Journal of Translational Medicine
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2025
·Vol. 23
·期 1
·1-18
·
IF 7.5
Tan Yanzhen,Li Hong,Cao Guojie,Xin Jialin,Yan Dongxu,Liu Yingying,Li Panpan,Zhang Yuxi,Shi Lei,Zhang Bing,Yi Wei,Sun Yang
Background In developed nations, myocardial infarction (MI) is one of the main causes of morbidity and mortality, resulting in a significant economic burden and becoming a global public health problem. C1q/tumor necrosis factor-related protein 9 (CTRP9) is a secreted protein comprising a variable domain, a collagenous region, and a C-terminal trimerizing globular C1q (gC1q) domain. In vivo, the full-length CTRP9 (fCTRP9) can be cleaved into the globular domain of CTRP9 (gCTRP9). Here, we tested the cardio-protective impacts of fCTRP9, gCTRP9, and N-terminal domain, including the variable and collagenous domain, of CTRP9 (nCTRP9) in the context of MI.Methods Studies comparing the protective properties of fCTRP9 and gCTRP9 against MI in mice hearts were performed both in vitro and in vivo. The role of matrix metalloproteinase-9 (MMP9) in CTRP9 cleavage was examined, and the effects of different CTRP9 domains on cardiac fibrosis and cardiac fibroblast (CF) activation were investigated.Results gCTRP9 exerted better protective effects than fCTRP9 against MI, demonstrating superior anti-apoptotic and anti-fibrotic properties. fCTRP9 was cleaved by MMP9, resulting in gCTRP9 and nCTRP9. MMP9 overexpression enhanced the cardioprotective effects of fCTRP9, while nCTRP9 supplementation aggravated cardiac fibrosis in MI mice. Mechanistically, nCTRP9 activated CFs via an increase in Rap1 expression and MEK 1/2 and ERK1/2 phosphorylation.Conclusion sDifferent domains of CTRP9 have distinct cardioprotective effects. gCTRP9 shows beneficial effects, while nCTRP9 promotes cardiac fibrosis. These findings highlight the importance of CTRP9 in cardiac function regulation and suggest prospective therapeutic options for MI treatment.
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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PubMed
高影响因子
PHYTOMEDICINE
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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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PubMed
高影响因子
MOLECULAR IMMUNOLOGY
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2024
·
IF 3.2
Zhou Si Yun,Song Zhihua,Tian Xuelian,Xia Min,Hu Rongjing,Luo Mei
Chlamydia trachomatis (CT) is the leading cause of bacterial sexually transmitted diseases worldwide, which can cause diseases such as pelvic inflammatory disease, and cervical and fallopian tube inflammation, and poses a threat to human health. Rosmarinic acid (RosA) is an active ingredient of natural products with anti-inflammatory and immunomodulatory effects. This study aimed to investigate the role of RosA in inhibiting autophagy-regulated immune cells-CD8+ T cells via the Ras/Raf/MEK/ERK signaling pathway in a CT-infected mouse model. Mice were inoculated with CT infection solution vaginally, and the mechanistic basis of RosA treatment was established using H&E staining, flow cytometry, immunofluorescence, transmission electron microscopy, and western blot. The key factors involved in RosA treatment were further validated using the MEK inhibitor cobimetinib. Experimental results showed that both RosA and the reference drug azithromycin could attenuate the pathological damage to the endometrium caused by CT infection; flow cytometry showed that peripheral blood CD8+ T cells increased after CT infection and decreased after treatment with RosA and the positive drug azithromycin (positive control); immunofluorescence showed that endometrial CD8 and LC3 increased after CT infection and decreased after RosA and positive drug treatment; the results of transmission electron microscopy showed that RosA and the positive drug azithromycin inhibited the accumulation of autophagosomes; western bolt experiments confirmed the activation of autophagy proteins LC3Ⅱ/Ⅰ, ATG5, Beclin-1, and p62 after CT infection, as well as the inhibition of Ras/Raf/MEK/ERK signaling. RosA and azithromycin inhibition of autophagy proteins activates Ras/Raf/MEK/ERK signaling. In addition, the MEK inhibitor cobimetinib attenuated RosA's protective effect on endometrium by further activating CD8+ T cells on a CT-induced basis, while transmission electron microscopy, immunofluorescence, and western blots showed that cobimetinib blocked ERK signals activation and further induced phagocytosis on a CT-induced basis. These data indicated that RosA can activate the Ras/Raf/MEK/ERK signaling pathway to inhibit autophagy, and RosA could also regulate the activation of immune cells-CD8+T cells to protect the reproductive tract of CT-infected mice.
研究领域:
免疫学
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微生物学
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药理学
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病理学
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DOI
PubMed
高影响因子
INFLAMMATION
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2025
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IF 5
Li Ying,Wang Lei,Guan Tianyue,Chen Yaru,Zhu Wenting,Liu Xiao,Li Yusa,Huang Hongyu,Dong Zibo,Zhang Honggang
Diabetic cardiomyopathy (DCM) is a major complication of diabetes, characterized by myocardial inflammation, oxidative stress, fibrosis, apoptosis, and RhoA activation, ultimately leading to heart failure. This study aimed to evaluate whether higenamine hydrochloride (HGN), a natural alkaloid with anti-inflammatory and antioxidant properties, could alleviate DCM and elucidate its underlying mechanisms. A DCM model was established via streptozotocin injection in mice, followed by HGN administration. Fasudil, a RhoA inhibitor, was used to assess pathway involvement. Histology, biochemical assays, flow cytometry, immunoblotting, ELISA, and qPCR were employed for evaluation. Results showed that HGN effectively alleviated cardiac histological abnormalities and myocardial injury in DCM mice. Further analysis revealed that HGN attenuated DCM-induced cardiac inflammation, oxidative stress, fibrosis, and apoptosis ( p < 0.05). In vitro, HGN also reduced high glucose-induced inflammation, oxidative stress, fibrosis, and apoptosis in H9C2 cardiomyocytes ( p < 0.05). Mechanistically, these protective effects were mediated by inhibition of RhoA, through which HGN suppressed the MEK/ERK signalling pathway, thereby mitigating cardiomyocyte injury ( p < 0.05). However, the RhoA inhibitor fasudil hydrochloride abolished the cardioprotective effects of HGN in DCM mice, specifically, fasudil hydrochloride reversed the HGN-induced improvements in cTnT, CK, and LDH levels. Additionally, echocardiographic parameters (IVSD, LVPWd, LVPWs, LVIDd, LVIDs, IVSs, EF, and FS) were also reversed to levels seen in untreated DCM mice, further confirming that HGN exerts its therapeutic actions via the RhoA/MEK/ERK axis ( p < 0.05). Overall, HGN mitigates cardiac inflammation, oxidative stress, fibrosis, and apoptosis in DCM by inhibiting the MEK/ERK pathway through RhoA. This study provides a scientific basis for developing DCM treatments and highlights the therapeutic potential of HGN. Graphical
研究领域:
心血管研究
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分子生物学
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药理学
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内分泌学
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糖尿病并发症
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PubMed
高影响因子
JOURNAL OF MOLECULAR MEDICINE-JMM
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2025
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IF 4.2
Wen Xin,Peng Yuefeng,Yang Wenqing,Zhu Yuzhong,Yu Fan,Geng Li,Wang Xianfeng,Wang Xiaoyan,Zhang Xiaodong,Tang Yi,Feng Lei,Zhou Tingting,Jia Hongliang,Yang Liu
Transient receptor potential canonical 1 (TRPC1) channel, a Ca 2+ -permeable ion channel widely expressed in vasculature, has been reported to be involved in various cardiovascular disorders. However, the pathophysiological function of vascular smooth muscle cell (VSMC)-derived TRPC1 in hypertension and hypertensive cardiovascular remodeling remains to be defined. In this study, we found increased TRPC1 expression in both angiotensin II (AngII)-treated VSMCs and aortas from AngII-infused mice. VSMC-specific TRPC1 deficiency strikingly attenuated AngII-induced vasoconstriction, hypertension, vascular remodeling, and cardiac hypertrophy. Mechanistically, AngII activated enhancer of zeste homolog 2 (EZH2) to stimulate TRPC1 expression, induced calcium influx and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK-ERK), which in turn triggered VSMC proliferation and migration and exacerbated hypertension and cardiovascular remodeling. Treatment with EZH2 inhibitor reduced VSMC proliferation and migration and alleviated vasoconstriction and hypertension in AngII-infused mice. Together, we revealed the pathogenic role of the EZH2-TRPC1-MEK/ERK pathway in AngII-induced hypertension and cardiovascular damage. TRPC1 or EZH2 inhibition may represent a desirable therapeutic target for the treatment of hypertension. Key messages
AngII activates AT1R-EZH2-TRPC1 pathway in VSMCs and aortas of hypertensive mice.
TRPC1 promotes VSMC proliferation and migration via MEK/ERK signaling.
Inhibition of TRPC1 or EZH2 alleviates hypertension and cardiovascular remodeling.
研究领域:
心血管病学
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分子生物学
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药理学
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Huangxi Fu,Feng Jiang,Anqi Xu,Taicheng Zhou,Ning Liu,Xueqin Chen,Zizheng Gao,Wentong Wu,Hao Yan,Xiaochun Yang,Bo Yang,Qiaojun He,Peihua Luo,Zhifei Xu
The cardiac complications caused by drugs, including cardiac dysfunction and heart failure, significantly limit the wide clinical application of drugs and lead to morbidity and mortality. High mobility group box 1 (HMGB1) plays an extensive role in drug-induced cardiotoxicity. However, the cardiotoxic mechanisms for most small-molecule kinase inhibitors (SMKIs) remains unknown. Here, we identify that accumulated HMGB1 is associated with the cardiac complications caused by a series of FDA-approved SMKIs, among which trametinib-induced cardiomyocyte death was most significantly reversed by HMGB1 knockout. Moreover, cardiomyocyte-specific Hmgb1 deletion in mice could improve cardiac muscle contraction, calcium regulation and cardiomyocyte apoptosis in autophagy- or inflammation-independent manner. We further show that trametinib leads to the aberrant accumulation of HMGB1 by increasing its stability via inhibiting zinc finger protein Zinc Finger MYND-Type Containing 8 (ZMYND8)-mediated ubiquitination and proteasomal degradation of HMGB1, identifying ZMYND8 as a novel negative regulator of HMGB1 stability in cardiomyocyte and a potential novel regulator of cardiac function. Glycyrrhizic acid, an HMGB1 inhibitor used in clinic, prevents trametinib-induced cardiac complications. These findings reveal the mechanism and propose an effective intervention strategy for trametinib-induced cardiac complications, which would contribute to the safe application of trametinib, cardiac safety evaluation of drugs or candidate compounds and novel drug development.
研究领域:
心血管药理学
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分子生物学
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毒理学
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肿瘤学
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药物开发
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DOI
PubMed
高影响因子
Bioactive Materials
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2021
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IF 14.593
Can Liu,Lei Fan,Zhenming Tian,Huiquan Wen,Lei Zhou,Pengfei Guan,Yian Luo,Chuncheung Chan,Guoxin Tan,Chengyun Ning,Limin Rong,Bin Liu
Conductive scaffolds have been shown to exert a therapeutic effect on patients suffering from peripheral nerve injuries (PNIs). However, conventional conductive conduits are made of rigid structures and have limited applications for impaired diabetic patients due to their mechanical mismatch with neural tissues and poor plasticity. We propose the development of biocompatible electroconductive hydrogels (ECHs) that are identical to a surgical dressing in this study. Based on excellent adhesive and self-healing properties, the thin film-like dressing can be easily attached to the injured nerve fibers, automatically warps a tubular structure without requiring any invasive techniques. The ECH offers an intimate and stable electrical bridge coupling with the electrogenic nerve tissues. The in vitro experiments indicated that the ECH promoted the migration and adhesion of the Schwann cells. Furthermore, the ECH facilitated axonal regeneration and remyelination in vitro and in vivo through the MEK/ERK pathway, thus preventing muscle denervation atrophy while retaining functional recovery. The results of this study are likely to facilitate the development of non-invasive treatment techniques for PNIs in diabetic patients utilizing electroconductive hydrogels.
研究领域:
生物医学工程
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神经科学
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材料科学
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2026
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IF 5.1
Sheng-Li Wu,Xiao-Feng He,Pianchou Gongpan,Xiao-Yan Huang,Chang-An Geng
DCA stimulated GLP-1 secretion in STC-1 and NCI-H716 cells. • DCA decreased fasting blood glucose levels by promoting GLP-1 secretion in db/db mice. • DCA ameliorated glucose intolerance and insulin resistance and lowered serum TC levels. • DCA promoted GLP-1 secretion through specific activation on TGR5/PKA/MEK/ERK pathway. Type 2 diabetes mellitus (T2DM) is a heterogeneous metabolic disorder characterized by insulin resistance and progressive β cell dysfunction. Deoxycalyxin A (DCA), a unique diarylheptanoid-chalcone hybrid isolated from Alpinia katsumadai , was identified as a novel stimulator of GLP 1 secretion in both STC-1 (EC 50 : 10.7 μM) and NCI-H716 (EC 50 : 13.4 μM) cells. Oral administration of DCA (40 and 80 mg/kg) in db/db mice significantly reduced fasting blood glucose, ameliorated glucose intolerance and insulin resistance by enhancing endogenous GLP-1 secretion, and lowered the total serum cholesterol levels. Mechanistic study demonstrated that DCA identify the TGR5 receptor, which induces a significant increase in intracellular cyclic AMP (cAMP) levels, which activates PKA with subsequent sequential phosphorylation of MEK1/2 and ERK activation, ultimately enhancing GLP-1 secretion. Our findings identify DCA as a novel TGR5 agonist to stimulate GLP-1 secretion via the TGR5/PKA/MEK/ERK pathway, which has the potential to be developed as a promising antidiabetic lead with a distinct mechanism of action. DCA, a unique diarylheptanoid-chalcone from Alpinia katsumadai , is a novel TGR5 agonist to stimulate GLP-1 secretion via PKA/MEK/ERK pathway, which has the potential to be developed as a promising antidiabetic candidate. Download: Download high-res image (123KB) Download: Download full-size image
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DOI
高影响因子
GENE
·
2022
·
IF 3.913
Xiang Li,Nan Wang,Yutong Wu,Yidan Liu,Ruoyu Wang
Background Aldehyde dehydrogenase 6 family member A1 (ALDH6A1) is associated with multiple diseases, but its pathogenesis in colon cancer (CC) is ambiguous and needs further study so that this research explores the function of ALDH6A1 in CC. Methods The level of ALDH6A1 in colon adenocarcinoma (COAD), CC tissues, and cells was measured by starBase v2.0, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot. Post transfection with overexpressed (oe)-ALDH6A1, cell biological behaviors, as well as apoptosis-, matrix metalloproteinase (MMP)-, and rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway-related markers were measured by cell function experiments, qRT-PCR, and western blot. Next, the effects of small interfering RNA targeting ALDH6A1 (si-ALDH6A1) and RAS/RAF inhibitor (MCP110) on cell biological behaviors, as well as apoptosis-, MMP-, and RAS/RAF/MEK/ERK pathway-related markers were detected again. Results ALDH6A1 was low-expressed in COAD, CC tissues, and cells. Oe-ALDH6A1 weakened cell vitality, migration and invasionbut facilitated apoptosis; while it reduced expression levels of Bcl-2, MMP-2, MMP-9 and the RAS/RAF/MEK/ERK pathway-related markers but promoted Bax level. However, the regulation of si-ALDH6A1 on cell biological behaviors and related genes was opposite to that of oe-ALDH6A1. Moreover, MCP110 rescued the regulation of si-ALDH6A1 on cell biological behaviors, expressions of apoptosis- MMP- as well as RAS/RAF/MEK/ERK pathway-related markers. To sum up, ALDH6A1 attenuated CC progression by down-regulating the expressions of RAS/RAF/MEK/ERK pathway-related markers.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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PubMed
高影响因子
APOPTOSIS
·
2026
·Vol. 31
·期 6
·150
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IF 9
Xu Jiang,Liu Longyan,Liu Shuheng,He Zesong,Meng Wei
To overcome resistance to MEK inhibitors such as selumetinib in neurofibroma, we developed a metabolism-targeted nanotherapeutic based on a pH-responsive silver nanoparticle platform (AgNP-PEG-TC) for delivering Triacsin C (TC), an inhibitor of long-chain acyl-CoA synthetases, to disrupt tumor-associated lipid metabolism. AgNP-PEG-TC was synthesized and characterized for its physicochemical properties, drug-loading efficiency, and pH-responsive release behavior. Its antitumor effects were assessed in human neurofibroma cells, including selumetinib-resistant cells, and in normal Schwann cells by examining proliferation, apoptosis, migration, and invasion. In vivo therapeutic efficacy and biosafety were evaluated in neurofibroma xenograft models. Bulk RNA sequencing, lipidomics, and protein analyses were performed to investigate the underlying mechanisms. AgNP-PEG-TC demonstrated stable colloidal properties and successful pH-sensitive release. It selectively reduced neurofibroma cell growth, migration, and invasion while promoting apoptosis, with minimal effects on normal cells. In xenograft models, AgNP-PEG-TC significantly inhibited tumor growth and showed good biocompatibility. Multi-omics analyses indicated that its antitumor activity was associated with ACSL4 downregulation, remodeling of arachidonic-acid-enriched phospholipids, enhanced lipid peroxidation, and increased lipid-droplet accumulation, suggesting heightened ferroptosis susceptibility. Notably, AgNP-PEG-TC synergized with MEK inhibitors and restored antitumor responses in resistant neurofibroma cells. These findings establish a metabolism-nanotechnology synergy in which AgNP-PEG-TC-mediated ACSL4 inhibition and lipid metabolic reprogramming resensitize MEK inhibitor-resistant neurofibromas to therapy. The platform functions as both a targeted drug carrier and a modulator of tumor lipid homeostasis, offering a promising combinatorial strategy. Graphical abstract The alternative text for this image may have been generated using AI.
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2019
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IF 4.825
Wensong Yao,Zhen Lin,Peiying Shi,Bing Chen,Gang Wang,Jianyong Huang,Yuxia Sui,Qicai Liu,Shaoguang Li,Xinhua Lin,Qicai Liu,Hong Yao
Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and tends to have drug resistance. Delicaflavone (DLF), a novel anticancer agent of biflavonoid from Selaginella doederleinii Hieron , showed strong anti-CRC activities, which has not yet been reported. In this study, we investigated the effects and possible anti-CRC mechanism of DLF in vitro and in vivo . It was shown that DLF significantly inhibited the cells viability and induced G2/M phase arrest, apoptosis , the loss of mitochondrial membrane potential (Δψm), generation of ROS and increase of intracellular Ca 2+ in HT29 and HCT116 cells by MTT assay, TEM, flow cytometry and inverted fluorescence microscope. Western blot and qPCR assays results further confirmed DLF induced caspase-dependent apoptosis and inhibited PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in CRC cells. Meanwhile, DLF significantly suppressed the tumor growth via activation of Caspase-9 and Caspase-3 protein and decrease of ki67 and CD34 protein without apparent side effects in vivo . In summary, these results indicated DLF induced ROS-mediated cell cycle arrest and apoptosis through ER stress and mitochondrial pathway accompanying with the inhibition of PI3K/AKT/mTOR and Ras/MEK/Erk signaling cascade. Thus DLF could be a potential therapeutic agent for CRC.
研究领域:
肿瘤学
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药理学
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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 MEDICAL VIROLOGY
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2025
·Vol. 97
·期 3
·e70267
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IF 4.6
Wenting Mao,Yi Wan,Yang Liu,Minmin Zhou,Xiaoying Jia,Yuxia Hou,Wei Wang
The lymphocytic choriomeningitis virus (LCMV) is a widespread pathogen that causes mild-to-severe infections to severe outcomes. In this study, we explored the potential of trametinib, a mitogen-activated protein kinase (MAPK) inhibitor, as an antiviral agent against LCMV. Trametinib demonstrated significant antiviral activity against two distinct LCMV strains, Armstrong and Cl13, with promising half-maximal inhibitory concentrations (IC 50 ) and selectivity indices (SI) indicating its potency and safety profile. Mechanistic investigations revealed that trametinib interfered with multiple stages of the LCMV life cycle, including membrane fusion and genomic replication, leading to the robust inhibition of viral proliferation. Furthermore, trametinib disrupted the MEK/ERK signaling pathway, which is crucial for LCMV infection. In both in vitro and in vivo experiments, trametinib effectively reduced viral loads and mitigated pathological damage to the spleen and liver tissues. Overall, our findings suggest that trametinib is a promising novel therapeutic option for combating LCMV infection by targeting key stages of the viral life cycle and disrupting host cellular signaling pathways. Further exploration of the antiviral properties of trametinib is likely to pave the way for its clinical development as a treatment for LCMV infections.
研究领域:
病毒学
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药物研发
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医学
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PubMed
高影响因子
危险品化学品经营许可证（带存储）