Frontiers in Immunology
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2026
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IF 7
Yang Yu,Fangyong Wang
Introduction Neuropathic pain (NP) after spinal cord injury (SCI) is intractable with limited efficacy of single treatments. This study investigated the additive analgesic effect and molecular mechanisms of Bumetanide (Bu, a NKCC1 inhibitor) combined with medial ganglionic eminence (MGE) cell transplantation on SCI-induced NP. Methods Ninety adult female C57BL/6N mice were randomly divided into 5 groups (Sham, SCI, Bu, Mge, Bu+Mge). A T10 moderate spinal cord contusion model was established, with treatments (Bu intraperitoneal injection and MGE orthotopic transplantation) on day 10 post-surgery. Behavioral assessments, ELISA, Western blotting, qRT-PCR, and immunofluorescence staining were used. Results Compared with monotherapy, Bu+Mge significantly relieved SCI-induced NP. Mechanistically, it alleviated inflammation by inhibiting NF-κB pathway and microglia activation, rectified spinal cord and dorsal root ganglion NKCC1/KCC2 imbalance, increased GABA-A receptors and GAD65/67 mRNA, reduced glial scarring, and protected neurons, axons and myelin sheaths. Discussion Bu combined with MGE cell transplantation relieves SCI-induced NP via multiple additive mechanisms, providing a novel theoretical basis and potential clinical strategy for NP treatment.
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PubMed
高影响因子
NEUROSCIENCE
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2022
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IF 3.708
Chunyan Chen,Ping Fan,Lirong Zhang,Kaige Xue,Jiaheng Hu,Juan Huang,Weitian Lu,Jin Xu,Shiye Xu,Guoping Qiu,Jianhua Ran,Shengwei Gan
Aquaporin-4 (AQP4) regulates retinal water homeostasis and participates in retinal oedema pathophysiology. β-dystroglycan (β-DG) is responsible for AQP4 polarization and can be cleaved by matrix metalloproteinase-9 (MMP9). Retinal oedema induced by ischemia–reperfusion (I/R) injury is an early complication. Bumetanide (BU) has potential efficacy against cytotoxic oedema. Our study investigated the effects of β-DG cleavage on AQP4 and the roles of BU in a rat retinal I/R injury model. The model was induced by applying 110 mm Hg intraocular pressure to the anterior eye chamber. BU and U0126 (a selective ERK inhibitor) were intraperitoneally administered 15 and 30 min, respectively, before I/R induction. Rhodamine isothiocyanate extravasation detection, quantitative real-time PCR, transmission electron microscopy, hematoxylin-eosin staining, immunofluorescence staining, western blotting, and TUNEL staining were performed. AQP4 lost its polarization in the retinal perivascular domain as a result of β-DG cleavage. BU rescued AQP4 depolarization, suppressed AQP4 protein expression, attenuated retinal cytotoxic oedema, and downregulated β-DG and AQP4 mRNA expression. BU suppressed glial responses and mitochondria-mediated apoptotic protein expression, including that of Caspase-3 and Cyto C, raised the Bcl-2/Bax ratio, and lowered the number of apoptotic cells in the retina. Both BU and U0126 downregulated p-ERK and MMP9 expression. Thus, BU treatment suppressed β-DG cleavage, recovered AQP4 polarization partially via inhibiting ERK/MMP9 signaling pathway, and possess potential neuroprotective efficacy in the rat retinal ischemia–reperfusion injury model.
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高影响因子
eLife
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2018
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IF 7.616
Dao-Lai Zhang,Yu-Jing Sun,Ming-Liang Ma,Yi-jing Wang,Hui Lin,Rui-Rui Li,Zong-Lai Liang,Yuan Gao,Zhao Yang,Dong-Fang He,Amy Lin,Hui Mo,Yu-Jing Lu,Meng-Jing Li,Wei Kong,Ka Young Chung,Fan Yi,Jian-Yuan Li,Ying-Ying Qin,Jingxin Li,Alex R B Thomsen,Alem W Kahsai,Zi-Jiang Chen,Zhi-Gang Xu,Mingyao Liu,Dali Li,Xiao Yu,Jin-Peng Sun
Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.
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高影响因子
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