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1.
J Ethnopharmacol ; : 113823, 2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33472092

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng saponins (PNS) were extracted from Panax notoginseng (Burkill) F.H. Chen, a natural product often used as a therapeutic agent in China. PNS has good results in heart failure (HF) treatment. However, its targets and pharmacological mechanisms remain elusive. AIM OF THE STUDY: This research attempted to determine both the effects and mechanisms of PNS involved in AMI treatment, namely, acute myocardial infarction-induced HF. MATERIALS AND METHODS: An AMI-induced HF model was generated by LAD ligation in rats. Transcriptome analyses were performed to identify differentially expressed genes (DEGs) and pathway enrichment. Real-time quantitative PCR (RT-qPCR) verified the HF-related genes differentially expressed after PNS treatment. Finally, a model of H9C2 cells subjected to OGD/R, which is equivalent to oxygen-glucose deprivation/reperfusion, was established to identify the potential mechanism of PNS in the treatment of HF. RESULTS: PNS ameliorated cardiac function and protected against structural alterations of the myocardium in HF rats. Transcriptome analysis showed that PNS upregulated 1749 genes and downregulated 1069 genes in the heart. Functional enrichment analysis demonstrated that the metabolic process was enriched among the DEGs. KEGG pathway analysis revealed that the PPAR signalling pathway was particularly involved in the protective function of PNS. The effects of PNS on the PPAR pathway were validated in vivo; PNS treatment effectively increased the expression of PPARα, RXRα, and PGC1α in rats with AMI-induced HF. In addition, PNS was shown to regulate the expression of downstream energy metabolism-related proteins. Interestingly, the addition of the PPARα inhibitor GW6471 abolished the beneficial effects of PNS. CONCLUSIONS: PNS exerts a cardioprotective function in a multicomponent and multitarget manner. The PPAR signalling pathway is one of the key pathways by which PNS protects against HF, and PPARα is a possible target for HF treatment.

2.
J Ethnopharmacol ; 266: 113404, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32976970

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Danqi Pill, composed of the root of Salvia miltiorrhiza Bunge and the root of Panax notoginseng, is effective in the clinical treatment of myocardial ischemia in coronary heart diseases. A number of studies have shown that autophagy plays an essential role in cardiac function and energy metabolism, and disordered autophagy is associated with the progression of heart failure. However, the effect and mechanism of Danqi pill on autophagy have not been reported yet. AIM OF THE STUDY: This study aims to elucidate whether Danqi pill restores autophagy to protect against HF and its potential mechanism. MATERIALS AND METHODS: Left anterior descending ligation was established to induce an HF rat model, H2O2-stimulated H9C2 cells model was conducted to clarify the effects and potential mechanism of Danqi pill. In vivo, Danqi pill (1.5 g/kg) were orally administered for four weeks and Fenofibrate (10 mg/kg) was selected as a positive group. In vitro, Danqi pill (10-200 µg/mL) was pre-cultured for 24 h and co-cultured with H2O2 stimulation for 4 h. Importantly, transmission electron microscopy and fluorescence GPF-mRFP-LC3 reporter system were combined to monitor autophagy flux. Furtherly, we utilized Compound C, a specific AMPK inhibitor, to validate whether the autophagy was mediated by AMPK-TSC2-mTOR pathway. RESULTS: Danqi pill significantly improved cardiac function and myocardial injury in HF rats. Intriguingly, Danqi pill potently regulated autophagy mainly by promoting the formation of autophagosomes in vivo. Further results demonstrated that expressions of p-AMPK (P < 0.001) and p-TSC2 (P < 0.001) in cardiac tissue were upregulated by Danqi pill, accompanied with downregulation of p-mTOR (P < 0.01) and p-ULK1(P < 0.01). In parallel with the vivo experiment, in vitro study indicated that Danqi pill dramatically restored autophagy flux and regulated expressions of critical autophagy-related molecules. Finally, utilization of Compound C abrogated the effects of Danqi pill on autophagy flux and the expressions of p-TSC2 (P < 0.05), p-mTOR (P < 0.01) and p-ULK1 (P < 0.05). CONCLUSION: Danqi pill could improve cardiac function and protect against cardiomyocytes injury by restoring autophagy via regulating the AMPK-TSC2-mTOR signaling pathway.


Assuntos
Autofagia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Insuficiência Cardíaca/prevenção & controle , Infarto do Miocárdio/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Insuficiência Cardíaca/etiologia , Masculino , Infarto do Miocárdio/complicações , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo
3.
J Cell Mol Med ; 24(18): 10677-10692, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32757377

RESUMO

Heart failure (HF) represents a major public health burden. Inflammation has been shown to be a critical factor in the progression of HF, regardless of the aetiology. Disappointingly, the majority of clinical trials targeting aspects of inflammation in patients with HF have been largely negative. Many clinical researches demonstrate that danshen has a good efficacy on HF, and however, whether danshen exerts anti-inflammatory effects against HF remains unclear. In our study, the employment of a water extracted and alcohol precipitated of danshen extract attenuated cardiac dysfunction and inflammation response in acute myocardial infarction-induced HF rats. Transcriptome technique and validation results revealed that TLR4 signalling pathway was involved in the anti-inflammation effects of danshen. In vitro, danshen reduced the release of inflammatory mediators in LPS-stimulated RAW264.7 macrophage cells. Besides, the LPS-stimulated macrophage conditioned media was applied to induce cardiac H9C2 cells injury, which could be attenuated by danshen. Furtherly, knock-down and overexpression of TLR4 were utilized to confirm that danshen ameliorated inflammatory injury via MyD88-dependent TLR4-TRAF6-NF-κB signalling pathway in cardiomyocytes. Furthermore, by utilizing co-immunoprecipitation, danshen was proved to suppress MD2/TLR4 complex formation and MyD88 recruitment. In conclusion, our results demonstrated that danshen ameliorates inflammatory injury by controlling MD2/TLR4-MyD88 complex formation and TLR4-TRAF6-NF-κB signalling pathway in acute myocardial infarction-induced HF.

4.
J Exp Clin Cancer Res ; 39(1): 93, 2020 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-32448281

RESUMO

BACKGROUND: Doxorubicin is effective in a variety of solid and hematological malignancies. Unfortunately, clinical application of doxorubicin is limited due to a cumulative dose-dependent cardiotoxicity. Dihydrotanshinone I (DHT) is a natural product from Salvia miltiorrhiza Bunge with multiple anti-tumor activity and anti-inflammation effects. However, its anti-doxorubicin-induced cardiotoxicity (DIC) effect, either in vivo or in vitro, has not been elucidated yet. This study aims to explore the anti-inflammation effects of DHT against DIC, and to elucidate the potential regulatory mechanism. METHODS: Effects of DHT on DIC were assessed in zebrafish, C57BL/6 mice and H9C2 cardiomyocytes. Echocardiography, histological examination, flow cytometry, immunochemistry and immunofluorescence were utilized to evaluate cardio-protective effects and anti-inflammation effects. mTOR agonist and lentivirus vector carrying GFP-TFEB were applied to explore the regulatory signaling pathway. RESULTS: DHT improved cardiac function via inhibiting the activation of M1 macrophages and the excessive release of pro-inflammatory cytokines both in vivo and in vitro. The activation and nuclear localization of NF-κB were suppressed by DHT, and the effect was abolished by mTOR agonist with concomitant reduced expression of nuclear TFEB. Furthermore, reduced expression of nuclear TFEB is accompanied by up-regulated phosphorylation of IKKα/ß and NF-κB, while TFEB overexpression reversed these changes. Intriguingly, DHT could upregulate nuclear expression of TFEB and reduce expressions of p-IKKα/ß and p-NF-κB. CONCLUSIONS: Our results demonstrated that DHT can be applied as a novel cardioprotective compound in the anti-inflammation management of DIC via mTOR-TFEB-NF-κB signaling pathway. The current study implicates TFEB-IKK-NF-κB signaling axis as a previously undescribed, druggable pathway for DIC.

5.
Front Pharmacol ; 11: 458, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32372956

RESUMO

Aim: Heart failure (HF) post-acute myocardial infarction (AMI) leads to a large number of hospitalizations and deaths worldwide. Danqi pill (DQP) is included in the 2015 national pharmacopoeia and widely applied in the treatment of HF in clinics in China. We examined whether DQP acted on glucose metabolism to protect against HF post-AMI via hypoxia inducible factor-1 alpha (HIF-1α)/peroxisome proliferator-activated receptor α co-activator (PGC-1α) pathway. Methods and Results: In this study, left anterior descending (LAD) artery ligation induced HF post-AMI rats and oxygen-glucose deprivation-reperfusion (OGD/R)-induced H9C2 cell model were structured to explore the efficacy and mechanism of DQP. Here we showed that DQP protected the heart against ischemic damage as evidenced by improved cardiac functions and attenuated inflammatory infiltration. The expressions of critical proteins involved in glucose intake and transportation such as GLUT4 and PKM2 were up-regulated, while negative regulatory proteins involved in oxidative phosphorylation were attenuated in the treatment of DQP. Moreover, DQP up-regulated NRF1 and TFAM, promoted mitochondrial biogenesis and increased myocardial adenosine triphosphate (ATP) level. The protection effects of DQP were significantly compromised by HIF-1α siRNA, suggesting that HIF-1α signaling pathway was the potential target of DQP on HF post-AMI. Conclusions: DQP exhibits the efficacy to improve myocardial glucose metabolism, mitochondrial oxidative phosphorylation and biogenesis by regulating HIF-1α/PGC-1α signaling pathway in HF post-AMI rats.

6.
J Ethnopharmacol ; 257: 112859, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32294506

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Danqi Pill (DQP), commonly known as a routinely prescribed traditional Chinese medicine (TCM), is composed of Salviae Miltiorrhizae Radix et Rhizoma and Notoginseng Radix et Rhizoma and effective in treating heart failure (HF) clinically due to their multicompound and multitarget properties. However, the exact active compounds and corresponding targets of DQP are still unknown. AIM OF THE STUDY: This study aimed to investigate active compounds and drug targets of DQP in heart failure based on the PPARs-RXRα pathway. MATERIALS AND METHODS: Network pharmacology was used to predict the compound-target interactions of DQP. Left anterior descending (LAD)-induced HF mouse model and oxygen-glucose deprivation/recovery (OGD/R)-induced H9C2 model were constructed to screen the active compounds of DQP. RESULTS: According to BATMAN-TCM (a bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine we previously developed), 24 compounds in DQP were significantly enriched in the peroxisome proliferator activated receptors-retinoid X receptor α (PPARs-RXRα) pathway. Among them, Ginsenoside Rb3 (G-Rb3) had the best pharmacodynamics against OGD/R-induced loss of cell viability, and it was selected to verify the compound-target interaction. In HF mice, G-Rb3 protected cardiac functions and activated the PPARs-RXRα pathway. In vitro, G-Rb3 protected against OGD/R-induced reactive oxygen species (ROS) production, promoted the expressions of RXRα and sirtuin 3 (SIRT3), thereafter improved the intracellular adenosine triphosphate (ATP) level. Immunofluorescent staining demonstrated that G-Rb3 could activate RXRα, and facilitate RXRα shifting to the nucleus. HX531, the specific inhibitor of RXRα, could abolish the protective effects of G-Rb3 on RXRα translocation. Consistently, the effect was also confirmed on RXRα siRNA cardiomyocytes model. Moreover, surface plasmon resonance (SPR) assays identified that G-Rb3 bound directly to RXRα with the affinity of KD = 10 × 10-5 M. CONCLUSION: By integrating network pharmacology and experimental validation, we identified that as the major active compound of DQP, G-Rb3 could ameliorate ROS-induced energetic metabolism dysfunction, maintain mitochondrial function and facilitate energy metabolism via directly targeting on RXRα. This study provides a promising strategy to dissect the effective patterns for TCM and finally promote the modernization of TCM.

7.
Biomed Pharmacother ; 126: 109862, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32120157

RESUMO

Hepatocellular carcinoma (HCC), as the major primary liver cancer, is one of the most prevalent malignant diseases with a high mortality rate worldwide. Prior studies have demonstrated that dihydroartemisinin (DHA), the semisynthetic derivative of artemisinin, possesses anti-HCC activity. The multikinase inhibitor sorafenib has been approved for the treatment of HCC. However, the anti-HCC efficacy of DHA combined with sorafenib has not been reported. In this study, we confirmed the significantly enhanced anti-HCC efficacy of DHA in combination with sorafenib compared with that of each agent alone. Tandem Mass Tag (TMT) peptide labeling coupled with LC-MS/MS was used to quantify the proteins from the control, DHA, sorafenib, and DHA + sorafenib groups. In total, 532, 426, 628 differentially expressed proteins (fold change >1.20 or <0.83 and P-value <0.05) were determined by comparing DHA versus control, sorafenib versus control and DHA + sorafenib versus control groups, respectively. Moreover, optimized screening was performed, and 101 optimized differentially expressed proteins were identified. The results of functional analysis of the optimized differentially expressed proteins suggested that they were enriched in cell components such as membrane-bound vesicles, extracellular vesicles, and organelle lumens, and they were mainly involved in biological processes such as cellular component organization, response to stress, and response to chemicals; in addition, they were related to various molecular functions such as protein binding, chromatin binding and enzyme binding. KEGG pathway analysis showed that the optimized differentially expressed proteins were enriched in pyrimidine metabolism, RNA polymerase, base excision repair, and osteoclast differentiation. Protein-protein interaction (PPI) networks of some of the optimized upregulated proteins suggested that they might not only affect vitamin and fat digestion and absorption but may also be involved in tight junctions. In the PPI network, some of the optimized downregulated proteins were enriched in base excision repair, RNA polymerase, purine metabolism, pyrimidine metabolism and mucin type O-glycan biosynthesis. Overall, this research explored the anti-HCC efficacy of DHA combined with sorafenib by using the TMT-based quantitative proteomics technique and might facilitate the understanding of the related anti-HCC molecular mechanism.

8.
J Ethnopharmacol ; 252: 112573, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31945401

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Qishen Granule (QSG) is a prevailing traditional Chinese medicine formula that displays impressive cardiovascular protection in clinical. However, underlying mechanisms by which QSG alleviates endoplasmic reticulum (ER) stress-induced apoptosis in myocardial ischemia still remain unknown. AIM OF THE STUDY: This study aims to elucidate whether QSG ameliorates ER stress-induced myocardial apoptosis to protect against myocardial ischemia via inositol requiring enzyme 1 (IRE-1)-αBcrystallin (CRYAB) signaling pathway. MATERIALS AND METHODS: Left anterior descending (LAD) ligation induced-ischemic heart model and oxygen-glucose deprivation-reperfusion (OGD/R)-induced H9C2 cells injury model were established to clarify the effects and potential mechanism of QSG. Ethanol extracts of QSG (2.352 g/kg) were orally administered for four weeks and Ginaton Tablets (100 mg/kg) was selected as a positive group in vivo. In vitro, QSG (800 µg/ml) or STF080310 (an inhibitor of IRE-1, 10 µM) was co-cultured under OGD/R in H9C2 cells. Inhibition of IRE-1 was conducted in H9C2 cells to further confirm the exact mechanism. Finally, to define the active components of anti-cardiomyocyte apoptosis in QSG which absorbed into the blood, we furtherly used the OGD/R-induced cardiomyocyte apoptosis model to evaluate the effects. RESULTS: QSG treatment improved cardiac function, ameliorated inflammatory cell infiltration and myocardial apoptosis. Similar effects were revalidated in OGD/R-induced H9C2 injury model. Western blots demonstrated QSG exerted anti-apoptotic effects by regulating apoptosis-related proteins, including increasing Bcl-2 and caspase 3/12, reducing the expressions of Bax and cleaved-caspase 3/12. Mechanistically, the IRE-1-CRYAB signaling pathway was significantly activated by QSG. Co-treatment with STF080310, the IRE-1 specific inhibitor significantly compromised the protective effects of QSG in vitro. Especially, the active components of QSG including Formononetin, Tanshinone IIA, Tanshinone I, Cryptotanshinon and Harpagoside showed significantly anti-apoptosis effects. CONCLUSION: QSG protected against ER stress-induced myocardial apoptosis via the IRE-1-CRYAB pathway, which is proposed as a promising therapeutic target for myocardial ischemia.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotônicos/uso terapêutico , Cristalinas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Cardiotônicos/farmacologia , Linhagem Celular , Cristalinas/genética , Masculino , Proteínas Associadas aos Microtúbulos/genética , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Miocárdio/patologia , Ratos Sprague-Dawley , Transdução de Sinais
9.
Biomed Pharmacother ; 120: 109483, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31629252

RESUMO

Lung cancer is the leading cause of cancer-related deaths. Ginsenoside Rg3 is the main ingredient of Ginseng which is used to treat non-small cell lung cancer (NSCLC). It has been found to enhance the efficiency of chemotherapy thereby reducing its side effects. Previous studies found that ginsenoside Rg3 can reduce the occurrence of NSCLC by inducing DNA damage. Yet, its anti-DNA damaging effects and mechanisms in tumor cells are still not fully understood. This study explored the effect of ginsenoside Rg3 on DNA repair and VRK1/P53BP1 signaling pathway. Ginsenoside Rg3 treatment significantly decreased the incidence and invasionin a mouse model of lung cancer induced by urethane. The results of cell survival assay and single cell gel electrophoresis showed that ginsenoside Rg3 protected lung adenocarcinoma cells from DNA damage as well as inhibited the proliferation of tumor cells. Ginsenoside Rg3 increased the mRNA and protein expression of VRK1 in NSCLC cells as measured by RT-qPCR and western blot, respectively. These findings suggests that ginsenoside Rg3 regulates VRK1 signaling. Immunofluorescence assays showed that P53BP1 and VRK1 protein level increased, and the VRK1 protein translocated between the nuclei and cytoplasm. Finally, this conclusion was confirmed by the reverse validation in VRK1-knockdown cells. Taken together, these results show that ginsenoside Rg3 upregulate VRK1 expression and P53BP1 foci formation in response to DNA damage thereby inhibiting the tumorigenesis and viability of cancer cells. These findings reveal the role of Rg3 in lung cancer and provides therapeutic targets for developing new drugs in the prevention and treatment of lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , Ginsenosídeos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Células A549 , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Panax/química , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacos
10.
Biomed Pharmacother ; 120: 109487, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31577975

RESUMO

Heart failure (HF) leads to an increase in morbidity and mortality globally. Disorders of energy metabolism and apoptosis of cardiomyocytes are critically involved in the progression of HF. Ginsenoside Rb3 (G-Rb3) is a natural product derived from ginseng that has cardio-protective effect. The pharmacological mechanism of G-Rb3 in the treatment of HF remains to be clarified. In this study, we aimed to explore the regulative effects of G-Rb3 on fatty acids oxidation and apoptosis by in vivo and in vitro studies. Myocardial infarction (MI)-induced HF mice model and a cellular H9C2 injury model was induced by oxygen-glucose deprivation/reperfusion (OGD/R) stimulation. The results showed that G-Rb3 could protect heart functions in MI-induced HF model. G-Rb3 treatment up-regulated expressions of key enzymes involved in ß-oxidation of fatty acids, including carnitine palmitoyltransterase-1α (CPT-1α), acyl-CoA dehydrogenase long chain (ACADL) and the major mitochondrial deacetylase enzyme sirtuin 3 (SIRT3). The upstream transcriptional regulator, peroxisome proliferator-activated receptor α (PPARα), was also up-regulated by G-Rb3 treatment. In vitro study demonstrated that G-Rb3 could protect mitochondrial membrane integrity and exert anti-apoptotic effects, in addition to regulating fatty acids oxidation. Impressively, after cells were co-treated with PPARα inhibitor, the regulative effects of G-Rb3 on energy metabolism and apoptosis were abrogated. Our study suggests that G-Rb3 is a promising agent and PPARα is potential target in the management of HF.


Assuntos
Apoptose/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Ginsenosídeos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , PPAR alfa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Oxirredução/efeitos dos fármacos , Panax/química , Substâncias Protetoras/farmacologia , Regulação para Cima/efeitos dos fármacos
11.
Cancers (Basel) ; 11(7)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261758

RESUMO

Clinical use of the anti-cancer drug doxorubicin (DOX) is largely limited due to its severe cardiotoxicity. Dysregulation of autophagy is implicated in DOX-induced cardiotoxicity (DIC). Prior studies have indicated that Beclin1 and lysosomal-associated membrane proteins-1 (LAMP1) are critical mediators of autophagy. In this work, by assessing autophagic flux in a DOX-stimulated H9C2 model, we observed autolysosome accumulation caused by interruption of autolysosome degradation. Tanshinone IIA (TSA) is a well-known small molecule that exerts impressive cardioprotective effects on heart failure. Here, we investigated the regulation of TSA in DOX-treated zebrafish, mice, and H9C2 models. Results demonstrated that TSA remarkably improved heart function and reversed pathological changes in vivo, while TSA restored autophagic flux by promoting autolysosome degradation and autophagosome formation. Further experiments demonstrated that these effects were mediated through upregulation of Beclin1 and LAMP1. The mTOR agonist MHY1485 was shown to abrogate the effect of TSA via the UNC-51-like kinase 1 (ULK1)-Beclin1/TFEB-LAMP1 signaling pathway in vitro, demonstrating that TSA protects against DIC by promoting autophagy via the Beclin1/LAMP1 signaling pathway. We further employed a U87 model to assess whether TSA would compromise the antitumor activity of DOX. Intriguingly, the co-treatment of TSA was able to synergistically inhibit proliferative activity. Collectively, in this study we uncover the novel insight that TSA is able to reduce the cardiotoxicity of DOX without compromising antitumor activity.

12.
Phytomedicine ; 62: 152949, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31102891

RESUMO

BACKGROUND: Cardiac fibrosis is a common pathological progress of cardiovascular disease resulting from the excessive accumulation of extracellular matrix (ECM). Transforming growth factor (TGF)-ß/SMADs pathway is a canonical signaling pathway which directly induces expressions of ECM related genes. Qishen Granule (QSG), a traditional Chinese formula developed from Zhen-Wu Decoration for heart failure (HF), has been proven to have definite therapeutic effects on cardiac fibrosis. However, its underlying mechanisms remain unclear. PURPOSE: To investigate the effects of QSG on TGF-ß pathway and the downstream mediators including Smad3 and Glycogen synthase kinase (GSK)-3ß. METHODS: HF model was induced by ligation of left coronary artery on male Sprague-Dawley (SD) rats. Rat were randomly divided into four groups including sham group, model group, QSG group and Fosinopril control group. Rats in each group were treated for 28 days, and 2D echocardiography was adopted to evaluate the heart function. The degree of cardiac fibrosis was assessed by Hematoxylin-Eosin (HE), Masson's trichrome and Picrosirius red (PSR) staining. Contents of collagen Ⅰ and Ⅲ were assessed by immunohistochemical method. Expressions of genes and proteins in TGF-ß/SMADs and PI3K-GSK-3 signaling pathways were detected by Real-time Fluorescence Quantitative PCR (RT-qPCR) and Western blot respectively. TGF-ß1-treated cardiac fibroblasts of neonatal SD rats were adopted for in vitro studies. RESULTS: 28 days after the surgery, cardiac ejection fraction (EF) and fractional shortening (FS) values in the model group showed a remarkable decrease, indicating the induction of HF model. QSG and Fosinopril elevated the EF and FS values, demonstrating cardio-protective effects. Pathological staining and immunohistochemistry showed that the contents of collagen I and III dramatically increased in the cardiac tissue of the model group compared with the sham group while QSG treatment reduced collagen contents. Furthermore, expressions of TGF-ß1, p-Smad3 and p-GSK-3ß were significantly decreased in the QSG treatment group compared with the model group, suggesting that the QSG may attenuate cardiac fibrosis through regulating TGF-ß/Smad3 pathway. In vitro study further showed that the productions of type Ⅰ and Ⅲ collagen and α-smooth muscle actin (α-SMA) of cardiac fibroblasts were significantly increased by incubation with TGF-ß1. QSG could markedly reduce the secretion of collagen Ⅰ and Ⅲ and α-SMA expression. Protein expressions of p-Smad3, PI3K, p-Akt and p-GSK-3ß were significantly up-regulated by stimulation of TGF-ß1. Treatment with QSG could suppress the activity of Smad3 and PI3K-GSK-3ß signaling pathway in cardiac fibroblasts. CONCLUSION: QSG improves cardiac function through inhibiting cardiac fibrosis. The anti-fibrotic effects are potentially mediated by the inhibition of the TGF-ß/Smad3 pathway and the phosphorylation of GSK-3ß.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Insuficiência Cardíaca/patologia , Miocárdio/patologia , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Colágeno Tipo I/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose , Coração/efeitos dos fármacos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
13.
Biomed Pharmacother ; 112: 108599, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798134

RESUMO

Heart failure (HF) leads to an increase in morbidity and mortality globally. Tanshinone IIA is an important traditional Chinese medicine monomer and has been shown to have remarkable protective effect against HF. Autophagy is critically involved in the progression of HF. The effect of Tanshinone IIA on autophagy has not been clarified yet. In this study, left anterior descending (LAD) ligation was used to induce HF model and a hydrogen peroxide-(H2O2-)-induced H9C2 cell injury model was established. in vivo, echocardiography results showed that Tanshinone IIA could significantly improve heart function. Western Blot result showed that Tanshinone IIA treatment enhanced autophagy and regulated expressions of key autophagy-related molecules, including protein 1 light chain 3 (LC3), p62 and Beclin1. Tanshinone IIA also inhibited apoptosis and regulated expressions of key apoptotic protein, including B cell lymphoma-2 (Bcl-2) and Bcl-2 Associated X Protein (Bax) and cleaved caspase-3 and -7. Further experiments demonstrated that the effects of Tanshinone IIA were mediated through upregulation of AMP-activated protein kinase (AMPK) and downregulation of mammalian target of rapamycin (mTOR) simultaneously. The mTOR agonist MHY1485 could abrogate the therapeutic effect of Tanshinone IIA in vitro. In conclusion, Tanshinone IIA protects cardiomyocytes and improves cardiac function by inhibiting apoptosis and inducing autophagy via activation of the AMPK-mTOR signaling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Abietanos/uso terapêutico , Autofagia/efeitos dos fármacos , Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/metabolismo , Infarto do Miocárdio/metabolismo , Abietanos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Autofagia/fisiologia , Cardiotônicos/farmacologia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Masculino , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/tratamento farmacológico , Ratos , Ratos Sprague-Dawley
14.
Discov Med ; 28(153): 139-147, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31926585

RESUMO

As an important derivative of the herb medicine Artemisia annua L., dihydroartemisinin (DHA) exhibits anti-hepatocellular carcinoma (HCC) activities. However, the underlying molecular mechanism is still unclear. In the present study, the network pharmacology method was used to construct the ingredient-target network of DHA that was responsible for the anti-HCC effect and 11 targets including ALB, ATP5A1, CCT3, CLIC1, ENO1, HSPA8, HSPB1, NPM1, PPIA, PRDX1, and ZYX were selected. Functional category analysis showed that the anti-HCC effect of DHA might be related to the biological process of cell-cell adhesion. ß1,6-branching of N-linked carbohydrate as one kind of glycosylation could participate in regulating cell-cell adhesion and has been reported to be overexpressed in HCC cells and tissues. Further lectin immunofluorescence and lectin blot analysis showed that DHA could down-regulate the expression of ß1,6-branching of N-linked carbohydrate by suppressing the transcription of MGAT5. This study will provide a scientific basis for the elucidation of the mechanisms of DHA in anti-HCC from the angle of glycosylation.


Assuntos
Antineoplásicos/farmacologia , Artemisininas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Artemisininas/uso terapêutico , Carcinoma Hepatocelular/patologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Glicosilação/efeitos dos fármacos , Humanos , Lectinas/metabolismo , Neoplasias Hepáticas/patologia , N-Acetilglucosaminiltransferases/antagonistas & inibidores , N-Acetilglucosaminiltransferases/metabolismo
15.
Front Pharmacol ; 9: 1414, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30564122

RESUMO

Coronary artery disease (CAD) is one of the leading causes of deaths worldwide. Energy metabolism disorders, including a reduction in fatty acids oxidation and upregulation of glycolysis pathway, are involved in the process of CAD. Therapeutic angiogenesis has become a promising treatment for CAD. Traditional Chinese medicines, such as Danqi Pill (DQP), have been proven to be effective in treating CAD in China for many years. However, the pro-angiogenic effects of DQP based on fatty acids oxidation are still unknown and the mechanism is worthy of investigation. In this study, left anterior descending (LAD) coronary artery was ligated to induce the CAD models in vivo, and cardiac functions were examined using echocardiography. Human umbilical vein endothelial cells (HUVEC) were subjected to H2O2-induced oxidative stress in vitro. The effects of DQP on CAD rat models and in vitro HUVEC were detected. Our results showed that DQP had cardio-protective effects in rat model. The intensity of capillaries in the marginal area of infarction of the rat heart was increased remarkably in DQP group, and the expression of PPARα and VEGF-2 were increased. The key enzymes involved in the transportation and intake of fatty acids, including CPT1A and CD36, both increased. In H2O2-induced endothelial cells injury models, DQP also showed protective roles and promoted capillary-like tube formation. DQP up-regulated key enzymes in fatty acids oxidation in H2O2-treated HUVEC. In addition, inhibition of CPT1A compromised the pro-angiogenic effects of DQP. In conclusion, fatty acids oxidation axis PPARα-CD36-CPT1A was involved in the pro-angiogenic roles of DQP against CAD. Cardiac CPT1A may serve as a target in therapeutic angiogenesis in clinics.

16.
Front Pharmacol ; 9: 1209, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405421

RESUMO

Aim: Danqi Pill (DQP), a Chinese medicine frequently prescribed in China, has been approved to improve cardiac function by regulating cardiac energy metabolism in heart failure (HF) after acute myocardial infarction (AMI) patients. The aim of this study was to explore whether the mechanism of DQP is associated to the lipid and glucose metabolism mediated via PPARγ (peroxisome proliferator-activated receptor gamma) pathway both in vivo and in vitro. Materials and Methods: Model of HF after AMI was established with ligation of left anterior descending artery on Sprague-Dawley (SD) rats. Twenty-eight days after treatment, hematoxylin-eosin (HE) staining was applied to visualize cardiomyocyte morphological changes. High performance liquid chromatography (HPLC) was performed to assess the contents of adenosine phosphates in heart. Positron emission tomography and computed tomography (PET-CT) was conducted to evaluate the cardiac glucose metabolism. Expressions of key molecules such as PPARγ, sterol carrier protein 2 (SCP2) and long chain acyl CoA dehydrogenase (ACADL) were measured by Western blotting (WB) and immunohistochemistry (IHC). Oxygen-glucose deprivation-reperfusion (OGD/R)-induced H9C2 injury cardiomyocyte model was adopted for potential mechanism research in vitro. Results: Treatment with DQP rescued hearts from structural and functional damages as well as inflammatory infiltration. Levels of adenosine triphosphate (ATP) and energy charge (EC) in DQP group were also up-regulated compared to model group. Further results demonstrated that critical enzymes both in lipid metabolism and glucose metabolism compromised in model group compared to sham group. Intriguingly, DQP could up-regulate critical enzymes including ACADL and SCP2 in lipid metabolism accompanying with promoting effect on molecules in glycolysis simultaneously. Results on upstreaming signaling pathway demonstrated that DQP could dramatically increase the expressions of PPARγ. In vitro study suggested the efficacy of DQP could be blocked by T0070907, a selective PPARγ inhibitor. Conclusion: DQP has cardioprotective effect in improving cardiac function and energy metabolism through regulating lipid and glucose metabolism. The effects may be mediated by PPARγ pathway.

17.
Front Physiol ; 9: 505, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867551

RESUMO

Aim: Heart failure (HF) post-acute myocardial infarction (AMI) contributes to increasing mortality and morbidity worldwide. Baoyuan decoction (BYD) is a well-known traditional Chinese medicine formula that exhibits myocardial protection clinically. The aim of this study was to identify the effects of BYD on oxidative stress-induced apoptosis in HF post-AMI and characterize the underlying mechanism. Methods and Results: In our study, we constructed left anterior descending (LAD)-induced AMI rat models and a macrophage-conditioned media (CM)-induced H9C2 injury model. In vivo, BYD could protect cardiac functions, decrease inflammatory cell infiltration and inhibit oxidative stress-induced apoptosis. In vitro, BYD inhibited cellular apoptosis and regulated the expressions of key apoptotic molecules, including reducing the expression of B cell lymphoma-2 (Bcl-2) associated X protein (Bax) and cleaved caspase-3 and -9. Interestingly, the P38 mitogen-activated protein kinase (MAPK)-αB-crystallin (CRYAB) signaling pathway was activated by BYD treatment, and the P38 MAPK inhibitor SB203580 could reverse the protective effects of BYD. Conclusion: This study identified that BYD protected against oxidative stress-induced myocardial apoptosis via the P38 MAPK-CRYAB pathway. CRYAB may become a novel therapeutic target for AMI.

18.
Front Pharmacol ; 9: 428, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29755358

RESUMO

Ischemic heart disease (IHD) is one of the primary causes of death around the world. Therapeutic angiogenesis is a promising innovative approach for treating IHD, improving cardiac function by promoting blood perfusion to the ischemic myocardium. This treatment is especially important for targeting patients that are unable to undergo angioplasty or bypass surgery. Chinese herbal medicines have been used for more than 2,500 years and they play an important role alongside contemporary medicines in China. Growing evidence in animal models show Chinese herbal medicines can provide therapeutic effect on IHD by targeting angiogenesis. Identifying the mechanism in which Chinese herbal medicines can promote angiogenesis in IHD is a major topic in the field of traditional Chinese medicine, and has the potential for advancing therapeutic treatment. This review summarizes the progression of research and highlights potential pro-angiogenic mechanisms of Chinese herbal medicines in IHD. In addition, an outline of the limitations of Chinese herbal medicines and challenges they face will be presented.

19.
PLoS Genet ; 14(1): e1007165, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29370161

RESUMO

Intellectual disability (ID), one of the most common human developmental disorders, can be caused by genetic mutations in Cullin 4B (Cul4B) and cereblon (CRBN). CRBN is a substrate receptor for the Cul4A/B-DDB1 ubiquitin ligase (CRL4) and can target voltage- and calcium-activated BK channel for ER retention. Here we report that ID-associated CRL4CRBN mutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the SCFFbxo7 ubiquitin ligase for proteasomal degradation. Glioma cell lines harbouring CRBN mutations record density-dependent decrease of BK currents, which can be restored by blocking Cullin ubiquitin ligase activity. Importantly, mice with neuron-specific deletion of DDB1 or CRBN express reduced BK protein levels in the brain, and exhibit similar impairment in learning and memory, a deficit that can be partially rescued by activating the BK channel. Our results reveal a competitive targeting of the BK channel by two ubiquitin ligases to achieve exquisite control of its stability, and support changes in neuronal excitability as a common pathogenic mechanism underlying CRL4CRBN-associated ID.


Assuntos
Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Aprendizagem/fisiologia , Memória/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Proteólise , Proteínas Ligases SKP Culina F-Box/antagonistas & inibidores , Complexos Ubiquitina-Proteína Ligase/metabolismo , Ubiquitina-Proteína Ligases/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Células Cultivadas , Feminino , Células HEK293 , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Ligases SKP Culina F-Box/metabolismo , Complexos Ubiquitina-Proteína Ligase/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
20.
Sci Rep ; 7(1): 14749, 2017 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-29116138

RESUMO

Peripheral vascular occlusive disease (PVOD) is a common manifestation of atherosclerosis, and it has a high rate of morbidity. Therapeutic angiogenesis would re-establish blood perfusion and rescue ischemic tissue. Vascular endothelial growth factor (VEGF) induces angiogenesis and can potentially be used to treat ischemic diseases, yet in clinical trials VEGF has not fulfilled its full potential with side effects. Whether amino acids promote angiogenesis and the molecular mechanisms are largely unknown. Here we showed that (1) Glycine significantly promoted angiogenesis both in vitro and in vivo and effectively protected mitochondrial function. (2) Activation of glycine transporter 1(GlyT1) induced by VEGF led to an increase in intracellular glycine. (3) Glycine directly bounded to voltage dependent anion channel 1 (VDAC1) on the mitochondrial outer membrane and inhibited its opening. These original results highlight glycine as a necessary mediator in VEGF signalling via the GlyT1-glycine-mTOR-VDAC1 axis pathway. Therefore, the findings in this study are of significance providing new mechanistic insights into angiogenesis and providing better understanding of glycine function in angiogenesis, which may provide valuable information for development of novel therapeutic targets for the treatment of angiogenic vascular disorders.


Assuntos
Glicina/metabolismo , Neovascularização Patológica/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Canal de Ânion 1 Dependente de Voltagem/antagonistas & inibidores , Animais , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo
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