CANCER RESEARCH
·
2022
·Vol. 82
·期 19
·3573-3587
·
IF 13.312
Li Yongxu,Wang Tiepeng,Wan Quan,Wang Qing,Chen Zhenzhong,Gao Yuan,Ye Yuchen,Lin Jiusheng,Zhao Bihuan,Wang Huaile,Yang Jinming,Zhao Kai,Lu Na
Glioblastoma (GBM) is the most common type of primary adult brain tumor. Glioma stem cell (GSC) residence and temozolomide (TMZ) resistance in GBM both contribute to poor patient outcome. TRAF4 is a scaffold protein with E3 ubiquitin ligase activity that has recently been discovered to promote invasion and metastasis in several malignancies, but the effects and functions of TRAF4 in GBM remain to be determined. Here, we report that TRAF4 is preferentially overexpressed in GSCs and is required for stem-like properties as well as TMZ sensitivity in GBM cells. TRAF4 specifically interacted with the N-terminal tail of Caveolin-1 (CAV1), an important contributor to the tumorigenicity of GBM cells. TRAF4 regulated CAV1 stability by preventing ZNRF1-mediated ubiquitination and facilitating USP7-mediated deubiquitination independently of its E3 ubiquitin ligase catalytic activity. TRAF4-mediated stabilization of CAV1 activated protumorigenic AKT/ERK1/2 signaling, and disruption of this axis resulted in defects in stemness maintenance. In addition, expression of TRAF4 and CAV1 was positively correlated and predicted poor prognosis in human GBM samples. Screening of common nervous system drugs identified risperidone interaction with TRAF4, and risperidone treatment resulted in the dissociation of TRAF4 and CAV1. Importantly, pharmacologic inhibition of TRAF4 with risperidone potently inhibited self-renewal, abrogated tumorigenicity, and reversed TMZ resistance in GBM. Overall, TRAF4-mediated stabilization of CAV1 promotes stemness and TMZ resistance in GBM, providing a therapeutic strategy that could improve patient outcomes. Significance: The identification of a TRAF4/Caveolin-1 axis that plays a crucial role in malignant progression of glioblastoma provides new insights into the function of TRAF4 in ubiquitin signaling and suggests TRAF4 as a potential therapeutic target.
研究领域:
肿瘤学
·
神经科学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2025
·Vol. 22
·期 1
·1-22
·
IF 10.1
Zhou Yanjie,Chen Wu,Zhang Yu,Yang Liu,Lu Fu,Yan Wen,Xie Qingfang,Huang Ying,Huang Wanbin,Wang Lintao,Zeng Ziming,Xiao Zheman
Background Caveolin-1 (CAV1), a scaffolding protein critical for caveolae formation, regulates G-protein-coupled receptor (GPCR) signaling via caveolae-mediated endocytosis. The calcitonin receptor-like receptor (CLR), a GPCR and core subunit of the calcitonin gene-related peptide (CGRP) receptor, is a therapeutic target for migraine. However, the role of CAV1 in CLR regulation and migraine remains unclear.Methods A migraine model was established in female mice via dural inflammatory soup (IS) application. Migraine-like behaviors were assessed using Von Frey filament, spontaneous pain behavior counts, light/dark box, and acetone test. CAV1 was overexpressed by lentivirus and downregulated by small interfering RNA (siRNA) technology. Methyl-β-cyclodextrin (MβCD) was used to inhibit caveolae-mediated endocytosis. The molecular mechanism of CAV1 on CLR and neuroinflammation was investigated using biochemistry, multiplex immunohistochemistry staining, internalization assay, and co-immunoprecipitation.Results Repeated IS stimulation elevated CLR expression and internalization in the trigeminal nucleus caudalis (TNC), concurrently activating ERK/CREB signaling, promoting microglial activation, and increasing inflammatory cytokines (TNFα, IL-1β). CAV1 directly interacted with CLR, promoting its degradation. CAV1 knockdown in the TNC exacerbated migraine pathology, characterized by CLR accumulation, enhanced ERK/CREB phosphorylation, and amplified neuroinflammation. Conversely, CAV1 overexpression or MβCD-mediated caveolae disruption normalized CLR levels, reduced signaling hyperactivity, and reversed nociceptive behaviors.Conclusion CAV1 negatively regulates CLR stability, suppressing ERK/CREB signaling and microglial inflammation in a preclinical female migraine model. These findings suggest that CAV1 contributes to migraine-related hyperalgesia and may represent a novel therapeutic target for migraine treatment.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2021
·
IF 12.479
Xueqing Zhou,Xuan Liu,Xiqin Yang,Li Wang,Yiling Hong,Keke Lian,Guoxi Qiu,Xuwei Shang,Zhongjun Ma,Hong Yuan,Fuqiang Hu
Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) play an important role in the development of tumors by secreting a variety of cytokines or directly communicating with tumor cells, making TAMs-targeted therapeutic strategies very attractive. It has been reported that oncogene c-Myc is related to every aspect of the oncogenic process of tumor cells and the alternative activation of macrophages. Hence, we constructed a glycolipid nanocarrier containing ROS-responsive peroxalate linkages (CSOPOSA) for ROS-triggered release of drugs and further modified it with Ex 26 (Ex 26-CSOPOSA), a selective sphingosine 1-phosphate receptor 1 (S1PR1) antagonist, to achieve the dual-targeted delivery of the c-Myc inhibitor JQ1 via S1PR1, which is overexpressed on both tumor cells and TAMs, thereby inducing apoptosis of tumor cells, and blocking M2 polarization of macrophages. More strikingly, our studies found that JQ1 could effectively inhibit the migration of tumor cells induced by M2 macrophages-derived exosomes via blocking Caveolin-1 related intercellular exosome exchange through lncRNA H19 and miR-107. The in vivo results revealed that this dual-targeted delivery strategy effectively inhibited tumor growth and metastasis with less systemic toxicity, providing a potential method for effective tumor treatment.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
纳米技术
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MATERIALS & DESIGN
·
2023
·
IF 8.4
Chao-ping He,Wen-juan Quan,Ya-ling Zeng,Hong-yan Zhou,Pei-dong You,Zhen-xian Li,Ya-mei Li,Li-mei Lin,Bin Liu,Duan-fang Liao,Qin-hui Tuo
Reducing lipid uptake of macrophages and stimulating cholesterol efflux are two necessary steps for atherosclerotic plaque regression. In this study, a compound of curcumin nicotinate (CN) was synthesized from nicotinic acid which can raise raising high-density lipoprotein (HDL) and curcumin which can lower lipid. However, the shortcomings of CN, such as poor water solubility and low bioavailability, limit its clinical application. In this article, a CN loaded biomimetic nanosystem was constructed by using Prussian blue nanoparticles (PB NPs) to improve its solubility, thereby changing its administration route. In addition, hyaluronic acid (HA) modification on the biomimetic PB NPs was adopted to prolong circulation time and improve the accumulation of drugs in the plaque region. Mechanism studies have shown that the constructed nanosystem could exert anti-AS effects through the pathway of Proprotein Convertase Subtilisin/Kexin Type 9(PCSK9) /Low-density lipoprotein receptor (LDL-R), ATP Binding Cassette Transporter A1(ABCA1) /Caveolin-1 /Liver X Receptor (LXR). These findings indicated that the designed nano-platform is expected to be used for prevention and targeted therapy of atherosclerosis.
研究领域:
纳米技术
·
药学
·
心血管疾病
✓ 已验证
产品关联
DOI
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2022
·
IF 4.46
Yuan-Lin Zhang,Hong-Xia Yuan,Jian Sun,Xiu-E Feng,Jin-Hong Ren,Yuan-Biao Qiao,Qing-Shan Li
Directly targeting caveolar caveolin-1 is a potential mechanism to regulate endothelial permeability, especially during oxidative stress , but little evidence on the topic limits therapeutics discoveries. In this study, we investigated the pharmacological effect of an antioxidant LM49 (5,2′-dibromo-2,4′,5′-trihydroxydiphenylmethanoe) and its five diphenylmethanone derivatives on endothelial permeability and establish two distinct mechanisms of action. Multiplex molecular assays with theoretical modeling indicate that diphenylmethanone molecules, including LM49, directly bind the caveolin-1 steric pocket of ASN53/ARG54, ILE49/ASP50, ILE18, LEU59, ASN60, GLU48 and ARG19 residues. They also indicated dynamic binding-affinity for diphenylmethanone derivatives. First, this molecular interaction at caveolin-1 pocket inhibits its phosphorylation at TYR14 residue in H 2 O 2 -injured endothelial cell. A positive correlation was established between diphenylmethanone derivative binding-affinity and caveolin-1 phosphorylation inhibition. Inhibition of caveolin-1 phosphorylation, however, was independent of the LM49-mediated variation of protein tyrosine kinase activity, suggesting a direct blockage of adenosine triphosphate substrate diffusion into cavelion-1 structure. Second, LM49 increases the expression of cellular adhesive and tight junction proteins , VE-cadherin and occludin , in H 2 O 2 -injured cell, in a dose dependent manner. A leakage assay of fluorescein isothiocyanate-labeled dextran 40 across cell monolayer suggested improvement in endothelial barrier integrity with diphenylmethanone treatments. Our results demonstrate a direct targeting effect of caveolin-1 on endothelial permeability, and should guide the diphenylmethanone therapy against oxidative stress-induced junction dysfunction, especially at caveolar membrane invagination.
研究领域:
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Frontiers
·
2023
·
IF 9.9
Pengde Lu,Jinfen Chen,Ying Chen,Xingping Quan,Jiayue Liu,Yan Han,Yiyang Li,Li Yang,Jian-Bo Wan,Yonghua Zhao
Ulcerative colitis (UC) is a digestive disease with a high incidence and is difficult to be cured due to its complex etiology. It has evidenced that intestinal barrier dysfunction plays a predominant role in UC. 20( S )-protopanaxadiol saponins (PDS) isolated from Panax notoginseng possess anti-inflammatory and antioxidative activities, suggesting its potential of treating UC. Herein, the therapeutic effects of PDS against UC and underlying mechanisms in the aspect of intestinal barrier dysfunction were investigated in vivo and in vitro. The results showed PDS had protective effects against dextran sulfate sodium–induced colitis, including attenuating weight loss, disease activity index score elevation, colon length shortening, and histological lesions. Additionally, PDS reduced the colonic activity of myeloperoxidase and the cytokine levels of TNF-α, IL-6, and IL-1β, decreased MDA production, and elevated colonic activities of SOD and GSH-Px in the colitis mice. The expressions of proteins related to tight junction (TJ), including ZO-1, claudin-5, occludin, caveolin-1 (Cav-1), and Nrf2 were downregulated, whereas that of Keap1 was upregulated after colitis induction. These changes were reversed by PDS. Cav-1 expression was downregulated in lipopolysaccharides (LPS)- and H 2 O 2 -induced HCT116 cells, and the expressions of ZO-1, claudin-5, and occludin were suppressed in HCT116 cells stimulated by LPS and H 2 O 2 combined with Cav-1 small interfering RNA transfection, which were ameliorated by PDS, suggesting PDS targeted Cav-1 against intestinal barrier damage. Collectively, PDS alleviates inflammatory injury and oxidative stress by regulating the Nrf2/Keap1 pathway, contributing to targeting Cav-1 against intestinal epithelial TJ proteins loss. It suggests PDS might be a promising therapeutic natural product for UC treatment.
研究领域:
药理学
·
胃肠病学
·
免疫学
·
分子生物学
✓ 已验证
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Lanxi Xu,Yan Feng,Xintian Zheng,Meiyu Wang,Yan Fang,Lin Li,Jiadong Xu,Yani Zhang,Weiru Jiang,Lisheng Chu
Neuronal loss following ischemic stroke (IS) is a major cause of long-term neurological dysfunction. Neural stem cell (NSC) transplantation holds great potential for neural tissue repair, but exogenous NSCs often over-differentiate into astrocytes, resulting in glial scar formation and poor neuronal maturation, which limits clinical application. Astragaloside IV (AS-IV), a plant-derived monomer, has been shown to regulate the proliferation, migration, and differentiation of endogenous NSCs. This study investigated whether AS-IV preconditioning could promote the neurogenesis of transplanted NSCs and improve functional recovery after IS. Primary NSCs were cultured and exposed to various concentrations of AS-IV, and 100 μM was selected for further use. A rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) was established, and AS-IV-preconditioned or untreated EGFP-labeled NSCs were transplanted into the striatum. Brain injury was assessed histologically. Neurological recovery was evaluated using the modified Neurological Severity Score, grip strength, adhesive removal, and Morris water maze tests. Immunofluorescence staining was used to assess graft survival, differentiation fate, synapse formation, and glial scar area. In vitro experiments explored the involvement of the miR-199a-5p/Caveolin-1 signaling pathway. AS-IV preconditioning significantly improved the survival and neuronal differentiation of grafted NSCs, reduced astrocytic lineage commitment and glial scar formation, and enhanced synaptic reconstruction. These effects were associated with improved sensorimotor and cognitive function. In conclusion, AS-IV pretreatment of NSCs promoted neuronal lineage commitment, inhibited glial scarring, and facilitated functional recovery after ischemic stroke. Targeting the miR-199a-5p/Caveolin-1 axis may offer a novel strategy for optimizing NSC-based therapy in stroke.
研究领域:
神经科学
·
干细胞治疗
·
分子生物学
·
再生医学
·
脑血管疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）