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1.
Mar Drugs ; 17(9)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480724

RESUMO

Mitochondria are considered to be the powerhouses of cells. They are the most commonly damaged organelles within dopaminergic neurons in patients with Parkinson's disease (PD). Despite the importance of protecting neuronal mitochondria in PD patients, the detailed mechanisms underlying mitochondrial dysfunction during pathogenesis and pathophysiological progression of PD have not yet been elucidated. We investigated the protective action of fucoidan against the detrimental action of 1-methyl-4-phenyl-pyridinium (MPP+), a neurotoxin used to model PD, in the mitochondria of SH-SY5Y neural cells. Fucoidan increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and protected the cells from MPP+-induced apoptosis by upregulating the 5' adenosine monophosphate-activated protein kinase (AMPK)-PGC-1α axis. These effects were blocked by the silencing of the PGC-1α axis. These results indicated that fucoidan protects SH-SY5Y cells from mitochondrial dysfunction and cell death caused by MPP+ treatment, via the AMPK-PGC-1α axis. These findings also suggest that fucoidan could potentially be used as a therapeutic agent for PD.


Assuntos
1-Metil-4-fenilpiridínio/farmacologia , Morte Celular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Neurônios/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Polissacarídeos/farmacologia , Adenilato Quinase/metabolismo , Linhagem Celular Tumoral , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Neurônios/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo
2.
Biomed Pharmacother ; 117: 109083, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387169

RESUMO

BACKGROUND: Mitochondrial dysfunction is an important mechanism of non-alcoholic fatty liver disease (NAFLD). Developing mitochondrial regulators/nutrients from natural products to remedy mitochondrial dysfunction represent attractive strategies for NAFLD therapy. In China, Polygonatum kingianum (PK) has been used as a herb and food nutrient for centuries. So far, studies in which the effects of PK on NAFLD are evaluated are lacking. Our study aims at identifying the effects and mechanism of action of PK on NAFLD based on mitochondrial regulation. METHODS: A NAFLD rat model was induced by a high-fat diet (HFD) and rats were intragastrically given PK (1, 2 and 4 g/kg) for 14 weeks. Changes in body weight, food intake, histological parameters, organ indexes, biochemical parameters and mitochondrial indicators involved in oxidative stress, energy metabolism, fatty acid metabolism, and apoptosis were investigated. RESULTS: PK significantly inhibited the HFD-induced increase of alanine transaminase, aspartate transaminase, total cholesterol (TC), and low density lipoprotein cholesterol in serum, and TC and triglyceride in the liver. In addition, PK reduced high density lipoprotein cholesterol and liver enlargement without affecting food intake. PK also remarkably inhibited the HFD-induced increase of malondialdehyde and the reduction of superoxide dismutase, glutathione peroxidase, ATP synthase, and complex I and II, in mitochondria. Moreover, mRNA expression of carnitine palmitoyl transferase-1 and uncoupling protein-2 was significantly up-regulated and down-regulated after PK treatment, respectively. Finally, PK notably inhibited the HFD-induced increase of caspase 9, caspase 3 and Bax expression in hepatocytes, and the decrease of expression of Bcl-2 in hepatocytes and cytchrome c in mitochondria. CONCLUSION: PK alleviated HFD-induced NAFLD by promoting mitochondrial functions. Thus, PK may be useful mitochondrial regulators/nutrients to remedy mitochondrial dysfunction and alleviate NAFLD.


Assuntos
Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Preparações de Plantas/farmacologia , Polygonatum/química , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Caspases/metabolismo , China , Dieta Hiperlipídica/efeitos adversos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Triglicerídeos/metabolismo , Regulação para Cima/efeitos dos fármacos
3.
Mar Drugs ; 17(8)2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31357588

RESUMO

Toxicity of particulate matter (PM) towards the epidermis has been well established in many epidemiological studies. It is manifested in cancer, aging, and skin damage. In this study, we aimed to show the mechanism underlying the protective effects of eckol, a phlorotannin isolated from brown seaweed, on human HaCaT keratinocytes against PM2.5-induced cell damage. First, to elucidate the underlying mechanism of toxicity of PM2.5, we checked the reactive oxygen species (ROS) level, which contributed significantly to cell damage. Experimental data indicate that excessive ROS caused damage to lipids, proteins, and DNA and induced mitochondrial dysfunction. Furthermore, eckol (30 µM) decreased ROS generation, ensuring the stability of molecules, and maintaining a steady mitochondrial state. The western blot analysis showed that PM2.5 promoted apoptosis-related protein levels and activated MAPK signaling pathway, whereas eckol protected cells from apoptosis by inhibiting MAPK signaling pathway. This was further reinforced by detailed investigations using MAPK inhibitors. Thus, our results demonstrated that inhibition of PM2.5-induced cell apoptosis by eckol was through MAPK signaling pathway. In conclusion, eckol could protect skin HaCaT cells from PM2.5-induced apoptosis via inhibiting ROS generation.


Assuntos
Dioxinas/farmacologia , Queratinócitos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Material Particulado/farmacologia , Pele/diagnóstico por imagem , Apoptose/efeitos dos fármacos , Linhagem Celular , Humanos , Queratinócitos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Alga Marinha/química , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo
4.
Life Sci ; 231: 116538, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176776

RESUMO

Apoptosis is a complicated process that involves activation of a series of intracellular signaling. Tissue injuries from diabetes mellitus mostly occur as a consequence of higher rate of apoptosis process due to activation of a series of molecular mechanisms. Several classes of anti-hyperglycaemic agents have been developed which could potentially modulate the apoptotic process resulting in fewer tissue damages. Novel types of anti-hyperglycaemic medications such as sodium glucose cotransporters-2 inhibitors, glucagon like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have shown to provide potent anti-hyperglycaemic effects, but their influences on diabetes-induced apoptotic injuries is largely unknown. Therefore, in the current study, we reviewed the published data about the possible effects of these anti-hyperglycaemic agents on apoptosis in diabetic milieu as well as in cancer cells.


Assuntos
Apoptose/efeitos dos fármacos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Glicemia/efeitos dos fármacos , Surdez/tratamento farmacológico , Surdez/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/agonistas , Humanos , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
5.
Int Rev Neurobiol ; 145: 83-126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31208528

RESUMO

Several first-line chemotherapeutic agents, including taxanes, platinum agents and proteasome inhibitors, are associated with the dose-limiting side effect of chemotherapy-induced peripheral neuropathy (CIPN). CIPN predominantly manifests as sensory symptoms, which are likely due to drug accumulation within peripheral nervous tissues rather than the central nervous system. No treatment is currently available to prevent or reverse CIPN. The causal mechanisms underlying CIPN are not yet fully understood. Mitochondrial dysfunction has emerged as a major factor contributing to the development and maintenance of CIPN. This chapter will provide an overview of both clinical and preclinical data supporting this hypothesis. We will review the studies reporting the nature of mitochondrial dysfunction evoked by chemotherapy in terms of changes in mitochondrial morphology, bioenergetics and reactive oxygen species (ROS) generation. Furthermore, we will discuss the in vivo effects of pharmacological interventions that counteract chemotherapy-evoked mitochondrial dysfunction and ameliorate pain-like behavior.


Assuntos
Antineoplásicos/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Metabolismo Energético/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Espécies Reativas de Oxigênio/metabolismo
6.
Iran J Kidney Dis ; 13(2): 74-86, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30988244

RESUMO

Mitochondrial dysfunction, apoptosis and oxidative stress, are the interrelated events underlining the pathology of  numerous diseases including cardiovascular, neurologic, and metabolic disorders. Due to playing a critical role in glucose and fatty acids' metabolism, L-carnitine probably has the potential to adjust these unfavorable events. The present review has evolved based on existing literature that investigated the mechanisms of L-carnitine and its derivatives based mitochondrial dysfunction, oxidative stress, and apoptosis related modulation. The released studies have been searched with the databases including Google Scholar, Scopus, and PubMed out of which overall 76 full-length articles have been chosen and recruited in this review. L-carnitine exerts protective effects against these cellular events in several manners including the maintenance of mitochondrial functions and decreasing the production of  reactive oxygen species at different points. In clinical setting, these effects could be applied to treat a variety of associated diseases.


Assuntos
Apoptose/efeitos dos fármacos , Carnitina/farmacologia , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Humanos , Mitocôndrias/patologia , Doenças Mitocondriais/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo
7.
Neurochem Res ; 44(7): 1703-1714, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30989480

RESUMO

Mitochondrial dysfunction has been proposed to be one of the earliest triggering events in isoflurane-induced neuronal damage. Lidocaine has been demonstrated to attenuate the impairment of cognition in aged rats induced by isoflurane in our previous study. In this study, we hypothesized that lidocaine could attenuate isoflurane anesthesia-induced cognitive impairment by reducing mitochondrial damage. H4 human neuroglioma cells and 18-month-old male Fischer 344 rats were exposed to isoflurane or isoflurane plus lidocaine. Cognitive function was tested at 14 days after treatment by the Barnes Maze test in male Fischer 344 rats. Morphology was observed under electron microscope, and mitochondrial transmembrane potential, electron transfer chain (ETC) enzyme activity, complex-I-IV activity, immunofluorescence and flow cytometry of annexin V-FITC binding, TUNEL assay, and Western blot analyses were applied. Lidocaine attenuated cognitive impairment caused by isoflurane in aged Fischer 344 rat. Lidocaine was effective in reducing mitochondrial damage, mitigating the decrease in mitochondrial membrane potential (ΔΨm), reversing isoflurane-induced changes in complex activity in the mitochondrial electron transfer chain and inhibiting the apoptotic activities induced by isoflurane in H4 cells and Fischer 344 rats. Additionally, lidocaine suppressed the ratio of Bax (the apoptosis-promoting protein) to Bcl-2 (the apoptosis-inhibiting protein) caused by isoflurane in H4 cells. Lidocaine proved effective in attenuating isoflurane-induced POCD by reducing mitochondrial damage.


Assuntos
Anestésicos/uso terapêutico , Disfunção Cognitiva/prevenção & controle , Lidocaína/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Anestésicos/administração & dosagem , Anestésicos Inalatórios , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Hipocampo/patologia , Humanos , Injeções Intravenosas , Isoflurano , Lidocaína/administração & dosagem , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/patologia , Doenças Mitocondriais/induzido quimicamente , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Endogâmicos F344 , Proteína X Associada a bcl-2/metabolismo
8.
BMJ Case Rep ; 12(3)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30936349

RESUMO

Mutations in the nuclear POLG1 gene compromise the integrity of mitochondrial DNA and show great allelic and clinical heterogeneity. Among adult POLG1-associated mitochondrial disease, the main clinical feature is chronic progressive external ophthalmoplegia. Other related clinical manifestations are sensory or cerebellar ataxia, peripheral neuropathy, myopathy or extrapyramidal symptoms. We report the case of a 72-year-old man who presented with a late onset sensory neuronopathy, chronic progressive external ophthalmoplegia, gait ataxia and parkinsonism. Genetic studies showed a compound heterozygosity of known pathogenic mutations in the POLG1 gene (variant T252I/P587 L in cis configuration in allele 1 and variant R807C in allele 2). Late life presentation highlights that mitochondrial disorders should be considered regardless of age of onset of symptoms.


Assuntos
Antiparkinsonianos/uso terapêutico , Polimerase do DNA Mitocondrial/genética , Levodopa/uso terapêutico , Doenças Mitocondriais/diagnóstico , Oftalmoplegia Externa Progressiva Crônica/diagnóstico , Transtornos Parkinsonianos/fisiopatologia , Idade de Início , Idoso , Blefaroptose , Progressão da Doença , Humanos , Masculino , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Doenças Mitocondriais/fisiopatologia , Oftalmoplegia Externa Progressiva Crônica/tratamento farmacológico , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/etiologia , Transtornos Parkinsonianos/genética , Mutação Puntual/genética , Resultado do Tratamento
9.
PLoS One ; 14(3): e0214250, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30921410

RESUMO

BACKGROUND: Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. METHODS: Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. RESULTS: EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). CONCLUSIONS: These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.


Assuntos
Carbolinas/farmacologia , Epilepsia/tratamento farmacológico , Doenças Mitocondriais/tratamento farmacológico , Ubiquinona/análogos & derivados , Araquidonato 15-Lipoxigenase/metabolismo , Linhagem Celular , Epilepsia/metabolismo , Epilepsia/patologia , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Ubiquinona/farmacologia
10.
Cells ; 8(4)2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925787

RESUMO

Mitochondrial fatty acid oxidation (FAO) and respiratory chain (RC) defects form a large group of inherited monogenic disorders sharing many common clinical and pathophysiological features, including disruption of mitochondrial bioenergetics, but also, for example, oxidative stress and accumulation of noxious metabolites. Interestingly, several transcription factors or co-activators exert transcriptional control on both FAO and RC genes, and can be activated by small molecules, opening to possibly common therapeutic approaches for FAO and RC deficiencies. Here, we review recent data on the potential of various drugs or small molecules targeting pivotal metabolic regulators: peroxisome proliferator activated receptors (PPARs), sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and protein kinase A (PKA)) or interacting with reactive oxygen species (ROS) signaling, to alleviate or to correct inborn FAO or RC deficiencies in cellular or animal models. The possible molecular mechanisms involved, in particular the contribution of mitochondrial biogenesis, are discussed. Applications of these pharmacological approaches as a function of genotype/phenotype are also addressed, which clearly orient toward personalized therapy. Finally, we propose that beyond the identification of individual candidate drugs/molecules, future pharmacological approaches should consider their combination, which could produce additive or synergistic effects that may further enhance their therapeutic potential.


Assuntos
Doenças Genéticas Inatas/tratamento farmacológico , Doenças Genéticas Inatas/patologia , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/patologia , Transdução de Sinais , Animais , Transporte de Elétrons , Metabolismo Energético , Humanos , Oxirredução
11.
EBioMedicine ; 42: 511-523, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30898651

RESUMO

BACKGROUND: The vast majority of mitochondrial disorders have limited the clinical management to palliative care. Rapamycin has emerged as a potential therapeutic drug for mitochondrial diseases since it has shown therapeutic benefits in a few mouse models of mitochondrial disorders. However, the underlying therapeutic mechanism is unclear, the minimal effective dose needs to be defined and whether this therapy can be generally used is unknown. METHODS: We have evaluated whether low and high doses of rapamycin administration may result in therapeutic effects in a mouse model (Coq9R239X) of mitochondrial encephalopathy due to CoQ deficiency. The evaluation involved phenotypic, molecular, image (histopathology and MRI), metabolomics, transcriptomics and bioenergetics analyses. FINDINGS: Low dose of rapamycin induces metabolic changes in liver and transcriptomics modifications in midbrain. The high dose of rapamycin induces further changes in the transcriptomics profile in midbrain due to the general inhibition of mTORC1. However, neither low nor high dose of rapamycin were able to improve the mitochondrial bioenergetics, the brain injuries and the phenotypic characteristics of Coq9R239X mice, resulting in the lack of efficacy for increasing the survival. INTERPRETATION: These results may be due to the lack of microgliosis-derived neuroinflammation, the limitation to induce autophagy, or the need of a functional CoQ-junction. Therefore, the translation of rapamycin therapy into the clinic for patients with mitochondrial disorders requires, at least, the consideration of the particularities of each mitochondrial disease. FUND: Supported by the grants from "Fundación Isabel Gemio - Federación Española de Enfermedades Neuromusculares - Federación FEDER" (TSR-1), the NIH (P01HD080642) and the ERC (Stg-337327).


Assuntos
Doenças Mitocondriais/tratamento farmacológico , Sirolimo/uso terapêutico , Animais , Autofagia , Respiração Celular/efeitos dos fármacos , Respiração Celular/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Metabolômica/métodos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/etiologia , Encefalomiopatias Mitocondriais/tratamento farmacológico , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/metabolismo , Fenótipo , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/farmacocinética , Resultado do Tratamento , Ubiquinona/análogos & derivados , Ubiquinona/genética , Ubiquinona/metabolismo
12.
Int J Biochem Cell Biol ; 110: 140-142, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30885675

RESUMO

Some mechanisms of cellular stress, aging, and apoptosis are related to proteolysis. With respect to ClpP, little is known about the mechanical manner in which the substrate is hydrolyzed in and released from the degradation chamber. Furthermore, what would be the real influence of ClpP in mammalian UPRmt?


Assuntos
Endopeptidase Clp/metabolismo , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/enzimologia , Terapia de Alvo Molecular/métodos , Proteólise/efeitos dos fármacos , Animais , Humanos , Doenças Mitocondriais/metabolismo
14.
Biomed Pharmacother ; 111: 1438-1446, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841459

RESUMO

Mitochondria play an important role in cell life and in the regulation of cell death. In addition, mitochondrial dysfunction contributes to a wide range of neuropathologies. The nucleoside Guanosine (GUO) is an endogenous molecule, presenting antioxidant properties, possibly due to its direct scavenging ability and/or from its capacity to activate the antioxidant defense system. GUO demonstrate a neuroprotective effect due to the modulation of the glutamatergic system and maintenance of the redox system. Thus, considering the few studies focused on the direct effects of GUO on mitochondrial bioenergetics, we designed a study to evaluate the in vitro effects of GUO on rat mitochondrial function, as well as against Ca2+-induced impairment. Our results indicate that GUO prevented mitochondrial dysfunction induced by Ca2+ misbalance, once GUO was able to reduce mitochondrial swelling in the presence of Ca2+, as well as ROS production and hydrogen peroxide levels, and to increase manganese superoxide dismutase activity, oxidative phosphorylation and tricarboxylic acid cycle activities. Our study indicates for the first time that GUO could direct prevent the mitochondrial damage induced by Ca2+ and that these effects were not related to its scavenging properties. Our data indicates that GUO could be included as a new pharmacological strategy for diseases linked to mitochondrial dysfunction.


Assuntos
Cálcio/metabolismo , Guanosina/farmacologia , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Antioxidantes/farmacologia , Ciclo do Ácido Cítrico/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Masculino , Mitocôndrias/metabolismo , Oxirredução/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
15.
Biomed Pharmacother ; 111: 901-908, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841469

RESUMO

AIMS: Bisphenol A (BPA) can induce intestinal epithelial cell barrier dysfunction; however, its effects on the intestinal mucus barrier remain unclear. We used LS174T cells as a model to investigate the effects of BPA on the functions of intestinal goblet cells. MAIN METHODS: This study used CCK-8, flow cytometry, ELISA and real-time PCR to investigate the effects of BPA on mitochondrial dynamics, oxidative stress and apoptosis in goblet cells. In addition, mucin synthesis and secretion were evaluated using PAS staining and a PAS assay, respectively. KEY FINDINGS: Our results indicate that BPA reduced cell viability in a time- and concentration-dependent manner. BPA induced mitochondrial dysfunction, as indicated by the depolarization of the mitochondrial membrane potential, inhibition of mitochondrial respiratory chain complex enzyme activity and reduction of ATP production. Moreover, BPA caused oxidative stress by significantly increasing the accumulation of ROS, as well as oxidative stress products, and reducing the antioxidant capacity. Furthermore, BPA induced intestinal goblet cell apoptosis, accompanied by increased DNA fragmentation, caspase-3, -8, -9,-10 gene expression and enzyme activity. Additionally, BPA inhibited the synthesis and secretion of mucin 2. SIGNIFICANCE: Our data suggest that BPA affected the secretory function of intestinal goblet cells by inducing mitochondrial dysfunction, oxidative stress, and apoptosis.


Assuntos
Compostos Benzidrílicos/farmacologia , Células Caliciformes/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Mucina-2/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Trifosfato de Adenosina/metabolismo , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Células Caliciformes/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Espécies Reativas de Oxigênio/metabolismo
16.
J Neurol ; 266(4): 953-959, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30710167

RESUMO

Muscle pain may be part of many neuromuscular disorders including myopathies, peripheral neuropathies and lower motor neuron diseases. Although it has been reported also in mitochondrial diseases (MD), no extensive studies in this group of diseases have been performed so far. We reviewed clinical data from 1398 patients affected with mitochondrial diseases listed in the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", to assess muscle pain and its features. Muscle pain was present in 164 patients (11.7%). It was commonly observed in subjects with chronic progressive external ophthalmoplegia (cPEO) and with primary myopathy without cPEO, but also-although less frequently-in multisystem phenotypes such as MELAS, MERFF, Kearns Sayre syndrome, NARP, MNGIE and Leigh syndrome. Patients mainly complain of diffuse exercise-related muscle pain, but focal/multifocal and at rest myalgia were often also reported. Muscle pain was more commonly detected in patients with mitochondrial DNA mutations (67.8%) than with nuclear DNA changes (32.2%). Only 34% of the patients showed a good response to drug therapy. Interestingly, patients with nuclear DNA mutations tend to have a better therapeutic response than patients with mtDNA mutations. Muscle pain is present in a significant number of patients with MD, being one of the most common symptoms. Although patients with a myopathic phenotype are more prone to develop muscle pain, this is also observed in patients with a multi system involvement, representing an important and disabling symptom having poor response to current therapy.


Assuntos
Doenças Mitocondriais/epidemiologia , Mialgia/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Doenças Mitocondriais/fisiopatologia , Mialgia/tratamento farmacológico , Mialgia/genética , Mialgia/fisiopatologia , Fenótipo , Prevalência , Estudos Retrospectivos , Adulto Jovem
17.
J Physiol Sci ; 69(3): 489-502, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30771091

RESUMO

An uncontrolled inflammatory response has been implicated in the progression of acute liver failure through poorly understood mechanisms. The aim of our study was to investigate whether suramin attenuates inflammation-mediated hepatocyte apoptosis by modulating mitochondrial homeostasis. Primary hepatocytes were isolated from mice and treated with LPS in vitro in the presence or absence of suramin. Western blotting, immunofluorescence staining, and ELISAs were used to evaluate the mitochondrial stress. The LPS treatment caused hepatocyte death via apoptosis. Interestingly, suramin supplementation attenuated LPS-mediated hepatocyte death by reducing Mst1 expression; the overexpression of Mst1 abolished the anti-apoptotic effects of suramin on LPS-treated hepatocytes. At the molecular level, suramin treatment repressed mitochondrial oxidative stress, sustained mitochondrial dynamics and blocked the caspase-9-mediated mitochondrial apoptosis pathway; these effects of suramin were achieved by reversing Mst1 expression. Furthermore, our study found that suramin modulated Mst1 expression via the JNK signaling pathway. Activation of JNK prevented the suramin-mediated Mst1 downregulation and concomitantly increased hepatocyte apoptosis and mitochondrial dysfunction. Taken together, our results confirmed the anti-apoptotic and anti-inflammatory effects of suramin on LPS-challenged hepatocytes. Suramin sustained hepatocyte viability and attenuated mitochondrial stress via repressing the JNK-Mst1 signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Suramina/farmacologia , Animais , Caspase 9/metabolismo , Regulação para Baixo/efeitos dos fármacos , Feminino , Hepatócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
18.
J Hum Genet ; 64(4): 351-353, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30631120

RESUMO

Since mitochondria are energy-generating micro-organisms, most of the disorders in patients with mitochondrial diseases (mt-disease) are considered secondary to defects in ATP synthesis, although some other factors such as reactive oxygen species may be involved. A simultaneous oral administration of febuxostat and inosine was reported to elevate both hypoxanthine and ATP levels in peripheral blood. Based on those results, we attempted co-administration of febuxostat and inosine in two patients with mitochondrial disease: one patient with mitochondrial cardiomyopathy and the other patient with mitochondrial diabetes. In the former case, brain natriuretic peptide (BNP), which is a specific marker for heart failure, was decreased by 31%, and in the latter case, the insulinogenic index increased 3.1 times, suggesting the favorable action of the treatment. Considering that there is no effective treatment available for this disorder, the present therapy may be quite useful for the management of patients with mitochondrial diseases.


Assuntos
Trifosfato de Adenosina/biossíntese , Mitocôndrias/metabolismo , Doenças Mitocondriais/tratamento farmacológico , Peptídeo Natriurético Encefálico/metabolismo , Idoso de 80 Anos ou mais , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Febuxostat/administração & dosagem , Feminino , Humanos , Hipoxantina/metabolismo , Inosina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Espécies Reativas de Oxigênio/metabolismo
19.
Hum Mol Genet ; 28(11): 1837-1852, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668749

RESUMO

Cysteamine bitartrate is a US Food and Drug Administration-approved therapy for nephropathic cystinosis also postulated to enhance glutathione biosynthesis. We hypothesized this antioxidant effect may reduce oxidative stress in primary mitochondrial respiratory chain (RC) disease, improving cellular viability and organismal health. Here, we systematically evaluated the therapeutic potential of cysteamine bitartrate in RC disease models spanning three evolutionarily distinct species. These pre-clinical studies demonstrated the narrow therapeutic window of cysteamine bitartrate, with toxicity at millimolar levels directly correlating with marked induction of hydrogen peroxide production. Micromolar range cysteamine bitartrate treatment in Caenorhabditis elegans gas-1(fc21) RC complex I (NDUFS2-/-) disease invertebrate worms significantly improved mitochondrial membrane potential and oxidative stress, with corresponding modest improvement in fecundity but not lifespan. At 10 to 100 µm concentrations, cysteamine bitartrate improved multiple RC complex disease FBXL4 human fibroblast survival, and protected both complex I (rotenone) and complex IV (azide) Danio rerio vertebrate zebrafish disease models from brain death. Mechanistic profiling of cysteamine bitartrate effects showed it increases aspartate levels and flux, without increasing total glutathione levels. Transcriptional normalization of broadly dysregulated intermediary metabolic, glutathione, cell defense, DNA, and immune pathways was greater in RC disease human cells than in C. elegans, with similar rescue in both models of downregulated ribosomal and proteasomal pathway expression. Overall, these data suggest cysteamine bitartrate may hold therapeutic potential in RC disease, although not through obvious modulation of total glutathione levels. Careful consideration is required to determine safe and effective cysteamine bitartrate concentrations to further evaluate in clinical trials of human subjects with primary mitochondrial RC disease.


Assuntos
Antioxidantes/farmacologia , Proteínas de Caenorhabditis elegans/genética , Cisteamina/farmacologia , Doenças Mitocondriais/tratamento farmacológico , NADH Desidrogenase/genética , Animais , Morte Encefálica/metabolismo , Morte Encefálica/patologia , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Relação Dose-Resposta a Droga , Transporte de Elétrons/efeitos dos fármacos , Proteínas F-Box/genética , Fertilidade/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Glutationa/genética , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Estresse Oxidativo/efeitos dos fármacos , Ubiquitina-Proteína Ligases/genética , Peixe-Zebra/genética
20.
Nat Commun ; 10(1): 38, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604764

RESUMO

Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4ß7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.


Assuntos
Colite Ulcerativa/genética , Genes Mitocondriais/genética , Mucosa Intestinal/metabolismo , Doenças Mitocondriais/genética , Transcriptoma/genética , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Criança , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Fezes/microbiologia , Feminino , Perfilação da Expressão Gênica , Glucocorticoides/uso terapêutico , Humanos , Integrinas/antagonistas & inibidores , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Mesalamina/uso terapêutico , Microbiota , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/microbiologia , Doenças Mitocondriais/patologia , Medicina de Precisão/métodos , Estudos Prospectivos , Reto/metabolismo , Reto/microbiologia , Reto/patologia , Indução de Remissão/métodos , Análise de Sequência de RNA , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
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