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1.
Gynecol Oncol ; 170: 59-69, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36630845

RESUMO

OBJECTIVES: This study aimed to investigate the frequency and clinicopathological characteristics of HPV-independent cervical squamous cell carcinoma (CSCC). METHODS: A total of 3869 patients with CSCC from 2017 to 2021 were searched. p16INK4a immunochemistry (IHC), two HPV-DNA(L1) polymerase chain reactions and HPV mRNA in situ hybridization were performed. Viral copies were detected using the 21 HPV quantitative test. RESULTS: Six cases showed negative results in all four assays (group 1, 0.16%). Twenty-seven cases showed discordant results (group 2), and 3836 cases presented all-positive results (group 3). p16INK4a IHC showed similar sensitivity, specificity, and positive predictive value compared to the other three direct HPV assays. 21 HPV genotyping showed 100% of negative predictive value. HPV copies were extremely lower in Group 2 than in Group 3 (P < 0.01), but were not significantly different from those in Group 1. Older age, advanced FIGO stage (III-IV) and abnormal p53 (p53abn) IHC were independent predictors of HPV-negative status in univariate and multivariate logistic regression. Group 2 had similar proportions of age >60 years and p53abn IHC with Group 1, but had fewer cases with advanced FIGO stage (P < 0.05) and TILs (P < 0.05). Groups 1 and 2 had worse disease-free survival (DFS) and disease-specific survival (DSS) than Group 3 (P < 0.01), while no significant difference was found between these two groups. HPV-negative status was a risk factor for both DFS (P < 0.05) and DSS (P < 0.01) in univariate but not multivariate Cox regression. CONCLUSIONS: Joint detection of multiple technologies and evaluation of clinicopathological characteristics discriminate between HPV-independent and low-copy HPV-associated CSCC cases that present similar prognoses. Additional attention should be paid to these low-copy HPV-associated cases in clinical practice.


Assuntos
Carcinoma de Células Escamosas , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Pessoa de Meia-Idade , Inibidor p16 de Quinase Dependente de Ciclina/análise , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/patologia , Neoplasias do Colo do Útero/patologia , DNA Viral/análise , Papillomaviridae/genética
2.
Org Biomol Chem ; 20(8): 1754-1758, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35147633

RESUMO

Development of an efficient process that employs easy to handle and shelf-stable reagents for the synthesis of trifluoromethylselenylated heterocyclics remains a daunting challenge in organic synthesis. Herein, we report a green and practical protocol using trifluoromethyl tolueneselenosulfonate and ortho-hydroxyarylenaminones to access a wide range of chromone derivatives under photocatalyst and oxidant free conditions. This reaction proceeded smoothly under photoirradiation conditions and various functional groups were tolerant of the reaction conditions.

3.
Org Biomol Chem ; 19(37): 8128-8132, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34473178

RESUMO

A convenient and efficient approach to (E)-2-iodo-3-(methylthio)acrylate has been developed through direct iodothiomethylation of alkynes with aqueous HI and DMSO under mild conditions. This novel protocol has demonstrated a unique difunctionalization of electron-deficient alkynes with a broad substrate scope and excellent functional-group tolerance. Preliminary mechanistic studies indicated that prior diiodination of alkynes, followed by nucleophilic substitution with in situ generated DMS led to the formation of (E)-2-iodo-3-(methylthio)acrylate.


Assuntos
Alcinos , Iodo , Acrilatos , Catálise , Elétrons
4.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071043

RESUMO

A de novo missense variant in Rag GTPase protein C (RagCS75Y) was recently identified in a syndromic dilated cardiomyopathy (DCM) patient. However, its pathogenicity and the related therapeutic strategy remain unclear. We generated a zebrafish RragcS56Y (corresponding to human RagCS75Y) knock-in (KI) line via TALEN technology. The KI fish manifested cardiomyopathy-like phenotypes and poor survival. Overexpression of RagCS75Y via adenovirus infection also led to increased cell size and fetal gene reprogramming in neonatal rat ventricle cardiomyocytes (NRVCMs), indicating a conserved mechanism. Further characterization identified aberrant mammalian target of rapamycin complex 1 (mTORC1) and transcription factor EB (TFEB) signaling, as well as metabolic abnormalities including dysregulated autophagy. However, mTOR inhibition failed to ameliorate cardiac phenotypes in the RagCS75Y cardiomyopathy models, concomitant with a failure to promote TFEB nuclear translocation. This observation was at least partially explained by increased and mTOR-independent physical interaction between RagCS75Y and TFEB in the cytosol. Importantly, TFEB overexpression resulted in more nuclear TFEB and rescued cardiomyopathy phenotypes. These findings suggest that S75Y is a pathogenic gain-of-function mutation in RagC that leads to cardiomyopathy. A primary pathological step of RagCS75Y cardiomyopathy is defective mTOR-TFEB signaling, which can be corrected by TFEB overexpression, but not mTOR inhibition.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/fisiologia , Cardiomiopatia Dilatada/genética , Mutação com Ganho de Função , Proteínas Monoméricas de Ligação ao GTP/genética , Mutação de Sentido Incorreto , Mutação Puntual , Serina-Treonina Quinases TOR/antagonistas & inibidores , Transporte Ativo do Núcleo Celular , Substituição de Aminoácidos , Animais , Autofagia , Sequência de Bases , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/biossíntese , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Cardiomiopatia Dilatada/terapia , Células Cultivadas , Técnicas de Introdução de Genes , Técnicas de Inativação de Genes , Ventrículos do Coração/citologia , Humanos , Camundongos , Proteínas Monoméricas de Ligação ao GTP/fisiologia , Miócitos Cardíacos/metabolismo , Fenótipo , Ratos Wistar , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição , Peixe-Zebra , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologia
5.
Molecules ; 26(5)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800264

RESUMO

Cardiotoxicity is one of the main side effects of doxorubicin (Dox) treatment. Dox could induce oxidative stress, leading to an opening of the mitochondrial permeability transition pore (mPTP) and apoptosis in cardiomyocytes. Previous studies have shown that Cryptotanshinone (Cts) has potential cardioprotective effects, but its role in Dox-induced cardiotoxicity (DIC) remains unknown. A Dox-stimulated H9C2 cell model was established. The effects of Cts on cell viability, reactive oxygen species (ROS), superoxide ion accumulation, apoptosis and mitochondrial membrane potential (MMP) were evaluated. Expressions of proteins in Akt-GSK-3ß pathway were detected by Western blot. An Akt inhibitor was applied to investigate the effects of Cts on the Akt-GSK-3ß pathway. The effects of Cts on the binding of p-GSK-3ß to ANT and the formation of the ANT-CypD complex were explored by immunoprecipitation assay. The results showed that Cts could increase cell viability, reduce ROS levels, inhibit apoptosis and protect mitochondrial membrane integrity. Cts increased phosphorylated levels of Akt and GSK-3ß. After cells were co-treated with an Akt inhibitor, the effects of Cts were abolished. An immunoprecipitation assay showed that Cts significantly increased GSK-3ß-ANT interaction and attenuated Dox-induced formation of the ANT-CypD complex, thereby inhibiting opening of the mPTP. In conclusion, Cts could ameliorate oxidative stress and apoptosis via the Akt-GSK-3ß-mPTP pathway.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/prevenção & controle , Fenantrenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenantrenos/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
J Cell Mol Med ; 22(10): 4794-4806, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30044532

RESUMO

Ovarian cancer is the leading malignancy of the female reproductive system and is associated with inconspicuous early invasion and metastasis. We have previously reported that the oncogene OTUB1 plays a crucial role in ovarian cancer progression, but the role of its isoform, the non-coding RNA OTUB1-isoform2, in ovarian cancer is still elusive. Here, we reported that OTUB1-isoform2 expression in ovarian cancer tissues was significantly higher than that in the paired paratumorous tissues (P < .01). The patients with high expression of OTUB1-isoform2 had larger tumours than those with low expression (P < .05). The high expression of OTUB1-isoform2 was correlated with the involvement of bilateral ovaries (P < .05), lymph node metastasis (P < .05), vascular invasion (P < .05), greater omentum involvement (P < .01), fallopian tube involvement (P < .05), advanced FIGO stages (P < .01) and recurrence (P < .01). Moreover, OTUB1-isoform2 served as an independent negative prognostic predictor for disease-free survival (DFS) and disease-specific survival (DSS). Overexpression of OTUB1-isoform2 in the ovarian cancer cells stimulated cell proliferation, migration and invasion both in vitro and in vivo. In summary, our study suggested that OTUB1-isoform2 is a novel prognostic biomarker with independent oncogenic functions for ovarian cancer.


Assuntos
Biomarcadores Tumorais/genética , Cisteína Endopeptidases/genética , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/genética , Fator 1 de Ribosilação do ADP/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Enzimas Desubiquitinantes/genética , Progressão da Doença , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Prognóstico , Isoformas de Proteínas/genética , RNA Longo não Codificante/genética
7.
Org Biomol Chem ; 16(46): 9064-9068, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30456395

RESUMO

A simple and practical method for the synthesis of alkenyl dithiocyanates and alkenyl diselenocyanates has been developed via stereoselective difunctionalization of alkynes with NaSCN or KSeCN at room temperature. Through this methodology, a series of alkenyl dithiocyanates and alkenyl diselenocyanates could be efficiently and conveniently obtained in moderate to good yields under mild and metal-free conditions by the simple use of oxone and PhI(OAc)2 as the oxidants.

8.
J Org Chem ; 81(1): 51-6, 2016 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-26673953

RESUMO

An interesting base-promoted protocol for the synthesis of 2-keto(hetero)aryl benzox(thi)azoles has been developed. Starting from commercially available 2-amino(thio)phenols and α,α-dihaloketones, moderate to good yields of the corresponding heterocycles can be achieved. Notably, only EtNH2 was required as the promoter here, and the reaction can be easily performed on a large scale.

9.
BMC Complement Altern Med ; 16(1): 514, 2016 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-27955667

RESUMO

BACKGROUND: DanQi pill (DQP) is prescribed widely in China and has definite cardioprotective effect on coronary heart disease. Our previous studies proved that DQP could effectively regulate plasma levels of high density lipoprotein (HDL) and low density lipoprotein (LDL). However, the regulatory mechanisms of DQP and its major components Salvianolic acids and Panax notoginseng saponins (DS) on lipid metabolism disorders haven't been comprehensively studied so far. METHODS: Rat model of coronary heart disease was induced by left anterior descending (LAD) artery ligation operations. Rats were divided into sham, model, DQP treated, DS treated and positive drug (clofibrate) treated groups. At 28 days after surgery, cardiac functions were assessed by echocardiography. Expressions of transcription factors and key molecules in energy metabolism pathway were measured by reverse transcriptase polymerase chain reaction or western blotting. RESULTS: In ischemic heart model, cardiac functions were severely injured but improved by treatments of DQP and DS. Expression of LPL was down-regulated in model group. Both DQP and DS could up-regulate the mRNA expression of LPL. Membrane proteins involved in lipid transport and uptake, such as FABP4 and CPT-1A, were down-regulated in ischemic heart tissues. Treatment with DQP and DS regulated lipid metabolisms by up-regulating expressions of FABP4 and CPT-1A. DQP and DS also suppressed expression of cytochrome P450. Furthermore, transcriptional factors, such as PPARα, PPARγ, RXRA and PGC-1α, were down-regulated in ischemic model group. DQP and DS could up-regulate expressions of these factors. However, DS showed a better efficacy than DQP on PGC-1α, a coactivator of PPARs. Key molecules in signaling pathways such as AKT1/2, ERK and PI3K were also regulated by DQP and DS simultaneously. CONCLUSIONS: Salvianolic acids and Panax notoginseng are the major effective components of DanQi pill in improving lipid metabolism in ischemic heart model. The effects may be mediated by regulating transcriptional factors such as PPARs, RXRA and PGC-1α.


Assuntos
Doença das Coronárias/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Alcenos/farmacologia , Alcenos/uso terapêutico , Animais , Colesterol/biossíntese , Medicamentos de Ervas Chinesas/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Coração/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Fitoterapia , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Receptor X Retinoide alfa/metabolismo , Saponinas/farmacologia , Saponinas/uso terapêutico
10.
BMC Complement Altern Med ; 15: 352, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26445960

RESUMO

BACKGROUND: Qi-shen-yi-qi (QSYQ), one of the most well-known traditional Chinese medicine (TCM) formulas, has been shown to have cardioprotective effects in rats with heart failure (HF) induced by acute myocardial infarction (AMI). However, the mechanisms of its therapeutic effects remain unclear. In this study, we aim to explore the mechanisms of QSYQ in preventing left ventricular remodelling in rats with HF. The anti-apoptosis an anti-inflammation effects of QSYQ were investigated. METHODS: Sprague-Dawley (SD) rats were randomly divided into 4 groups: sham group, model group, QSYQ treatment group and aspirin group. Heart failure model was induced by ligation of left anterior descending (LAD) coronary artery. 28 days after surgery, hemodynamics were detected. Echocardiography was adopted to evaluate heart function. TUNEL assay was applied to assess myocardial apoptosis rates. Protein expressions of cyclooxygenase1 and 2 (COX1and COX2), Fas ligand (FasL), P53 and MDM2 were measured by western-blot. RT-PCR was applied to detect expressions of our subtype receptors of PGE2 (EP1, 2, 3, and 4). RESULTS: Ultrasonography showed that EF and FS values decreased significantly and abnormal hemodynamic alterations were observed in model group compared to sham group. These indications illustrated that HF models were successfully induced. Levels of inflammatory cytokines (TNF-α and IL-6) in myocardial tissue were up-regulated in the model group as compared to those in sham group. Western-blot analysis showed that cyclooxygenase 2, which is highly inducible by inflammatory cytokines, increased significantly. Moreover, RT-PCR showed that expressions of EP2 and EP4, which are the receptors of PGE2, were also up-regulated. Increased expressions of apoptotic pathway factors, including P53 and FasL, might be induced by the binding of PGE2 with EP2/4. MDM2, the inhibitor of P53, decreased in model group. TUNEL results manifested that apoptosis rates of myocardial cells increased in the model group. After treatment with QSYQ, expressions of inflammatory factors, including TNF-α, IL-6 and COX2, were reduced. Expressions of EP2 and EP4 receptors also decreased, suggesting that PGE2-mediated apoptosis was inhibited by QSYQ. MDM2 was up-regulated and P53 and FasL in the apoptotic pathway were down-regulated. Apoptosis rates in myocardial tissue in the QSYQ group decreased compared with those in the model group. CONCLUSIONS: QSYQ exerts cardiac protective efficacy mainly through inhibiting the inflammatory response and down-regulating apoptosis. The anti-inflammatory and anti-apoptosis efficacies of QSYQ are probably achieved by inhibition of COXs-induced P53/FasL pathway. These findings provide experimental evidence for the beneficial effects of QSYQ in the clinical application for treating patients with HF.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Infarto do Miocárdio/complicações , Animais , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Remodelação Ventricular/efeitos dos fármacos
11.
J Org Chem ; 79(23): 11378-82, 2014 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-25407142

RESUMO

The highly stereoselective bromination of alkynes has been realized by using copper(II) bromide as both the reacting partner and the catalyst, offering a generally efficient synthesis of (E)-dibromoalkenes. The reaction conditions are exceptionally mild, and a wide range of functional groups are well tolerated.

12.
Artigo em Inglês | MEDLINE | ID: mdl-37403397

RESUMO

BACKGROUND: To investigate the active ingredients and the mechanisms of Si-miaoyong- an Decoction (SMYA) in the treatment of coronary heart disease (CHD) by using network pharmacology, molecular docking technology, and in vitro validation. METHODS: Through the Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), Uniprot database, GeneCards database, and DAVID database, we explored the core compounds, core targets and signal pathways of the effective compounds of SMYA in the treatment of CHD. Molecular docking technology was applied to evaluate the interactions between active compounds and key targets. The hypoxia-reoxygenation H9C2 cell model was applied to carry out in vitro verification experiments. A total of 109 active ingredients and 242 potential targets were screened from SMYA. A total of 1491 CHD-related targets were retrieved through the Gene- Cards database and 155 overlapping CHD-related SMYA targets were obtained. PPI network topology analysis indicated that the core targets of SMYA in the treatment of CHD include interleukin- 6 (IL-6), tumor suppressor gene (TP53), tumor necrosis factor (TNF), vascular endothelial growth factor A (VEGFA), phosphorylated protein kinase (AKT1) and mitogen-activated protein kinase (MAPK). KEGG enrichment analysis demonstrated that SMYA could regulate Pathways in cancer, phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling pathway, hypoxiainducible factor-1(HIF-1) signaling pathway, VEGF signaling pathway, etc. Results: Molecular docking showed that quercetin had a significant binding activity with VEGFA and AKT1. In vitro studies verified that quercetin, the major effective component of SMYA, has a protective effect on the cell injury model of cardiomyocytes, partially by up-regulating expressions of phosphorylated AKT1 and VEGFA. CONCLUSION: SMYA has multiple components and treats CHD by acting on multiple targets. Quercetin is one of its key ingredients and may protect against CHD by regulating AKT/VEGFA pathway.


Assuntos
Doença das Coronárias , Medicamentos de Ervas Chinesas , Humanos , Proteínas Proto-Oncogênicas c-akt , Fator A de Crescimento do Endotélio Vascular , Farmacologia em Rede , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases , Quercetina , Doença das Coronárias/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Interleucina-6
13.
Front Oncol ; 13: 1108586, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36994196

RESUMO

COL1A1-PDGFB gene fusion uterine sarcoma is an especially rare malignant mesenchymal tumor that was previously classified as an undifferentiated uterine sarcoma due to the lack of specific features of differentiation. Till now, only five cases have been reported, and here we presented another case recently diagnosed in a Chinese woman who had vaginal bleeding. She presented with a cervical mass at the anterior lip of the cervix invading the vagina and was treated with laparoscopic total hysterectomy plus bilateral salpingo-oophorectomy (TH+BSO) and partial vaginal wall resection with the final pathology of COL1A1-PDGFB fusion uterine sarcoma. Our aim is to emphasize the importance of differential diagnosis of this rare tumor, as early precise diagnosis may allow patients to benefit from the targeted therapy imatinib. This article also serves as further clinical evidence of this disease, serving to increase clinical awareness of this rare sarcoma to avoid misdiagnosis.

14.
Front Microbiol ; 14: 1202768, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37396388

RESUMO

Introduction: Qishen Granule (QSG), a clinically approved traditional Chinese medicine, has been researched for treating heart failure (HF) for many years. However, the effect of QSG on intestinal microecology remains unconfirmed. Therefore, this study aimed to elucidate the possible mechanism of QSG regulating HF in rats based on intestinal microecological changes. Methods: A rat model with HF induced by myocardial infarction was prepared by left coronary artery ligation. Cardiac functions were assessed by echocardiography, pathological changes in the heart and ileum by hematoxylin-eosin (HE) and Masson staining, mitochondrial ultrastructure by transmission electron microscope, and gut microbiota by 16S rRNA sequencing. Results: QSG administration improved cardiac function, tightened cardiomyocytes alignment, decreased fibrous tissue and collagen deposition, and reduced inflammatory cell infiltration. Electron microscopic observation of mitochondria revealed that QSG could arrange mitochondria neatly, reduce swelling, and improve the structural integrity of the crest. Firmicutes were the dominant component in the model group, and QSG could significantly increase the abundance of Bacteroidetes and Prevotellaceae_NK3B31_group. Furthermore, QSG significantly reduced plasma lipopolysaccharide (LPS), improved intestinal structure, and recovered barrier protection function in rats with HF. Conclusion: These results demonstrated that QSG was able to improve cardiac function by regulating intestinal microecology in rats with HF, suggesting promising therapeutic targets for HF.

15.
Biomed Pharmacother ; 154: 113661, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36942602

RESUMO

A causal relationship between ginsenoside Rb3 (G-Rb3) and improved inflammation and cardiac function has not been established. To determine which specific signaling pathways were involved in G-Rb3 improvement of inflammation and myocardial function. In vivo, we found that G-Rb3 decreased the levels of both nuclear factor κB (NF-κB p65) and CD45, an inflammatory marker. G-Rb3 also enhanced key proteins of the contraction unit (cardiac troponin protein I (cTnI) and α-actinin) to improve cardiac function. G-Rb3 inhibited NF-κB p65 nuclear translocation in vitro, as verified by western blot and IF. When NF-κB p65 was overexpressed, a decrease in cyclic nucleotide phosphodiesterase 3B (PDE3B) and SERCA2a expression, while no statistical significance was observed in the expressions of cAMP, PKA, and calcium/calmodulin-dependent protein kinase type II (CaMKⅡ) in each group. The NF-κB p65 plasmid blocked the SERCA2a promoter, as verified by the luciferase reporter system, and G-Rb3 truncated the NF-κB p65 block on the SERCA2a promoter. qPCR was also used to confirm that G-Rb3 increased the mRNA of SERCA2a. In conclusion, we confirmed that the mechanisms of G-Rb3 on ventricular systolic dysfunction causing inflammation are not via the cAMP/PKA pathway, but via suppressing the blockage of NF-κB p65 on the SERCA2a promoter and increasing the SERCA2a expression.


Assuntos
Miócitos Cardíacos , NF-kappa B , Inflamação/metabolismo , Miócitos Cardíacos/metabolismo , NF-kappa B/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Animais
16.
Phytomedicine ; 99: 154009, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35217438

RESUMO

BACKGROUND: Mitophagy can regulate mitochondrial homeostasis, preserve energy metabolism and cardiomyocytes survival effectively to restrain the development of heart failure (HF). Danqi Pill (DQP), composed of the dry roots of Salvia miltiorrhiza Bunge and Panax notoginseng, is included in the 2015 national pharmacopeia and effective in the clinical treatment of coronary heart diseases. Our previous studies have approved that DQP exerted remarkable cardioprotective effects on HF. However, the effect and mechanism of DQP on mitophagy have not been proved yet. HYPOTHESIS/PURPOSE: We aim to explore whether DQP regulates mitophagy to protect against HF and to elucidate the in-depth mechanism. STUDY DESIGN: The HF rat model for evaluating DQP's efficacy was established with left anterior descending coronary artery ligation. The oxygen-glucose deprivation-reperfusion-induced cardiomyocyte model was conducted to clarify the potential mechanism of DQP. METHODS: The mitochondria-targeted fluorescent protein Keima (mt-Keima) was applied for detecting mitophagy flux. Co-immunofluorescence and co-immunoprecipitation were performed to detect protein co-localization. Flow cytometry for JC-1 and Annexin-FITC/PI staining was utilized for assessing mitochondrial activity and function. RESULTS: In vivo, medium dose of DQP (1.5 g/kg) notably improved cardiac function and inhibited cardiac apoptosis in HF rats. Co-immunofluorescent staining of LC3B and TOM20 showed that DQP restored mitophagy. Further co-immunoprecipitation demonstrated that DQP increased the co-localization of FUNDC1 with either ULK1 or PGAM5. In vitro, DQP markedly protected mitochondrial membrane potential damage, reduced cardiomyocytes apoptosis, decreased the level of mitochondrial ROS, and increased the ATP level. Parallel with the in vitro results, DQP increased the interaction of FUNDC1 and LC3B, while knockdown of FUNDC1 diminished the interaction. Besides, Mt-Keima signaling detection further confirmed that DQP significantly promoted mitophagy. Intriguingly, knockdown of ULK1 or PGAM5 separately weakened rather than eliminated these effects of DQP on FUNDC1-mediated mitophagy, mitochondrial homeostasis and energy metabolism. CONCLUSION: Our results demonstrated that DQP protected against HF by improving FUNDC1-mediated mitophagy to perverse energy metabolism through the coordinated regulation of ULK1 and PGAM5.

17.
Artigo em Inglês | MEDLINE | ID: mdl-35140803

RESUMO

Qingre Jiedu (QJ) recipe exerted significant cardioprotective efficacy against heart failure (HF), which is a growing health concern that continues to endanger patients' lives. To investigate the protective properties and mechanism of the QJ recipe, we established hydrogen peroxide (H2O2)-induced H9C2 cells and HF rats. The predicted targets and significant pathways of QJ against HF were collected and screened based on network pharmacology from key ingredients and validated by in vivo and in vitro experiments. The decoction of QJ (0.823 g/kg/day) was intragastrically administered for four weeks. QJ (400 µg/mL) was cultured with H2O2 stimulated in the H9C2 cells. A total of 31 effective active compounds were screened in QJ and covered 277 targets, of which 85 were shared with HF-related targets. In vivo, the QJ recipe remarkably protected heart function and reduced serum IL-1, IL-6, PIIINP, and CIV levels. Furthermore, QJ downregulated the key proteins mediating inflammatory responses (p-IKKα/ß, p-NFκB, and IL-6) and cardiac fibrosis (STAT3 and MMP-9). In vitro, QJ protected the cardiomyocytes against H2O2-stimulated reactive oxygen species (ROS) production and upregulated PI3K and AKT expressions. Further experiments demonstrate that PI3K inhibitor LY294002 remarkably compromised the effects of QJ. In conclusion, our findings indicate that QJ could exert a cardioprotective effect and inhibit fibrosis and inflammation in HF rats via the PI3K-AKT signaling pathway.

18.
Front Physiol ; 13: 1026884, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36523549

RESUMO

Transverse aortic constriction (TAC) is a frequently used model to investigate pressure overload-induced progressive heart failure (HF); however, there is considerable phenotypic variation among different mouse strains and even sub-strains. Moreover, less is known about the TAC model in ICR mice. Therefore, to determine the suitability of the ICR strain for TAC-induced HF research, we compared the effects of TAC on ICR and C57BL/6J mice at one, two and four weeks post-TAC via echocardiography, organ index, morphology, and histology. At the end of the study, behavior and gene expression patterns were assessed, and overall survival was monitored. Compared to the sham-operated mice, ICR and C57BL/6J mice displayed hypertrophic phenotypes with a significant increase in ventricle wall thickness, heart weight and ratio, and cross-sectional area of cardiomyocytes after a 2-week TAC exposure. In addition, ICR mice developed reduced systolic function and severe lung congestion 4 weeks post-TAC, whereas C57BL/6J did not. Besides, ICR mice demonstrated comparable survival, similar gene expression alteration but severer fibrotic remodeling and poor behavioral performance compared to the C57BL/6J mice. Our data demonstrated that ICR was quite sensitive to TAC-induced heart failure and can be an ideal research tool to investigate mechanisms and drug intervention for pressure overload-induced HF.

19.
Front Pharmacol ; 13: 828061, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35264961

RESUMO

Aim: Inflammation and fibrosis have been shown to be critical factors in heart failure (HF) progression. Calycosin (Cal) is the major active component of Astragalus mongholicus Bunge and has been reported to have therapeutic effects on the cardiac dysfunction after myocardial infarction. However, whether Cal could ameliorate myocardial infarction (MI)-induced inflammation and fibrosis and precise mechanisms remain uncertain. The aim of this study is to explore the role of Cal in HF and to clarify the underlying mechanisms. Methods: For in vivo experiments, rats underwent left anterior descending artery ligation for heart failure model, and the cardioprotective effects of Cal were measured by echocardiographic assessment and histological examination. RNA-seq approach was applied to explore potential differential genes and pathways. For further mechanistic study, proinflammatory-conditioned media (conditioned media)-induced H9C2 cell injury model and TGFß-stimulated cardiac fibroblast model were applied to determine the regulatory mechanisms of Cal. Results: In the in vivo experiments, echocardiography results showed that Cal significantly improved heart function. GO and reactome enrichment revealed that inflammation and fibrosis pathways are involved in the Cal-treated group. KEGG enrichment indicated that the PI3K-AKT pathway is enriched in the Cal-treated group. Further experiments proved that Cal alleviated cardiomyocyte inflammatory responses evidenced by downregulating the expressions of phosphorylated IκB kinase α/ß (p-IKKα/ß), phosphorylated nuclear factor kapa B (p-NFκB), and tumor necrosis factor α (TNFα). Besides, Cal effectively attenuated cardiac fibrosis through the inhibitions of expressions and depositions of collagen I and collagen III. In the in vitro experiments, the phosphatidylinositol three kinase (PI3K) inhibitor LY294002 could abrogate the anti-inflammation and antifibrosis therapeutic effects of Cal, demonstrating that the cardioprotective effects of Cal were mediated through upregulations of PI3K and serine/threonine kinase (AKT). Conclusion: Cal inhibited inflammation and fibrosis via activation of the PI3K-AKT pathway in H9C2 cells, fibroblasts, and heart failure in postacute myocardial infarction rats.

20.
Biomed Pharmacother ; 137: 111375, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33761601

RESUMO

Anthracyclines are highly effective chemotherapeutics for antineoplastic treatment. However, cumulative cardiotoxicity is the main side effect with poor prognosis. No mechanism-based therapy is currently available to reverse chronic anthracycline-induced cardiotoxicity (AIC) after the deterioration of cardiac function. Calycosin (CA) is the main compound extracted from the traditional Chinese medicine Astragalus, and it has diverse beneficial effects, including autophagy modulation, anti-inflammatory and anti-tumor effects. Autophagy dysregulation is an important pathological event in AIC. Our study demonstrated a cardioprotective effect of CA in a zebrafish embryonic AIC model. To assess the effect of CA on late-onset chronic AIC, adult zebrafish were treated with CA 28 days after doxorubicin (DOX) injection, at which point heart function was obviously impaired. The results demonstrated that DOX blocked autophagic activity in adult zebrafish 8 weeks post-injection, and CA treatment improved heart function and restored autophagy. Further in vitro experiments demonstrated that atg7, which encodes an E1-like activating enzyme, may play an essential role in the CA regulation of autophagy. In conclusion, we used a rapid pharmacological screening system in embryo-adult zebrafish in vivo and elucidated the mechanism of gene targeting in vitro.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Autofagia/efeitos dos fármacos , Cardiotônicos/farmacologia , Cardiotoxicidade , Doxorrubicina/antagonistas & inibidores , Doxorrubicina/toxicidade , Isoflavonas/farmacologia , Peixe-Zebra , Animais , Proteína 7 Relacionada à Autofagia/efeitos dos fármacos , Embrião não Mamífero , Coração/efeitos dos fármacos , Testes de Função Cardíaca , Miocárdio/patologia , Análise de Sobrevida
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