion concentration, the expression levels of microtubule associated protein 1 light chain 3α (LC3) progressively increased, P62 decreased, autophagic flow increased and mROS levels increased. After the addition of an autophagy inhibitor Bafilomycin A1 and Mito­TEMPO, a mitochondrial antioxidant, the production of mROS was inhibited, the level of autophagy was decreased and cell activity was improved. In addition, with increased Ti ion concentration, the activity of SOD2 decreased, the acetylation level of SOD2 increased, the SIRT3 mRNA and protein expression levels decreased, and the activity of SIRT3 was significantly decreased. Furthermore, it was demonstrated that SIRT3 overexpression reduced the acetylation of SOD2 and increased the activity of SOD2, as well as reducing the production of mROS and the expression level of LC3, thus increasing cell viability. Therefore, the present results suggested that excessive production of mROS induced by Ti ions led to autophagic cell death of osteoblasts, which is dependent on the SIRT3/SOD2 pathway.


Assuntos
Morte Celular Autofágica/genética , Mitocôndrias/metabolismo , Osteoblastos/metabolismo , Sirtuína 3/metabolismo , Superóxido Dismutase/metabolismo , Titânio/toxicidade , Acetilação , Antioxidantes/farmacologia , Morte Celular Autofágica/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Autofagia/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Humanos , Íons/metabolismo , Íons/toxicidade , Macrolídeos/farmacologia , Proteínas Associadas aos Microtúbulos/metabolismo , Compostos Organofosforados/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/enzimologia , Piperidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Sirtuína 3/genética , Regulação para Cima
14.
Cell Mol Life Sci ; 77(19): 3729-3743, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32468094

RESUMO

Osteoarthritis is the most common degenerative joint disease and causes major pain and disability in adults. It has been reported that mitochondrial dysfunction in chondrocytes is associated with osteoarthritis. Sirtuins are a family of nicotinamide adenine dinucleotide-dependent histone deacetylases that have the ability to deacetylate protein targets and play an important role in the regulation of cell physiological and pathological processes. Among sirtuin family members, sirtuin 3, which is mainly located in mitochondria, can exert its deacetylation activity to regulate mitochondrial function, regeneration, and dynamics; these processes are presently recognized to maintain redox homeostasis to prevent oxidative stress in cell metabolism. In this review, we provide present opinions on the effect of mitochondrial dysfunction in osteoarthritis. Furthermore, the potential protective mechanism of SIRT3-mediated mitochondrial homeostasis in the progression of osteoarthritis is discussed.


Assuntos
Mitocôndrias/metabolismo , Osteoartrite/patologia , Sirtuína 3/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Matriz Extracelular/metabolismo , Humanos , Mitocôndrias/genética , Mitofagia , Osteoartrite/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
15.
Life Sci ; 255: 117846, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32470451

RESUMO

AIMS: Compared to normal cells, tumor cells maintain higher concentrations of reactive oxygen species (ROS) to support proliferation, invasion, and metastasis. Chemotherapeutic drugs often induce tumor cell apoptosis by increasing intracellular ROS concentrations to highly toxic levels. ABT737, which inhibits the apoptosis regulator B cell lymphoma 2 (Bcl2), increases the sensitivity of ovarian cancer cells to chemotherapeutic drugs by regulating the glucose metabolism, but the underlying mechanisms remain unclear. Therefore, we aimed to determine whether ABT737 promoted H2O2-induced tumor cell apoptosis by reversing glycolysis in ovarian cancer cells. MAIN METHODS: SKOV3 ovarian cancer cells were treated with H2O2, ABT737, or both. Cell viability was compared using methyl thiazolyl tetrazolium (MTT), and flow cytometry was used to detect differences in apoptosis, ROS, and mitochondrial membrane potential. The relative expression levels of proteins associated with apoptosis and the glucose metabolism were measured using immunoblotting. Finally, glucose uptake and lactate secretion were measured using kits and compared. KEY FINDINGS: ABT737 downregulated proteins associated with glucose uptake (GLUT1) and glycolysis (LHDA, PKM2 and HK2) via the Sirt3-HIF1α axis, reducing glucose uptake and lactate secretion in SKOV3 cells. This reversed glycolysis in the tumor cells, and promoted H2O2-induced apoptosis. SIGNIFICANCE: The Bcl2 inhibitor ABT737 enhanced the anti-tumor effect of oxidative stress by reversing the Warburg effect in ovarian cancer cells, providing powerful theoretical support for further clinical applications of Bcl2 inhibitors.


Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Nitrofenóis/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Piperazinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/metabolismo
16.
J Dairy Sci ; 103(7): 6557-6568, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32331890

RESUMO

Sirtuin 3 (SIRT3), a mitochondrial deacetylase, is a key regulator of energy metabolism in the liver. In nonruminants, the hepatic abundance of SIRT3 is decreased in individuals with nonalcoholic fatty liver diseases, and recovery of SIRT3 alleviates hepatic triacylglycerol (TG) deposition. However, the level of SIRT3 expression and its effects on lipid metabolism in dairy cows have not been characterized. Here we studied the hepatic expression of SIRT3 in cows with fatty liver and the role of SIRT3 in fatty acid metabolism in bovine hepatocytes. This in vivo study involved 10 healthy cows and 10 cows with fatty liver, from which we collected samples of liver tissue and blood. Primary hepatocytes were isolated from Holstein calves and treated with 0, 0.5, or 1.0 mM nonesterified fatty acids (NEFA) for 24 h or transinfected with SIRT3 overexpression adenovirus (Ad-SIRT3)/SIRT3-short interfering (si)RNA for 48 h. Cows with fatty liver displayed lower serum glucose concentrations but higher serum NEFA and ß-hydroxybutyrate concentrations relative to healthy cows. Cows with fatty liver also had significant lower mRNA and protein abundance of hepatic SIRT3. Incubation of primary hepatocytes with NEFA reduced SIRT3 abundance in primary hepatocytes in a dose-dependent manner. Fatty acid (1 mM) treatment also markedly increased the abundance of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) but significantly decreased the abundance of carnitine palmitoyltransferase I (CPT1A), carnitine palmitoyltransferase II (CPT2), and acyl-CoA oxidase (ACO). Knockdown of SIRT3 by SIRT3-siRNA downregulated the mRNA abundance of CPT1A, CPT2, and ACO. In contrast, overexpression of SIRT3 by Ad-SIRT3 upregulated the mRNA abundance of CPT1A, CPT2, and ACO; downregulated the mRNA abundance of ACC1 and FAS; and consequently, decreased intracellular TG concentrations. Overexpression of SIRT3 ameliorated exogenous NEFA-induced TG accumulation by downregulating the abundance of ACC1 and FAS and upregulating the abundance of CPT1A, CPT2, and ACO in calf hepatocytes. Our data demonstrated that cows with fatty liver had lower hepatic SIRT3 contents, and an increase in SIRT3 abundance by overexpression mitigated TG deposition by modulating the expression of lipid metabolism genes in bovine hepatocytes. These data suggest a possible role of SIRT3 as a therapeutic target for fatty liver disease prevention in periparturient dairy cattle.


Assuntos
Doenças dos Bovinos/metabolismo , Ácidos Graxos não Esterificados/administração & dosagem , Fígado Gorduroso/veterinária , Metabolismo dos Lipídeos/efeitos dos fármacos , Sirtuína 3/metabolismo , Ácido 3-Hidroxibutírico/sangue , Acetil-CoA Carboxilase/efeitos dos fármacos , Acil-CoA Oxidase/efeitos dos fármacos , Animais , Carnitina O-Palmitoiltransferase/efeitos dos fármacos , Bovinos , Doenças dos Bovinos/prevenção & controle , Ácidos Graxos/metabolismo , Ácidos Graxos não Esterificados/sangue , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Mitocôndrias/enzimologia , Sirtuína 3/genética , Triglicerídeos/metabolismo
17.
Gene ; 745: 144629, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32229158

RESUMO

Small-cell lung cancer (SCLC) is the most invasive of all lung cancer subtypes, and is characterized by its rapid response to chemotherapy resistance. Overcoming chemotherapy resistance is therefore the key to treating SCLC. P53 is mutated in most SCLCs, which has an effect of enhancing chemotherapy resistance. Regulation of p53 proteins by a variety of post-translational modifications, such as acetylation, which affects their function. Acetylation and deacetylation of p53 may be potential targets for modulating chemosensitivity. Recent studies have shown that SIRT3 acts as a deacetylase that regulates acetylation of p53. However, whether SIRT3 can regulate the post-translational modification of mutant p53 has not been studied. In the present study, we found that SIRT3 can deacetylate mutant p53, thus reducing its expression, inducing apoptosis in SCLC cells, and increasing SCLC chemosensitivity. The relationship between SIRT3 and mutant p53 could be the basis of a new SCLC treatment approach.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Sirtuína 3/metabolismo , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Acetilação , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Mutação , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Proteólise , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Ubiquitina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Yakugaku Zasshi ; 140(3): 383-389, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115557

RESUMO

Caloric restriction (CR) improves whole-body metabolism, suppresses various age-related pathophysiological changes, and extends lifespan. The beneficial actions of CR are regulated in growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signal-dependent and -independent manners. To clarify the GH/IGF-1-independent mechanism, we compared gene expression profiles in white adipose tissue (WAT) between CR and GH/IGF-1 suppression, and found that CR upregulated sterol regulatory element-binding protein 1c (SREBP-1c) regulatory gene expression. To validate the impact of SREBP-1c as a beneficial mediator of CR, we compared the responses to CR between wild-type and SREBP-1c knockout (KO) mice. CR extended lifespan, upregulated gene expression involved in FA biosynthesis, activated mitochondrial biogenesis, and suppressed oxidative stress predominantly in WAT. In contrast, most of these findings were not observed in KO mice. Furthermore, SREBP-1c was implicated in CR-associated mitochondrial activation through upregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. Sirtuin-3 (SIRT3) regulates mitochondrial quality and is also involved in the beneficial actions of CR. We observed that CR upregulated the mature form of SIRT3 protein and mitochondrial intermediate peptidase (MIPEP), a mitochondrial signal peptidase (MtSPase), in WAT. MIPEP cleaved precursor form of SIRT3 to mature form, and activated certain mitochondrial matrix proteins, suggesting that MIPEP might contribute to maintenance of mitochondrial quality during CR via SIRT3 activation. Taken together, CR induces SREBP-1c-dependent metabolic remodeling, including enhancement of FA biosynthesis and mitochondrial activation, via PGC-1α, and improvement of mitochondria quality via Mipep in WAT, resulting in beneficial actions.


Assuntos
Tecido Adiposo Branco/metabolismo , Envelhecimento/metabolismo , Restrição Calórica , Animais , Expressão Gênica , Humanos , Longevidade , Camundongos , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 3/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Regulação para Cima
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