TOXICOLOGY AND APPLIED PHARMACOLOGY
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2023
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IF 3.8
Hao Zhao,Xin Lin,Qingfeng Chen,Xiaoyue Wang,Yongya Wu,Xiaoxia Zhao
Sepsis-induced cardiomyopathy (SIC) has high morbidity and mortality. Quercetin (QUE) has been used to treat many inflammatory diseases related to pyroptosis . However, its effect on SIC has not been reported before. We aimed to explore the therapeutic mechanism of QUE on SIC. We found that the expression levels of NOX2, markers of myocardial injury and inflammatory factors related to pyroptosis were upregulated in the serum of SIC patients. QUE improved the viability and reduced the death rate of LPS-treated H9C2 cells. It could downregulate the expression level of NOX2 and alleviate NOX2-induced mitochondrial damage to inhibit the ROS-mediated NF-κB/TXNIP pathway thus ameliorating cell pyroptosis. Overexpression of NOX2 partially attenuated the anti-pyroptotic effects of QUE on LPS-treated H9C2 cells in vitro. Besides, the results of animal experiments reported that the mitochondrial damage was reduced by QUE treatment, which subsequently inhibited the ROS-mediated NF-κB/TXNIP pathway to ameliorate cell pyroptosis to further alleviate myocardial injury in CLP-induced rats in vivo. To conclude, QUE suppressed the NOX2/ROS-mediated NF-κB/TXNIP signaling pathway to ameliorate pyroptosis of cardiomyocytes to relieve SIC.
研究领域:
药理学
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心脏病学
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免疫学
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细胞生物学
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分子生物学
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PubMed
高影响因子
Molecular Medicine Reports
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2021
·Vol. 25
·期 2
·1-9
·
IF 2.952
Fa-Xiu Chen,Qin Wan,Qing-Ling Li,Jing Fang,Le Peng,Jian Hu
The function of substance P (SP) in myocardial ischemia is well understood, but its effects on congestive heart failure are unclear. The present study aimed to use in vitro and in vivo approaches to investigate the effects of SP on doxorubicin‑induced cardiomyocyte injury. Pathological changes, apoptosis, cardiomyocyte ultrastructure and molecular mechanisms were evaluated in vitro and in vivo. The effects of SP on cell viability of H9c2 myocardial cells were evaluated using the Cell Counting Kit‑8 and flow cytometry. B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax), Beclin‑1 and microtubule‑associated protein 1A/1B‑light chain 3 (LC3) were detected by western blotting. Heart failure in rats was established by intraperitoneal injection of doxorubicin. The in vitro data demonstrated that SP at concentrations of 1 µg/ml inhibited doxorubicin‑induced apoptosis of H9c2 cells. Administration of doxorubicin reduced Bcl‑2, Beclin‑1 and LC3 expression levels in H9c2 cells, while having no effect on Bax levels. Administration of SP to these doxorubicin‑treated cells did not affect Bcl‑2 or Bax expression, but further reduced Beclin‑1 while inhibiting the reduction in LC3 expression. In vivo, food intake was significantly increased in rats in the SP group compared with the model group. Cardiomyocytes in the heart‑failure group underwent dysfunctional autophagy as ascertained by transmission electron microscopy. Compared with the heart‑failure group, these pathological changes, including loss of striations and vacuolation, were inhibited by SP treatment, which promoted Bax expression, reduced Beclin‑1 expression and inhibited the reduction in LC3 expression. Taken together, SP reduced cardiomyocyte apoptosis in doxorubicin‑induced cardiomyocyte injury, likely by promoting autophagy, which suggested that SP is a potential therapeutic target for doxorubicin‑induced heart failure.
研究领域:
药理学
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心脏病学
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分子生物学
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细胞生物学
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高影响因子
CARDIOVASCULAR DRUGS AND THERAPY
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2023
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IF 3.4
Zhang Lingxi,Hu Chenghong,Jin Bo,Bai Bin,Liao Jing,Jin Leiming,Wang Minxiu,Zhu Weiwei,Wu Xuedan,Zheng Li,Xu Xuelian,Jiang Yongsheng,Wang Yi,He Ying
Purpose Diabetic cardiomyopathy (DCM) is a common and severe complication of diabetes. Inflammation and oxidative stress play important roles in DCM development. Bicyclol is a hepatoprotective drug in China that exerts anti-inflammatory effects by inhibiting the MAPK and NF-κB pathways to prevent obesity-induced cardiomyopathy. Our purpose was to explore the effect and mechanism of bicyclol on DCM. Methods A type 1 diabetes mouse model was established using C57BL/6 mice by intraperitoneal injection of STZ. The therapeutic effect of bicyclol was evaluated in both heart tissues of diabetic mice and high concentration of glucose (HG)-stimulated H9c2 cells. Results We showed that bicyclol significantly attenuated diabetes-induced cardiac hypertrophy and fibrosis, which is accompanied by the preservation of cardiac function in mice. In addition, bicyclol exhibited anti-inflammatory and anti-oxidative effects both in vitro and in vivo. Furthermore, bicyclol inhibited the hyperglycemia-induced activation of MAPKs and NF-κB pathways, while upregulating the Nrf-2/HO-1 pathway to exhibit protective effects. Conclusion Our data indicate that bicyclol could be a promising cardioprotective agent in the treatment of DCM.
研究领域:
药理学
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心脏病学
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糖尿病研究
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分子生物学
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DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
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2019
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IF 4.868
Li-Ming Yu,Xue Dong,Jian Zhang,Zhi Li,Xiao-Dong Xue,Hong-Jiang Wu,Zhong-Lu Yang,Yang Yang,Hui-Shan Wang
Endoplasmic reticulum (ER) stress and oxidative stress contribute greatly to myocardial ischemia-reperfusion (MI/R) injury. Naringenin, a flavonoid derived from the citrus genus, exerts cardioprotective effects. However, the effects of naringenin on ER stress as well as oxidative stress under MI/R condition and the detailed mechanisms remain poorly defined. This study investigated the protective effect of naringenin on MI/R-injured heart with a focus on cyclic guanosine monophosphate- (cGMP-) dependent protein kinase (PKG) signaling. Sprague-Dawley rats were treated with naringenin (50 mg/kg/d) and subjected to MI/R surgery with or without KT5823 (2 mg/kg, a selective inhibitor of PKG) cotreatment. Cellular experiment was conducted on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were incubated with naringenin (80 μmol/L). PKGIα siRNA was employed to inhibit PKG signaling. Our in vivo and in vitro data showed that naringenin effectively improved heart function while it attenuated myocardial apoptosis and infarction. Furthermore, pretreatment with naringenin suppressed MI/R-induced oxidative stress as well as ER stress as evidenced by decreased superoxide generation, myocardial MDA level, gp91phox expression, and phosphorylation of PERK, IRE1α, and EIF2α as well as reduced ATF6 and CHOP. Importantly, naringenin significantly activated myocardial cGMP-PKGIα signaling while inhibition of PKG signaling with KT5823 (in vivo) or siRNA (in vitro) not only abolished these actions but also blunted naringenin’s inhibitory effects against oxidative stress and ER stress. In summary, our study demonstrates that naringenin treatment protects against MI/R injury by reducing oxidative stress and ER stress via cGMP-PKGIα signaling. Its cardioprotective effect deserves further clinical study.
研究领域:
心脏病学
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药理学
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分子生物学
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PubMed
高影响因子
FASEB JOURNAL
·
2023
·Vol. 37
·期 6
·e22964
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IF 4.8
Fei Sun,Cheng An,Can Liu,Ying Hu,Yue Su,Zhixiang Guo,Hong Che,Shenglin Ge
Cardiac ischemia/reperfusion (I/R) injury is a complicated pathological event, which has close association with pyroptosis. This study uncovered the regulatory mechanisms of fat mass and obesity-associated protein (FTO) in NLRP3-mediated pyroptosis during cardiac I/R injury. H9c2 cells were stimulated with oxygen–glucose deprivation/reoxygenation (OGD/R). Cell viability and pyroptosis were detected by CCK-8 and flow cytometry. Western blotting or RT-qPCR was performed to analyze target molecule expression. NLRP3 and Caspase-1 expression was observed by immunofluorescence staining. IL-18 and IL-1β production was detected by ELISA. The total m6A and m6A level of CBL was determined by dot blot assay and methylated RNA immunoprecipitation-qPCR, respectively. The interaction between IGF2BP3 and CBL mRNA was confirmed by RNA pull-down and RIP assays. The protein interaction between CBL and β-catenin and β-catenin ubiquitination were evaluated by Co-IP. Myocardial I/R model was established in rats. We determined infarct size by TTC staining and pathological changes by H&E staining. LDH, CK-MB, LVFS, and LVEF were also assessed. FTO and β-catenin were down-regulated, while CBL was up-regulated by OGD/R stimulation. FTO/β-catenin overexpression or CBL silencing restrained OGD/R-induced NLRP3 inflammasome-mediated pyroptosis. CBL repressed β-catenin expression via ubiquitination and degradation. FTO reduced the mRNA stability of CBL by inhibiting m6A modification. CBL-mediated ubiquitination and degradation of β-catenin were involved in FTO-induced pyroptosis inhibition during myocardial I/R injury. FTO inhibits NLRP3-mediated pyroptosis to attenuate myocardial I/R injury via repressing CBL-induced ubiquitination degradation of β-catenin.
研究领域:
心脏病学
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分子生物学
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细胞生物学
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病理学
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PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Zhenbo Yang,Yilin Xie,Mengyang Li,Wenxian Chen,Changsheng Zhong,Jin Ju,Qin Deng,Huifang Wang,Ting Cheng,Lei Zhang,Weijie Du,Haihai Liang
Reperfusion stands as a pivotal intervention for ischemic heart disease. However, the restoration of blood flow to ischemic tissue always lead to further damage, which is known as myocardial ischemia/reperfusion injury (MIRI). Ramelteon is an orally administered drug used to improve sleep quality, which is famous for its high bioadaptability and absence of notable addictive characteristics. However, the specific mechanism by which it improves MIRI is still unclear. Sirtuin-3 (Sirt3), primarily located in mitochondria, is crucial in mitigating many cardiac diseases, including MIRI. Based on the structure of Sirt3, we simulated molecular docking and identified several potential amino acid binding sites between it and ramelteon. Therefore, we propose a hypothesis that ramelteon may exert cardioprotective effects by activating the Sirt3 signaling pathway. Our results showed that the activation levels and expression level of Sirt3 were significantly decreased in MIRI tissue and H 2 O 2 stimulated H9C2 cells, while ramelteon treatment upregulated Sirt3 activity and expression. After treat with 3-TYP, a classic Sirt3 activity inhibitor, we constructed myocardial ischemia/reperfusion surgery in vivo and induced H9C2 cells with H 2 O 2 in vitro. The results showed that the myocardial protection and anti-apoptotic effects of ramelteon were antagonized by 3-TYP, indicating that the activation of Sirt3 is a key mechanism for ramelteon to exert myocardial protection. In summary, our results confirm a novel mechanism by which ramelteon improves MIRI by activating Sirt3 signaling pathway, providing strong evidence for the treatment of MIRI with ramelteon.
研究领域:
心脏病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
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2021
·
IF 9.381
Jie Liu,Hong-da Wang,Fei-fei Yang,Bo-xue Chen,Xue Li,Qing-xia Huang,Jing Li,Xiang-yan Li,Zheng Li,He-shui Yu,De-an Guo,Wen-zhi Yang
The role of polysaccharides in quality control of ginseng is underestimated. Large-scale comparison on the polysaccharides of Panax ginseng (PG), P. quinquefolius (PQ), P. notoginseng (PN), Red ginseng (RG), P. japonicus (ZJS), and P. japonicus var. major (ZZS), was performed by both chemical and biological approaches. Holistic fingerprinting at polysaccharide and the hydrolyzed oligosaccharide and monosaccharide levels utilized various chromatography methods, while OGD and OGD/R models on H9c2 cells were introduced to evaluate the protective effects on cell viability and mitochondrial function. Polysaccharides from six ginseng species exhibited remarkable content difference (RG > PG/ZZS/ZJS/PQ > PN), but weak differentiations in molecular weight distribution and oligosaccharide profiles, while Glc and GalA were richer for monosaccharide compositions of PG and RG polysaccharides, respectively. RG polysaccharides (25/50/100 μg/mL) showed significant cardiomyocyte protection by regulating mitochondrial functions. These new evidences may provide support for the supplementary role of polysaccharides in quality control of ginseng.
研究领域:
药用植物学
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药物化学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Artificial Cells Nanomedicine and Biotechnology
·
2019
·
IF 4.462
Yongqiang Zheng,Lingli Lu,Zhengli Yan,Sufang Jiang,Shanyi Yang,Yingzi Zhang,Kangwei Xu,Chunlian He,Xiaojun Tao,Qiufang Zhang
Icariin (ICA), a major active ingredient from Chinese medicine, has unique pharmacological effects on ischaemic heart disease. However, its hydrophobic property limits its administration and leads to poor efficacy. This work aimed to change its hydrophobic property and improve the treatment efficacy. We designed a new nano-drug to increase the ICA delivery. ICA was modified with hydrophilic polyethylene glycol monomethyl ether (mPEG) by a succinic anhydride linker to form a polyethylene glycol-icariin (mPEG-ICA) polymer. The structure of this polymer was identified by Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. The content of ICA in the polymer was 32% as detected by ultraviolet spectrophotometry. mPEG-ICA nanoparticles, of 143.3 nm, were prepared by the dialysis method, and zeta potential was 0.439 mV by dynamic light scattering. The nanoparticles had a spherical shape on transmission electron microscopy. In media with pH 7.4 and 6.8, ICA release from mPEG-ICA nanoparticles after 72 h was about 0.78% and 64.05%, respectively, so the ICA release depended on the release media pH. On MTT and lactate dehydrogenase activity assay, mPEG-ICA nanoparticles could reduce cell damage induced by oxgen-glucose deprivation. Hoechst 33258 staining and TUNEL and AnnexinV-FITC/PI double staining showed that ICA nanoparticles could increase the activity of H9c2 cardiomyocytes under oxgen-glucose deprivation conditions by decreasing apoptosis. ICA modified by hydrophilic mPEG could improve its efficacy.
研究领域:
药理学
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纳米医学
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心脏病学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Ming-Li Sun,Jun-Min Dong,Chen Liu,Pu Li,Chao Zhang,Jie Zhen,Wei Chen
Background A phase II clinical trial of metformin (MET) for the treatment of doxorubicin (DOX)-induced cardiotoxicity (NCT02472353) failed. Objectives The aims of this study were to confirm MET-mediated protection against DOX-induced cardiotoxicity and its mechanism using H9C2 cells, and to establish a Wistar rat model of DOX-induced cardiotoxicity. Subsequently, Wistar rats were utilized to identify clinically relevant indicators for evaluating MET-mediated protection against DOX-induced cardiotoxicity, thereby facilitating early transition towards successful clinical trials. Methods MET-mediated protection was assessed using cell viability and cytotoxicity experiments. Additionally, intramitochondrial reactive oxygen species (ROS) levels were measured using an ROS fluorescent probe (dihydroethidium) to confirm the oxidative stress mechanism. Eighteen Wistar rats were randomly allocated to the control, DOX, and DOX+MET groups; and the body weight, adverse drug reactions (ADRs), myocardial injury, cardiac function, oxidative stress, and histopathology of heart tissues were compared between groups. Results H9C2 cells treated with MET/Dexrazoxane demonstrated dose-dependent protection against DOX-induced cardiotoxicity. The fluorescence intensity of H9C2 cells suggested DOX-induced cardiomyocyte toxicity and MET-mediated protection against DOX-induced cardiotoxicity. In vivo experiments confirmed that a rat model of DOX-induced cardiotoxicity was successfully established, but MET-mediated protection against DOX-induced cardiotoxicity was not demonstrated. This was attributed to insufficient energy intake because of ADRs, such as vomiting. Conclusions We confirmed the MET-mediated protection against DOX-induced cardiomyocyte toxicity and its mechanism involving the inhibition of oxidative stress in vitro experiments. It is imperative to investigate the optimal conditions for MET-mediated protection against DOX-induced cardiotoxicity in vivo or clinical trials.
研究领域:
药理学
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心脏病学
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毒理学
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细胞生物学
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动物模型
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产品关联
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PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY A
·
2019
·
IF 3.858
Run-Zhou Liu,Rui Wang,Hai-Ming An,Xin-Guang Liu,Chao-Ran Li,Ping Li,Hua Yang
Cell membrane chromatography (CMC) is a bioaffinity chromatographic method used to screen active compounds from natural products. However, since the receptor capacity of CMC column is limited, high content/affinity compounds may cause column overloading and thus lead to ignorance of other positive candidates. For avoiding this effect and comprehensively discovering bioactive components, a strategy based on two-dimensional CMC and component-knockout approach was proposed. As an illustrative case study, red yeast rice (RYR), a rice product with good myocardial protective effect in clinical studies, was selected as the model experimental sample. For discovering its potential cardioprotective compounds, a CMC model with H9c2 rat cardiac myoblasts (H9c2/CMC) with good selectivity, stability and reproducibility was established. By using two-dimensional H9c2/CMC-HPLC coupled with QTOF MS system, three components were firstly screened out. After knocking out high content/affinity compound, another four bioactive compounds were then found. By this two-round screening, column overloading caused by high concentration or infinity compounds was avoided, and trace compounds were enriched. As a result, one pigment and six monacolins from RYR were fished out. The results indicate the proposed strategy might be used to discover active compounds from complex matrix.
研究领域:
药理学
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分析化学
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生物技术
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DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2023
·
IF 3.8
Yixin Sun,Danyang Guo,Saiding Yue,Mingyan Zhou,Dongxu Wang,Fengjiao Chen,Lingling Wang
Background Doxorubicin (DOX), a chemotherapeutic drug, could relieve the progressions of various diseases. However, its clinical application is limited due to its cardiotoxicity. This study aimed to investigate the effects of afzelin (a flavonol glycoside found in Houttuynia cordata ) on the cardiotoxicity induced by DOX. Methods In ex-vivo, H9C2 cells were incubated with 20, 40, or 80 μM afzelin for 12 h, followed by the treatment with 1 μM DOX for 12 h. In vivo, C57BL/6 J mice were intraperitoneally injected with 4 mg/kg/day DOX on days 1, 7, and 14. Meanwhile, starting from day 1, mice were intragastrically administrated with 5 mg/kg/day or 10 mg/kg/day afzelin for 20 days. The cardiac function of mice was evaluated by detecting hemodynamic parameters using the M-mode echocardiography. Results DOX decreased the cell survival rate, and elevated apoptotic rate, as well as induced the oxidative stress and mitochondrial dysfunction in H9C2 cells. All these changes were alleviated by afzelin treatment in a concentration-dependent manner. The results were further proven by the mitigation of cardiac injury in vivo, as evidenced by the elevation of fractional shortening, heart weight/tibia length, and the rate of the increase/decrease of left ventricular pressure in mice subjected to DOX-induced cardiotoxicity. Furthermore, afzelin upregulated the expression of p-AMP-activated protein kinase alpha (AMPKα) and sirtuin1 (SIRT1). Dorsomorphin (an AMPKα inhibitor) abrogated the anti-cardiotoxicity effects of afzelin in H9C2 cells induced by DOX. Conclusion Afzelin protected against DOX-induced cardiotoxicity by promoting the AMPKα/SIRT1 signaling pathway.
研究领域:
药理学
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心脏病学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Xiong Chen,Jinfu Qian,Shiqi Liang,Jianchang Qian,Wu Luo,Yujuan Shi,Hong Zhu,Xiang Hu,Gaojun Wu,Xiaokun Li,Guang Liang
Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NF κ B signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.
研究领域:
心脏病学
·
糖尿病
·
分子生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
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