RESUMO
BACKGROUND: Timosaponin Bâ ¡ (TBâ ¡), one of the primary bioactive compounds from Anemarrhena asphodeloides Bunge, possesses potential cardioprotective effects. However, the mechanism underlying TBâ ¡-mediated cardioprotection, especially the involvement of endoplasmic reticulum stress, remains largely unknown. PURPOSE: This study was designed to evaluate the role of TBâ ¡ in myocardial injury protection and explore its possible mechanisms. METHODS: In vivo models of isoproterenol-induced myocardial injury and H2O2-induced cytotoxicty were established to investigate the effect of anti-myocardial injury of TBâ ¡. The potential mechanisms were investigated in vitro and in vivo using multiple detection methods like electrocardiography, histo-pathological examination, JC-1 staining, TUNEL staining, ELISA technology, and western blot analysis. RESULTS: In vivo study revealed that TBâ ¡ improved electrocardiography and heart vacuolation, reduced myocyte apoptosis, and improved the antioxidant potential. In vitro investigation demonstrated that TBâ ¡ pretreatment inhibited ER stress-mediated apoptosis pathways. Further investigation of the underlying mechanisms revealed that TBâ ¡ prevented H2O2-induced H9c2 cardiomyocytes injury by the PI3K/Akt pathways, whereas the addition of LY294002, the pharmacologic antagonist of PI3K, attenuated TBâ ¡-induced expression of apoptotic protein and cytoprotective effects. CONCLUSION: These results suggested that TBâ ¡ protects against myocardial injury in vitro and enhances cellular defense capacity by inhibiting ER stress-mediated apoptosis pathways in vivo by activating the PI3K/Akt pathways.
Assuntos
Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Saponinas/farmacologia , Esteroides/farmacologia , Animais , Apoptose/fisiologia , Células Cultivadas , Cromonas/farmacologia , Eletrocardiografia , Estresse do Retículo Endoplasmático/fisiologia , Peróxido de Hidrogênio/toxicidade , Isoproterenol/toxicidade , Masculino , Morfolinas/farmacologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-DawleyRESUMO
Acute lung injury (ALI), a severe and life-threatening inflammation of the lung, with high morbidity and mortality, underscoring the urgent need for novel treatments. Ge-Gen-Qin-Lian decoction (GQD), a classic Chinese herbal formula, has been widely used to treat intestine-related diseases in the clinic for centuries. In recent years, a growing number of studies have found that GQD has a favorable anti-inflammatory effect. With the further study on the viscera microbiota, the link between the lungs and the gut-the gut-lung axis has been established. Based on the theory of the gut-lung axis, we used systems pharmacology to explore the effects and mechanisms of GQD treatment in ALI. Hypothesizing that GQD inhibits ALI progression, we used the experimental model of lipopolysaccharide (LPS)-induced ALI in Balb/c mice to evaluate the therapeutic potential of GQD. Our results showed that GQD exerted protective effects against LPS-induced ALI by reducing pulmonary edema and microvascular permeability. Meanwhile, GQD can downregulate the expression of LPS-induced TNF-α, IL-1ß, and IL-6 in lung tissue, bronchoalveolar lavage fluid (BLAF), and serum. To further understand the molecular mechanism of GQD in the treatment of ALI, we used the network pharmacology to predict the disease targets of the active components of GQD. Lung tissue and serum samples of the mice were separately analyzed by transcriptomics and metabolomics. KEGG pathway analysis of network pharmacology and transcriptomics indicated that PI3K/Akt signaling pathway was significantly enriched, suggesting that it may be the main regulatory pathway for GQD treatment of ALI. By immunohistochemical analysis and apoptosis detection, it was verified that GQD can inhibit ALI apoptosis through PI3K/Akt signaling pathway. Then, we used the PI3K inhibitor LY294002 to block the PI3K/Akt signaling pathway, and reversely verified that the PI3K/Akt signaling pathway is the main pathway of GQD anti-ALI. In addition, differential metabolites in mice serum samples indicate that GQD can inhibit the inflammatory process of ALI by reversing the imbalance of energy metabolism. Our study showed that, GQD did have a better therapeutic effect on ALI, and initially elucidated its molecular mechanism. Thus, GQD could be exploited to develop novel therapeutics for ALI. Moreover, our study also provides a novel strategy to explore active components and effective mechanism of TCM formula combined with TCM theory to treat ALI.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Pulmão/efeitos dos fármacos , Biologia de Sistemas , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Metabolômica , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Edema Pulmonar/prevenção & controle , Transdução de Sinais , TranscriptomaRESUMO
Acute lung injury (ALI) is a common and serious disease. Numerous treatment options are available but they do not improve quality of life or reduce mortality for ALI patients. Here, we review the treatments for ALI to provide basic data for ALI drug therapy research and development. Chinese Materia Medica (CMM) has long been the traditional clinical approach in China for the treatment of ALI and it has proven efficacy. The continued study of CMM has disclosed new potential therapeutic ingredients for ALI. However, few reviews summarize the currently available CMM-based anti-ALI drugs. Therefore, the systematic analysis of research progress in anti-ALI CMM is of great academic and clinical value. The aim of the present review is to describe CMM-based research progress in ALI treatment. Data were compiled by electronic retrieval (CNKI, SciFinder, PubMeds, Google Scholar, Web of Science) and from articles, patents and ethnopharmacological literature in university libraries were systematically studied. This review introduces progress in research on the etiology and mechanisms of ALI, the anti-ALI theory and modes of action in traditional Chinese medicine (TCM), anti-ALI active constituents of CMM, research progress in experimental methods of CMM anti-ALI, the anti-ALI molecular mechanisms of CMM, the anti-ALI efficacy of CMM formulae, and the potential toxicity of CMM and the antidotes for it. Scholars have investigated the anti-ALI molecular mechanism of CMM from various direction and have made substantial progress. This research explored the above aspects, enriched the anti-ALI theory of CMM and established the clinical significance and developmental prospects of ALI treatment by CMM. Because of the high frequency of drugs such as glucocorticoids or antibiotics, Western medicine lacks the advantages of CMM in terms of overall anti-ALI efficacy. In the future, the development of CMM-based anti-ALI therapies will become a major trend in the field of ALI drug development. Successful clinical safety and efficacy validations will promote and encourage the use of CMM. It provides fundamental theoretical support for the discovery and use of CMM resources through the comprehensive analysis of various anti-ALI CMM report databases.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Materia Medica/farmacologia , Materia Medica/uso terapêutico , Animais , Povo Asiático , Humanos , Medicina Tradicional Chinesa/métodosRESUMO
CALB-3, a purified acidic hetero-polysaccharide isolated from Fructus aurantii, has been shown to exert cardioprotective effects in vitro. Recently, we investigated the protective effects of CALB-3 on myocardial injury and its possible mechanisms of action using a rat model of myocardial ischemia. In this study, a myocardial ischemia model was established via intragastric administration of 2â¯mg/kg isoproterenol (ISO) to male Sprague-Dawley rats (200-220â¯g) daily for 3â¯days. We found that pretreatment with CALB-3 (50, 100, and 200â¯mg/kg, i.g.) daily for 21â¯days prevented ISO-induced myocardial damage, including improvement in electrocardiographic parameters, and decrease in serum cardiac enzymes, heart vacuolation, and TUNEL-positive cells. We used western blotting to identify the underlying mechanisms and determine the possible signal pathways involved. We found that CALB-3 pretreatment prevented apoptosis, increased the expression of antioxidant enzymes, and enhanced the binding of Nrf2 to the antioxidant response element. In addition, CALB-3 activated the phosphorylation of PI3K/Akt and ERK to increase the cytoprotective effect. Overall, our results show that CALB-3 is a promising polysaccharide for protecting against myocardial injury induced by ISO.
Assuntos
Cardiotônicos/farmacologia , Citrus/química , Isoproterenol/toxicidade , Isquemia Miocárdica/prevenção & controle , Estresse Oxidativo , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Agonistas Adrenérgicos beta/toxicidade , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Masculino , Isquemia Miocárdica/induzido quimicamente , Isquemia Miocárdica/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Bacterial leaf streak of rice (BLS) caused by Xanthomonas oryzae pv. oryzicola (Xoc) is a widely-spread disease in the main rice-producing areas of the world. Investigating the genes that play roles in rice-Xoc interactions helps us to understand the defense signaling pathway in rice. Here we report a differentially expressed protein gene (DEPG1), which regulates susceptibility to BLS. DEPG1 is a nucleotide-binding site (NBS)-leucine rich repeat (LRR) gene, and the deduced protein sequence of DEPG1 has approximately 64% identity with that of the disease resistance gene Pi37. Phylogenetic analysis of DEPG1 and the 18 characterized NBS-LRR genes revealed that DEPG1 is more closely related to Pi37. DEPG1 protein is located to the cytoplasm, which was confirmed by transient expression of DEPG1-GFP (green fluorescent protein) fusion construct in onion epidermal cells. Semi-quantitative PCR assays showed that DEPG1 is widely expressed in rice, and is preferentially expressed in internodes, leaf blades, leaf sheaths and flag leaves. Observation of cross sections of leaves from the transgenic plants with a DEPG1-promoter::glucuronidase (GUS) fusion gene revealed that DEPG1 is also highly expressed in mesophyll tissues where Xoc mainly colonizes. Additionally, Xoc negatively regulates expression of DEPG1 at the early stage of the pathogen infection, and so do the three defense-signal compounds including salicylic acid (SA), methyl jasmonate (MeJA) and 1-aminocyclopropane-1-carboxylic-acid (ACC). Transgenic rice plants overexpressing DEPG1 exhibit enhanced susceptibility to Xoc compared to the wild-type controls. Moreover, enhanced susceptibility to Xoc may be mediated by inhibition of the expression of some SA biosynthesis-related genes and pathogenesis-related genes that may contribute to the disease resistance. Taken together, DEPG1 plays roles in the interactions between rice and BLS pathogen Xoc.