Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.966
Filtrar
1.
Nat Commun ; 11(1): 3955, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769998

RESUMO

Cellular therapy to treat heart failure is an ongoing focus of intense research, but progress toward structural and functional recovery remains modest. Engineered augmentation of established cellular effectors overcomes impediments to enhance reparative activity. Such 'next generation' implementation includes delivery of combinatorial cell populations exerting synergistic effects. Concurrent isolation and expansion of three distinct cardiac-derived interstitial cell types from human heart tissue, previously reported by our group, prompted design of a 3D structure that maximizes cellular interaction, allows for defined cell ratios, controls size, enables injectability, and minimizes cell loss. Herein, mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and c-Kit+ cardiac interstitial cells (cCICs) when cultured together spontaneously form scaffold-free 3D microenvironments termed CardioClusters. scRNA-Seq profiling reveals CardioCluster expression of stem cell-relevant factors, adhesion/extracellular-matrix molecules, and cytokines, while maintaining a more native transcriptome similar to endogenous cardiac cells. CardioCluster intramyocardial delivery improves cell retention and capillary density with preservation of cardiomyocyte size and long-term cardiac function in a murine infarction model followed 20 weeks. CardioCluster utilization in this preclinical setting establish fundamental insights, laying the framework for optimization in cell-based therapeutics intended to mitigate cardiomyopathic damage.


Assuntos
Microambiente Celular , Miocárdio/patologia , Cicatrização , Animais , Animais Recém-Nascidos , Capilares/patologia , Agregação Celular , Morte Celular , Linhagem da Célula , Tamanho Celular , Citoproteção , Células Progenitoras Endoteliais/citologia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Processamento de Imagem Assistida por Computador , Recém-Nascido , Células-Tronco Mesenquimais/citologia , Camundongos Endogâmicos NOD , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/citologia , Estresse Oxidativo , Comunicação Parácrina , Ratos Sprague-Dawley , Transcrição Genética
2.
Int J Nanomedicine ; 15: 4859-4876, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764923

RESUMO

Introduction: CoenzymeQ10 (CoQ10) is a well-known antioxidant and anti-inflammatory agent with cardioprotective properties. However, clinical trials based on its oral administration have failed to provide significant effect on cardiac functionality. The main limitation of CoQ10 is based on its very low oral bioavailability and instability that limit dramatically its effects as a cardioprotective agent. Herein, we loaded CoQ10 in high bioavailable nano-emulsions (NEs) coated with chitosan or chitosan and hyaluronic acid in order to improve its performance. Methods: We tested cardioprotective and hepatoprotective effects of CoQ10-loaded nano-carriers against Doxorubicin and Trastuzumab toxicities in cardiomyocytes and liver cells through analysis of cell viability, lipid peroxidation, expression of leukotrienes, p65/NF-kB and pro-inflammatory cytokines involved in anticancer-induced cardio and hepatotoxicity. Results: Nano-carriers showed high stability and loading ability and increased cell viability both in hepatocytes and cardiomyocytes during anticancer treatments. We observed that these effects are mediated by the inhibition of lipid peroxidation and reduction of the inflammation. CoQ10-loaded nano-emulsions showed also strong anti-inflammatory effects reducing leukotriene B4 and p65/NF-κB expression and Interleukin 1ß and 6 production during anticancer treatments. Discussion: Anthracyclines and Human epidermal growth factor receptor (HER2) inhibitors have shown significant anticancer effects in clinical practice but their use is characterized by cardiotoxicity and hepatotoxicity. Nano-carriers loaded with CoQ10 showed cardio and hepatoprotective properties mediated by reduction of oxidative damages and pro-inflammatory mediators. These results set the stage for preclinical studies of cardio and hepatoprotection in HER2+ breast cancer-bearing mice treated with Doxorubicin and Trastuzumab.


Assuntos
Antraciclinas/efeitos adversos , Fígado/citologia , Miócitos Cardíacos/efeitos dos fármacos , Nanoestruturas/química , Trastuzumab/efeitos adversos , Ubiquinona/análogos & derivados , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Cápsulas , Cardiotônicos/química , Cardiotônicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Feminino , Hepatócitos/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Ubiquinona/química , Ubiquinona/farmacologia
3.
Trends Pharmacol Sci ; 41(9): 598-610, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32711925

RESUMO

Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 is largely the result of a dysregulated host response, followed by damage to alveolar cells and lung fibrosis. Exacerbated proinflammatory cytokines release (cytokine storm) and loss of T lymphocytes (leukopenia) characterize the most aggressive presentation. We propose that a multifaceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2) can be deployed against the virus. The strategy provides robust cytoprotection by restoring redox and protein homeostasis, promoting resolution of inflammation, and facilitating repair. NRF2 activators such as sulforaphane and bardoxolone methyl are already in clinical trials. The safety and efficacy information of these modulators in humans, together with their well-documented cytoprotective and anti-inflammatory effects in preclinical models, highlight the potential of this armamentarium for deployment to the battlefield against COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Viral/tratamento farmacológico , Citoproteção , Granulócitos/efeitos dos fármacos , Granulócitos/virologia , Homeostase , Humanos , Oxirredução , Pandemias
4.
Nat Commun ; 11(1): 3427, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647171

RESUMO

The contribution of inflammation to the chronic joint disease osteoarthritis (OA) is unclear, and this lack of clarity is detrimental to efforts to identify therapeutic targets. Here we show that chondrocytes under inflammatory conditions undergo a metabolic shift that is regulated by NF-κB activation, leading to reprogramming of cell metabolism towards glycolysis and lactate dehydrogenase A (LDHA). Inflammation and metabolism can reciprocally modulate each other to regulate cartilage degradation. LDHA binds to NADH and promotes reactive oxygen species (ROS) to induce catabolic changes through stabilization of IκB-ζ, a critical pro-inflammatory mediator in chondrocytes. IκB-ζ is regulated bi-modally at the stages of transcription and protein degradation. Overall, this work highlights the function of NF-κB activity in the OA joint as well as a ROS promoting function for LDHA and identifies LDHA as a potential therapeutic target for OA treatment.


Assuntos
Condrócitos/metabolismo , Lactato Desidrogenase 5/metabolismo , Terapia de Alvo Molecular , Osteoartrite/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Aerobiose , Animais , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Citoproteção/efeitos dos fármacos , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/farmacologia , Articulação do Joelho/patologia , Meniscos Tibiais/cirurgia , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos Endogâmicos C57BL , NAD/metabolismo , NF-kappa B/metabolismo , Osteoartrite/genética , Osteoartrite/patologia
5.
J Biosci Bioeng ; 130(3): 283-289, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32507385

RESUMO

A novel exopolysaccharide (EPS) from Paenibacillus polymyxa PYQ1 was extracted, well purified and characterized. This EPS was homogeneous glucomannan-type polysaccharide with the average molecular weight of 4.38 × 106 Da. Structural characterization indicated that the monosaccharides of EPS were pyranoses connected by ß-glycosidic linkages. Furthermore, our results showed the protective benefits of EPS against UVC induced cytotoxicity in HaCaT cells through scavenging excessive reactive oxygen species, mitigating the decrease of mitochondrial membrane potential, improving catalase activity and maintaining membrane integrity. Taken together, this study qualified EPS from P. polymyxa PYQ1 was a promising natural polymer which worth further investigation as a skin-care agent.


Assuntos
Citoproteção/efeitos dos fármacos , Paenibacillus polymyxa/metabolismo , Polissacarídeos Bacterianos/isolamento & purificação , Polissacarídeos Bacterianos/farmacologia , Raios Ultravioleta/efeitos adversos , Catalase/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos da radiação , Peso Molecular , Monossacarídeos/análise , Polissacarídeos Bacterianos/biossíntese , Polissacarídeos Bacterianos/química , Espécies Reativas de Oxigênio/metabolismo
6.
Nutr Metab Cardiovasc Dis ; 30(7): 1216-1226, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32482454

RESUMO

BACKGROUND AND AIMS: Successful islet transplantation as a promising treatment of diabetes type 1 is threatened with the loss of islets during the pre-transplant culture due to hypoxia and oxidative stress-induced apoptosis. Therefore, optimization of culture in order to preserve the islets is a critical point. In this study, we investigated the effect of resveratrol, as a cytoprotective agent, on the cultured human islets. METHODS AND RESULTS: Isolated islets were treated with different concentrations of resveratrol for 24 and 72 h. Islets' viability, apoptosis, apoptosis markers, and insulin and C-peptide secretion, along with the production of reactive oxygen species (ROS), hypoxia inducible factor 1 alpha (HIF-1α), and its target genes in the islets were investigated. Our findings showed that the islets were exposed to hypoxia and oxidative stress after isolation and during culture. This insult induced apoptosis and decreased viability during 72 h. The presence of resveratrol significantly attenuated HIF-1α and ROS production, reduced apoptosis, promoted the VEGF secretion, and increased the insulin and C-peptide secretion. In this regard, resveratrol improved the islet's survival and function in the culture period. CONCLUSIONS: Using resveratrol can attenuate the stressful condition for the islets in the pre-transplant culture and subsequently ameliorate their viability and functionality that lead to successful outcome after clinical transplantation.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Resveratrol/farmacologia , Adulto , Idoso , Peptídeo C/metabolismo , Hipóxia Celular , Sobrevivência Celular/efeitos dos fármacos , Citoproteção , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Técnicas de Cultura de Tecidos , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
PLoS One ; 15(5): e0223344, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365104

RESUMO

Stilbenes are a group of chemicals characterized with the presence of 1,2-diphenylethylene. Previously, our group has demonstrated that synthesized (E)-N-(2-(3, 5-dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) possesses potential chemopreventive activity specifically inducing NAD(P)H:quinone oxidoreductase 1 (NQO1) protein expression and activity. In this study, the cytoprotective effects of BK3C231 on cellular DNA and mitochondria were investigated in normal human colon fibroblast, CCD-18Co cells. The cells were pretreated with BK3C231 prior to exposure to the carcinogen 4-nitroquinoline 1-oxide (4NQO). BK3C231 was able to inhibit 4NQO-induced cytotoxicity. Cells treated with 4NQO alone caused high level of DNA and mitochondrial damages. However, pretreatment with BK3C231 protected against these damages by reducing DNA strand breaks and micronucleus formation as well as decreasing losses of mitochondrial membrane potential (ΔΨm) and cardiolipin. Interestingly, our study has demonstrated that nitrosative stress instead of oxidative stress was involved in 4NQO-induced DNA and mitochondrial damages. Inhibition of 4NQO-induced nitrosative stress by BK3C231 was observed through a decrease in nitric oxide (NO) level and an increase in glutathione (GSH) level. These new findings elucidate the cytoprotective potential of BK3C231 in human colon fibroblast CCD-18Co cell model which warrants further investigation into its chemopreventive role.


Assuntos
4-Nitroquinolina-1-Óxido/toxicidade , Colo/efeitos dos fármacos , Citoproteção , Dano ao DNA/efeitos dos fármacos , Furanos/farmacologia , Mutagênicos/toxicidade , Estilbenos/farmacologia , Linhagem Celular , Colo/citologia , Reparo do DNA/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Furanos/química , Humanos , Mitocôndrias/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estilbenos/química
8.
Nat Commun ; 11(1): 2376, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398747

RESUMO

Naked mole-rat (NMR), the longest-living rodent, produces very-high-molecular-mass hyaluronan (vHMM-HA), compared to other mammalian species. However, it is unclear if exceptional polymer length of vHMM-HA is important for longevity. Here, we show that vHMM-HA (>6.1 MDa) has superior cytoprotective properties compared to the shorter HMM-HA. It protects not only NMR cells, but also mouse and human cells from stress-induced cell-cycle arrest and cell death in a polymer length-dependent manner. The cytoprotective effect is dependent on the major HA-receptor, CD44. We find that vHMM-HA suppresses CD44 protein-protein interactions, whereas HMM-HA promotes them. As a result, vHMM-HA and HMM-HA induce opposing effects on the expression of CD44-dependent genes, which are associated with the p53 pathway. Concomitantly, vHMM-HA partially attenuates p53 and protects cells from stress in a p53-dependent manner. Our results implicate vHMM-HA in anti-aging mechanisms and suggest the potential applications of vHMM-HA for enhancing cellular stress resistance.


Assuntos
Citoproteção/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular , Citoproteção/fisiologia , Regulação da Expressão Gênica/fisiologia , Técnicas de Inativação de Genes , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/isolamento & purificação , Ácido Hialurônico/metabolismo , Longevidade/fisiologia , Camundongos , Ratos-Toupeira/fisiologia , Peso Molecular , Cultura Primária de Células , Mapas de Interação de Proteínas/efeitos dos fármacos , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Especificidade da Espécie , Estresse Fisiológico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
9.
Int J Nanomedicine ; 15: 2287-2302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32280221

RESUMO

Background: Mitochondrial dysfunction played a vital role in the pathogenesis of various diseases, including acute lung injury (ALI). However, few strategies targeting mitochondria were developed in treating ALI. Recently, we fabricated a porous Se@SiO2 nanoparticles (NPs) with antioxidant properties. Methods: The protective effect of Se@SiO2 NPs was assessed using confocal imaging, immunoblotting, RNA-seq, mitochondrial respiratory chain (MRC) activity assay, and transmission electron microscopy (TEM) in airway epithelial cell line (Beas-2B). The in vivo efficacy of Se@SiO2 NPs was evaluated in a lipopolysaccharide (LPS)-induced ALI mouse model. Results: This study demonstrated that Se@SiO2 NPs significantly increased the resistance of airway epithelial cells under oxidative injury and shifted lipopolysaccharide-induced gene expression profile closer to the untreated controls. The cytoprotection of Se@SiO2 was found to be achieved by maintaining mitochondrial function, activity, and dynamics. In an animal model of ALI, pretreated with the NPs improved mitochondrial dysfunction, thus reducing inflammatory responses and diffuse damage in lung tissues. Additionally, RNA-seq analysis provided evidence for the broad modulatory activity of our Se@SiO2 NPs in various metabolic disorders and inflammatory diseases. Conclusion: This study brought new insights into mitochondria-targeting bioactive NPs, with application potential in curing ALI or other human mitochondria-related disorders.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Selênio/farmacologia , Dióxido de Silício/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular , Citoproteção , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Humanos , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Mitocôndrias/metabolismo , Nanopartículas/uso terapêutico , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Porosidade , Selênio/química , Dióxido de Silício/química
10.
Nutr Metab Cardiovasc Dis ; 30(5): 829-842, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32278611

RESUMO

BACKGROUND AND AIM: The transcription factor GATA-4 plays an important role in myocardial protection. Astragaloside IV (Ast-IV) was reported with the effects on improving cardiac function after ischemia. In this study, we explored how Ast-IV interacts with GATA-4 to protect myocardial cells H9c2 against Hypoxia/Reoxygenation (H/R) stress. METHODS AND RESULTS: H9c2 cells were cultured under the H/R condition. Various cell activity and morphology assays were used to assess the rates of apoptosis and autophagy. In these H/R injured H9c2 cells, increased apoptosis (P < 0.01) and autophagosome number (P < 0.01) were observed, and the addition of Ast-IV ameliorated this tendency. Mechanistically, we used the RT-qPCR and Western blot to evaluate the expressions of various molecules. The results showed that Ast-IV treatment upregulated gene expression of GATA-4 (P < 0.01) and the survival factors (Bcl-2, P < 0.05; p62, P < 0.01), but suppressed apoptosis and autophagy related genes (PARP, Caspase-3, Beclin-1, and LC3-II; All P < 0.01). Furthermore, overexpressing of GATA-4 by its agonist phenylephrine can also protect H/R injured H9c2 cells, and the addition of Ast-IV further enhanced this protection of GATA-4. In contrast, silencing GATA-4 expression abolished the H/R protection of Ast-IV, which demonstrated that the myocardial protection of Ast-IV is mediated by GATA-4. Lastly, along with GATA overexpression, enhanced interactions between Bcl-2 and Beclin-1 were detected by Chromatin immunoprecipitation (P < 0.01). CONCLUSION: Ast-IV rescued the H/R injury induced apoptosis and autophagy in H9c2 cells. Ast-IV treatment can stimulate the overexpression of GATA-4, and further enhanced the myocardial protection effect of GATA-4.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Fator de Transcrição GATA4/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Hipóxia Celular , Linhagem Celular , Citoproteção , Fator de Transcrição GATA4/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Transdução de Sinais , Regulação para Cima
12.
Artigo em Inglês | MEDLINE | ID: mdl-32292063

RESUMO

Both reactive nitrogen and oxygen species (RNS and ROS), such as nitric oxide, peroxynitrite, and hydrogen peroxide, have been implicated as mediators of pancreatic ß-cell damage during the pathogenesis of autoimmune diabetes. While ß-cells are thought to be vulnerable to oxidative damage due to reportedly low levels of antioxidant enzymes, such as catalase and glutathione peroxidase, we have shown that they use thioredoxin reductase to detoxify hydrogen peroxide. Thioredoxin reductase is an enzyme that participates in the peroxiredoxin antioxidant cycle. Peroxiredoxins are expressed in ß-cells and, when overexpressed, protect against oxidative stress, but the endogenous roles of peroxiredoxins in the protection of ß-cells from oxidative damage are unclear. Here, using either glucose oxidase or menadione to continuously deliver hydrogen peroxide, or the combination of dipropylenetriamine NONOate and menadione to continuously deliver peroxynitrite, we tested the hypothesis that ß-cells use peroxiredoxins to detoxify both of these reactive species. Either pharmacological peroxiredoxin inhibition with conoidin A or specific depletion of cytoplasmic peroxiredoxin 1 (Prdx1) using siRNAs sensitizes INS 832/13 cells and rat islets to DNA damage and death induced by hydrogen peroxide or peroxynitrite. Interestingly, depletion of peroxiredoxin 2 (Prdx2) had no effect. Together, these results suggest that ß-cells use cytoplasmic Prdx1 as a primary defense mechanism against both ROS and RNS.


Assuntos
Dano ao DNA , Peróxido de Hidrogênio/toxicidade , Células Secretoras de Insulina/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peroxirredoxinas/metabolismo , Ácido Peroxinitroso/toxicidade , Animais , Morte Celular , Linhagem Celular Tumoral , Citoplasma/enzimologia , Citoproteção , Inibidores Enzimáticos/farmacologia , Células Secretoras de Insulina/enzimologia , Células Secretoras de Insulina/patologia , Masculino , Peroxirredoxinas/antagonistas & inibidores , Peroxirredoxinas/genética , Quinoxalinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Tiorredoxina Redutase 1/metabolismo
13.
PLoS One ; 15(3): e0219275, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163417

RESUMO

Pathogenic bacteria often damage tissues by secreting toxins that form pores in cell membranes, and the most common pore-forming toxins are cholesterol-dependent cytolysins. During bacterial infections, glutamine becomes a conditionally essential amino acid, and glutamine is an important nutrient for immune cells. However, the role of glutamine in protecting tissue cells against pore-forming toxins is unclear. Here we tested the hypothesis that glutamine supports the protection of tissue cells against the damage caused by cholesterol-dependent cytolysins. Stromal and epithelial cells were sensitive to damage by the cholesterol-dependent cytolysins, pyolysin and streptolysin O, as determined by leakage of potassium and lactate dehydrogenase from cells, and reduced cell viability. However, glutamine deprivation increased the leakage of lactate dehydrogenase and reduced the viability of cells challenged with cholesterol-dependent cytolysins. Without glutamine, stromal cells challenged with pyolysin leaked lactate dehydrogenase (control vs. pyolysin, 2.6 ± 0.6 vs. 34.4 ± 4.5 AU, n = 12), which was more than three-fold the leakage from cells supplied with 2 mM glutamine (control vs. pyolysin, 2.2 ± 0.3 vs. 9.4 ± 1.0 AU). Glutamine cytoprotection did not depend on glutaminolysis, replenishing the Krebs cycle via succinate, changes in cellular cholesterol, or regulators of cell metabolism (AMPK and mTOR). In conclusion, although the mechanism remains elusive, we found that glutamine supports the protection of tissue cells against the damage caused by cholesterol-dependent cytolysins from pathogenic bacteria.


Assuntos
Colesterol/metabolismo , Citoproteção/efeitos dos fármacos , Citotoxinas/toxicidade , Glutamina/farmacologia , Animais , Proteínas de Bactérias/toxicidade , Toxinas Bacterianas/toxicidade , Bovinos , Células HeLa , Proteínas Hemolisinas/toxicidade , Humanos , L-Lactato Desidrogenase/metabolismo , Estreptolisinas/toxicidade , Células Estromais/efeitos dos fármacos
14.
Chem Biol Interact ; 323: 109061, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32194039

RESUMO

Oncogenic alterations in the BRAF gene are identified in an estimate of 50% of melanomas and cause melanoma development. BRAF kinase inhibitors (BRAFi), including vemurafenib and dabrafenib, were discovered and used in the clinical treatment of BRAF-mutant metastatic melanoma. Though, BRAFi's therapeutic advantages are short term and short-lived associated with drug resistance. Although a few pathways of developed BRAFi resistance have also been established, in approximately 40% of melanomas, the cause for inherited resistance remains unclear. Recognizing a new process of developed BRAFi resistance might provide new possibilities to successfully treat BRAF mutant melanoma. In this study, we are exploring the compensatory alternative pathway followed by BRAFi/MEKi treated resistant cell for maintaining the long-term integrity and survival.


Assuntos
Citoproteção , Resistencia a Medicamentos Antineoplásicos , Melanoma/patologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Transdução de Sinais , Neoplasias Cutâneas/patologia , Humanos , Proteínas Proto-Oncogênicas B-raf/metabolismo
15.
Nat Commun ; 11(1): 1270, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152280

RESUMO

Prolonged cell survival occurs through the expression of specific protein isoforms generated by alternate splicing of mRNA precursors in cancer cells. How alternate splicing regulates tumor development and resistance to targeted therapies in cancer remain poorly understood. Here we show that RNF113A, whose loss-of-function causes the X-linked trichothiodystrophy, is overexpressed in lung cancer and protects from Cisplatin-dependent cell death. RNF113A is a RNA-binding protein which regulates the splicing of multiple candidates involved in cell survival. RNF113A deficiency triggers cell death upon DNA damage through multiple mechanisms, including apoptosis via the destabilization of the prosurvival protein MCL-1, ferroptosis due to enhanced SAT1 expression, and increased production of ROS due to altered Noxa1 expression. RNF113A deficiency circumvents the resistance to Cisplatin and to BCL-2 inhibitors through the destabilization of MCL-1, which thus defines spliceosome inhibitors as a therapeutic approach to treat tumors showing acquired resistance to specific drugs due to MCL-1 stabilization.


Assuntos
Proteínas de Ligação a DNA/genética , Genes Ligados ao Cromossomo X , Spliceossomos/metabolismo , Síndromes de Tricotiodistrofia/genética , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Processamento Alternativo/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/genética , Cisplatino/farmacologia , Citoproteção/efeitos dos fármacos , Dano ao DNA/genética , Proteína Quinase Ativada por DNA/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Íntrons/genética , Camundongos Endogâmicos NOD , Camundongos SCID , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas de Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Subunidades Proteicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo
16.
Arch Med Res ; 51(1): 82-94, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113058

RESUMO

BACKGROUND AND AIM: Possible Hepato-protective effects of L-carnitine have been reported in previous studies. Present study was conducted to systematically review the efficacy of L-carnitine supplementation on liver enzymes. METHODS: The following databases were searched up to December 2018: PubMed, Scopus, ISI Web of Science, and the Cochrane library. Only randomized controlled trials (RCTs) evaluating the effects of L-carnitine supplementation on liver enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) were included. Pooled effect size measured using random effect model (Dersimonian-Liard). RESULTS: A total of 16 studies (including 1025 participants) were included in the present meta-analysis. Pooled analysis indicated that L-carnitine supplementation significantly decreased ALT (weighted mean difference (WMD): -10.729 IU/L, 95% CI: -13.787, -7.672, p <0.001; I2 = 95.9%), AST (WMD: -7.149 IU/L, 95% CI: -9.202, -5.096, p <0.001; I2 = 93.5%) and GGT (WMD: -7.395: IU/L, 95% CI: -9.171, -5.619, p <0.001; I2 = 80.1%). Subgroup analysis revealed that effect of L-carnitine supplementation on liver enzymes was not significant in normal weight and healthy subjects. Baseline BMI and health status were the potential source of heterogeneity. CONCLUSION: L-carnitine supplementation showed beneficial hepato-protective effects on circulating liver enzymes.


Assuntos
Carnitina/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Alanina Transaminase/efeitos dos fármacos , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/efeitos dos fármacos , Aspartato Aminotransferases/metabolismo , Carnitina/administração & dosagem , Citoproteção/efeitos dos fármacos , Suplementos Nutricionais , Humanos , Fígado/metabolismo , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacologia , gama-Glutamiltransferase/efeitos dos fármacos , gama-Glutamiltransferase/metabolismo
17.
Invest Ophthalmol Vis Sci ; 61(3): 13, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32176263

RESUMO

Purpose: To investigate the efficacy of intravitreal administration of resveratrol (RSV) in a microbead-induced high intraocular pressure (IOP) murine model for glaucoma. Methods: Experiments were performed using adult C57BL/6JJcl mice. Polystyrene microbeads were injected into the anterior chamber to induce IOP elevation. Retinal flat-mounts and sections were assessed by immunohistochemistry to detect the expression of reactive oxygen species and acetyl-p53 in retinal ganglion cells (RGCs), brain-derived neurotrophic factor (BDNF) in Müller glial cells (MGCs), and the receptor tropomyosin receptor kinase B (TrkB) in RGCs. Light cycler real-time PCR was also used for confirming gene expression of BDNF in primary cultured MGCs exposed to RSV. Results: Microbeads induced high IOP followed by RGC death and axon loss. Administration of RSV rescued RGCs via decreased reactive oxygen species generation and acetyl-p53 expression in RGCs and upregulated BDNF in MGCs and TrkB expression in RGCs, which exhibited a strong cytoprotective action against cell death through multiple pathways under high IOP. Conclusions: Our data suggest that administration of RSV may delay the progress of visual dysfunction during glaucoma and may therefore have therapeutic potential.


Assuntos
Antioxidantes/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Resveratrol/uso terapêutico , Células Ganglionares da Retina/efeitos dos fármacos , Acetilação , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Citoproteção/fisiologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Pressão Intraocular/efeitos dos fármacos , Injeções Intravítreas , Masculino , Camundongos Endogâmicos C57BL , Microesferas , Hipertensão Ocular/etiologia , Hipertensão Ocular/metabolismo , Hipertensão Ocular/patologia , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/administração & dosagem , Resveratrol/farmacologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo
18.
Am J Physiol Renal Physiol ; 318(4): F1041-F1052, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150448

RESUMO

Cisplatin is a widely used chemotherapy drug with notorious nephrotoxicity. Na+-glucose cotransporter 2 inhibitors are a class of novel antidiabetic agents that may have other effects in the kidneys besides blood glucose control. In the present study, we demonstrated that canagliflozin significantly attenuates cisplatin-induced nephropathy in C57BL/6 mice and suppresses cisplatin induced renal proximal tubular cell apoptosis in vitro. The protective effect of canagliflozin was associated with inhibition of p53, p38 and JNK activation. Mechanistically, canagliflozin partially reduced cisplatin uptake by kidney tissues in mice and renal tubular cells in culture. In addition, canagliflozin enhanced the activation of Akt and inhibited the mitochondrial pathway of apoptosis during cisplatin treatment. The protective effect of canagliflozin was diminished by the phosphatidylinositol 3-kinase/Akt inhibitor LY294002. Notably, canagliflozin did not affect the chemotherapeutic efficacy of cisplatin in A549 and HCT116 cancer cell lines. These results suggest a new application of canagliflozin for renoprotection in cisplatin chemotherapy. Canagliflozin may protect kidneys by reducing cisplatin uptake and activating cell survival pathways.


Assuntos
Apoptose/efeitos dos fármacos , Canagliflozina/farmacologia , Cisplatino , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Células Cultivadas , Citocromos c/metabolismo , Citoproteção , Modelos Animais de Doenças , Ativação Enzimática , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Rim/enzimologia , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/enzimologia , Nefropatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Ratos , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Rev Mal Respir ; 37(3): 193-196, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-32146057

RESUMO

In addition to its role in erythropoiesis, erythropoietin (Epo) plays a role in tissue protection, which includes cardioprotective, nephroprotective and neuroprotective effects. The presence of Epo and its receptor (Epo-R) in pulmonary tissue also suggests a cytoprotective effect of Epo in the lung. Our project aims to document this role in a murine model under-expressing Epo. The obtained results will lead to a better understanding of the cytoprotective effects of Epo and will also give an appreciation of its beneficial effects in cases of lung injury.


Assuntos
Lesão Pulmonar Aguda/patologia , Citoproteção , Eritropoetina/farmacologia , Eritropoetina/fisiologia , Rim , Animais , Citoproteção/efeitos dos fármacos , Citoproteção/genética , Modelos Animais de Doenças , Eritropoetina/genética , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiologia , Camundongos
20.
Arch Med Res ; 51(1): 32-40, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32086107

RESUMO

BACKGROUND AND AIMS: P-Coumaric acid (PCA) is one the compound that has free radical scavenging effects. This study investigates the protective effect of PCA on tissue damage in DOX-induced nephrotoxicity. METHODS: Thirty two Wistar rats were divided into control, PCA, DOX (15 mg/kg, i.p.) and DOX plus PCA (100 mg/kg, orally) groups. DOX-induced nephrotoxicity was indicated by marked increase in blood urea nitrogen (BUN) and serum creatinine (Cr) compared to controls. DOX group also showed elevations in lipid peroxidation and reductions in enzyme activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT). Expression of renal inflammatory cytokines including tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) and apoptosis were also elevated in the DOX group. RESULTS: PCA significantly reversed, nephrotoxicity induced by DOX via lowering BUN, serum Cr and improving histopathological scores as compared to the DOX group. PCA also decreased lipid peroxidation, increased activities of GPx, SOD and CAT, to levels relatively comparable to control. Significant reductions in expression of TNF-α, IL-1ß and apoptosis were also observed following Co-administration of PCA relative to the DOX group. CONCLUSIONS: Results describe a protective effect of PCA against DOX-induced nephrotoxicity. This effect is likely facilitated through inhibition of oxidative stress, inflammation and apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Inflamação/prevenção & controle , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Propionatos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Citoproteção/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Inflamação/metabolismo , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Nefrite/induzido quimicamente , Nefrite/metabolismo , Nefrite/prevenção & controle , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA