Materials Today Bio
·
2023
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IF 8.2
Zebin Wu,Qiao Li,Lizhen Wang,Yang Zhang,Wei Liu,Shudong Zhao,Xuezheng Geng,Yubo Fan
Biomaterial tissue engineering scaffolds play a critical role in providing mechanical support, promoting cells growth and proliferation. However, due to the insulation and inappropriate stiffness of most biomaterials, there is an unmet need to engineer a biomimetic nanofibrous cardiac tissue engineering scaffold with tailorable mechanical and electrical properties. Here, we demonstrate for the first time the feasibility to generate a novel type of biocompatible fibrous scaffolds by blending elastic poly(glycerol sebacate) (PGS) and conductive polyaniline (PANI) with the help of a nontoxic carrier polymer, poly (vinyl alcohol) (PVA). Aligned and random PGS/PANI scaffolds are successfully obtained after electrospinning, cross-linking, water and ethanol wash. Incorporating of different concentrations of PANI into PGS fibers, the fibrous sheets show enhanced conductivity and slower degradation rates while maintaining the favorable hemocompatibility. The elastic modulus of the PGS/PANI scaffolds is in the range of 0.65–2.18 MPa under wet conditions, which is similar to that of natural myocardium. All of these fibrous mats show good cell viability and were able to promote adhesion and proliferation of H9c2 cells. Furthermore, the in vivo host responses of both random and aligned scaffolds confirm their good biocompatibility. Therefore, these PGS/PANI scaffolds have great potential for cardiac tissue engineering.
研究领域:
组织工程
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生物材料
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纳米技术
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生物医学工程
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2020
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IF 4.545
Gaojun Wu,Zhengxian Wang,Peiren Shan,Shanjun Huang,Shuang Lin,Weijian Huang,Zhouqing Huang
Background Myocardial remodeling caused by angiotensin II (Ang II) is essential for the pathological process of heart failure. Netrin-1, which is an axonal guidance cue, has been shown to be involved in the inflammatory response, tumorigenesis, and angiogenesis in non-neuronal tissues. However, the role of Netrin-1 in cardiac remodeling has not been fully elucidated. Methods The rat cardiomyocyte cell line H9c2 and primary neonatal rat cardiomyocytes were treated with Ang II. Cells were transfected with siRNA to silence Netrin-1 expression. Real-time polymerase chain reaction and Western blot analysis were used to detect the markers for fibrosis, apoptosis, and hypertrophy in cardiomyocytes. An Annexin V-EGFP/PI cell apoptosis detection kit was used to measure the level of apoptosis caused by angiotensin II. Results We found that Netrin-1 expression was upregulated in the H9c2 cells and the neonatal rat cardiomyocytes stimulated by Ang II. The increased Netrin-1 expression was decreased by valsartan to block AT1R. Importantly, the application of Netrin-1 siRNA significantly alleviated the degrees of myocardial hypertrophy, fibrosis (reflected by Myhc, collagen I, and TGF-β) and apoptosis (reflected by the level of Caspase 3, Bax, and Bcl-2) induced by Ang II. In addition, the silencing of Netrin-1 substantially decreased the phosphorylation of PKCα, JNK, and P38. We treated H9c2 cells with LY317615, SP600125, and SB203580, inhibitors of PKCα, JNK, and P38, respectively, thereby resulting in a substantial decrease in hypertrophy, fibrosis, and apoptosis. Conclusions Ang II produces cardiac hypertrophy, fibrosis, and apoptosis through the upregulation of Netrin-1 and the activation of the AT1R/PKCα/MAPK (JNK, P38) pathway. Suppression of Netrin-1 can relieve Ang II-induced cardiac remodeling via inhibition of the PKCα/MAPK (JNK and P38) signaling pathway. Thus, Netrin-1 may be a novel therapeutic target for Ang II-mediated cardiac remodeling.
研究领域:
心脏病学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Yi Ouyang,JingTong Liu,Mengli Chang,Jing Xu,Guanghuan Tian,Xixian Kong,Shaowei Hu,Dong Zhang,Fangbo Zhang,Hongwei Wu,Liying Tang,Hongjun Yang
Background Myocardial injury (MI) after acute ischemic stroke (AIS) poses a significant threat to patient prognosis. However, effective intervention strategies are currently lacking. Purpose To elucidate the mechanism of MI after AIS and effects of Naoxintong capsule (NXT) therapy. Method In vivo , after a rat model of middle cerebral artery occlusion (MCAO)-induced MI was established and assessed. NXT was administered prophylactically to evaluate its pharmacodynamic effects and mechanisms. In vitro , a noradrenaline (NA)-induced damage cell model was constructed. Subsequently, the NXT was applied to the cell models to examine its cardioprotective effects and potential mechanisms. Results The in vivo findings revealed that following MCAO, there was a notable upregulation of TH expression in the rat brain, which subsequently triggered an increase in serum levels of various biomarkers, including AD, NA, AST, cTnT, CK-MB, and NT-proBNP. Histological analysis employing H&E staining and TUNEL assay disclosed significant pathological alterations and an escalation in apoptotic activity within the myocardial tissue. The myocardial tissue exhibited elevated levels of MDA alongside diminished CAT activity. Additionally, a marked increase in the Bax/Bcl-2 ratio, Cytochrome C release, and Caspase-3 activation was observed, all of which are indicative of heightened apoptotic activity. Administration of the NXT intervention successfully attenuated TH expression in the brains of rats subjected to MCAO, consequently leading to a reduction in circulating levels of catecholamines (CAs). NXT also exhibited significant efficacy at ameliorating cardiac oxidative stress and reducing apoptosis. In vitro , stimulation with NA led to an increase in ROS levels and calcium ion concentration in H9c2 cardiomyocytes. However, the administration of NXT has been found to effectively alleviate these adverse effects, thereby protecting H9c2 cardiomyocytes from the deleterious consequences of oxidative stress and calcium dyshomeostasis. Conclusion Overall, this study has demonstrated that increased CAs synthesis in the brain after AIS in experimental rats led to a surge in circulating CAs, ultimately leading to MI. NXT can alleviate MI due to cerebral ischemia by increasing improving brain catecholamine synthesis, cardiac oxidative stress, and apoptosis.
研究领域:
神经病学
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心脏病学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
Food Bioscience
·
2021
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IF 4.24
Yao Pan,Hongyan Li,Xuan Chen,Yawei Fan,Bing Zhang,Rong Liu,Ze-yuan Deng
Lipophilic (lycopene, β-carotene) and hydrophilic (caffeic acid, p -coumaric acid) phytochemicals were mixed in molar mass at different concentrations/ratios to explore the antioxidant interactions on H 2 O 2 -treated H9c2 cells. Reactive oxide species (ROS), expression of antioxidant enzymes , and oxidation products were analyzed and evaluated by synergistic rate (SR) and combination index (CI). At constant concentrations, antioxidant interactions were influenced by ratios. Group contained more hydrophilic compounds (eg., p -coumaric acid:β-carotene=9:1) showed antioxidant synergism (SR=22.33±1.23, SR>0) at 3.0 μM, while groups that contained more lipophilic compounds (eg., p -coumaric acid:β-carotene=1:9) showed antioxidant antagonism (SR=-11.68±1.25, SR<0) at 3.0 μM. Antioxidant interactions were also influenced by concentrations. From results, ROS generation of group ( p -coumaric acid:β-carotene=1:9) changed from synergism (SR=12.27±2.34, SR>0) to antagonism (SR=-11.68±1.25, SR<0) as their total concentrations increased from 1.5 μM to 3.0 μM. Therefore, this study discussed the possible mechanism of ratio and concentration on the antioxidant interaction among hydrophilic and lipophilic phytochemicals. It also suggested that proper concentrations/ratios of hydrophilic and lipophilic phytochemicals should be considered in diet and formulation of functional foods.
研究领域:
药理学
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营养学
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生物化学
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DOI
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2023
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IF 5
Changsheng Zhong,Yilin Xie,Huifang Wang,Wenxian Chen,Zhenbo Yang,Lei Zhang,Qin Deng,Ting Cheng,Mengyang Li,Jin Ju,Yanyan Liu,Haihai Liang
Diabetes cardiomyopathy (DCM) refers to myocardial dysfunction and disorganization resulting from diabetes. In this study, we investigated the effects of berberine on cardiac function in male db/db mice with metformin as a positive control. After treatment for 8 weeks, significant improvements in cardiac function and a reduction in collagen deposition were observed in db/db mice. Furthermore, inflammation and pyroptosis were seen to decrease in these mice, as evidenced by decreased expressions of p-mTOR, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), IL-1β, IL-18, caspase-1, and gasdermin D (GSDMD). In vitro experiments on H9C2 cells showed that glucose exposure at 33 mmol/L induced pyroptosis, whereas berberine treatment reduced the expression of p-mTOR and NLRP3 inflammasome components. Moreover, berberine treatment was seen to inhibit the generation of mitochondrial reactive oxygen species (mtROS) and effectively improve cell damage in high glucose-induced H9C2 cells. The mTOR inhibitor, Torin-1, showed a therapeutic effect similar to that of berberine, by reducing the expression of NLRP3 inflammasome components and inhibiting mtROS generation. However, the activation of mTOR by MHY1485 partially nullified berberine's protective effects during high glucose stress. Collectively, our study reveals the mechanism that berberine regulates the mTOR/mtROS axis to inhibit pyroptosis induced by NLRP3 inflammasome activation, thereby alleviating DCM.
研究领域:
药理学
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心脏病学
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糖尿病
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细胞生物学
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炎症
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Wenting Wang,Zi Wang,Zhaojie Meng,Shuang Jiang,Zhi Liu,Hong-yan Zhu,Xin-dian Li,Jing tian Zhang,Wei Li
The current study aimed to assess the effectiveness of pharmacological intervention with Platycodin D (PD), a critically active compound isolated from the roots of Platycodon grandiflorum, in mitigating cardiotoxicity in a murine model of type 2 diabetes-induced cardiac injury and in H9c2 cells in vitro. Following oral administration for 4 weeks, PD (2.5 mg/kg) significantly suppressed the elevation of fasting blood glucose (FBG) levels, improved dyslipidemia, and effectively inhibited the rise of the cardiac injury markers creatine kinase isoenzyme MB (CK-MB) and cardiac troponin T (cTnT). PD treatment could ameliorate energy metabolism disorders induced by impaired glucose uptake by activating AMPK protein expression in the DCM mouse model, thereby promoting the GLUT4 transporter and further activating autophagy-related proteins. Furthermore, in vitro experiments demonstrated that PD exerted a concentration-dependent increase in cell viability while also inhibiting palmitic acid and glucose (HG-PA)-stimulated H9c2 cytotoxicity and activating AMPK protein expression. Notably, the AMPK activator AICAR (1 mM) was observed to upregulate the expression of AMPK in H9c2 cells after high-glucose and -fat exposure. Meanwhile, we used AMPK inhibitor Compound C (20 μM) to investigate the effect of PD activation of AMPK on cells. In addition, the molecular docking approach was employed to dock PD with AMPK, revealing a binding energy of −8.2 kcal/mol and indicating a tight interaction between the components and the target. PD could reduce the expression of autophagy-related protein p62, reduce the accumulation of autophagy products, promote the flow of autophagy, and improve myocardial cell injury. In conclusion, it has been demonstrated that PD effectively inhibits cardiac injury-induced type 2 diabetes in mice and enhances energy metabolism in HG-PA-stimulated H9c2 cells by activating the AMPK signaling pathway. These findings collectively unveil the potential cardioprotective effects of PD via modulation of the AMPK signaling pathway.
研究领域:
药理学
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糖尿病
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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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DOI
PubMed
高影响因子
Journal of Biomedical Research
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2018
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IF 0
Li-xing Wu,Yu-yu Xu,Zhi-jian Yang,Qing Feng
Myocardial infarction triggers massive biochemical changes, even cardiac cell death. Endoplasmic reticulum stress is involved in the pathology of myocardial infarction-mediated apoptosis. In the present study, myocardial cell line H9c2 cells were treated with cobalt chloride (CoCl 2 ) to induce hypoxia. Isoproterenol was used for two successive days to induce myocardial infarction in SD rats. The cardioprotective effect of olive leaf extract (OLE) and its main constituent hydroxytyrosol and the underlying mechanisms were evaluated. The results showed that hydroxytyrosol markedly protected H9c2 cells against CoCl 2 -induced apoptosis. Hydroxytyrosol could reduce the mRNA and protein expression of GRP78 and CHOP induced by CoCl 2 in vitro . In vivo , the decreased ejection fraction and fractional shortening, increased heart weight/body ratio, the formation of infarction, disordered cardiac muscle fibers and infiltration of inflammatory cells induced by isoproterenol could be significantly ameliorated by pretreatment with OLE for a month. Similarly, OLE could also reverse the increase of GRP78 and CHOP expression induced by isoproterenol. Therefore, OLE and hydroxytyrosol exert a cardioprotective effect through endoplasmic reticulum stress, which could be a new target for the prevention and treatment of cardiovascular diseases.
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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产品关联
DOI
PubMed
MOLECULAR MEDICINE
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2024
·Vol. 30
·期 1
·1-16
·
IF 6
Fang Lini,Tao Yang,Che Guoying,Yun Yongzi,Ren Min,Liu Yujie
Background Reperfusion is the most effective strategy for myocardial infarct, but induces additional injury. WD repeat and SOCS box containing protein 1 (WSB1) plays a protective role in ischemic cells. This study aims to investigate the effects of WSB1 on myocardial ischemia–reperfusion (IR) injury.Methods The myocardial IR was induced by left anterior descending (LAD) ligation for 45 min and subsequent reperfusion. The overexpression of WSB1 was mediated by tail vein injection of AAV9 loaded with WSB1 encoding sequence two weeks before IR surgery. H9c2 myocardial cells underwent oxygen-sugar deprivation/reperfusion (OGD/R) to mimic IR, and transfected with WSB1 overexpression or silencing plasmid to alter the expression of WSB1.Results WSB1 was found highly expressed in penumbra of myocardial IR rats, and the WSB1 overexpression relieved IR-induced cardio dysfunction, myocardial infarct and pathological damage, and cardiomyocyte death in penumbra. The ectopic expression of WSB1 in H9c2 myocardial cells mitigated OGD/R-caused apoptosis, and silencing of WSB1 exacerbated the apoptosis. In addition, WSB1 activated β-catenin signaling, which was deactivated under the ischemic condition. The co-immunoprecipitation results revealed that WSB1 mediated ubiquitination and degradation of glycogen synthase kinase 3 beta (GSK3β) as an E3 ligase in myocardial cells. The effects of WSB1 on myocardial cells under ischemic conditions were abolished by an inhibitor of β-catenin signaling.Conclusion WSB1 activated β-catenin pathway by promoting the ubiquitination of GSK3β, and restrained IR-induced myocardial injury. These findings might provide novel insights for clinical treatment of myocardial ischemic patients.
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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产品关联
DOI
PubMed
高影响因子
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
·
2022
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IF 3.511
Wentao Sun,Yang Zhou,Hongmei Xue,Haitao Hou,Guowei He,Qin Yang
Although the association of elevated homocysteine level with cardiac hypertrophy has been reported, the molecular mechanisms by which homocysteine induces cardiac hypertrophy remain inadequately understood. In this study we aim to uncover the roles of cyclic nucleotide phosphodiesterase 1 (PDE1) and endoplasmic reticulum (ER) stress and their relationship to advance the mechanistic understanding of homocysteine-induced cardiac cell hypertrophy. H9c2 cells and primary neonatal rat cardiomyocytes are exposed to homocysteine with or without ER stress inhibitor TUDCA or PDE1-specific inhibitor Lu AF58027, or transfected with siRNAs targeting PDE1 isoforms prior to homocysteine-exposure. Cell surface area is measured and ultrastructure is examined by transmission electron microscopy. Hypertrophic markers, PDE1 isoforms, and ER stress molecules are detected by q-PCR and western blot analysis. Intracellular cGMP and cAMP are measured by ELISA. The results show that homocysteine causes the enlargement of H9c2 cells, increases the expressions of hypertrophic markers β-MHC and ANP, upregulates PDE1A and PDE1C, promotes the expressions of ER stress molecules, and causes ER dilatation and degranulation. TUDCA and Lu AF58027 downregulate β-MHC and ANP, and alleviate cell enlargement. TUDCA decreases PDE1A and PDE1C levels. Silencing of PDE1C inhibits homocysteine-induced hypertrophy, whereas PDE1A knockdown has minor effect. Both cAMP and cGMP are decreased after homocysteine-exposure, while only cAMP is restored by Lu AF58027 and TUDCA. TUDCA and Lu AF58027 also inhibit cell enlargement, downregulate ANP, β-MHC and PDE1C, and enhance cAMP level in homocysteine-exposed primary cardiomyocytes. ER stress mediates homocysteine-induced hypertrophy of cardiac cells via upregulating PDE1C expression Cyclic nucleotide, especially cAMP, is the downstream mediator of the ER stress-PDE1C signaling axis in homocysteine-induced cell hypertrophy.
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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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2022
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IF 6.656
Siyuan Shen,Gaojun Wu,Wu Luo,Weixin Li,Xiaobo Li,Chengyi Dai,Weijian Huang,Guang Liang
Background Hypertension is a common risk factor for heart failure, and excessive angiotensin II (Ang II) leads to hypertensive cardiac alterations such as hypertrophy, cardiac fibrosis, remodeling, and dysfunction. Leonurine is the major active alkaloid compound obtained from the traditional Chinese herbal medicine, Leonurus japonicus Houtt. The effects of leonurine on Ang II-induced hypertensive cardiac injury remain unknown. Hypothesis/Purpose In the present study, we investigated the cardioprotective effects of leonurine in Ang II-infused mice and explored the underlying mechanisms in cardiomyocytes. Methods Cardiac injury was induced by Ang II infusion in experimental mice with or without leonurine (at 10 or 20 mg/kg) treatment. H9c2 cells and neonatal rat primary cardiomyocytes were used to investigate the mechanisms through which leonurine exerts its protection effects. Results The results showed that leonurine significantly alleviated Ang II-induced cardiac hypertrophy, fibrosis, and inflammation in both mice and cultured cardiomyocytes. Echocardiography revealed that leonurine preserved cardiac function in mice. Further investigations revealed that leonurine inhibited the activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways to reduce inflammatory response and injuries in Ang II-challenged cardiomyocytes. Inhibition of MAPKs and NF-κB in cardiomyocytes abolished the anti-inflammatory effects of leonurine. Conclusions Our study provides evidence that leonurine exerts protective effects against Ang II-induced hypertensive cardiac remodeling and dysfunction by inhibiting the MAPK and NF-κB pathways. Leonurine may be a promising agent for treating hypertensive heart failure.
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
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2022
·Vol. 395
·期 10
·1209-1224
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IF 3.195
Li Wendi,Li Shanshan,Cao Zhenju,Sun Yi,Qiu Wei,Jia Mei,Su Ming
Although anthracyclines improve the long-term survival rate of patients with cancer, severe and irreversible myocardial damage limits their clinical application. Amino acid (AA) metabolism in cardiomyocytes can be altered under pathological conditions. Therefore, exploring the AA metabolic signature in anthracycline-induced cardiotoxicity (AIC) is important for identifying novel mechanisms. We established mouse and cellular models of Adriamycin (ADR)-induced cardiac injury. We observed a decreased expression of troponins I (cTnI) after ADR treatment and ADR accelerated the degradation of cTnI, implying that AA metabolism could be altered in AIC. Using a targeted AA metabolomics approach based on ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS), the AA metabolic signatures in the sera of AIC mice and supernatant samples of ADR-treated H9c2 cardiomyocytes were analyzed. The levels of 14 AA metabolites were altered in ADR-treated mice ( p < 0.05). Via bioinformatics analysis, we identified nine differential AA metabolites in mice and five differential AA metabolites in ADR-treated H9c2 cardiomyocytes. Three AAs with increased levels ( l -glutamate, l -serine, and l -tyrosine) overlapped in the two models, suggesting a possible mechanism of AA metabolic impairment during AIC. The metabolic pathways perturbed by AIC involved aminoacyl-tRNA biosynthesis and alanine, aspartate, and glutamate metabolism. Our data suggests that ADR perturbed AA metabolism in AIC models. Moreover, the targeted AA metabolomics approach based on UPLC-MS/MS can be a unique platform to provide new clues for the prevention and treatment of AIC.
研究领域:
药理学
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心脏病学
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代谢组学
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生物化学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2022
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IF 6.656
Linhao Xu,Daqiang He,Yirong Wu,Lishui Shen,Yongmei Wang,Yizhou Xu
Background Heart failure (HF) is a common cardiovascular syndrome. Tanshinone IIA (Tan IIA) is a pharmacologically active monomer that exerts a significant cardioprotective effect in the clinic; however, the specific mechanisms are not fully understood. Purpose We mainly investigated the protective effects of Tan IIA on doxorubicin (DOX)-induced HF. Methods In an in vitro study, H9C2 and HL-1 cells were cultured and treated with DOX and Tan IIA for 24 h, we investigated the mechanism underlying Tan IIA-mediated protection. In an in vivo study, a model of DOX-induced HF was established in C57BL/6 mice that were divided into the six groups randomly: a control group, a DOX group, DOX groups treated with Tan IIA (DOX+Tan IIA) at dosages of 2.5, 5 and 10 mg/kg/day and DOX groups treated with N-acetylcysteine (NAC) at dosages of 200 mg/kg/day. Result The results demonstrated that Tan IIA significantly increased cell viability and protected against DOX-induced apoptosis. RNA-sequencing showed that the genes expression associated with the apoptotic signaling pathway was altered by Tan IIA. Among the differentially expressed genes, death-domain associated protein (DAXX), which plays an critical role in apoptotic signaling, exhibited increased expression under Tan IIA treatment. In addition, RNA interference was used to silence the expression of DAXX, which abolished Tan IIA-mediated protection against DOX-induced apoptosis; this effect was associated with extracellular signal-regulated protein kinase 1/2 (ERK1/2) and mitogen-activated protein kinase (MEK) expression. In the in vivo study, the echocardiography results revealed that heart function was rescued by Tan IIA, and the histomorphology results showed that Tan IIA prevented myocardial structural alteration and myofibril disruption. Furthermore, Tan IIA induced the expressions of DAXX, p-ERK1/2 and p-MEK. Tan IIA also inhibited apoptosis by suppressing the expression of cleaved caspase-8, p-P38 and cleaved caspase-3. Conclusion Our results provide novel interpretations into the important role of DAXX in DOX-induced cardiotoxicity and show that Tan IIA may be a novel agent strategy for HF treatment via activating the DAXX/MEK/ERK1/2 pathway.
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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细胞生物学
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产品关联
DOI
PubMed
高影响因子
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