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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(8): 707-713, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31638568

RESUMO

Objective To investigate the relationship between mitochondria and systemic sclerosis (SSc) by analyzing the expression of mitochondrial function-related genes in skin biopsy samples from patients with SSc. Methods Gene chip expression profile of SSc skin biopsy in Gene Expression Omnibus (GEO) database was used, and differently expressed genes (DEGs) related to mitochondrial function were identified by t test and fold change (FC). What's more, functional annotation, functional enrichment and protein interaction network analysis were performed. Results A total of 422 significant DEGs were identified between the SSc group and the normal group. Among them, 23 DEGs were mitochondrial function-related genes. Functional annotation and enrichment analysis of 23 DEGs revealed that abnormally expressed mitochondrial function-related genes mainly affected several biological processes, such as mitochondrial energy supply and cell metabolism. Conclusion The dysregulation of mitochondrial function-related genes in SSc patients affects the function of mitochondria, suggesting that the abnormality of mitochondrial function may be associated with the development of SSc.


Assuntos
Biologia Computacional , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Mitocôndrias , Escleroderma Sistêmico , Perfilação da Expressão Gênica , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/fisiopatologia , Transcriptoma
2.
Toxicol Lett ; 316: 60-72, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520699

RESUMO

Cholestasis is a significant decrease in bile flow. The liver is the primary organ affected by cholestasis. Chronic cholestasis could entail to tissue fibrotic changes and liver cirrhosis. Other organs, including heart, kidneys, nervous system, skeletal muscles, as well as the reproductive system, might also be affected during cholestasis. Although the cholestasis-associated pathological and biochemical alterations in organs such as liver have been widely investigated, there is little information about complications such as cholestasis-induced reproductive toxicity. The current study aimed to evaluate the pathologic effects of cholestasis on reproductive organs in both male and female animals. Rats underwent bile duct ligation (BDL) surgery. Markers of reproductive toxicity, including serum hormonal changes, tissue histopathological alterations, biomarkers of oxidative stress, and markers of mitochondrial impairment, were evaluated. Increased serum markers of liver injury and elevated level of cytotoxic molecules such as bile acids and bilirubin were evident in BDL animals. On the other hand, the serum level of hormones such as testosterone was suppressed in BDL rats. Significant histopathological alterations were also evident in the testis and ovary of BDL animals. A significant increase in oxidative stress markers, including ROS formation, lipid peroxidation, protein carbonylation, and depleted glutathione and antioxidant reservoirs were also detected in BDL rats. Moreover, mitochondrial depolarization decreased dehydrogenases activity, and depleted ATP content was detected in sperm isolated from the BDL group. These data indicate that cholestasis-associated reproductive toxicity in male and female rats is restrictedly coupled with severe oxidative stress and mitochondrial impairment.


Assuntos
Colestase/metabolismo , Mitocôndrias/metabolismo , Ovário/metabolismo , Estresse Oxidativo , Reprodução , Espermatozoides/metabolismo , Testículo/metabolismo , Animais , Colestase/etiologia , Colestase/fisiopatologia , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Feminino , Ligadura , Peroxidação de Lipídeos , Masculino , Mitocôndrias/patologia , Ovário/patologia , Ovário/fisiopatologia , Carbonilação Proteica , Ratos Sprague-Dawley , Medição de Risco , Testículo/patologia , Testículo/fisiopatologia
3.
Nat Neurosci ; 22(10): 1635-1648, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31551592

RESUMO

In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.


Assuntos
Astrócitos/patologia , Inflamação/patologia , Microglia/patologia , Mitocôndrias/patologia , Degeneração Neural/patologia , Animais , Morte Celular , Dinaminas/genética , Espaço Extracelular , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/genética , Neurônios/patologia , Ratos , Ratos Sprague-Dawley
4.
Adv Exp Med Biol ; 1158: 71-82, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452136

RESUMO

Proteins oxidation by reactive species is implicated in the aetiology or progression of a panoply of disorders and diseases such as neurodegenerative disorders. It is becoming increasingly evident that redox imbalance in the brain mediates neurodegeneration. Free radicals, as reactive species of oxygen (ROS) but also reactive nitrogen species (RNS) and reactive sulfur species (RSS), are generated in vivo from several sources. Within the cell the mitochondria represent the main source of ROS and mitochondrial dysfunction is both the major contributor to oxidative stress (OS) as well its major consequence.To date there are no doubts that a condition of OS added to other factors as mitochondrial damage in mtDNA or mitochondrial respiratory chain, may contribute to trigger or amplify mechanisms leading to neurodegenerative disorders.In this chapter, we aim at illustrate the molecular interplay occurring between mitochondria and OS focusing on Amyotrophic Lateral Sclerosis, describing a phenotypic reprogramming mechanism of mitochondria in complex neurological disorder.


Assuntos
Esclerose Amiotrófica Lateral , Mitocôndrias , Estresse Oxidativo , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/fisiopatologia , DNA Mitocondrial/genética , Humanos , Mitocôndrias/patologia , Espécies Reativas de Nitrogênio , Espécies Reativas de Oxigênio/metabolismo
5.
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
6.
Adv Exp Med Biol ; 1158: 217-246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452143

RESUMO

Mitochondria maintain and express their own genome, referred to as mtDNA, which is required for proper mitochondrial function. While mutations in mtDNA can cause a heterogeneous array of disease phenotypes, there is currently no cure for this collection of diseases. Here, we will cover characteristics of the mitochondrial genome important for understanding the pathology associated with mtDNA mutations, and review recent approaches that are being developed to treat and prevent mtDNA disease. First, we will discuss mitochondrial replacement therapy (MRT), where mitochondria from a healthy donor replace maternal mitochondria harbouring mutant mtDNA. In addition to ethical concerns surrounding this procedure, MRT is only applicable in cases where the mother is known or suspected to carry mtDNA mutations. Thus, there remains a need for other strategies to treat patients with mtDNA disease. To this end, we will also discuss several alternative means to reduce the amount of mutant mtDNA present in cells. Such methods, referred to as heteroplasmy shifting, have proven successful in animal models. In particular, we will focus on the approach of targeting engineered endonucleases to specifically cleave mutant mtDNA. Together, these approaches offer hope to prevent the transmission of mtDNA disease and potentially reduce the impact of mtDNA mutations.


Assuntos
Terapia Genética , Doenças Mitocondriais , Animais , DNA Mitocondrial , Modelos Animais de Doenças , Terapia Genética/tendências , Genoma Mitocondrial , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/terapia , Mutação
7.
Adv Exp Med Biol ; 1158: 257-267, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452145

RESUMO

Mitochondrial disease can arise due to pathogenic sequence variants in the mitochondrial DNA (mtDNA) that prevent cells from meeting their energy demands. Mitochondrial diseases are often fatal and currently there are no treatments directed towards the underlying cause of disease. Pathogenic variants in mtDNA often exist in a state of heteroplasmy, with coexistence of pathogenic and wild type mtDNA. The load of heteroplasmy, defined as the relative amount of pathogenic mtDNA to wild type mtDNA, corresponds to timing and symptom severity. Thus, changing the heteroplasmy load may lead to a shift in disease onset and symptom severity. Here we review techniques aimed at preventing inheritance of pathogenic mtDNA via mitochondrial replacement therapy (MRT) and strategies geared toward shifting of heteroplasmy in individuals with active mitochondrial disease. MRT strategies seek to create embryos with the nuclear genetic makeup of the intended parents and wild type mtDNA from a donor in order to avoid known maternal pathogenic variants. Heteroplasmy shift approaches in patients are of two categories: nuclease dependent and nuclease independent strategies. Despite initial success in mouse models and patient cells, these techniques have not reached clinical use. Translational attempts in this area are urgently needed to improve therapies for a currently untreatable set of disorders.


Assuntos
Terapia Genética , Doenças Mitocondriais , Animais , Núcleo Celular , DNA Mitocondrial/genética , Terapia Genética/tendências , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/terapia
8.
Adv Exp Med Biol ; 1158: 269-277, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452146

RESUMO

Mitochondria play a central role in maintaining normal cellular homeostasis as well as contributing to the pathogenesis of numerous disease states. The advent of CRISPR-Cas9 screening technologies has greatly accelerated the study of mitochondrial biology. In this chapter, we review the various CRISPR-Cas9 screening platforms that are currently available and prior studies that leveraged this technology to identify genes involved in mitochondrial biology in both healthy and disease states. In addition, we discuss the challenges associated with current CRISPR-Cas9 platforms and potential solutions to further enhance this promising technology.


Assuntos
Sistemas CRISPR-Cas , Mitocôndrias , Doenças Mitocondriais , Fenômenos Fisiológicos Celulares/genética , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Pesquisa/tendências
9.
Adv Exp Med Biol ; 1165: 501-524, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399982

RESUMO

Mitochondria are important organelles in eukaryotic cells and perform a variety of biosynthetic and metabolic functions. Many human diseases are closely related to mitochondrial dysfunction. Kidney is an organ with high-energy requirements, which is distributed with a large number of mitochondria. Mitochondrial dysfunction plays a crucial role in the pathogenesis of kidney disease, and studies have shown that mitochondrial dysfunction is involved in the physiological process of renal fibrosis. This review introduced the biogenesis and pathophysiology of mitochondria, illustrated the involvement of mitochondrial dysfunction in renal fibrosis based on various kinds of cells, and finally summarized the latest mitochondria-targeted therapies.


Assuntos
Nefropatias/fisiopatologia , Rim/patologia , Mitocôndrias/patologia , Fibrose , Humanos
11.
Life Sci ; 233: 116684, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351083

RESUMO

Traumatic brain injury (TBI) is a devastating condition that often triggers a sequel of neurological disorders that can last throughout lifespan. From a metabolic viewpoint, the compromising of the energy metabolism of the brain has produced evidence linking the severity of brain injury to the extent of disturbances in the cerebral metabolism. The cerebral metabolic crisis, however, displays that regional heterogeneity varies temporally post-injury. It is important to note that energy generation and mitochondrial function are closely related and interconnected with delayed secondary manifestations of brain injury, including early neuromotor dysfunction, cognitive impairment, and post-traumatic epilepsy (PTE). Given the extent of post-traumatic changes in neuronal function and the possibility of amplifying secondary cascades, different therapies designed to minimize damage and retain/restore cellular function after TBI are currently being studied. One of the possible strategies may be the inclusion of ergogenic compounds, which is a class of supplements that typically includes ingredients used by athletes to enhance their performance. The combination of these compounds offers specific physiological advantages, which include enhanced energy availability/metabolism and improved buffering capacity. However, the literature on their effects in certain biological systems and neurological diseases, such as TBI, has yet to be determined. Thus, the present review aims to discuss the role of ergogenic compounds popularly used in secondary damage induced by this neurological injury. In this narrative review, we also discuss how the results from animal studies can be applied to TBI clinical settings.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Disfunção Cognitiva/tratamento farmacológico , Epilepsia Pós-Traumática/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Doenças Neuromusculares/tratamento farmacológico , Animais , Arginina/farmacologia , Cafeína/farmacologia , Carnitina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Creatina/farmacologia , Metabolismo Energético , Epilepsia Pós-Traumática/etiologia , Epilepsia Pós-Traumática/fisiopatologia , Glutamina/farmacologia , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Neuromusculares/etiologia , Doenças Neuromusculares/fisiopatologia , Taurina/farmacologia
12.
Expert Opin Drug Metab Toxicol ; 15(8): 659-669, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31293190

RESUMO

Introduction: Although the hepatotoxicity of acetaminophen is a well-known problem, the search for reliable biomarker of toxicity is still a current issue as clinical tools are missing to assess patients intoxicated following chronic use, sequential ingestion, use of modified release formulations or in case of delayed arrival to hospital. The need for new specific and robust biomarkers for acetaminophen toxicity has prompted many studies exploring the use of blood levels of acetaminophen derivatives, mitochondrial damage markers, liver cell apoptosis and/or necrosis markers and circulating microRNAs. Areas covered: In this review, we present a concise overview of the most promising biomarkers currently under evaluation including descriptions of their properties with respect to exposure type, APAP specificity, and potential clinical application. In addition, we illustrate the power of new technologies for biomarker research and describe their current application to the field of acetaminophen-induced hepatotoxicity. Expert opinion: Recently the use of extracellular vesicles isolation in combination with omics techniques has opened a new perspective to the field of biomarker research. However, the potential of those new technologies for the prediction and monitoring of hepatic diseases and acetaminophen toxicity has not yet been fully taken into consideration.


Assuntos
Acetaminofen/efeitos adversos , Analgésicos não Entorpecentes/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Acetaminofen/administração & dosagem , Acetaminofen/farmacocinética , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/farmacocinética , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Humanos , MicroRNAs/metabolismo , Mitocôndrias/patologia , Projetos de Pesquisa
13.
Chem Biol Interact ; 310: 108734, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276661

RESUMO

This work aimed to evaluate the mechanisms involved in the apoptosis induction of isorhamnetin-3-O-glucosyl-pentoside (IGP) in metastatic human colon cancer cells (HT-29). To achieve this, we assessed phosphatidylserine (PS) exposure, cell membrane disruption, chromatin condensation, cell cycle alterations, mitochondrial damage, ROS production, and caspase-dependence on cell death. Our results showed that IGP induced cell death on HT-29 cells through PS exposure (48%) and membrane permeabilization (30%) as well as nuclear condensation (54%) compared with control cells. Moreover, IGP treatment induced cell cycle arrest in G2/M phase. Bax/Bcl-2 ratio increased and the loss of mitochondrial membrane potential (63%) was observed in IGP-treated cells. Finally, as apoptosis is a caspase-dependent cell death mechanism, we used a pancaspase-inhibitor (Q-VD-OPh) to demonstrate that the cell death induced by IGP was caspase-dependent. Overall these results indicated that IGP induced apoptosis through caspase-dependent mitochondrial damage in HT-29 colon cancer cells.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Glicosídeos/farmacologia , Mitocôndrias/efeitos dos fármacos , Opuntia/química , Quercetina/análogos & derivados , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Flavonóis , Glicosídeos/isolamento & purificação , Glicosídeos/uso terapêutico , Células HT29 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/patologia , Extratos Vegetais/farmacologia , Quercetina/isolamento & purificação , Quercetina/farmacologia , Quercetina/uso terapêutico
14.
Nature ; 571(7766): 565-569, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31316206

RESUMO

Parkinson's disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson's disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo5-8. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens9, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson's disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1-/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson's disease, which highlights the relevance of the gut-brain axis in the disease10.


Assuntos
Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/fisiopatologia , Intestinos/microbiologia , Doença de Parkinson/genética , Doença de Parkinson/microbiologia , Proteínas Quinases/deficiência , Proteínas Quinases/genética , Animais , Apresentação do Antígeno/imunologia , Autoantígenos/imunologia , Axônios/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Citrobacter rodentium/imunologia , Citrobacter rodentium/patogenicidade , Modelos Animais de Doenças , Neurônios Dopaminérgicos/imunologia , Neurônios Dopaminérgicos/patologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/patologia , Feminino , Intestinos/imunologia , Intestinos/patologia , Levodopa/uso terapêutico , Masculino , Camundongos , Mitocôndrias/imunologia , Mitocôndrias/patologia , Neostriado/imunologia , Neostriado/microbiologia , Neostriado/patologia , Neostriado/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Proteínas Quinases/imunologia , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
15.
Vet Microbiol ; 234: 51-60, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31213272

RESUMO

E5 protein, the major oncoprotein of the bovine Deltapapillomavirus genus, has been detected in 17 of the 19 urothelial cancers by molecular and morphological procedures. In 10 urothelial cancers, the oxygen sensitive subunit HIF-1α, which is upregulated by hypoxia, was overexpressed. Mitophagy, the selective autophagic removal of dysfunctional mitochondria, was upregulated in hypoxic neoplastic cells infected by BPVs which was mediated by FUNDC1, a mitochondrial outer-membrane protein. The FUNDC1 receptor was amplified by PCR, and amplicon sequencing showed a 100% homology with bovine FUNDC1 sequences deposited in GenBank (accession number: NM_001104982). Both transcripts and protein levels of FUNDC1 were significantly decreased in hypoxic neoplastic cells relative to healthy, non-neoplastic cells. FUNDC1 interacted with the LC3 protein, a marker of autophagosome (mitophagosome) membrane, the Hsc70/Hsp70 chaperone, and Bag3 co-chaperone. Bag3 may play a role in mitophagosome formation together with the Synpo2 protein, and may be involved in the degradation of Hsc70/Hsp70-bound CHIP-ubiquitinated cargoes, in association with its chaperone. Ultrastructural findings revealed the presence of mitochondria exhibiting severe fragmentation and loss of cristae, as well as numerous mitochondria-containing autophagosomes. Total and phosphorylated GTPase dynamin-related protein 1 (DRP1), which plays a crucial role in mitochondrial fission, a pre-requisite for mitophagy, was overexpressed at the mitochondrial level. Total and phosphorylated mitochondrial fission factor (Mff), mitochondrial fission protein 1 (Fis1), mitochondrial dynamics 51 (MiD51), and MiD49, which are DRP1 receptors responsible and/or co-responsible for its mitochondrial recruitment were overexpressed.


Assuntos
Deltapapillomavirus/patogenicidade , Mitocôndrias/patologia , Degradação Mitocondrial , Proteínas Mitocondriais/metabolismo , Urotélio/virologia , Animais , Bovinos , Feminino , Proteínas de Ligação ao GTP/genética , Hipóxia , Microscopia Eletrônica de Transmissão , Mitocôndrias/ultraestrutura , Mitocôndrias/virologia , Proteínas Mitocondriais/genética , Proteínas Oncogênicas Virais/genética , Fosforilação , Urotélio/citologia , Urotélio/patologia
16.
Toxicol Lett ; 313: 42-49, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31154016

RESUMO

Astrocytes are the major glial cell type in the central nervous system (CNS), and the distal part of the astrocyte forms the blood-brain barrier with nearby blood vessels. They maintain the overall metabolism, growth, homeostasis of neurons, and signaling in the CNS. Ochratoxin A is considered a carcinogen and immunotoxic, nephrotoxic, and neurotoxic mycotoxin. Specifically, it exhibits neurotoxicity with high affinity for the brain. Despite some previous studies about the effects of ochratoxin A in glial cells, the intracellular working mechanism in astrocytes is not fully understood. In this study, we studied the specific working mechanism of ochratoxin A in the human astrocyte cell line, NHA-SV40LT. Ochratoxin A reduced cell proliferation with sub G0/G1 cell cycle arrest by inhibiting CCND1, CCNE1, CDK4, and MYC expression. It induced apoptosis of NHA-SV40LT cells through mitochondrial membrane potential (MMP) loss and up-regulation of BAX and TP53. In addition, ochratoxin A increased cytosolic and mitochondrial calcium levels, resulting in an increase in MMP2 and PLAUR mRNA expression in NHA-SV40LT cells. Furthermore, ochratoxin A regulated the phosphorylation of AKT, ERK1/2, and JNK signal molecules of human astrocytes. Collectively, ochratoxin A exerts neurotoxicity through anti-proliferation and mitochondria-dependent apoptosis in human astrocytes.


Assuntos
Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Cálcio/metabolismo , Mitocôndrias/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Ocratoxinas/toxicidade , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Sinalização do Cálcio/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
17.
Eur J Med Chem ; 179: 26-37, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31233920

RESUMO

PDT is a well-established therapeutic modality for many types of cancer. Photoluminescent cyclometalated iridium(III) complexes are one of the most commonly used classes of organometallic compounds with potential beneficial applications in bioimaging and as promising anticancer agents. In the present study, three new cyclometalated iridium(III) complexes (Ir1-Ir3) containing guanidinium ligands were found to exert excellent cytotoxic effects on different types of cancer cells upon light irradiation at 425 nm. Notably, Ir1 conferred almost no dark toxicity (IC50 > 100 µM) to HepG2 cells, but the value decreased by 387-fold to 0.36 µM following 10 min of light irradiation (425 nm). Further mechanistic investigation revealed that complex Ir1 could induce apoptosis via the activation of reactive oxygen species (ROS)-mediated mitochondrial signaling pathways in the presence or absence of light irradiation. In vivo studies demonstrated that Ir1 significantly inhibited tumor growth in HepG2 xenograft-bearing mice under light irradiation at 425 nm. Taken together, these findings indicate that designing PDT-based Ir(III) complexes may hold a great deal of promise for anticancer drug development.


Assuntos
Antineoplásicos/farmacologia , Guanidina/farmacologia , Irídio/farmacologia , Mitocôndrias/efeitos dos fármacos , Imagem Óptica , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Guanidina/química , Células Hep G2 , Humanos , Irídio/química , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Mitocôndrias/patologia , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Relação Estrutura-Atividade
18.
Mol Vis ; 25: 222-236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057322

RESUMO

Purpose: Glaucoma is characterized by optic nerve damage and retinal ganglion cell loss. The glycoprotein neuromedin B-associated (Gpnmb) gene is well-known to be involved in the glaucoma disease process. The purpose of this study is to identify a downstream gene through which Gpnmb affects the glaucoma phenotypes using a systems genetics approach. Methods: Retinal gene expression data for the BXD recombinant inbred (RI) strains (n=75) have previously been generated in our laboratory for a glaucoma study, and these data were used for genetic and bioinformatics analysis. Expression quantitative trait locus (eQTL) mapping and genetic correlation methods were used to identify a gene downstream of Gpnmb. Gene-set enrichment analysis was used to evaluate gene function and to construct coexpression networks. Results: The level of Gpnmb expression is associated with a highly statistically significant cis-eQTL. Stanniocalcin 1 (Stc1) has a significant trans-eQTL mapping to the Gpnmb locus. The expression of Gpnmb and Stc1 is highly correlated in the retina and other tissues, as well as with glaucoma-related phenotypes. Gene Ontology and pathway analysis showed that Stc1 and its covariates are highly associated with apoptosis, oxidative stress, and mitochondrial activity. A generated gene network indicated that Gpnmb and Stc1 are directly connected to and interact with other genes with similar biologic functions. Conclusions: These results suggest that Stc1 may be a downstream candidate of Gpnmb, and that both genes interact with other genes in a network to develop glaucoma pathogenesis through mechanisms such as apoptosis and oxidative stress.


Assuntos
Proteínas do Olho/genética , Redes Reguladoras de Genes , Glaucoma/genética , Glicoproteínas/genética , Glicoproteínas de Membrana/genética , Animais , Apoptose , Biologia Computacional/métodos , Modelos Animais de Doenças , Proteínas do Olho/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Glaucoma/metabolismo , Glaucoma/patologia , Glicoproteínas/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Anotação de Sequência Molecular , Estresse Oxidativo , Fenótipo , Mapeamento de Interação de Proteínas , Locos de Características Quantitativas , Transdução de Sinais
19.
Artif Cells Nanomed Biotechnol ; 47(1): 1746-1757, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31062618

RESUMO

To evaluate the safety and efficacy of novel cobalt complex with sulindac (Co-SLD), the zebrafish and oral squamous cell carcinoma CAL27 were investigated in the present study. The developmental toxicity of Co-SLD ranging from 5 to 20 µM was determined by exposure to 3-144-h post-fertilization (hpf) zebrafish. Our data showed that Co-SLD did not cause to the appreciable toxicity at low concentration (5 and 10 µM). A remarkable toxicity was observed at high concentration (20 µM), including increased mortality and malformation, delayed hatchability, reduced heart rate as well as suppressed behaviour. With regard to the antitumor activity of Co-SLD, inhibited cell growth and migration capability were outstandingly observed in oral squamous cell carcinoma treated with 10 and 20 µM Co-SLD, which could be mainly attributed to the Co-SLD-elicited mitochondrial damage as marked by the depression of mitochondrial membrane potential, ROS accumulation and ATP depletion. Furthermore, administration of 10 µM Co-SLD was an optimal concentration not only to avoid the normal tissue toxicity, but also to enhance the killing of cancer cells via disrupting mitochondrial dysfunction. Taken together the above results demonstrated the desirable response of oral squamous cell carcinoma to Co-SLD.


Assuntos
Carcinoma de Células Escamosas/patologia , Cobalto/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias Bucais/patologia , Sulindaco/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/toxicidade , Relação Dose-Resposta a Droga , Humanos , Locomoção/efeitos dos fármacos , Mitocôndrias/patologia , Peixe-Zebra
20.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083373

RESUMO

Liquid crystal displays (LCDs) are used as screens in consumer electronics and are indispensable in the modern era of computing. LCDs utilize light-emitting diodes (LEDs) as backlight modules and emit high levels of blue light, which may cause retinal photoreceptor cell damage. However, traditional blue light filters may decrease the luminance of light and reduce visual quality. We adjusted the emitted light spectrum of LED backlight modules in LCDs and reduced the energy emission but maintained the luminance. The 661W photoreceptor cell line was used as the model system. We established a formula of the ocular energy exposure index (OEEI), which could be used as the indicator of LCD energy emission. Cell viability decreased and apoptosis increased significantly after exposure to LCDs with higher emitted energy. Cell damage occurred through the induction of oxidative stress and mitochondrial dysfunction. The molecular mechanisms included activation of the NF-κB pathway and upregulation of the expression of proteins associated with inflammation and apoptosis. The effect was correlated with OEEI intensity. We demonstrated that LCD exposure-induced photoreceptor damage was correlated with LCD energy emission. LCDs with lower energy emission may, therefore, serve as suitable screens to prevent light-induced retinal damage and protect consumers' eye health.


Assuntos
Luz , Cristais Líquidos/química , Células Fotorreceptoras de Vertebrados/patologia , Células Fotorreceptoras de Vertebrados/efeitos da radiação , Animais , Apoptose/efeitos da radiação , Caspase 3/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos da radiação , Inflamação/patologia , Camundongos , Mitocôndrias/patologia , Mitocôndrias/efeitos da radiação , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos da radiação , Exposição à Radiação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos da radiação
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