更新于：2024-11-01

CYBB x TRPV4

更新于：2024-11-01

基本信息

关联

项与 CYBB x TRPV4 相关的药物

M12 (Jiangnan University)

靶点

CYBB x TRPV4

作用机制

CYBB调节剂 [+1]

在研机构

江南大学

原研机构

江南大学

在研适应症

肥胖

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 CYBB x TRPV4 相关的临床结果

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100 项与 CYBB x TRPV4 相关的转化医学

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0 项与 CYBB x TRPV4 相关的专利（医药）

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项与 CYBB x TRPV4 相关的文献（医药）

2022-06-01·Acta Pharmacologica Sinica1区 · 医学

Small molecule compound M12 reduces vascular permeability in obese mice via blocking endothelial TRPV4–Nox2 interaction

1区 · 医学

Article

作者: Han, Jing ; Li, Hong-Juan ; Han, Xi-Ping ; Ma, Xin ; Tang, Chun-Lei ; Kan, Hao ; Zhang, Peng ; Zhu, Yi-Fei ; Gao, Meng-Ru

Transient receptor potential channel TRPV4 and nicotinamide adenine dinucleotide phosphate oxidase (Nox2) are involved in oxidative stress that increases endothelial permeability. It has been shown that obesity enhances the physical association of TRPV4 and Nox2, but the role of TRPV4-Nox2 association in obesity has not been clarified. In this study we investigated the function of TRPV4-Nox2 complex in reducing oxidative stress and regulating abnormal vascular permeability in obesity. Obesity was induced in mice by feeding a high-fat diet (HFD) for 14 weeks. The physical interaction between TRPV4 and Nox2 was measured using FRET, co-immunoprecipitation and GST pull-down assays. The functional interaction was measured by rhodamine phalloidin, CM-H₂DCFDA in vitro, the fluorescent dye dihydroethidium (DHE) staining assay, and the Evans blue permeability assay in vivo. We demonstrated that TRPV4 physically and functionally associated with Nox2, and this physical association was enhanced in aorta of obese mice. Furthermore, we showed that interrupting TRPV4-Nox2 coupling by TRPV4 knockout, or by treatment with a specific Nox2 inhibitor Nox2 dstat or a specific TRPV4 inhibitor HC067046 significantly attenuated obesity-induced ROS overproduction in aortic endothelial cells, and reversed the abnormal endothelial cytoskeletal structure. In order to discover small molecules disrupting the over-coupling of TPRV4 and Nox2 in obesity, we performed molecular docking analysis and found that compound M12 modulated TRPV4-Nox2 association, reduced ROS production, and finally reversed disruption of the vascular barrier in obesity. Together, this study, for the first time, provides evidence for the TRPV4 physically interacting with Nox2. TRPV4-Nox2 complex is a potential drug target in improving oxidative stress and disruption of the vascular barrier in obesity. Compound M12 targeting TRPV4-Nox2 complex can improve vascular barrier function in obesity.

2021-08-01·Journal of Molecular and Cellular Cardiology2区 · 医学

Blocking endothelial TRPV4-Nox2 interaction helps reduce ROS production and inflammation, and improves vascular function in obese mice

2区 · 医学

Article

作者: Han, Jing ; Gao, Mengru ; Xiao, Wang ; Tang, Chunlei ; Zhu, Yifei ; Liu, Liangliang ; Ma, Xin

Obesity induces inflammation and oxidative stress, and ultimately leads to vasodilatory dysfunction in which Transient receptor potential vanilloid type 4 (TRPV4) and Nicotinamide Adenine Dinucleotide Phosphate Oxidase (Nox2) have been reported to be involved. However, little attention has been paid to the role of the TRPV4-Nox2 complex in these problems. The purpose of this study was to figure out the role of the TRPV4-Nox2 complex in obesity-induced inflammation, oxidative stress, and vasodilatory dysfunction. Using fluorescence resonance energy transfer and immunoprecipitation assays, we found enhanced TRPV4 and Nox2 interactions in obese mice. Using q-PCR, fluorescent dye dihydroethidium staining, and myotonic techniques, we found that obesity caused inflammation, oxidative stress, and vasodilatory dysfunction. Using adeno-associated viruses, we found that enhancement or attenuation of TRPV4-Nox2 interaction altered the vaso-function. Based on these findings, we found a small-molecule drug, M12, that interrupted the TRPV4-Nox2 interaction, thereby reducing inflammatory factors and reactive oxygen species production and helping to restore the vasodilatory function. In summary, our results revealed a new mechanism by which obesity-induced inflammation, oxidative stress, and vasodilatory dysfunction is caused by enhanced TRPV4-Nox2 interactions. Using M12 to interrupt the TRPV4-Nox2 interaction may have anti-inflammatory and anti-oxidative stress effects and help restore vasodilatory function and thus provide a new therapeutic approach to obesity.

2020-07-01·Bone2区 · 医学

TRPV4 calcium influx controls sclerostin protein loss independent of purinergic calcium oscillations

2区 · 医学

Article

作者: Leser, Jenna M ; Ward, Christopher W ; Williams, Katrina M ; Gould, Nicole R ; Khairallah, Ramzi J ; Joca, Humberto C ; Stains, Joseph P ; Lyons, James S

Skeletal remodeling is driven in part by the osteocyte's ability to respond to its mechanical environment by regulating the abundance of sclerostin, a negative regulator of bone mass. We have recently shown that the osteocyte responds to fluid shear stress via the microtubule network-dependent activation of NADPH oxidase 2 (NOX2)-generated reactive oxygen species and subsequent opening of TRPV4 cation channels, leading to calcium influx, activation of CaMKII, and rapid sclerostin protein downregulation. In addition to the initial calcium influx, purinergic receptor signaling and calcium oscillations occur in response to mechanical load and prior to rapid sclerostin protein loss. However, the independent contributions of TRPV4-mediated calcium influx and purinergic calcium oscillations to the rapid sclerostin protein downregulation remain unclear. Here, we showed that NOX2 and TRPV4-dependent calcium influx is required for calcium oscillations, and that TRPV4 activation is both necessary and sufficient for sclerostin degradation. In contrast, calcium oscillations are neither necessary nor sufficient to acutely decrease sclerostin protein abundance. However, blocking oscillations with apyrase prevented fluid shear stress induced changes in osterix (Sp7), osteoprotegerin (Tnfrsf11b), and sclerostin (Sost) gene expression. In total, these data provide key mechanistic insights into the way bone cells translate mechanical cues to target a key effector of bone formation, sclerostin.