RESUMO
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease which affects about 0.5-1% of people with symptoms that significantly impact a sufferer's lifestyle. The cells involved in propagating RA tend to display pro-inflammatory and cancer-like characteristics. Medical drug treatment is currently the main avenue of RA therapy. However, drug options are limited due to severe side effects, high costs, insufficient disease retardation in a majority of patients, and therapeutic effects possibly subsiding over time. Thus there is a need for new drug therapies. Endoplasmic reticulum (ER) stress, a condition due to accumulation of misfolded proteins in the ER, and subsequent cellular responses have been found to be involved in cancer and inflammatory pathologies, including RA. ER stress protein markers and their modulation have therefore been suggested as therapeutic targets, such as GRP78 and CHOP, among others. Some current RA therapeutic drugs have been found to have ER stress-modulating properties. Traditional Chinese Medicines (TCMs) frequently use natural products that affect multiple body and cellular targets, and several medicines and/or their isolated compounds have been found to also have ER stress-modulating capabilities, including TCMs used in RA treatment by Chinese Medicine practitioners. This review encourages, in light of the available information, the study of these RA-treating, ER stress-modulating TCMs as potential new pharmaceutical drugs for use in clinical RA therapy, along with providing a list of other ER stress-modulating TCMs utilized in treatment of cancers, inflammatory diseases and other diseases, that have potential use in RA treatment given similar ER stress-modulating capacity.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Articulações/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Articulações/imunologia , Articulações/metabolismo , Medicina Tradicional ChinesaRESUMO
The present study was designed to investigate whether Araloside C, one of the major triterpenoid compounds isolated from Aralia elata known to be cardioprotective, can improve heart function following ischaemia/reperfusion (I/R) injury and elucidate its underlying mechanisms. We observed that Araloside C concentration-dependently improved cardiac function and depressed oxidative stress induced by I/R. Similar protection was confirmed in isolated cardiomyocytes characterized by maintaining Ca2+ transients and cell shortening against I/R. Moreover, the potential targets of Araloside C were predicted using the DDI-CPI server and Discovery Studio software. Molecular docking analysis revealed that Araloside C could be stably docked into the ATP/ADP-binding domain of the heat shock protein 90 (Hsp90) protein via the formation of hydrogen bonds. The binding affinity of Hsp90 to Araloside C was detected using nanopore optical interferometry and yielded KD values of 29 µM. Araloside C also up-regulated the expression levels of Hsp90 and improved cell viability in hypoxia/reoxygenation-treated H9c2 cardiomyocytes, whereas the addition of 17-AAG, a pharmacologic inhibitor of Hsp90, attenuated Araloside C-induced cardioprotective effect. These findings reveal that Araloside C can efficiently attenuate myocardial I/R injury by reducing I/R-induced oxidative stress and [Ca2+ ]i overload, which was possibly related to its binding to the Hsp90 protein.
Assuntos
Cardiotônicos/uso terapêutico , Proteínas de Choque Térmico HSP90/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Saponinas/uso terapêutico , Animais , Cardiotônicos/química , Cardiotônicos/farmacologia , Citoproteção/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/química , Homeostase/efeitos dos fármacos , Cinética , Masculino , Camundongos , Simulação de Acoplamento Molecular , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Saponinas/química , Saponinas/farmacologia , Sarcômeros/efeitos dos fármacos , Sarcômeros/metabolismoRESUMO
Atherosclerosis-related cardiovascular disease is still the predominant cause of death worldwide. Araloside C (AsC), a natural saponin, exerts extensive anti-inflammatory properties. In this study, we explored the protective effects and mechanism of AsC on macrophage polarization in atherosclerosis in vivo and in vitro. Using a high-fat diet (HFD)-fed ApoE-/- mouse model and RAW264.7 macrophages exposed to ox-LDL, AsC was evaluated for its effects on polarization and autophagy. AsC significantly reduced the plaque area in atherosclerotic mice and lipid accumulation in ox-LDL-treated macrophages, promoted M2 phenotype macrophage polarization, increased the number of autophagosomes and modulated the expression of autophagy-related proteins. Moreover, the autophagy inhibitor 3-methyladenine and BECN1 siRNA obviously abolished the antiatherosclerotic and M2 macrophage polarization effects of AsC. Mechanistically, AsC targeted Sirt1and increased its expression, and this increase in expression was associated with increased autophagy and M2 phenotype polarization. In contrast, the effects of AsC were markedly blocked by EX527 and Sirt1 siRNA. Altogether, AsC attenuates foam cell formation and lessens atherosclerosis by modulating macrophage polarization via Sirt1-mediated autophagy.
Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Ácido Oleanólico/farmacologia , Sirtuína 1/genética , Animais , Apolipoproteínas E/deficiência , Aterosclerose/patologia , Biomarcadores , Dieta Hiperlipídica , Modelos Animais de Doenças , Expressão Gênica , Imunofenotipagem , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/genética , Macrófagos/ultraestrutura , Camundongos , Camundongos Knockout , Modelos Biológicos , Modelos Moleculares , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ligação Proteica , Sirtuína 1/química , Sirtuína 1/metabolismo , Relação Estrutura-AtividadeRESUMO
Araloside C (AsC) has potential cardioprotective properties. However, the underlying mechanism of AsC-mediated cardioprotection, especially the role of mitochondrial function, remains largely unknown. Here, we used H9c2 cardiomyocytes to study the cardioprotective mechanisms of AsC through H2O2-induced oxidative stress. Cell viability, lactate dehydrogenase release, mitochondrial functions and bioenergetics were evaluated. Western blot analysis was used to measure the protein expression levels of apoptosis and the phosphorylation of AMP-activated protein kinase (AMPK). Results revealed that AsC increased cell viability, improved mitochondrial membrane potential disruption, decreased mitochondrial reactive oxygen species level, elevated cellular ATP levels and alleviated impaired mitochondrial respiration in H2O2-induced H9c2 cardiomyoblasts injury. Furthermore, AsC modulated apoptosis-associated protein expression and AMPK pathway in H9c2 cells under oxidative stress. In conclusion, AsC potentially protects H9c2 cardiomyoblasts against oxidative stress by regulating mitochondrial function and AMPK activation. AsC may be an effective therapeutic agent for the prevention of oxidative stress in cardiac injury.
Assuntos
Cardiotônicos/farmacologia , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Ácido Oleanólico/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Peróxido de Hidrogênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Araloside C (AsC) is a cardioprotective triterpenoid compound that is mainly isolated from Aralia elata. This study aims to determine the effects of AsC on hypoxia-reoxygenation (H/R)-induced apoptosis in H9c2 cardiomyocytes and its underlying mechanisms. Results demonstrated that pretreatment with AsC (12.5 µM) for 12 h significantly suppressed the H/R injury in H9c2 cardiomyocytes, including improving cell viability, attenuating the LDH leakage and preventing cardiomyocyte apoptosis. AsC also inhibited H/R-induced ER stress by reducing the activation of ER stress pathways (PERK/eIF2α and ATF6), and decreasing the expression of ER stress-related apoptotic proteins (CHOP and caspase-12). Moreover, AsC greatly improved the expression level of HSP90 compared with that in the H/R group. The use of HSP90 inhibitor 17-AAG and HSP90 siRNA blocked the above suppression effect of AsC on ER stress-related apoptosis caused by H/R. Taken together, AsC could reduce H/R-induced apoptosis possibly because it attenuates ER stress-dependent apoptotic pathways by increasing HSP90 expression.