Journal of Cardiovascular Translational Research
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2024
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IF 2.4
Zhang Ning,Liu Liangju,Lv Xiaowang,Wang Yixuan,Zhang Wei,Wen Xin,Yu Fan,Zhou Tingting
Trimethylamine oxide (TMAO) is an intestinal flora metabolite associated with risk of cardiovascular diseases. Transient receptor potential vanilloid 4 (TRPV4) is a Ca 2+ -permeable ion channel that is essential for vasodilation and endothelial function. Currently, there are few studies on the effect of TMAO on TRPV4 channels. In the present study, Ca 2+ imaging of vascular tissue showed that TMAO inhibited TRPV4-mediated Ca 2+ influx into aortic endothelial cells in a dose-dependent manner. Furthermore, a whole-cell patch clamp assay showed that TMAO blocked TRPV4-mediated cation currents. Notably, results of aortic vascular tension measurement showed that TMAO impaired endothelium-dependent vasodilation in mouse aortic vessels through the TRPV4-NO pathway. Our results indicated that TMAO inhibited Ca 2+ entry in endothelial cells and impaired vasodilation through the TRPV4-NO pathway in mice. These results provide scientific evidence for novel pathogenic mechanisms underlying the role of TMAO in cardiovascular disease. Graphical Abstract TMAO impairs mouse aortic vasodilation by inhibiting TRPV4-NO pathway in endothelial cells.
研究领域:
药理学
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心血管生理学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY
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2025
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IF 2.6
Jie-Fang Gao,Tong-Xuan Li,Guo-Qiang Zhang
The skin serves as the primary defensive barrier of the human body against external stimuli and damage. Keratinocytes, which are the predominant cell type in the human epidermis, undergo a differentiation process that is crucial for the formation of the skin barrier. Myricetin, a dietary flavonoid present in various fruits and vegetables, is known to play a significant role in maintaining intestinal barrier function; however, its impact on the skin barrier remains inadequately understood. Consequently, this study investigates the effects of myricetin on the differentiation of epidermal keratinocytes and the integrity of the skin barrier. Differentiation of primary mouse keratinocytes was induced using 1.8 mM CaCl2. tudy demonstrated that myricetin effectively suppresses cell proliferation and induces both cell cycle arrest and calcium ion (Ca2+) influx, without influencing apoptosis. Concurrently, myricetin enhances the expression of differentiation markers, including K10, TGase1, Filaggrin, and Involucrin, and facilitates the formation of tight junctions. Upon examining the underlying mechanisms, we discovered that myricetin activates the TRPV4 channel, and the promotion of keratinocyte differentiation by myricetin is contingent upon the activation of this channel. In summary, these findings suggested that myricetin could promote keratinocytes differentiation and have well-established skin barrier protective function.
研究领域:
细胞生物学
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皮肤病学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF TOXICOLOGICAL SCIENCES
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2021
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IF 2.196
Chunsong Yang,Mengqing Si,Jing Zhou
Excessive use of Ketamine (KET) has a neurotoxic effect on the brain. This study explored the effect of Transient Receptor Potential Vanilloid 4 (TRPV4) on KET-induced neurotoxicity in the hippocampus. We extracted and identified rat hippocampal neuronal cells. The hippocampal neurons were treated with different concentrations (0, 0.1, 1, 10, 100, 300 and 1000 μmol/L) of KET (6, 12 and 24 hr). Cell viability was detected by cell counting Kit-8 (CCK-8), and TRPV4 expression was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and western blot. After silencing TRPV4, we tested cell viability and apoptosis. The contents of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and catalase (CAT) were detected by colorimetry, and the contents of TNF-α, IL-1β, IL-6 and reactive oxygen species (ROS) were detected by Enzyme-Linked ImmunoSorbent Assay (ELISA). Finally, the expression levels of apoptosis-related proteins Bcl-2, Bax and Cleaved caspase-3, and phosphorylated-p65 (p-65), p65, phosphorylated-IκBα (p-IκBα) and IκBα were detected by qRT-PCR and western blot. KET inhibited the viability of hippocampal neurons in a dose-dependent manner, and up-regulated TRPV4 expression. SiTRPV4 inhibits KET-induced decrease in cell viability and promotes apoptosis. SiTRPV4 reduced MDA and ROS content, increased SOD, GSH and CAT levels. The release of proinflammatory factors TNF-α, IL-1β and IL-6 was also inhibited by siTRPV4. In addition, siTRPV4 up-regulated KET-induced Bcl-2 expression in hippocampal neurons, down-regulated Bax and Cleaved caspase-3, and inhibited the activation of the inflammatory pathway. Silencing TRPV4 partially reverses the neurotoxic effects induced by KET through regulating apoptosis-related proteins and p65/IκBα pathway.
研究领域:
神经科学
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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
CELLULAR SIGNALLING
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2025
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IF 3.7
Yuyan Sun,Ziyu Luo,Haiqi Zhou,Sha Wu,Hongwei Shen,Yuanyuan Fu,Thai Namanh Ngo,Wen Wang,Yuanrong Wang,Ying Kong
Chondrocyte mechanotransduction dysfunction is a key feature of osteoarthritis (OA). Previous studies have demonstrated that primary cilia play a crucial role in chondrocyte mechanosensation and signal transduction. Transient Receptor Potential Vanilloid 4(TRPV4), which is highly expressed on primary cilia, is a critical mechanotransduction protein and one of the most important Ca 2+ channels. However, the interplay between the mechanism of primary cilia-mediated signaling and that of TRPV4 channel regulation remains poorly understood. Here, we demonstrate that OA chondrocytes and Intraflagellar Transport Protein 88(Ift88) conditional knockout (cKO) mice exhibit reduced ciliary incidence. This results in cartilage degeneration. TRPV4 expression inversely correlated with ciliary integrity, increasing as cilia were lost. In cilia-intact healthy chondrocytes, TRPV4 antagonism inhibited Ca 2+ -dependent NF-κB activation while promoting type II collagen(COL2) synthesis. These effects were abolished by Interleukin-1 beta(IL-1β)-induced ciliary defect or IFT88 deficiency. Chromatin immunoprecipitation(ChIP) analysis revealed disrupted p65 binding to the COL2 promoter upon the loss of ciliary integrity. Crucially, Ift88 cKO chondrocytes showed unresponsive of the TRPV4 channel, as confirmed by Ca 2+ flux and changes in the expression levels of NF-κB and COL2. Our findings position primary cilia as indispensable regulators of TRPV4-mediated NF-κB - COL2 signaling, offering mechanistic insights into OA pathogenesis and identifying IFT88 as a therapeutic checkpoint.
研究领域:
分子生物学
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细胞生物学
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骨关节炎病理学
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信号转导
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转化医学
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软骨生物学
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机械生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Shuhui Lei,Kaiqun Liu,Cong Liu,Ran An,Zilu Bao,Huan Zhang,Min Zou,Jianqiu Chen,HuiHui Zhang,Liangkai Wei,Zhou Lan,Lvyi Chen
s Background Inflammation is a vital biological defense mechanism, yet uncontrolled or prolonged inflammation can cause tissue damage. The NLRP3 inflammasome, a central component of innate immunity, drives inflammation by activating caspase-1 and promoting the release of cytokines like IL-1β. Monosodium urate (MSU) crystals are potent NLRP3 inflammasome activators implicated in diseases such as gout. While resveratrol, a natural polyphenol, exhibits anti-inflammatory properties, the specific mechanisms by which its cis-isomer (Cis-Resv) inhibits NLRP3 inflammasome activation remain poorly understood. Purpose This study aims to investigate the inhibitory effect of Cis-Resv on MSU-induced NLRP3 inflammasome activation and elucidate the underlying molecular mechanisms. Methods Bone marrow-derived macrophages (BMDMs) from C57BL/6J mice were stimulated with MSU crystals. The effects of Cis-Resv on IL-1β secretion, caspase-1 activation, and ASC oligomerization were evaluated using ELISA, Western blot, and immunoprecipitation, respectively. Transcriptomic analysis was employed to identify potential signaling pathways involved. The in vivo efficacy of Cis-Resv was assessed in MSU-induced acute gouty arthritis and air-pouch models by measuring joint swelling, inflammatory cytokines levels, and histopathological changes. Results Cis-Resv significantly inhibited MSU-induced NLRP3 inflammasome activation in BMDMs, reducing caspase-1 activation, IL-1β secretion, andassociated pyroptosis. Furthermore, Cis-Resv impeded ASC oligomerization, a critical step in inflammasome assembly. Transcriptomic analysis and subsequent functional validation revealed that Cis-Resv exerts these effects primarily through the TRPV4-Ca²⁺-phagocytosis-ROS signaling axis. Specifically, Cis-Resv inhibited macrophage TRPV4 channel activity, leading to decreased Ca²⁺ influx, impaired MSU crystal phagocytosis, and attenuated reactive oxygen species (ROS) accumulation. This reduction in ROS modulated the ROS-TXNIP pathway, diminishing the interaction between TXNIP and NLRP3, thereby suppressing inflammasome activation. In vivo , Cis-Resv effectively alleviated MSU-induced joint swelling, lowered IL-1β and TNF-α levels, and ameliorated histopathological damage in both gouty arthritis and air-pouch models. Conclusion Cis-Resv suppresses MSU-induced NLRP3 inflammasome activation by targeting the TRPV4-Ca²⁺-phagocytosis-ROS axis. This study identifies a novel mechanism and suggests Cis-Resv as a potential therapeutic agent for NLRP3-driven inflammatory conditions like gout.
研究领域:
免疫学
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炎症研究
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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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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Lin Niu,Shilong Wang,Yanyan Xu,Xingwang Zu,Xinyu You,Qiuyang Zhang,Pengwei Zhuang,Min Jiang,Jie Gao,Xiaotao Hou,Yanjun Zhang,Gang Bai,Jiagang Deng
Ethnopharmacological relevance As a classic traditional Chinese medicine , Magnolia officinalis ( M . officinalis ) is widely used in digestive diseases . It has rich gastrointestinal activity including inflammatory bowel disease (IBD) treatment, but the mechanism is not clear. Aim of the study In recent years, there has been a growing interest in investigating the regulatory effects of herbal compounds on transient receptor potential (TRP) channel proteins. Transient receptor potential vanilloid 4 (TRPV4), a subtype involved in endothelial permeability regulation, was discussed as the target of M . officinalis in the treatment of IBD in the study. Based on the targeting effect of TRPV4, this study investigated the active ingredients and mechanism of M . officinalis extract in treating IBD. Materials and methods To reveal the connection between the active ingredients in M . officinalis and TRPV4, a bioactivity-guided high performance liquid chromatography system coupled with mass spectrometry identification was utilized to screen for TRPV4 antagonists. TRPV4 siRNA knockdown experiment was employed to validate the significance of TRPV4 as a crucial target in regulating endothelial permeability by honokiol (HON). The interaction of the active ingredient representing HON with TRPV4 was confirmed by molecular docking, fluorescence-based thermal shift and live cell calcium imaging experiments. The potential binding sites and inhibitory mechanisms of HON in TRPV4 were analyzed by molecular dynamics simulation and microscale thermophoresis. The therapeutic effect of HON based on TRPV4 was discussed in DSS-IBD mice. Results Our finding elucidated that the inhibitory activity of M . officinalis against TRPV4 is primarily attributed to HON analogues. The knockdown of TRPV4 expression significantly impaired the calcium regulation and permeability protection in endothelial cells. The mechanism study revealed that HON specifically targets the Q239 residue located in the ankyrin repeat domain of TRPV4, and competitively inhibits channel opening with adenosine triphosphate (ATP) binding. The immunofluorescence assay demonstrated that the administration of HON enhances the expression and location of VE-Cadherin to protect the endothelial barrier and attenuates immune cell infiltration. Conclusions The finding suggested that HON alleviates IBD by improving endothelial permeability through TRPV4. The discovery provides valuable insights into the potential therapeutic strategy of active natural products for alleviating IBD.
研究领域:
药理学
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民族药理学
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胃肠病学
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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
FREE RADICAL BIOLOGY AND MEDICINE
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2024
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IF 7.1
Xiaowen Liu,Huamei Cai,Liang Peng,Hongli Ma,Yun Yan,Weixia Li,Jing Zhao
Remifentanil-induced hyperalgesia (RIH) represents a significant clinical challenge due to the widespread use of opioids in pain management. However, the molecular and cellular mechanisms underlying RIH remain elusive. This study aimed to unravel the role of spinal cord microglia, focusing on the Nrf2/HO-1 signaling pathway and TRPV4 channels in the development of RIH. We used both in vivo and in vitro models to investigate the activation state of spinal cord microglia, the expression of TRPV4 channels, and the modulation of the Nrf2/HO-1 pathway under remifentanil exposure. In addition, we evaluated the potential therapeutic effects of dexmedetomidine, a perioperative α2-adrenergic agonist, on RIH and its related molecular pathways. Our results revealed a prominent role of spinal cord microglia in RIH, demonstrating an apparent microglial M1 polarization and increased TRPV4 channel expression. A notable observation was the downregulation of the Nrf2/HO-1 pathway, which was associated with increased neuroinflammation and mechanical allodynia. By upregulating or overexpressing Nrf2, we confirmed its ability to inhibit TRPV4 and thereby attenuate RIH-associated mechanical allodynia, M1 polarization, and neuroinflammation. Encouragingly, dexmedetomidine demonstrated therapeutic potential by positively modulating the Nrf2-TRPV4 nexus, attenuating mechanical allodynia, and reducing microglial inflammation. Our research highlights the critical role of spinal cord microglia in RIH mediated by the Nrf2-TRPV4 axis. The ability of dexmedetomidine to modulate this axis suggests its potential as an adjunctive therapy to remifentanil in mitigating RIH. Further studies are imperative to explore the broader implications and practical applicability of our findings.
研究领域:
疼痛管理
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神经科学
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药理学
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炎症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2023
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IF 7.2
Lin Niu,Yu-jie Lu,Xing-wang Zu,Wen Yang,Fu-kui Shen,Yan-yan Xu,Min Jiang,Yang Xie,Su-yun Li,Jie Gao,Gang Bai
Transient receptor potential vanilloid 4 (TRPV4) plays a role in regulating pulmonary fibrosis (PF). While several TRPV4 antagonists including magnolol (MAG), have been discovered, the mechanism of action is not fully understood. This study aimed to investigate the effect of MAG on alleviating fibrosis in chronic obstructive pulmonary disease (COPD) based on TRPV4, and to further analyze its mechanism of action on TRPV4. COPD was induced using cigarette smoke and LPS. The therapeutic effect of MAG on COPD-induced fibrosis was evaluated. TRPV4 was identified as the main target protein of MAG using target protein capture with MAG probe and drug affinity response target stability assay. The binding sites of MAG at TRPV4 were analyzed using molecular docking and small molecule interaction with TRPV4-ankyrin repeat domain (ARD). The effects of MAG on TRPV4 membrane distribution and channel activity were analyzed by co-immunoprecipitation, fluorescence co-localization, and living cell assay of calcium levels. By targeting TRPV4-ARD, MAG disrupted the binding between phosphatidylinositol 3 kinase γ and TRPV4, leading to hampered membrane distribution on fibroblasts. Additionally, MAG competitively impaired ATP binding to TRPV4-ARD, inhibiting TRPV4 channel opening activity. MAG effectively blocked the fibrotic process caused by mechanical or inflammatory signals, thus alleviating PF in COPD. Targeting TRPV4-ARD presents a novel treatment strategy for PF in COPD.
研究领域:
药理学
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肺科学
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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
ENVIRONMENTAL POLLUTION
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2024
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IF 7.6
Rui Huang,Zijun Liu,Yunrui Pan,Zheng Ma,Huili Wang,Bin Wan,Jianzhong Li,Jing Chang
Pyrifluquinazon (PFQ), a novel insecticide containing a heptafluoroisopropyl moiety, has seen increasing use. However, limited research has been conducted on the toxicological effects and mechanisms of PFQ in aquatic organisms. To investigate the toxicity and underlying mechanisms of PFQ and its primary metabolite dPFQ in aquatic organisms, morphological, behavioral, hormonal, multi-omics analyses, and molecular docking studies were conducted on zebrafish larvae after exposure. The results showed that both PFQ and dPFQ induced developmental abnormalities, behavioral impairment, hormonal disruptions, and alterations in neurologically related metabolites and gene expression in early-stage zebrafish. Notably, delayed retinal vascular development was observed, which is also likely linked to the neurodevelopmental toxicity. Subsequently, identification and relative quantification of PFQ metabolites suggested that its toxicity might be primarily attributed to dPFQ. Finally, an Adverse Outcome Pathway (AOP) was proposed, initiating with the binding of dPFQ to the TRPV4 protein and ultimately leading to neurodevelopmental toxicity. This study delineated the neurodevelopmental toxicity of PFQ and its toxicological mechanisms in zebrafish, emphasizing the hazards posed by pesticide metabolites to non-target organisms and highlighting inherent limitations of extrapolating in vitro toxicity experiments.
研究领域:
毒理学
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环境科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Hui Dai,Qiao Liu,Xin mei Zhang,Jing cheng Zhang,Fang zhou Yin,Wu Yin
Ethnopharmacological relevance Fructus Meliae Toosendan (FMT) is a widely utilized natural medicine across various traditional medical systems, with a long history of extensive application. However, excessive use of FMT may result in severe intestinal toxicity. The specific components responsible for this toxicity and the underlying mechanisms remain unclear. Materials and methods The compositional differences between FMT and stir-fried FMT (SFFMT) were identified using ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS). Subsequently, bioinformatics analysis, molecular docking, kinetic modeling and microscale thermophoresis (MST) were employed to ascertain that toosendanin (TSN) targets intestinal transient receptor potential vanilloid receptor 4 (TRPV4). Calcium ion (Ca 2+ ) fluorescent probes, flow cytometry, immunofluorescence analysis and western blotting were employed to assess the elevation of calcium ions induced by TSN, which subsequently resulted in intestinal barrier damage. Finally, H&E staining, mouse endoscopy and immunofluorescence analysis confirmed that excessive oral administration of TSN leads to intestinal barrier damage in mice. Results Firstly, the content of TSN in SFFMT significantly decreased compared to that in FMT. Secondly, we present that TSN activates TRPV4, and that excessive TSN intake leads to elevated Ca 2+ levels and overload in colonic epithelial cells, which induces acute colonic toxicity by damaging the colonic barrier. It has been demonstrated in mouse models that high doses of TSN induce colonic barrier damage. Conclusions Excessive TSN induces abnormal activation of TRPV4, leading to an elevation of intracellular calcium ions. This phenomenon is recognized as the primary cause of colonic toxicity associated with FMT.
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产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
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2023
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IF 6.2
Xiaopeng Fan,Renjian Xie,Wenjing Song,Kunfu Ouyang,Li Ren
Bionic mimics using natural cartilage matrix molecules can modulate the corresponding metabolic activity by improving the microenvironment of chondrocytes. A bionic brush polymer, HA/PX, has been found to reverse the loss of cartilage extracellular matrix (ECM) and has promising applications in the clinical treatment of osteoarthritis (OA). However, the unknown bioremediation mechanism of HA/PX severely hinders its clinical translation. In OA, the massive loss of the ECM may be attributed to a decrease in transient receptor potential vanilloid 4 (TRPV4) activity, which affects reactive oxygen species (ROS) clearance and [Ca2+]i signaling, initiating downstream catabolic pathways. In this study, we investigated the bioremediation mechanism of HA/PX in a model of interleukin 1β (IL-1β)-induced inflammation. Through TRPV4, HA/PX reduced ROS accumulation in chondrocytes and enhanced [Ca2+]i signaling, reflecting a short-term protection capacity for chondrocytes. In addition, HA/PX balanced the metabolic homeostasis of chondrocytes via TRPV4, including promoting the secretion of type II collagen (Col-II) and aggrecan, the major components of the ECM, and reducing the expression of matrix metal-degrading enzyme (MMP-13), exerting long-term protective effects on chondrocytes. Molecular dynamics (MD) simulations showed that HA/PX could act as a TRPV4 activator. Our results suggest that HA/PX can regulate chondrocyte homeostasis via ROS/Ca2+/TRPV4, thereby improving cartilage regeneration. Because the ECM is a prevalent feature of various cell types, HA/PX holds promising potential for improving regeneration and disease modification for not only cartilage-related healthcare but many other tissues and diseases.
研究领域:
生物材料
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生物力学
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组织工程
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再生医学
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骨科
✓ 已验证
DOI
PubMed
高影响因子
Biomed Research International
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2022
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IF 3.246
Chuanying Li,Rong Cheng,Lin Li,Miaomiao Chen,Cheng Wu
Duodenal ulcer seriously affects the quality of life and life safety of children, but the pathogenesis of children with duodenal ulcer is still unclear. As an important second messenger in the body, Ca2+ participates in the physiological and pathological processes of various diseases. Therefore, transient receptor potential vanilloid type 4 (TRPV4) as one of the channels that mediate Ca2+ has attracted widespread attention in recent years. Here, we found that TRPV4 is highly expressed in children with duodenal ulcer and has good diagnostic value through specimens of children with duodenal ulcer, and animal experiments have proved that TRPV4 is also highly expressed in duodenal ulcer mice. In addition, TRPV4 can enhance intestinal permeability, thereby promoting further infiltration of inflammatory factors. In summary, these results indicate that TRPV4 is involved in the occurrence and development of duodenal ulcer. Therefore, this study provides the diagnostic and therapeutic value of TRPV4 in children with duodenal ulcer.
研究领域:
胃肠病学
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儿科
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分子生物学
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病理生理学
✓ 已验证
DOI
PubMed
高影响因子
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