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1.
Adv Exp Med Biol ; 1131: 747-770, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646533

RESUMO

The pioneering work of Richard Altman on the presence of mitochondria in cells set in motion a field of research dedicated to uncovering the secrets of the mitochondria. Despite limitations in studying the structure and function of the mitochondria, advances in our understanding of this organelle prompted the development of potential treatments for various diseases, from neurodegenerative conditions to muscular dystrophy and cancer. As the powerhouses of the cell, the mitochondria represent the essence of cellular life and as such, a selective advantage for cancer cells. Much of the function of the mitochondria relies on Ca2+ homeostasis and the presence of effective Ca2+ signaling to maintain the balance between mitochondrial function and dysfunction and subsequently, cell survival. Ca2+ regulates the mitochondrial respiration rate which in turn increases ATP synthesis, but too much Ca2+ can also trigger the mitochondrial apoptosis pathway; however, cancer cells have evolved mechanisms to modulate mitochondrial Ca2+ influx and efflux in order to sustain their metabolic demand and ensure their survival. Therefore, targeting the mitochondrial Ca2+ signaling involved in the bioenergetic and apoptotic pathways could serve as potential approaches to treat cancer patients. This chapter will review the role of Ca2+ signaling in mediating the function of the mitochondria and its involvement in health and disease with special focus on the pathophysiology of cancer.


Assuntos
Sinalização do Cálcio , Cálcio , Mitocôndrias , Neoplasias , Apoptose , Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Homeostase , Humanos , Mitocôndrias/fisiologia , Neoplasias/fisiopatologia
2.
Adv Exp Med Biol ; 1185: 513-517, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884663

RESUMO

Inherited retinal dystrophies (IRDs) are a broad group of neurodegenerative disorders associated with reduced or deteriorating visual system. In the retina, cells are under constant oxidative stress, leading to elevated reactive oxygen species (ROS) generation that induces mitochondrial dysfunction and alteration of the mitochondrial network. This mitochondrial dysfunction combined with mutations in mitochondrial DNA and nuclear genes makes photoreceptors and retinal ganglion cells more susceptible to cell death. In this minireview, we focus on mitochondrial dynamics and their contribution to neuronal degeneration underlying IRDs, with particular attention to Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA), and propose targeting cell resilience and mitochondrial dynamics modulators as potential therapeutic approaches for retinal disorders.


Assuntos
Mitocôndrias/fisiologia , Atrofia Óptica Autossômica Dominante/patologia , Atrofia Óptica Hereditária de Leber/patologia , Estresse Oxidativo , Retina/citologia , DNA Mitocondrial/genética , Humanos
4.
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
5.
EMBO J ; 38(22): e101056, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31609012

RESUMO

The mitochondrial membrane potential (ΔΨm ) is the main driver of oxidative phosphorylation (OXPHOS). The inner mitochondrial membrane (IMM), consisting of cristae and inner boundary membranes (IBM), is considered to carry a uniform ΔΨm . However, sequestration of OXPHOS components in cristae membranes necessitates a re-examination of the equipotential representation of the IMM. We developed an approach to monitor ΔΨm at the resolution of individual cristae. We found that the IMM was divided into segments with distinct ΔΨm , corresponding to cristae and IBM. ΔΨm was higher at cristae compared to IBM. Treatment with oligomycin increased, whereas FCCP decreased, ΔΨm heterogeneity along the IMM. Impairment of cristae structure through deletion of MICOS-complex components or Opa1 diminished this intramitochondrial heterogeneity of ΔΨm . Lastly, we determined that different cristae within the individual mitochondrion can have disparate membrane potentials and that interventions causing acute depolarization may affect some cristae while sparing others. Altogether, our data support a new model in which cristae within the same mitochondrion behave as independent bioenergetic units, preventing the failure of specific cristae from spreading dysfunction to the rest.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Potencial da Membrana Mitocondrial , Mitocôndrias/fisiologia , Membranas Mitocondriais/metabolismo , Mioblastos/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Células Cultivadas , Feminino , Células HeLa , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/metabolismo , Mioblastos/citologia , Fosforilação Oxidativa
6.
BMC Bioinformatics ; 20(1): 494, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604427

RESUMO

BACKGROUND: Literature derived knowledge assemblies have been used as an effective way of representing biological phenomenon and understanding disease etiology in systems biology. These include canonical pathway databases such as KEGG, Reactome and WikiPathways and disease specific network inventories such as causal biological networks database, PD map and NeuroMMSig. The represented knowledge in these resources delineates qualitative information focusing mainly on the causal relationships between biological entities. Genes, the major constituents of knowledge representations, tend to express differentially in different conditions such as cell types, brain regions and disease stages. A classical approach of interpreting a knowledge assembly is to explore gene expression patterns of the individual genes. However, an approach that enables quantification of the overall impact of differentially expressed genes in the corresponding network is still lacking. RESULTS: Using the concept of heat diffusion, we have devised an algorithm that is able to calculate the magnitude of regulation of a biological network using expression datasets. We have demonstrated that molecular mechanisms specific to Alzheimer (AD) and Parkinson Disease (PD) regulate with different intensities across spatial and temporal resolutions. Our approach depicts that the mitochondrial dysfunction in PD is severe in cortex and advanced stages of PD patients. Similarly, we have shown that the intensity of aggregation of neurofibrillary tangles (NFTs) in AD increases as the disease progresses. This finding is in concordance with previous studies that explain the burden of NFTs in stages of AD. CONCLUSIONS: This study is one of the first attempts that enable quantification of mechanisms represented as biological networks. We have been able to quantify the magnitude of regulation of a biological network and illustrate that the magnitudes are different across spatial and temporal resolution.


Assuntos
Algoritmos , Encéfalo/metabolismo , Doenças Neurodegenerativas/metabolismo , Biologia de Sistemas/métodos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Regulação da Expressão Gênica , Humanos , Redes e Vias Metabólicas , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Mapas de Interação de Proteínas , Transdução de Sinais
7.
BMC Plant Biol ; 19(1): 395, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31510917

RESUMO

BACKGROUND: Leaf morphology and spikelet number are two important traits associated with grain yield. To understand how genes coordinating with sink and sources of cereal crops is important for grain yield improvement guidance. Although many researches focus on leaf morphology or grain number in rice, the regulating molecular mechanisms are still unclear. RESULTS: In this study, we identified a prohibitin complex 2α subunit, NAL8, that contributes to multiple developmental process and is required for normal leaf width and spikelet number at the reproductive stage in rice. These results were consistent with the ubiquitous expression pattern of NAL8 gene. We used genetic complementation, CRISPR/Cas9 gene editing system, RNAi gene silenced system and overexpressing system to generate transgenic plants for confirming the fuctions of NAL8. Mutation of NAL8 causes a reduction in the number of plastoglobules and shrunken thylakoids in chloroplasts, resulting in reduced cell division. In addition, the auxin levels in nal8 mutants are higher than in TQ, while the cytokinin levels are lower than in TQ. Moreover, RNA-sequencing and proteomics analysis shows that NAL8 is involved in multiple hormone signaling pathways as well as photosynthesis in chloroplasts and respiration in mitochondria. CONCLUSIONS: Our findings provide new insights into the way that NAL8 functions as a molecular chaperone in regulating plant leaf morphology and spikelet number through its effects on mitochondria and chloroplasts associated with cell division.


Assuntos
Oryza/genética , Proteínas de Plantas/genética , Proteínas Repressoras/genética , Sequência de Aminoácidos , Cloroplastos/fisiologia , Inflorescência/genética , Inflorescência/crescimento & desenvolvimento , Mitocôndrias/fisiologia , Oryza/crescimento & desenvolvimento , Oryza/metabolismo , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Alinhamento de Sequência
8.
Reprod Domest Anim ; 54 Suppl 3: 22-28, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31512320

RESUMO

The biological nature of age-related declines in fertility in males of any species, including stallions, has been elusive. In horses, the economic costs to the breeding industry are frequently extensive. Mitochondrial function in ejaculated sperm, which is essential for sperm motility, is reflected by adenosine triphosphate production, mitochondrial oxidative efficiency and production of reactive oxygen species, and that this balance may become compromised in ageing stallions and during the process of cryopreservation. This presentation will focus on mitochondrial integrity and function as an avenue for understanding the pathophysiology of sperm when undergoing cryopreservation and male ageing. We discuss the importance of understanding the differences and similarities of sperm mitochondria to that of somatic cells regarding structure and mitochondrial biochemistry relating to sperm function. The roles of oxidative phosphorylation and glycolysis in sperm mitochondria are outlined as is the method of determining oxygen consumption and calcium homoeostasis in sperm mitochondria. Further, we outline the role of oxidative stress and reactive oxygen species.


Assuntos
Cavalos/fisiologia , Mitocôndrias/fisiologia , Espermatozoides/fisiologia , Envelhecimento/fisiologia , Animais , Criopreservação/veterinária , Fertilidade/fisiologia , Glicólise , Masculino , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Técnicas de Reprodução Assistida/veterinária , Motilidade Espermática/fisiologia , Espermatozoides/citologia , Espermatozoides/metabolismo
9.
Neurochem Res ; 44(9): 2031-2043, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31410709

RESUMO

As one of the major cell organelles responsible for ATP production, it is important that neurons maintain mitochondria with structural and functional integrity; this is especially true for neurons with high metabolic requirements. When mitochondrial damage occurs, mitochondria are able to maintain a steady state of functioning through molecular and organellar quality control, thus ensuring neuronal function. And when mitochondrial quality control (MQC) fails, mitochondria mediate apoptosis. An apparently key molecule in MQC is the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α). Recent findings have demonstrated that upregulation of PGC-1α expression in neurons can modulate MQC to prevent mitochondrial dysfunction in certain in vivo and in vitro aging or neurodegenerative encephalopathy models, such as Huntington's disease, Alzheimer's disease, and Parkinson's disease. Because mitochondrial function and quality control disorders are the basis of pathogenesis in almost all neurodegenerative diseases (NDDs), the role of PGC-1α may make it a viable entry point for the treatment of such diseases. This review focuses on multi-level MQC in neurons, as well as the regulation of MQC by PGC-1α in these major NDDs.


Assuntos
Doença de Alzheimer/fisiopatologia , Doença de Huntington/fisiopatologia , Mitocôndrias/fisiologia , Doença de Parkinson/fisiopatologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Animais , Humanos , Neurônios/fisiologia , Biogênese de Organelas
10.
Hum Exp Toxicol ; 38(11): 1266-1274, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31446784

RESUMO

Cyclophosphamide (CYP) and methotrexate (MTX) have been evaluated for their ability to induce toxicity in human peripheral blood lymphocytes (PBLs) and the protective role of mitochondrial and lysosomal stabilizing agents. The potential toxicity effects of CYP and MTX were measured in vitro by cellular parameters assays such as cellular viability, reactive oxygen species (ROS) formation, mitochondrial membrane permeability transition (mitochondrial membrane potential (MMP)) collapse, lysosomal membrane damage, intracellular reduced glutathione (GSH), extracellular oxidized glutathione (GSSG), and lipid peroxidation. Separately, human lymphocytes were treated with concentrations of 0.1, 0.2, 0.4, 0.8, and 1.6 ng/mL for CYP and 1, 2, 5, and 10 µg/mL for MTX for 6 h. Statistical evaluations showed that CYP and MTX significantly decreased the cell viability at the three highest concentrations when compared with both the negative and solvent controls. In addition, CYP and MTX were significantly induced ROS formation, MMP collapse, lysosomal membrane damage, lipid peroxidation, and GSH depletion compared with the controls. Mitochondrial and lysosomal protective agents like cyclosporine A and chloroquine, respectively, decreased cytotoxicity and oxidative stress induced by CYP and MTX. The present results indicate that CYP and MTX are toxic to human PBLs and their toxicity could be ameliorated by mitochondrial and lysosomal protective agents.


Assuntos
Antineoplásicos/toxicidade , Ciclofosfamida/toxicidade , Imunossupressores/toxicidade , Linfócitos/efeitos dos fármacos , Metotrexato/toxicidade , Substâncias Protetoras/farmacologia , Adolescente , Adulto , Hidroxitolueno Butilado/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cloroquina/farmacologia , Ciclosporina/farmacologia , Glutationa/metabolismo , Humanos , Linfócitos/metabolismo , Lisossomos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Adulto Jovem
11.
Sheng Li Xue Bao ; 71(4): 625-636, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31440760

RESUMO

Mitochondrial dynamics, involving mitochondrial fusion, fission and autophagy, plays an important role in maintaining cellular physiological function and homeostasis. Mitochondria are the "energy plant" of human body, so the changes of mitochondrial fusion, division and autophagy are important for cell respiration and energy production. On the other hand, energy metabolism influences mitochondrial dynamics in turn. This paper reviewed the recent advances in studies on the relationship between energy metabolism and the proteins regulating mitochondrial fusion, fission and autophagy. The association of mitochondrial dynamics with electron chain complex expression, oxidative phosphorylation and ATP synthesis upon exercise intervention will provide theoretical references for the further studies in sports training and disease intervention.


Assuntos
Autofagia , Metabolismo Energético , Exercício , Mitocôndrias/fisiologia , Dinâmica Mitocondrial , Trifosfato de Adenosina/biossíntese , Humanos , Proteínas Mitocondriais/metabolismo
12.
Adv Exp Med Biol ; 1158: 183-196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452141

RESUMO

The term 'mitochondrial dynamics' is commonly used to refer to ongoing fusion and fission of mitochondrial structures within a living cell. A growing number of diseases, from Charcot Marie Tooth Type 2a neuropathies to cancer, is known to be associated with the dysregulation of mitochondrial dynamics, leading to irregularities of mitochondrial network morphology that are associated with aberrant metabolism and cellular dysfunction. Studying these phenomena, and potential pharmacological interventions to correct them, in cultured cells is a powerful approach to developing treatments or cures. Appropriately designed experiments and quantitative approaches for characterizing mitochondrial morphology and function are essential for furthering our understanding. In this chapter, we discuss the importance of cell incubation conditions, choices around imaging modalities, and data analysis tools with respect to experimental outcomes and the interpretation of results from studies of mitochondrial dynamics. We focus primarily on the quantitative analysis of mitochondrial morphology, providing an overview of the available tools and approaches currently being used and discussing some of the strengths and weaknesses associated with each. Finally, we discuss how the ongoing development of imaging and analysis tools continues to improve our ability to study normal and aberrant mitochondrial physiology in vitro and in vivo.


Assuntos
Mitocôndrias , Dinâmica Mitocondrial , Proteínas Mitocondriais , Técnicas de Cultura de Células , Linhagem Celular , Doença de Charcot-Marie-Tooth/fisiopatologia , Humanos , Mitocôndrias/patologia , Mitocôndrias/fisiologia , Dinâmica Mitocondrial/fisiologia , Proteínas Mitocondriais/metabolismo , Neoplasias/fisiopatologia
13.
J Therm Biol ; 84: 236-244, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31466759

RESUMO

The present study aimed to analyze the time- and temperature-responses of boar sperm and clarify the mechanism underlying the protective effects of L-arginine on heat-induced low sperm motility. Mature boar sperm was used to evaluate the effects of temperature, exposure time, L-arginine level and their interactions on sperm motility, respectively. Results showed increasing exposure time resulted in the decreased total motility and rate of rapid progressive sperm, and the increased rates of the immotile sperm and the sperm shaking in place at 38 and 39 °C, respectively (P < 0.05). L-arginine supplementation at the dose of 1.0 mM increased total motility and decreased rate of immotile sperm (P < 0.05). Heat at 39 °C decreased total motile and rate of rapid progressive sperm (P < 0.05), increased the level of sperm reactive oxygen species (ROS) (P < 0.05), reduced mitochondrial membrane potential (ΔΨm), ATP content and the activities of mitochondrial respiratory chain complexes (MRCC) ΙΙΙ and V (P < 0.05), which were attenuated by L-arginine supplementation. There were significant increases in the relative mRNA expression of nuclear respiratory factor 1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha in heat-exposed group without L-arginine supplementation. In conclusion, the rising temperatures impacted boar sperm motility in a time-dependent manner. In vitro addition of L-arginine to boar semen had a dose-dependent effect on sperm motility and sperm incubated with 1.0 mM L-arginine showed elevated motility. L-arginine supplementation can ameliorate heat-induced increase in ROS level and decreases in MRCC activities, which further maintain mitochondrial oxidative phosphorylation function, ATP synthesis and boar sperm motility.


Assuntos
Arginina/farmacologia , Temperatura Alta/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Motilidade Espermática/efeitos dos fármacos , Animais , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/fisiologia , Fator 1 Relacionado a NF-E2/genética , Fosforilação Oxidativa , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Espécies Reativas de Oxigênio/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Suínos
14.
In Vitro Cell Dev Biol Anim ; 55(7): 548-558, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313007

RESUMO

Recently, the mean maternal age at first birth has been continuing to increase. The decline in the age-related fertility is due to the reduction in the number and the quality of the oocyte. An elevation in intra-ovarian reactive oxygen species (ROS) is correlated with the increase in maternal age, and the oxidative stress is involved in the decline in oocyte quality. Although ß-carotene, a very effective quencher of ROS, has been found to have the beneficial contribution to the ovarian development and steroidogenesis, it is unknown the effect of ß-carotene on the oocyte development especially oocyte maturation. This investigation aimed to explore the beneficial contribution of ß-carotene on oocyte maturation under oxidative stress and the underlying mechanism. We found that the oxidative stress induced by ROS reagent Rosup inhibited oocyte development/maturation and parthenogenetic activation which could be dramatically rescued by ß-carotene (57.1 ± 4.7% vs 78.9 ± 3.8%; p < 0.05) in vitro. The underlying mechanisms include that ß-carotene not only reduces ROS formation and cell apoptosis, but also it can restore actin expression, cortical granule-free domain (CGFD) formation, mitochondria homogeneous distribution, and nuclear maturation. The data suggest that ß-carotene acts as a potential antioxidant in the oocyte. Therefore, the findings from this investigation provide the fundamental 7knowledge for using ß-carotene as an antioxidant to improve the oocyte quality and even the ovarian function.


Assuntos
Antioxidantes/farmacologia , Oócitos/citologia , Oogênese/fisiologia , Estresse Oxidativo/efeitos dos fármacos , beta Caroteno/farmacologia , Actinas/biossíntese , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Feminino , Idade Materna , Camundongos , Mitocôndrias/fisiologia , Espécies Reativas de Oxigênio/metabolismo
15.
Food Chem Toxicol ; 132: 110672, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31306686

RESUMO

The aim of this study was to evaluate the inhibitory potential of aqueous extracts from coffee silverskin (CSE) and husk (CHE) and their main phenolics on adipogenesis, obesity-related inflammation, mitochondrial dysfunction, and insulin resistance, in vitro. Coffee by-products extracts (31-500 µg mL-1) and pure phenolics (100 µmol L-1) reduced lipid accumulation and increased mitochondrial activity in 3T3-L1 adipocytes. Also reduced the expression of inducible nitric oxide synthase and cyclooxygenase-2 and diminished secretion of pro-inflammatory factors in LPS-stimulated RAW2643.7 macrophages. Cytokine release diminished (tumor necrosis factor α: 23-57%; monocyte chemoattractant protein 1: 42-60%; interleukin-6: 30-39%) and adiponectin increased (7-13- fold) in adipocytes treated with macrophage-conditioned media. ROS scavenging and activation of peroxisome proliferator-activated receptor γ coactivator 1-α pathway counteracted mitochondrial dysfunction. Increases in insulin receptor (1.4 to 4-fold), phosphoinositide 3-kinase (2 to 3-fold) and protein kinase B (1.3 to 3-fold) phosphorylation, in conjunction with a decrease in serine phosphorylation of insulin receptor substrate 1, evoked glucose transporter 4 translocation (8-15-fold) and glucose uptake (44-85%). CSE and CHE phenolics inhibited adipogenesis and elicited adipocytes browning. Suppressing macrophages-adipocytes interaction alleviated inflammation-triggered mitochondrial dysfunction and insulin resistance. CSE and CHE are beneficial in reducing adipogenesis and inflammation-related disorders.


Assuntos
Adipogenia/efeitos dos fármacos , Café/química , Inflamação/patologia , Resistência à Insulina , Mitocôndrias/efeitos dos fármacos , Fenóis/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Meios de Cultivo Condicionados , Camundongos , Mitocôndrias/fisiologia , Fenóis/isolamento & purificação , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo
16.
Eur J Pharm Sci ; 137: 104984, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276740

RESUMO

Zinc pyrithione (ZPT), a zinc coordination complex, is used as an antimicrobial agent. This study investigated the molecular mechanisms underlying ZPT-induced spermatozoa immobilization by examining plasma membrane integrity, mitochondrial dysfunction, and the cAMP/PKA signaling pathway response. ZPT inhibited spermatozoa motility and movement patterns in a concentration-dependent manner. The 100% effective concentration (EC100) and median effective concentration (EC50) at which ZPT-induced spermatozoa immobilization at 20 s were 40 µmol/L and 16.19 µmol/L, respectively. ZPT did not significantly disrupt spermatozoa plasma membranes, but it exerted a strong and significant effect on the depolarization of mitochondria. In addition, ZPT exposure induced intracellular H+ accumulation and Ca2+ dissipation in spermatozoa, accompanied by suppression of the cAMP/PKA signaling pathway. Thus, ZPT induces spermatozoa immobilization without significant plasma membrane injury and so could be a candidate microbicidal spermicide.


Assuntos
Anti-Infecciosos/toxicidade , Compostos Organometálicos/toxicidade , Piridinas/toxicidade , Motilidade Espermática/efeitos dos fármacos , Espermicidas/toxicidade , Espermatozoides/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Cálcio/metabolismo , Membrana Celular/efeitos dos fármacos , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Humanos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Mitocôndrias/ultraestrutura , Transdução de Sinais/efeitos dos fármacos , Espermatozoides/fisiologia , Espermatozoides/ultraestrutura
17.
Cells ; 8(7)2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284394

RESUMO

Mitochondria are best known as the sites for production of respiratory ATP and are essential for eukaryotic life. They have their own genome but the great majority of the mitochondrial proteins are encoded by the nuclear genome and are imported into the mitochondria. The mitochondria participate in critical central metabolic pathways and they are fully integrated into the intracellular signalling networks that regulate diverse cellular functions. It is not surprising then that mitochondrial defects or dysregulation have emerged as having key roles in ageing and in the cytopathological mechanisms underlying cancer, neurodegenerative and other diseases. This special issue contains 12 publications-nine review articles and three original research articles. They cover diverse areas of mitochondrial biology and function and how defects in these areas can lead to disease. In addition, the articles in this issue highlight how model organisms have contributed to our understanding of these processes.


Assuntos
Mitocôndrias/fisiologia , Envelhecimento/fisiologia , Doença , Saúde , Humanos , Redes e Vias Metabólicas/fisiologia , Mitocôndrias/patologia
18.
J Steroid Biochem Mol Biol ; 194: 105432, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31344443

RESUMO

Oxidative stress and mitochondrial dysfunction contribute to the pathogenesis of neurodegenerative diseases and favor lipid peroxidation, leading to increased levels of 7ß-hydroxycholesterol (7ß-OHC) which induces oxiapoptophagy (OXIdative stress, APOPTOsis, autoPHAGY). The cytoprotective effects of dimethylfumarate (DMF), used in the treatment of relapsing remitting multiple sclerosis and of monomethylfumarate (MMF), its main metabolite, were evaluated on murine oligodendrocytes 158 N exposed to 7ß-OHC (50 µM, 24 h) with or without DMF or MMF (25 µM). The activity of 7ß-OHC in the presence or absence DMF or MMF was evaluated on several parameters: cell adhesion; plasma membrane integrity measured with propidium iodide (PI), trypan blue and fluoresceine diacetate (FDA) assays; LDH activity; antioxidant enzyme activities (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)); generation of lipid peroxidation products (malondialdehyde (MDA), conjugated dienes (CDs)) and protein oxidation products (carbonylated proteins (CPs)); reactive oxygen species (ROS) overproduction conducted with DHE and DHR123. The effect on mitochondria was determined with complementary criteria: measurement of succinate dehydrogenase activity, evaluation of mitochondrial potential (ΔΨm) and mitochondrial superoxide anions (O2●-) production using DiOC6(3) and MitoSOX, respectively; quantification of mitochondrial mass with Mitotracker Red, and of cardiolipins and organic acids. The effects on mitochondrial and peroxisomal ultrastructure were determined by transmission electron microscopy. Intracellular sterol and fatty acid profiles were determined. Apoptosis and autophagy were characterized by staining with Hoechst 33,342, Giemsa and acridine orange, and with antibodies raised against caspase-3 and LC3. DMF and MMF attenuate 7ß-OHC-induced cytotoxicity: cell growth inhibition; decreased cell viability; mitochondrial dysfunction (decrease of succinate dehydrogenase activity, loss of ΔΨm, increase of mitochondrial O2●- production, alteration of the tricarboxilic acid (TCA) cycle, and cardiolipins content); oxidative stress induction (ROS overproduction, alteration of GPx, CAT, and SOD activities, increased levels of MDA, CDs, and CPs); changes in fatty acid and cholesterol metabolism; and cell death induction (caspase-3 cleavage, activation of LC3-I in LC3-II). Ultrastructural alterations of mitochondria and peroxisomes were prevented. These results demonstrate that DMF and MMF prevent major dysfunctions associated with neurodegenerative diseases: oxidative stress, mitochondrial dysfunction, apoptosis and autophagy.


Assuntos
Fumarato de Dimetilo/farmacologia , Fumaratos/farmacologia , Maleatos/farmacologia , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular , Colesterol/metabolismo , Hidroxicolesteróis/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Mitocôndrias/ultraestrutura , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Estresse Oxidativo/efeitos dos fármacos
19.
Int Immunopharmacol ; 74: 105649, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31185450

RESUMO

Rheumatoid arthritis is a common autoimmune disease primarily characterized by chronic inflammation, the formation of an invasive pannus, and destruction of the joints. In the present study, we employed real-time PCR and western blot analysis to investigate the role of dulaglutide in human fibroblast-like synoviocytes (FLS). The results of our study show that dulaglutide exerted a powerful protective effect by rescuing mitochondrial membrane potential, inhibiting the production of NOX-4, and abrogating TNF-α-induced downregulation of the antioxidant GSH. Our findings demonstrate that dulaglutide significantly ameliorated the expression of proinflammatory cytokines and chemokines including IL-1ß, IL-6, MCP-1, and HMGB-1. Matrix metalloproteinases mediate cartilage destruction, thereby aiding in pannus formation. Our findings indicate that dulaglutide treatment significantly downregulated the expression of MMP-3 and MMP-13, two crucial degradative enzymes. Importantly, the results of our study demonstrate that the beneficial effects of dulaglutide are mediated through the JNK/NF-κB signaling pathway, which has been suggested as a potential treatment target against RA. Taken together, the results of this study show that dulaglutide may exert significant protective effects against the progression of RA induced by TNF-α.


Assuntos
Anti-Inflamatórios/farmacologia , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Sinoviócitos/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Fibroblastos , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sinoviócitos/metabolismo
20.
Adv Gerontol ; 32(1-2): 29-37, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31228365

RESUMO

The effect of chromic continuous consumption of 5 and 10% ethyl alcohol over 6 months on the respiratory function and oxidant/antioxidant status of rats' cardiac mitochondria of different gender and age has been studied. A decrease in oxygen consumption rate by cardiomyocyte mitochondria in the metabolic conditions V2, V3, V4 according to Chance involving activation of respiratory chain complexes I, I+II and II in elderly (24-month old) animals as compared to young (11-month old) animals. As the rats were ageing, the concentration of lipid peroxidation (LPO) products (malondialdehyde) was increasing, while the activity of antioxidant enzymes (superoxide dismutase and glutathione peroxidase) was decreasing in cardiomyocyte mitochondria. Chronic alcoholization of 24-month old rats of both genders resulted in a more pronounced decline in the respiratory function activity of cardiac mitochondria, uncoupling of respiration and oxidative phosporylation, reduced activity of antiradical protection enzymes and increased LPO products as compared to younger rats.


Assuntos
Intoxicação Alcoólica , Mitocôndrias , Estresse Oxidativo , Animais , Antioxidantes , Feminino , Glutationa , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos , Masculino , Mitocôndrias/fisiologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
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