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1.
Chemosphere ; 239: 124758, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31514009

RESUMO

Trace elements such as copper (Cu) and arsenic (As) are two of the major contaminants and well-known inducers of cognitive deficits and neurobehavioral changes. This study evaluated the immunotoxicity of their individual or combined exposure on different brain regions in chickens. Consequently, nuclear damage and organelle lesions, especially mitochondria were observed under Cu or/and As stress, in which positive regulation of key proteins, dynamin-related protein 1 (Drp1), Cytochrome C (Cyt c), BCL2-associated X (Bax), Caspases 3 and P53 was detected by qRCR and Western blot analyses, indicating disturbed mitochondrial dynamic equilibrium and apoptosis execution. In addition, qRCR analysis confirmed the involvement of cytokines secreted by different populations of helper T cells, indicative of cellular immunity. Gene expression studies showed marked up regulation of Th1/Th17 cytokines along with heat shock protein (HSP) 70, a synergism was noted in co-administration group. Interesting, lower apoptosis index was noted in brainstem compared to cerebrum and cerebellum. An intense immunosuppression and heat shock response against Cu or/and As was also seen in cerebrum and cerebellum but not in brainstem. In conclusion, our study suggests a synergistic neurotoxicity in chickens under Cu and As exposure. These findings provide a basic understanding of mitochondrial abnormality-initiated neuropathology in response to environmental pollutant mixtures, suggesting an adaptive response to the frangibility of the central nerve system.


Assuntos
Arsenitos/toxicidade , Encéfalo/efeitos dos fármacos , Galinhas/imunologia , Cobre/toxicidade , Tolerância Imunológica/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Encéfalo/patologia , Poluentes Ambientais/toxicidade , Resposta ao Choque Térmico/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Masculino , Dinâmica Mitocondrial/efeitos dos fármacos
2.
Chemosphere ; 238: 124607, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31524603

RESUMO

A fluoride exposure mouse model is established to evaluate the relationship between mitochondrial respiratory chain complexes and renal dysfunction. Morphological changes in kidney tissues were observed. Renal function and cell proliferation in the kidneys were evaluated. The expression of mitochondrial fusion protein including mitofusin-1 (Mfn1) and optic atrophy 1 (OPA1), and mitochondrial respiratory chain complex subunits, including NDUFV2, SDHA, CYC1 and COX Ⅳ, were detected via real-time polymerase chain reaction, immunohistochemistry staining and Western blot, respectively. Results showed that the structures of renal tubule, renal glomerulus and renal papilla were seriously damaged. Renal function was impaired, and cell proliferation was remarkably inhibited by excessive fluoride in kidney. The mRNA and protein expression levels of Mfn1, OPA1, NDUFV2, CYC1 and COX Ⅳ were significantly increased after excessive fluoride exposure. However, the mRNA and protein expression of SDHA significantly decreased. Overall, our findings revealed that excessive fluoride can damage kidney structure, inhibit renal cell proliferation, interfere with the expression of mitochondrial respiratory chain complexes and elevate mitochondrial fusion. Consequently, renal function disorder occurred.


Assuntos
Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Fluoretos/toxicidade , Doenças Mitocondriais/induzido quimicamente , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Insuficiência Renal/induzido quimicamente , Animais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Transporte de Elétrons , GTP Fosfo-Hidrolases/metabolismo , Rim/patologia , Camundongos , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , RNA Mensageiro/biossíntese
3.
Ecotoxicol Environ Saf ; 186: 109749, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31622878

RESUMO

Hexavalent chromium [Cr(VI)] is a common heavy metal pollutant widely used in various industrial fields. It is well known that mitochondria are the most vulnerable targets of heavy metals, but the key molecule/event that directly mediated mitochondrial dysfunction after Cr(VI) exposure is still unclear. The present study was aimed to explore whether Cr(VI) exposure could affect the mitochondrial fission/fusion process, and whether the related abnormal mitochondrial dynamics have been implicated in Cr(VI)-induced mitochondrial dysfunction. We found that the mitochondrial dysfunction caused by Cr(VI) exposure was characterized by decreased mitochondrial respiratory chain complex (MRCC) I/II activities and levels, collapsed mitochondrial membrane potential (MMP), depleted ATP, and increased reactive oxygen species (ROS) level. Cr(VI) induced abnormal mitochondrial fission/fusion events, the antioxidant Nacetyl-L-cysteine (NAC) restored the abnormal mitochondrial function as well as the fission/fusion dynamics. ROS was the up-stream regulator of extracellular regulated protein kinases (ERK) signaling, and the application of a specific ERK1/2 inhibitor PD98059 confirmed that activation of ERK1/2 signaling was associated with the abnormal mitochondrial fission/fusion and mitochondrial dysfunction. We also demonstrated that treatment with dynamic-like protein 1 (DLP1)-siRNA rescued mitochondrial dysfunction in Cr(VI)-exposed L02 hepatocytes. We reached the conclusion that blockage of ROS-ERK-DLP1 signaling and mitochondrial fission alleviates Cr(VI)-induced mitochondrial dysfunction in L02 hepatocytes, which may provide the new avenue for developing effective strategies to protect against Cr(VI)-induced hepatotoxicity.


Assuntos
Antioxidantes/farmacologia , Cromo/toxicidade , Dinaminas/farmacologia , Fígado/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Carcinógenos Ambientais , Dinaminas/metabolismo , Flavonoides/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Humanos , Fígado/citologia , Fígado/metabolismo , Fígado/fisiopatologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/fisiologia , Dinâmica Mitocondrial/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais
4.
Ecotoxicol Environ Saf ; 185: 109678, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31557571

RESUMO

Arsenic and copper are naturally occurring element. Contamination from natural processes and anthropogenic activities can be discovered all over the world and their unique interactions with the environment lead to widespread toxicity. When the content was excessive, the organism would be hurt seriously. The glandular stomach is an important organ of the poultry gastrointestinal tract. This study was aimed to investigate the toxicity of arsenic trioxide or/and copper sulfate (As or/and Cu) on chicken glandular stomach. Seventy-two 1-day-old Hy-Line chickens were randomly divided into control (C) group, arsenic trioxide (As) group, copper sulfate (Cu) group and arsenic trioxide and copper sulfate (AsCu) group, and exposed to 30 mg/kg arsenic trioxide or/and 300 mg/kg copper sulphates for 12 weeks. The indicators of mitochondrial dynamics, apoptosis and autophagy were tested in the glandular stomach. The results showed that exposure to As or/and Cu caused mitochondrial dynamic imbalance. Additionally, the levels of pro-apoptosis and autophagy indicators were increased and the levels of anti-apoptosis indicators were decreased in the treatment groups. Beyond that, in the treatment groups, we could clearly see karyopyknosis and chromatin condensation were associated with increased apoptosis rate, as well as the disappearance of the nuclear membrane, the swelling of mitochondria and the accumulation of autophagosomes were involved in the death of cells. It was worth noting that the glandular stomach lesions were time-dependent, and the combination of As and Cu were worse than the As and Cu alone. Collectively, our results suggest that As or/and Cu aggravate mitochondrial dysfunction, apoptosis and autophagy in a time-dependent manner, and the combined toxicity of As and Cu was higher.


Assuntos
Apoptose/efeitos dos fármacos , Trióxido de Arsênio/toxicidade , Autofagia/efeitos dos fármacos , Galinhas , Sulfato de Cobre/toxicidade , Poluentes Ambientais/toxicidade , Dinâmica Mitocondrial/efeitos dos fármacos , Estômago/efeitos dos fármacos , Animais , Sinergismo Farmacológico , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Estômago/patologia
5.
Ecotoxicol Environ Saf ; 183: 109578, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442807

RESUMO

Hydrogen sulfide (H2S), as an environmental gas pollutant, has harmful effects on many tissues and organs, including myocardium. However, the underlying mechanisms of H2S-induced myocardia toxicity remain poorly understood. The present study was designed to investigate the effect of H2S on myocardia injury in broilers from the perspective of apoptosis. 30 ppm H2S was administered in the broiler chamber for 2, 4 and 6 week, respectively, and the myocardial samples in control groups and H2S groups were collected immediately after euthanized broilers. Transmission electron microscope, test kits, qRT-PCR and western blot were performed. Results showed that H2S exposure decreased the activities of catalase (CAT) and total antioxidant capability (T-AOC), whereas the content of hydrogen peroxide (H2O2) and the activity of inducible nitric oxide synthase (iNOS) enhanced. Besides, we found the excessive expression of mitochondrial fission genes (Drp1 and Mff) by H2S, the dynamic balance of mitochondrial fission and fusion is destroyed. Furthermore, the levels of pro-apoptotic gene (including CytC, Cas3, Cas8, Cas9, TNF-α and Bax) increased after H2S exposure, as well as the expression level of anti-apoptotic gene bcl-2 decreased. At the same time, the activities of ATPase (including Na+-K+-ATPase, Ca2+-ATPase, Mg2+-ATPase and Ca2+-Mg2+-ATPase) weakened under H2S exposure. Therefore, we conclude that H2S induced oxidative stress and then leaded to excessive mitochondrial fission, which involved in apoptosis and damage broiler myocardia.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotoxicidade/veterinária , Sulfeto de Hidrogênio/toxicidade , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doenças das Aves Domésticas/patologia , Animais , Apoptose/genética , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Galinhas , Regulação da Expressão Gênica/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Dinâmica Mitocondrial/genética , Doenças das Aves Domésticas/metabolismo
6.
Int J Mol Sci ; 20(16)2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31443187

RESUMO

Background: New treatments are needed to reduce myocardial infarct size (MI) and prevent heart failure (HF) following acute myocardial infarction (AMI), which are the leading causes of death and disability worldwide. Studies in rodent AMI models showed that genetic and pharmacological inhibition of mitochondrial fission, induced by acute ischemia and reperfusion, reduced MI size. Whether targeting mitochondrial fission at the onset of reperfusion is also cardioprotective in a clinically-relevant large animal AMI model remains to be determined. Methods: Adult pigs (30-40 kg) were subjected to closed-chest 90-min left anterior descending artery ischemia followed by 72 h of reperfusion and were randomized to receive an intracoronary bolus of either mdivi-1 (1.2 mg/kg, a small molecule inhibitor of the mitochondrial fission protein, Drp1) or vehicle control, 10-min prior to reperfusion. The left ventricular (LV) size and function were both assessed by transthoracic echocardiography prior to AMI and after 72 h of reperfusion. MI size and the area-at-risk (AAR) were determined using dual staining with Tetrazolium and Evans blue. Heart samples were collected for histological determination of fibrosis and for electron microscopic analysis of mitochondrial morphology. Results: A total of 14 pigs underwent the treatment protocols (eight control and six mdivi-1). Administration of mdivi-1 immediately prior to the onset of reperfusion did not reduce MI size (MI size as % of AAR: Control 49.2 ± 8.6 vs. mdivi-1 50.5 ± 11.4; p = 0.815) or preserve LV systolic function (LV ejection fraction %: Control 67.5 ± 0.4 vs. mdivi-1 59.6 ± 0.6; p = 0.420), when compared to vehicle control. Similarly, there were no differences in mitochondrial morphology or myocardial fibrosis between mdivi-1 and vehicle control groups. Conclusion: Our pilot study has shown that treatment with mdivi-1 (1.2 mg/kg) at the onset of reperfusion did not reduce MI size or preserve LV function in the clinically-relevant closed-chest pig AMI model. A larger study, testing different doses of mdivi-1 or using a more specific Drp1 inhibitor are required to confirm these findings.


Assuntos
Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Quinazolinonas/uso terapêutico , Animais , Modelos Animais de Doenças , Ecocardiografia , Feminino , Dinâmica Mitocondrial/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Projetos Piloto , Suínos , Função Ventricular Esquerda/efeitos dos fármacos
7.
Mol Cell Biochem ; 461(1-2): 65-72, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31327095

RESUMO

Azoramide is identified as a new compound with the dual properties for the improvement of ER-folding capacity in various cells as well as for the treatment of T2DM. Although the effect of azoramide in glucose-homeostasis in mammalians is not known very well, a limited number of experimental studies showed that it could improve the insulin sensitivity in genetically obese mice. Therefore, here, we aimed to investigate the direct effect of azoramide on insulin signaling in insulin-resistant (IR) cardiomyocytes using IR-modelled ventricular cardiomyocytes. This model was established in H9c2 cells using palmitic acid incubation (50-µM for 24-h). The development of IR in cells was verified by monitoring the cellular 2-DG6P uptake assays in these treated cells. The 2-DG6P uptake was 50% less in the IR-cells compared to the control cells, while azoramide treatment (20-µM for 48-h) could prevent fully that decrease. In addition, azoramide treatment markedly preserved the IR-induced less ATP production and high-ROS production in these IR-cells. Furthermore, this treatment prevented the functional changes in mitochondria characterized by depolarized mitochondrial membrane potential and mitochondrial fusion or fusion-related protein levels as well as cellular ATP level. Moreover, this treatment provided marked protection against IR-associated changes in the insulin signaling pathway in cells, including recovery in the phosphorylation of IRS1 and Akt as well as the protein level of GLUT4 and Akt. Our present results, for the first time, demonstrated that azoramide plays an important protective role in IR-cardiomyocytes, at most, protective action on mitochondria. Therefore, one can suggest that azoramide, as a novel regulator, can provide direct cardioprotection in the IR-heart, at most, via affecting mitochondria and can be a good candidate as a new drug for the treatment of IR-associated cardiovascular disorders in mammalians with systemic IR.


Assuntos
Amidas/farmacologia , Resistência à Insulina , Mitocôndrias/metabolismo , Ácido Palmítico/toxicidade , Tiazóis/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Glucose/metabolismo , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295873

RESUMO

Cisplatin is one of the worldwide anticancer drugs and, despite its toxicity and frequent recurrence of resistance phenomena, it still remains the only therapeutic option for several tumors. Circumventing cisplatin resistance remains, therefore, a major goal for clinical therapy and represents a challenge for scientific research. Recent studies have brought to light the fundamental role of mitochondria in onset, progression, and metastasis of cancer, as well as its importance in the resistance to chemotherapy. The aim of this review is to give an overview of the current knowledge about the implication of mitochondria in cisplatin resistance and on the recent development in this research field. Recent studies have highlighted the role of mitochondrial DNA alterations in onset of resistance phenomena, being related both to redox balance alterations and to signal crosstalk with the nucleus, allowing a rewiring of cell metabolism. Moreover, an important role of the mitochondrial dynamics in the adaptation mechanism of cancer cells to challenging environment has been revealed. Giving bioenergetic plasticity to tumor cells, mitochondria allow cells to evade death pathways in stressful conditions, including chemotherapy. So far, even if the central role of mitochondria is recognized, little is known about the specific mechanisms implicated in the resistance. Nevertheless, mitochondria appear to be promising pharmacological targets for overcoming cisplatin resistance, but further studies are necessary.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Animais , Núcleo Celular/metabolismo , DNA Mitocondrial , Resistencia a Medicamentos Antineoplásicos , Humanos , Mitocôndrias/genética , Dinâmica Mitocondrial/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Transdução de Sinais
9.
J Neuroinflammation ; 16(1): 149, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324254

RESUMO

BACKGROUND: Unrestrained activation of Th1 and Th17 cells is associated with the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). While inactivation of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, can reduce EAE severity by protecting myelin from demyelination, its effect on immune responses in EAE has not yet been studied. METHODS: We investigated the effect of Mdivi-1, a small molecule inhibitor of Drp1, on EAE. Clinical scores, inflammation, demyelination and Drp1 activation in the central nervous system (CNS), and T cell responses in both CNS and periphery were determined. RESULTS: Mdivi-1 effectively suppressed EAE severity by reducing demyelination and cellular infiltration in the CNS. Mdivi-1 treatment decreased the phosphorylation of Drp1 (ser616) on CD4+ T cells, reduced the numbers of Th1 and Th17 cells, and increased Foxp3+ regulatory T cells in the CNS. Moreover, Mdivi-1 treatment effectively inhibited IFN-γ+, IL-17+, and GM-CSF+ CD4+ T cells, while it induced CD4+ Foxp3+ regulatory T cells in splenocytes by flow cytometry. CONCLUSIONS: Together, our results demonstrate that Mdivi-1 has therapeutic potential in EAE by modulating the balance between Th1/Th17 and regulatory T cells.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Quinazolinonas/farmacologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Animais , Inibidores Enzimáticos/farmacologia , Feminino , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas de Ligação a RNA/antagonistas & inibidores , Linfócitos T Auxiliares-Indutores/imunologia
10.
Mediators Inflamm ; 2019: 7329131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263382

RESUMO

Apoptosis of CD4+ T cells plays a central role in the progression of sepsis because it is associated with subsequent immunosuppression and the lack of specific treatment. Thus, developing therapeutic strategies to attenuate the apoptosis of CD4+ T cells in sepsis is critical. Several studies have demonstrated that Mdivi-1, which is a selective inhibitor of the dynamin-related protein 1 (Drp1), attenuates apoptosis of myocardial cells and neurons during various pathologic states. The present study revealed the impact of Mdivi-1 on the apoptosis of CD4+ T cells in sepsis and the potential underlying mechanisms. We used lipopolysaccharide (LPS) stimulation and cecal ligation and puncture (CLP) surgery as sepsis models in vitro and in vivo, respectively. Our results showed that Mdivi-1 attenuated the apoptosis of CD4+ T cells both in vitro and in vivo. The potential mechanism underlying the protective effect of Mdivi-1 involved Mdivi-1 reestablishing mitochondrial fusion-fission balance in sepsis, as reflected by the expression of the mitofusin 2 (MFN2) and optic atrophy 1 (OPA1) , Drp1 translocation, and mitochondrial morphology, as observed by electron microscopy. Moreover, Mdivi-1 treatment reduced reactive oxygen species (ROS) production and prevented the induction of endoplasmic reticulum stress (ERS) and associated apoptosis. After using tunicamycin to activate ER stress, the protective effect of Mdivi-1 on CD4+ T cells was reversed. Our results suggested that Mdivi-1 ameliorated apoptosis in CD4+ T cells by reestablishing mitochondrial fusion-fission balance and preventing the induction of endoplasmic reticulum stress in experimental sepsis.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Quinazolinonas/uso terapêutico , Sepse/tratamento farmacológico , Sepse/metabolismo , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , GTP Fosfo-Hidrolases/metabolismo , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Atrofia Óptica Autossômica Dominante/metabolismo , Espécies Reativas de Oxigênio/metabolismo
11.
Int J Mol Sci ; 20(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336911

RESUMO

Mitochondrial dysfunction is associated with cardiovascular diseases and diabetes. Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, and the abnormal proliferation, apoptosis and migration of pulmonary arterial smooth muscle cells (PASMCs). The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, has been shown to prevent pulmonary hypertension in monocrotaline-exposed rats. The aim of this study was to investigate the effect of liraglutide on autophagy, mitochondrial stress and apoptosis induced by platelet-derived growth factor BB (PDGF-BB). PASMCs were exposed to PDGF-BB, and changes in mitochondrial morphology, fusion-associated protein markers, and reactive oxygen species (ROS) production were examined. Autophagy was assessed according to the expressions of microtubule-associated protein light chain 3 (LC3)-II, LC3 puncta and Beclin-1. Western blot analysis was used to assess apoptosis, mitochondrial stress and autophagy markers. Liraglutide significantly inhibited PDGF-BB proliferation, migration and motility in PASMCs. PDGF-BB-induced ROS production was mitigated by liraglutide. Liraglutide increased the expression of α-smooth muscle actin (α-SMA) and decreased the expression of p-Yes-associated protein (p-YAP), inhibited autophagy-related protein (Atg)-5, Atg-7, Beclin-1 and the formation of LC3-ß and mitochondrial fusion protein dynamin-related (Drp)1. Therefore, liraglutide can mitigate the proliferation of PASMCs via inhibiting cellular Drp1/nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) pathways and Atg-5/Atg-7/Beclin-1/LC3ß-dependent pathways of autophagy in PAH.


Assuntos
Autofagia/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , /metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Becaplermina/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Liraglutida/farmacologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Modelos Biológicos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
12.
Food Chem Toxicol ; 132: 110694, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31344369

RESUMO

The present study evaluates the effects of low-level long-term exposure to bisphenol A (BPA) and bisphenol S (BPS) on serum biochemical markers, glucose homeostasis, mitochondrial energy metabolism, biogenesis and dynamics, and redox status in livers of Wistar rats. While only the exposure to BPS induces a significant body mass gain after 21 weeks, both compounds alter serum lipid levels and lead to the development of glucose intolerance. Regarding mitochondrial metabolism, both bisphenols augment the electron entry by complex II relative to complex I in the mitochondrial respiratory chain (MRC), and reduce mitochondrial content; BPA reduces OXPHOS capacity and uncouples respiration (relative to maximal capacity of MRC) but promotes a significant increase in fatty acid oxidation. Either exposure to BPA or BPS leads to an increase in mitochondrial-derived reactive oxygen species, mainly at complex I. Additionally, BPA and BPS significantly upregulate the expression levels of dynamin-related protein 1 related to mitochondrial fission, while BPA downregulates the expression of proliferator-activated receptor gamma coactivator 1 alpha, a master regulator of mitochondrial biogenesis. In summary, our data shows that exposure to both compounds alters metabolic homeostasis and mitochondrial energy metabolism, providing new mechanisms by which BPA and BPS impair the mitochondrial metabolism.


Assuntos
Compostos Benzidrílicos/farmacologia , Teste de Tolerância a Glucose , Mitocôndrias Hepáticas/efeitos dos fármacos , Fenóis/farmacologia , Sulfonas/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Lipídeos/sangue , Masculino , Mitocôndrias Hepáticas/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Oxirredução , Fosforilação Oxidativa/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo
13.
Nat Commun ; 10(1): 3390, 2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358769

RESUMO

Accumulating evidence illustrates a fundamental role for mitochondria in lung alveolar type 2 epithelial cell (AEC2) dysfunction in the pathogenesis of idiopathic pulmonary fibrosis. However, the role of mitochondrial fusion in AEC2 function and lung fibrosis development remains unknown. Here we report that the absence of the mitochondrial fusion proteins mitofusin1 (MFN1) and mitofusin2 (MFN2) in murine AEC2 cells leads to morbidity and mortality associated with spontaneous lung fibrosis. We uncover a crucial role for MFN1 and MFN2 in the production of surfactant lipids with MFN1 and MFN2 regulating the synthesis of phospholipids and cholesterol in AEC2 cells. Loss of MFN1, MFN2 or inhibiting lipid synthesis via fatty acid synthase deficiency in AEC2 cells exacerbates bleomycin-induced lung fibrosis. We propose a tenet that mitochondrial fusion and lipid metabolism are tightly linked to regulate AEC2 cell injury and subsequent fibrotic remodeling in the lung.


Assuntos
GTP Fosfo-Hidrolases/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Metabolismo dos Lipídeos , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Células Cultivadas , Colesterol/metabolismo , GTP Fosfo-Hidrolases/genética , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Camundongos Knockout , Camundongos Transgênicos , Dinâmica Mitocondrial/efeitos dos fármacos , Dinâmica Mitocondrial/genética , Fosfolipídeos/biossíntese
14.
Int J Oncol ; 55(2): 415-424, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173174

RESUMO

IR­783, a near­infrared heptamethine cyanine dye, has been reported to possess cancer targeting and anticancer effects; Ηowever, the molecular mechanism by which IR­783 exhibits anti­breast cancer activity is unclear. In the present study, the inhibitory effects of IR­783 on the proliferation and migration of breast cancer cells were investigated. Our results revealed that IR­783 inhibited MDA­MB­231 and MCF­7 cell proliferation in a dose­ and time­dependent manner by inducing cell cycle arrest at the G0/G1 phase. In addition, a Transwell assay demonstrated that IR­783 treatment suppressed the migratory ability of MDA­MB­231 and MCF­7 cells. Furthermore, IR­783 treatment decreased the expression levels of matrix metalloproteinase (MMP)­2 and MMP­9 in MDA­MB­231 cells. Furthermore, IR­783 induced MDA­MB­231 and MCF­7 cell mitochondrial fission, and also decreased the levels of ATP. This was accompanied with a decrease in polymerized filamentous actin, which is the fundamental component of filopodia at the cell surface. Collectively, the results of the present study demonstrated that IR­783 inhibited the proliferation and migration of MDA­MB­231 and MCF­7 cells by inducing mitochondrial fission and subsequently decreasing ATP levels, resulting in cell cycle arrest and filopodia formation suppression. These findings suggest that IR­783 may be developed into an effective novel drug for treating breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Corantes Fluorescentes/farmacologia , Indóis/farmacologia , Dinâmica Mitocondrial/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Raios Infravermelhos , Células Tumorais Cultivadas
15.
Int J Mol Sci ; 20(12)2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31242698

RESUMO

High-fat diets rich in fish oil (HFO diet, mainly ω3-PUFAs), in contrast to high-fat diets rich in lard (HL diet, mainly saturated fatty acids) have been shown to induce improvement in mitochondrial function and fusion processes associated with a reduction in reactive oxygen species production in both liver and skeletal muscle. High-fat diets may also impair testicular function, and mitochondria represent important cellular organelles with a pivotal role in reproductive function. Mitochondria are dynamic organelles that frequently undergo fission/fusion processes. A shift toward mitochondrial fusion process has been associated with improvement of mitochondrial function, as well as with ω3-PUFAs protective effects. The present study aimed to analyze the effect of chronic overfeeding (six weeks) with HFO or HL diet on testicular tissue histology, oxidative stress, antioxidant defenses, and mitochondrial fusion (mitofusin 2) and fission (dynamic related protein 1) protein. Our results showed that HFO diet induced less testicular histology impairment, oxidative stress, and apoptosis compared to a HL diet. This finding was associated with an increase in antioxidant activities and a shift toward mitochondrial fusion processes induced by HFO diet compared to HL diet, suggesting that ω3-PUFAs may act as bioactive compound targeting mitochondria dynamics to prevent testicular impairment.


Assuntos
Antioxidantes/farmacologia , Dieta Hiperlipídica , Óleos de Peixe , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Testículo/metabolismo , Animais , Apoptose/efeitos dos fármacos , Peso Corporal , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Tamanho do Órgão , Estresse Oxidativo/efeitos dos fármacos , Ratos , Testículo/efeitos dos fármacos
16.
J Steroid Biochem Mol Biol ; 192: 105413, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31202858

RESUMO

In steroid-producing cells, cholesterol transport from the outer to the inner mitochondrial membrane is the first and rate-limiting step for the synthesis of all steroid hormones. Cholesterol can be transported into mitochondria by specific mitochondrial protein carriers like the steroidogenic acute regulatory protein (StAR). StAR is phosphorylated by mitochondrial ERK in a cAMP-dependent transduction pathway to achieve maximal steroid production. Mitochondria are highly dynamic organelles that undergo replication, mitophagy and morphology changes, all processes allowed by mitochondrial fusion and fission, known as mitochondrial dynamics. Mitofusin (Mfn) 1 and 2 are GTPases involved in the regulation of fusion, while dynamin-related protein 1 (Drp1) is the major regulator of mitochondrial fission. Despite the role of mitochondrial dynamics in neurological and endocrine disorders, little is known about fusion/fission in steroidogenic tissues. In this context, the present work aimed to study the role of angiotensin II (Ang II) in protein subcellular compartmentalization, mitochondrial dynamics and the involvement of this process in the regulation of aldosterone synthesis. We demonstrate here that Ang II stimulation promoted the recruitment and activation of PKCε, ERK and its upstream kinase MEK to the mitochondria, all of them essential for steroid synthesis. Moreover, Ang II prompted a shift from punctate to tubular/elongated (fusion) mitochondrial shape, in line with the observation of hormone-dependent upregulation of Mfn2 levels. Concomitantly, mitochondrial Drp1 was diminished, driving mitochondria toward fusion. Moreover, Mfn2 expression is required for StAR, ERK and MEK mitochondrial localization and ultimately for aldosterone synthesis. Collectively, this study provides fresh insights into the importance of hormonal regulation in mitochondrial dynamics as a novel mechanism involved in aldosterone production.


Assuntos
Neoplasias das Glândulas Suprarrenais/metabolismo , Carcinoma Adrenocortical/metabolismo , Angiotensina II/farmacologia , Colesterol/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas Quinases/metabolismo , Vasoconstritores/farmacologia , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/patologia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Transporte Biológico , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fosforilação , Células Tumorais Cultivadas
17.
Life Sci ; 232: 116561, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247208

RESUMO

AIMS: The poor prognosis of ovarian cancer is mainly caused by chemotherapy resistance. Studies show that the Bcl-2 inhibitor ABT737 can significantly improve the effect of cisplatin and induce mitochondrial pathway apoptosis. However, the mechanism of ABT737 increases sensitivity to cisplatin by regulating mitochondrial function remains unclear in ovarian cancer cells. Sirt3, as a histone deacetylase, is involved in the regulation of mitochondrial function in cancers. In this study, we intend to explore the mechanistic link between Sirt3 and mitochondrial dysfunction induced by ABT737 and cisplatin in ovarian cancer cells. MAIN METHODS: Apoptosis was examined by flow cytometry following Annexin V and PI staining. Sirt3 activity was assessed using Sirt3 deacetylase fluorometric assay. The mitochondrial membrane potential was examined by flow cytometry following JC-1 staining. Overexpression and knock-down of Sirt3 were confirmed by western blot analysis. Mitochondrial fission/fusion dynamics were detected by immunofluorescence staining or western blot analysis. KEY FINDINGS: Cisplatin accompanied with ABT737 promoted apoptosis and decreased mitochondrial membrane potential. ABT737 enhanced the sensitivity of ovarian cancer cells to cisplatin, which was partly achieved by activating Sirt3 to regulate the mitochondrial fission process. SIGNIFICANCE: This study identified the activation of Sirt3 played an important role in increasing sensitivity of ovarian cancer cells to cisplatin induced by ABT737. Furthermore, Sirt3 might represent a potential therapeutic target for ovarian cancer.


Assuntos
Compostos de Bifenilo/farmacologia , Nitrofenóis/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Sirtuína 3/metabolismo , Sulfonamidas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/metabolismo , Cisplatino/farmacologia , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Neoplasias Ovarianas/fisiopatologia , Ovário/metabolismo , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
Chemosphere ; 234: 822-829, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31247492

RESUMO

Mercury is one of the 10 toxic chemicals with major public health concerns. Continuous exposure to low levels of heavy metals including mercury is related to renal injury, especially in children. This study investigated the possible molecular mechanism of inorganic mercury-induced kidney injury. Twenty eight Kunming mice were divided into four groups (n = 7), and treated with 0, 20, 40, 80 mg/L mercuric chloride (HgCl2) in drinking water for 16 weeks respectively. All the HgCl2 exposure mice displayed different degrees of renal injury, which was diagnosed by hematoxylin and eosin stain, biochemical analysis, and ultrastructure examination. The treatment of HgCl2 inhibited the silent information regulator two ortholog 1 (Sirt1)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) signaling pathway and resulted the disorder of mitochondrial dynamics, as evidenced by the increasing expression of dynamin-related protein 1 and decreasing expression of mitofusin 2. Meanwhile, HgCl2 inhibited the nuclear factor erythroid 2-related factor 2 (Nrf2) axis. The abnormality of mitochondrial dynamics and the suppression of Nrf2 axis exacerbated oxidative stress, and then induced cell apoptosis. These findings demonstrated that the disorder of mitochondrial dynamics induced by HgCl2 activated oxidative stress, and further resulted in renal apoptosis through inhibiting the Sirt1/PGC-1α signaling pathway and the Nrf2 axis.


Assuntos
Apoptose , Rim/lesões , Cloreto de Mercúrio/toxicidade , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo , Animais , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Dinaminas/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo
19.
Oxid Med Cell Longev ; 2019: 4508762, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31236191

RESUMO

Much evidence demonstrates that mitochondrial dysfunction plays a crucial role in the pathogenesis of vascular complications of diabetes. However, the signaling pathways through which hyperglycemia leads to mitochondrial dysfunction of endothelial cells are not fully understood. Here, we treated human umbilical vein endothelial cells (HUVECs) with high glucose and examined the role of translocase of mitochondrial outer membrane (Tom) 22 on mitochondrial dynamics and cellular function. Impaired Tom22 expression and protein expression of oxidative phosphorylation (OXPHOS) as well as decreased mitochondrial fusion were observed in HUVECs treated with high glucose. The deletion of Tom22 resulted in reduced mitochondrial fusion and ATP production and increased apoptosis in HUVECs. The overexpression of Tom22 restored the balance of mitochondrial dynamics and OXPHOS disrupted by high glucose. Importantly, we found that Tom22 modulates mitochondrial dynamics and OXPHOS by interacting with mitofusin (Mfn) 1. Taken together, our findings demonstrate for the first time that Tom22 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following high-glucose exposure.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Células Endoteliais da Veia Umbilical Humana/patologia , Mitocôndrias/patologia , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Apoptose , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Transdução de Sinais
20.
Neurotox Res ; 36(2): 334-346, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31055771

RESUMO

Aluminum (Al) exposure impairs learning and memory function in humans and in animal models. Several studies have shown that the neurotoxicity of Al is associated with damage to mitochondrial morphology and mitochondrial dysfunction, but the molecular mechanism is unclear. The present study was performed to elucidate the possible molecular mechanism related to the Al-induced abnormal mitochondrial dynamics that lead to learning and memory disorders. SD rats were exposed to Al-maltolate complex (Al(mal)3) (blank, 0, 0.41, 0.81, or 1.62 mg/kg) for 30, 60, or 90 days, and neurobehavior, mitochondrial morphology, mitochondrial function, the levels of fission proteins such as dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1), and the levels of fusion proteins such as optic atrophy 1 (Opa1), mitofusin 1 (Mfn1), and mitofusin 2 (Mfn2) were explored. The results indicated that exposure to Al(mal)3 increased the concentration of Al in the brain in a time- and dose-dependent manner and impaired spatial learning and memory. Al(mal)3 damaged mitochondrial morphology and impaired mitochondrial function in the hippocampus. Dose-dependent elevations in the levels of mitochondrial fission (Drp1 and Fis1) and fusion (Opa1, Mfn1, and Mfn2) proteins were observed. In addition, the upregulation of calcineurin (CaN) and the reduced phosphorylation of Drp1 (s637) may have disturbed the balance of mitochondrial fission and fusion in the hippocampus. These results showed that Al-induced learning and memory impairment may be related to mitochondrial fission and fusion disorders.


Assuntos
Alumínio/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Dinâmica Mitocondrial/fisiologia , Ratos , Ratos Sprague-Dawley
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