Journal of Materials Chemistry B
·
2024
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IF 6.1
Ying Tan,Yali Nie,Lei ZhengWen,Zhi Zheng
In cardiac tissue engineering, myocardial surface patches and hydrogel intramyocardial injections represent the two primary hydrogel-based strategies for myocardial infarction (MI) treatment. However, the comparative effectiveness of these two treatments remains uncertain. Therefore, this study aimed to compare the effects of the two treatment modalities by designing a simple and reproducible hydrogel cross-linked with γ-PGA and 4-arm-PEG-SG. To improve mitochondrial damage in cardiomyocytes (CMs) during early MI, we incorporated the mitochondria-targeting antioxidant MitoQ into the hydrogel network. The hydrogel exhibited excellent biodegradability, biocompatibility, adhesion, and injectability in vitro. The hydrogel was utilized for rat MI treatment through both patch adhesion and intramyocardial injections. In vivo results demonstrated that the slow release of MitoQ peptide from the hydrogel hindered ROS production in CM, alleviated mitochondrial damage, and enhanced CM activity within 7 days, effectively inhibiting MI progression. Both hydrogel intramyocardial injections and patches exhibited positive therapeutic effects, with intramyocardial injections demonstrating superior efficacy in terms of cardiac function and structure in equivalent treatment cycles. In conclusion, we developed a MitoQ/hydrogel system that is easily prepared and can serve as both a myocardial patch and an intramyocardial injection for MI treatment, showing significant potential for clinical applications.
研究领域:
心脏组织工程
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生物医学工程
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心脏病学
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药学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2023
·
IF 8.2
Wang Wei,Chen Xiao-kang,Zhou Lu,Wang Feng,He Yan-ji,Lu Bing-jun,Hu Ze-gang,Li Zhu-xin,Xia Xue-wei,Wang Wei Eric,Zeng Chun-yu,Li Liang-peng
Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 μg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 μM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 μM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.
研究领域:
心脏病学
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分子生物学
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再生医学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
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IF 6.2
Minzhi Zhou,Wen Li,Lin Zheng,Mouming Zhao
This study aimed to investigate the protective effects of bovine myocardium hydrolysates prepared from different protein fractions on H2O2-induced myocardial injury in H9c2 cells and to develop an effective way to explore potential myocardial protective peptides. Results showed that, as compared with bovine heart and its water-soluble protein fraction, myocardium hydrolysate prepared from salt-soluble protein fraction demonstrated better myocardial protective activity, significantly increasing cell viability and activities of antioxidant enzymes (SOD and CAT), while reducing contents of myocardial injury markers (LDH, CK-MB, and cTnT). Ten novel myocardial protective peptides (FR, LK, LPF, RVL, SLL, FDIF, FQPS, GLPPILN, SEAPPHIF, and TEAPLNPK) were identified following a peptidomics-activity guided strategy integrating multivariate analysis and a random forest model. Molecular docking analysis revealed potential molecular mechanisms that might act on myocardial injury-related targets such as AKT1, STAT3, and MMP9. This study may provide insights for the rapid identification of food-derived myocardial protective peptides.
研究领域:
食品科学
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肽组学
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分子生物学
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心血管药理学
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营养生物化学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
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IF 4.2
Liu-Gen Cui,Miao-Miao Zhai,Jian-Jian Yin,Zhi-Mo Wang,Shu-Hui Wang,Yue-Jiao Zhou,Pei-Pei Li,Yang Wang,Li Xia,Pei Wang,Xue-Xiang Cha,Li-Rong Zhang,Sheng-Na Han
Several studies have associated the epitranscriptomic RNA modification of N6-methyladenosine (m 6 A) with cardiovascular diseases; however, how m 6 A modification affects cardiomyocyte pyroptosis after myocardial infarction (MI) remains unknown. Here, we showed that AlkB homolog 5 (ALKBH5), an m 6 A demethylase, is crucial in cardiomyocyte pyroptosis after MI. We used MI rat and mouse models, a cell hypoxia model of rat primary cardiomyocytes (RCMs), and rat embryonic ventricle cell line (H9c2) to explore the functional role of m 6 A modification and ALKBH5 in the heart and cardiomyocytes. Using plasmids and small interfering RNAs, the expressions of ALKBH5 and NOD-like receptor family pyrin domain-containing 3 (NLRP3) were determined to study their functions in regulating cardiomyocyte m 6 A and pyroptosis, respectively. We characterized the role of ALKBH5, which exhibited elevated expression in the ischemic heart tissue of rats and mice and hypoxic cardiomyocytes (RCMs and H9c2 cells). ALKBH5 knockdown alleviated hypoxia-induced H9c2 cell pyroptosis by inhibiting NLRP3 inflammasome activation, whereas ALKBH5 overexpression had the opposite effect. NLRP3 knockdown alleviated hypoxia-induced H9c2 cardiomyocyte pyroptosis by inhibiting ALKBH5 expression, whereas NLRP3 overexpression had the opposite effect. Mechanistically, ALKBH5 mediated m 6 A modification of NLRP3 mRNA in an IGF2BP2-dependent manner, and NLRP3, as a nuclear transcription factor, regulated the ALKBH5 transcription process. Targeting the ALKBH5-NLRP3 loop with the small-molecule inhibitors alleviated cardiomyocyte pyroptosis. Our results highlight that ALKBH5-NLRP3 forms a positive feedback loop that promotes cardiomyocyte pyroptosis after MI. Therefore, inhibiting the ALKBH5-NLRP3 loop is a potential strategy for treating cardiovascular diseases.
研究领域:
心血管疾病
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表观转录组学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
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IF 13.3
Xuhong Guo,Lingyu Sun,Dongyu Xu,Yuanjin Zhao
Many Chinese medicines have shown protective effects on the heart, while their specific effects and modes of action are still lacking of intuitive studies. In this paper, we propose a structural color heart-on-a-chip from layer assembly for evaluating the myocardial protection effects of traditional Chinese medicine. The structural color scaffolds are imparted with a striped microstructure on one side for inducing the alignment of cardiomyocytes, and an inverse opal nanostructure on the other side for optical sensing. Because the scaffold could generate obvious color changes upon cardiomyocyte contraction, its integration into a microfluidic chip provides a simple screening platform to study the pre-protective effects of Chinese medicine against cardiac injury. We have demonstrated that with the induction of doxorubicin, the injured cardiomyocytes presented abnormal morphology, disappeared sarcomere and depressed beating behaviors that could be reflected by reduced structural color changes. On the contrary, traditional Chinese medicine pre-protection can increase the vitality of cardiomyocytes, reduce reactive oxygen species production, and improve the contractile function of cardiomyocytes, which is highly consistent with the known conclusion. These results indicated that our structural color heart-on-a-chip with real-time visualization characteristics could provide an ideal platform for traditional Chinese medicine development and drug screening.
研究领域:
生物医学工程
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药理学
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传统医学
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产品关联
DOI
高影响因子
Biochemistry and Cell Biology
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2020
·Vol. 98
·期 2
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IF 2.46
Xue-liang Zhou,Xia Wu,Rong-rong Zhu,Hua Xu,Yun-yun Li,Qi-rong Xu,Sheng Liu,Song-qing Lai,Xinping Xu,Li Wan,Qi-cai Wu,Ji-chun Liu
Both the Notch1 and Keap1–Nrf2 signaling pathways have cardioprotective effects, but the role of Notch1–Nrf2 crosstalk in myocardial ischemia–reperfusion injury is unclear. In this study, we established hypoxia–reoxygenation in neonate rat myocardial cells and employed γ-secretase inhibitor and curcumin to inhibit and activate the Notch1 and Keap1–Nrf2 signaling pathways, respectively. We found that the combined action of the Notch1 and Keap1–Nrf2 signaling pathways significantly increased cardiomyocyte viability, inhibited cardiomyocyte apoptosis, reduced the formation of reactive oxygen species, and increased antioxidant activities. In conclusion, these findings suggest that Notch1–Nrf2 crosstalk exerts myocardial protection by reducing the formation of reactive oxygen species.
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Chinese Medicine
·
2024
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IF 5.3
MingShan Zhang,YuFei Zhang,JingGang He,XinRui Wang,YinYin Wang,LinYan Li,Ling Tao,Min Zhang,Xiangchun Shen
Background Diabetic cardiomyopathy (DCM), characterized by myocardial fibrosis, is a major cause of mortality and morbidity in diabetic patients; the inhibition of cardiac fibrosis is a fundamental strategy for treating DCM. Gastrodin (GAS), a compound extracted from Gastrodia elata protects against DCM, but the molecular mechanism underlying its antifibrotic effect has not been elucidated. Methods In vivo, the effects of GAS were investigated using C57BL/6 mice with DCM, which was induced by administering a high-sugar, high-fat (HSF) diet and streptozotocin (STZ). We assessed the cardiac function in these mice and detected histopathological changes in their hearts and the degree of cardiac fibrosis. In vitro, neonatal rat cardiac fibroblasts (CFs) were transformed into myofibroblasts by exposing them to high glucose combined with high palmitic acid (HG-PA), and CFs were induced by pEX-1 (pGCMV/MCS/EGFP/Neo) plasmid-mediated overexpression of KLK8, which contains the rat KLK8 gene. The KLK8 siRNA was knocked down to study the effects of GAS on CF differentiation, collagen synthesis, and cell migration by specific mechanisms of action of GAS. Results GAS attenuated pathological changes in the hearts of DCM mice, rescued impaired cardiac function, and attenuated cardiac fibrosis. Additionally, the results of molecular docking analysis showed that GAS binds to kinin-releasing enzyme-related peptidase 8 (KLK8) to inhibit the increase in protease-activated receptor-1 (PAR-1), thus attenuating myocardial fibrosis. Specifically, GAS attenuated the transformation of neonatal rat CFs to myofibroblasts exposed to HG-PA. Overexpressing KLK8 promoted CF differentiation, collagen synthesis, and cell migration, and KLK8 siRNA attenuated HG-PA-induced CF differentiation, collagen synthesis, and cell migration. Further studies revealed that a PAR-1 antagonist, but not a PAR-2 antagonist, could attenuate CF differentiation, collagen synthesis, and cell migration. Additionally, GAS inhibited KLK8 upregulation and PAR1 activation, thus blocking the differentiation, collagen synthesis, and cell migration of HG-PA-exposed CFs and triggering TGF-β1/Smad3 signaling. Conclusion GAS alleviated pathological changes in the hearts of DCM model mice induced by an HSF diet combined with STZ. KLK8 mediated HG-PA-induced differentiation, collagen synthesis, and the migration of CFs. GAS attenuated the differentiation, collagen synthesis, and migration of CFs by inhibiting the KLK8-PAR1 signaling axis, a process in which TGF-β1 and Smad3 are involved. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s13020-024-01035-4.
研究领域:
医学
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药理学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Ying Hao,RuiLin Li,ChengHui Fan,Yang Gao,Xia Hou,Wei wen,YunLi Shen
Introduction: Acute myocardial infarction (AMI) is a critical condition that can lead to ischemic cardiomyopathy (ICM), a subsequent heart failure state characterized by compromised cardiac function.Methods: This study investigates the role of mitophagy in the transition from AMI to ICM. We analyzed AMI and ICM datasets from GEO, identifying mitophagy-related differentially expressed genes (MRDEGs) through databases like GeneCards and Molecular Signatures Database, followed by functional enrichment and Protein-Protein Interaction analyses. Logistic regression, Support Vector Machine, and LASSO (Least Absolute Shrinkage and Selection Operator) were employed to pinpoint key MRDEGs and develop diagnostic models, with risk stratification performed using LASSO scores. Subgroup analyses included functional enrichment and immune infiltration analysis, along with protein domain predictions and the integration of regulatory networks involving Transcription Factors, miRNAs, and RNA-Binding Proteins, leading to drug target identification. Results: The TGFβ pathway showed significant differences between high- and low-risk groups in AMI and ICM. Notably, in the AMI low-risk group, MRDEGs correlated positively with activated CD4+ T cells and negatively with Type 17 T helper cells, while in the AMI high-risk group, RPS11 showed a positive correlation with natural killer cells. In ICM, MRPS5 demonstrated a negative correlation with activated CD4+ T cells in the low-risk group and with memory B cells, mast cells, and dendritic cells in the high-risk group. The diagnostic accuracy of RPS11 was validated with an area under the curve (AUC) of 0.794 across diverse experimental approaches including blood samples, animal models, and myocardial hypoxia/reoxygenation models.Conclusions: This study underscores the critical role of mitophagy in the transition from AMI to ICM, highlighting RPS11 as a highly significant biomarker with promising diagnostic potential and therapeutic implications.
研究领域:
心血管病学
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分子生物学
·
生物信息学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
·
2021
·
IF 6.684
Xu Yifeng,Wang Boqian,Liu Xiaoxiao,Deng Yunfei,Zhu Yanqi,Zhu Feng,Liang Yanyan,Li Hongli
Myocardial ischemia–reperfusion injury (MIRI), characterized by post-ischemic cardiomyocytes death and reperfusion myocardial damage, is a lethal yet unresolved complication in the treatment of acute myocardial infarction (AMI). Previous studies have demonstrated that poly(ADP-ribose) polymerase-1 (PARP1) participates in the progression of various cardiovascular diseases, and various reports have proved that PARP1 can be a therapeutic target in these diseases, but whether it plays a role in MIRI is still unknown. Therefore, in this study, we aimed to explore the role and mechanism of PARP1 in the development of MIRI. Firstly, we demonstrated that PARP1 was activated during MIRI-induced myocardial autophagy in vitro. Moreover, PARP1 inhibition protected cardiomyocytes from MIRI through the inhibition of autophagy. Next, we discovered that specificity protein1 (Sp1), as a transcription factor of PARP1, regulates its target gene PARP1 through binding to its target gene promoter during transcription. Furthermore, silencing Sp1 protected cardiomyocytes from MIRI via the inhibition of PARP1. Finally, the functions and mechanisms of PARP1 in the development of MIRI were also verified in vivo with SD rats model. Based on these findings, we concluded that PARP1 inhibition protects cardiomyocytes from MIRI through the inhibition of autophagy, which is targeted by Sp1 suppression. Therefore, the utilization of PARP1 exhibits great therapeutic potential for MIRI treatment in future.
研究领域:
心血管疾病
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2016
·
IF 4.492
Zhuo Fan,Ting Wen,Yaoxu Chen,Lijie Huang,Wei Lin,Chunxia Yin,Wen Tan
channel is an important mediator or factor in physiological and pathological metabolic pathway. Activation of channel has been identified to be a critical step in the cardioprotective mechanism against IR injury. On the other hand, desensitization of the channel to its opener or the metabolic ligand ATP in pathological conditions, like cardiac hypertrophy, would decrease the adaption of myocardium to metabolic stress and is a disadvantage for drug therapy. Isosteviol, obtained by acid hydrolysis of stevioside, has been demonstrated to play a cardioprotective role against diseases of cardiovascular system, like anti-IR injury, antihypertension, antihyperglycemia, and so forth. The present study investigated the effect of isosteviol (STV) on sarc channel current induced by pinacidil and mitochondrial flavoprotein oxidation induced by diazoxide. Our results showed that preincubating cells with STV not only increased the current amplitude and activating rate of sarc channels induced by pinacidil but also potentiated diazoxide-elicited oxidation of flavoprotein in mitochondria.
研究领域:
药理学
·
心血管生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2025
·
IF 3.9
Xu Qiuling,Liu Zhuoxi,Wang Liyuan,Liu Guoyang,Zhao Long,Yue Hui,Liu Yong
Diabetic cardiomyopathy (DCM) requires a systematic approach for effective management. Focusing on key signaling pathways in myocardial fibrosis could offer novel therapeutic approaches for DCM. The objective of this research is to investigate new biomarker and the underlying mechanisms by which baicalin intervenes in the progression of DCM. Swiss Target Prediction databases and weighted correlation network analysis (WGCNA) were employed to collect and analyze targets of baicalin and DCM. Intersection targets were obtained through venn online website, network visualization was conducted through STRING database and Cytoscape 3.7.2 software. Molecular docking validation was completed via AutoDock Vina software. Western blotting, RT-qPCR and histology were carried out to validate the direct targets of baicalin and explore the molecular mechanism during DCM progression. In mice induced to DCM, we observed that disruptor of telomeric silencing 1-like (DOT1L) was upregulated. Baicalin (BC) reduced myocardial fibrosis in mice as indicated by the reduced expression levels of fibrosis markers COL-1 and TGF-β. The inhibitory effect of BC was reversed by overexpressed DOT1L and further enhanced by silenced DOT1L. Our results indicate that cardiomyocyte DOT1L exerts a pathogenic role in DCM and BC specifically targets DOT1L/COL-1 signaling to reduce myocardial fibrosis in DCM.
✓ 已验证
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
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分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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