iScience
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2024
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IF 4.6
Shengze Zhang,Chuming Luo,Qiqi Chen,Nina Li,Xinzhong Liao,Jiani Wu,Haolu Zha,Ting Xie,Shaohui Bai,Weijian Tian,Lin Zhu,Xuan Zou,Shisong Fang,Caijun Sun,Ying Jiang,Jianhui Yuan,Yuelong Shu,Nan Wu,Huanle Luo
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is crucial in flavivirus infections, modulating the host immune response through interactions with viral proteins. Despite its importance, the relationship between TRAF6 and Zika virus (ZIKV) remains poorly understood. Our prior proteomics analysis revealed reduced TRAF6 protein levels in ZIKV-infected human trophoblast cells compared to non-infected controls. Subsequent studies in cell models and murine tissues confirmed a significant reduction in both TRAF6 mRNA and protein levels post-ZIKV infection. Further investigations unveiled that ZIKV induces P62-mediated degradation of TRAF6, with NS1 identified as the primary contributor. Co-localization and interaction studies demonstrated that NS1 promotes the association of P62, a key autophagy mediator, with TRAF6. Notably, our findings revealed TRAF6 enhances ZIKV infection, NS1 ubiquitination, NS1 expression, and the production of inflammatory cytokines and chemokines. These insights highlight the intricate TRAF6-ZIKV relationship, offering potential for drug targeting NS1-TRAF6 interactions to manage ZIKV infections effectively.
研究领域:
病毒学
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免疫学
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分子生物学
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传染病学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2021
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IF 5.34
Zi-ling Zou,Ming-hui Sun,Wei-feng Yin,Lei Yang,Ling-yi Kong
Background Osteoarthritis (OA) is an intractable degenerative disease of the whole joint, which is characterized by synovitis inflammation, cartilage damage, and chronic pain. Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) performs an important role in OA. Purpose We aim to investigate avicularin to protect cartilage extracellular matrix degradation (ECM) and suppresses inflammation both in rat and human chondrocytes . Methods 5-Ethynyl-2′-deoxyuridine (EdU) staining, Quantitative real-time PCR, TRAF6 plasmid transfection, Western blot , Measurement of nitric oxide (NO), ROS detection and Immunofluorescence were utilized in vitro . micro-CT scanning, Safranin O-Fast Green, toluidine blue and immunohistochemistry staining were performed in vivo . Results In vitro , avicularin attenuates the degradation of ECM and inflammation, which could inhibit the activation of TRAF6/MAPK pathway via targeting TRAF6. Increased MMP3 and MMP13 expressions and decreased Aggrecan and Collagen Ⅱ levels were observed in anterior cruciate ligament transection (ACLT) induced osteoarthritic rats. Interestingly, intra-articular injection of avicularin attenuates this phenomenon. Conclusions Taken together, our results indicate that avicularin suppresses cartilage extracellular matrix degradation and inflammation via TRAF6/MAPK activation by targeting TRAF6. These observations identify TRAF6 as a relevant drug target, and avicularin may as a potential therapeutic agent in osteoarthritis.
研究领域:
药理学
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风湿病学
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骨科
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细胞生物学
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DOI
PubMed
高影响因子
YONSEI MEDICAL JOURNAL
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2020
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IF 1.914
Guang Yang,Yuan Zhao
Purpose Neonatal hypoxic ischemic encephalopathy (HIE) is an essential factor underlying neonatal death and disability. This study sought to explore the role of miR-146b-5p in regulating neonatal HIE. Materials and Methods In vitro and in vivo HIE models were established in PC12 cells and 10-day neonatal Sprague Dawley rats, respectively. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to assess miR-146b-5p expression and inflammatory factors [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] in brain lesions and PC12 cells, while enzyme-linked immunosorbent assay was employed to detect the expression of oxidative stress factors (SOD and GSH-Px). Gain- and loss-assays of miR-146b-5p were conducted to verify its role in modulating the viability and apoptosis of PC12 cells under oxygen-glucose deprivation (OGD) treatment. Expression of TLR4, IRAK1, TRAF6, TAK1, and NF-κB were examined by qRT-PCR and/or Western blot. Dual luciferase activity assay was conducted to identify relationships between miR-146b-5p and IRAK1. Results In the HIE models, significant oxidative stress and inflammatory responses emerged upon upregulation of TLR4/IRAK1/TRAF6/TAK1/NF-κB signaling. Overexpression of miR-146b-5p greatly inhibited OGD-induced PC12 cell injury, inflammatory responses, and oxidative stress. Inhibiting miR-146b-5p, however, had the opposite effects. IRAK1 was found to be a target of miR-146b-5p, and miR-146b-5p overexpression suppressed the activation of IRAK1/TRAF6/TAK1/NF-κB signaling. Conclusion This study demonstrated that miR-146b-5p overexpression alleviates HIE-induced neuron injury by inhibiting the IRAK1/TRAF6/TAK1/NF-κB pathway.
研究领域:
神经科学
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分子生物学
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儿科
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Li Hu,Haiping Liu,Haixiang Ma,Xingyue Zeng,Yongkai Cao,Bing Liu,Huijun Li,Xiaohan Zhang
AKT, also known as protein kinase B (PKB), serves as a crucial regulator of numerous biological functions, including cell growth, metabolism, and tumorigenesis. Increasing evidence suggests that the kinase activity of AKT is regulated via ubiquitination by various E3 ligase enzymes in response to different stimuli. However, the molecular mechanisms underlying insulin-induced AKT ubiquitination are not yet fully understood. Here, we show that activation of the insulin receptor (IR) leads to enhanced ubiquitination of AKT1 at K8 and K14 residues, facilitated by the cytosolic E3 ubiquitin ligase enzyme, TRAF6. Further investigation using AKT1 mutants with modified nucleocytoplasmic shuttling properties reveals that TRAF6-mediated AKT1 ubiquitination occurs within the nucleus in a β-Arr2-dependent manner. The nuclear entry of TRAF6 depends on importin β1, while β-Arr2 regulates this process by facilitating the interaction between TRAF6 and importin β1. Additionally, the ubiquitination of AKT1 is essential for its translocation to the activated IR on the plasma membrane, where it plays a functional role in recruiting Glut4 and facilitating glucose uptake. This study uncovers the cellular components and processes involved in insulin-induced ubiquitination and activation of AKT1, providing insights and detailed strategies for manipulating AKT1.
研究领域:
细胞生物学
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分子生物学
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内分泌学
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信号转导
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DOI
PubMed
高影响因子
JOURNAL OF PSYCHIATRIC RESEARCH
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2022
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IF 5.25
Rui Peng,Wen Dai,Di Li,Yan Li
Gonadal hormone deficiency is associated with the development of depression, but what mediates this association is unclear. To test the possibility that it reflects neuroimmune and neuroinflammatory processes, we analyzed how gonadal hormone deficiency and replacement affect microglial activation and inflammatory response during the development of depressive symptomatology in gonadectomized male mice. Testosterone level and the ratio of testosterone to estradiol in the serum and brain tissue of mice exposed to 3–35 days of chronic unpredictable stress were much lower than in control animals. Gonadal hormone sustained deficiency in gonadectomized mice and subsequent led to acute inflammation at day 7 following castration. Activating microglia in mice exposed to 7 days of castration subsequently suppressed the proliferation of microglia, such that their numbers in hippocampus and cortex were lower than the numbers in sham-operated mice after 30 days of castration. Here, we showed that gonadal hormone deficiency induces Traf6-mediated microglia activation, a type of inflammatory mediator. Microglia treated in this way for long time showed down-regulation of activation markers, abnormal morphology and depressive-like behaviors. Restoration and maintenance of a fixed ratio of testosterone to estradiol significantly suppressed microglial activation, neuronal necroptosis, dramatically inducing hippocampal neurogenesis and reducing depressive behaviors via the suppression of Traf6/TAK1 pathway. These findings suggest that activated or immunoreactive microglia contribute to gonadal hormone deficiency-induced depression, as well as testosterone and estradiol exert synergistic anti-depressant effects via suppressing microglial activaton in gonadectomized male mice, possibly through Traf6 signaling.
研究领域:
神经科学
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免疫学
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内分泌学
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精神病学
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DOI
PubMed
高影响因子
Cell Communication and Signaling
·
2024
·Vol. 22
·期 1
·1-21
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IF 8.2
Wu Chengyan,Hu Li,Liu Bing,Zeng Xingyue,Ma Haixiang,Cao Yongkai,Li Huijun,Zhang Xiaohan
Background Desensitization of G protein–coupled receptors (GPCRs) refers to the attenuation of receptor responsiveness by prolonged or intermittent exposure to agonists. The binding of β-arrestin to the cytoplasmic cavity of the phosphorylated receptor, which competes with the G protein, has been widely accepted as an extensive model for explaining GPCRs desensitization. However, studies on various GPCRs, including dopamine D 2 -like receptors (D 2 R, D 3 R, D 4 R), have suggested the existence of other desensitization mechanisms. The present study employed D 2 R/D 3 R variants with different desensitization properties and utilized loss-of-function approaches to uncover the mechanisms underlying GPCRs homologous desensitization, focusing on the signaling cascade that regulates the ubiquitination of AKT. Results AKT undergoes K8/14 ubiquitination by TRAF6, which occurs in the nucleus and promotes its membrane recruitment, phosphorylation and activation under receptor desensitization conditions. The nuclear entry of TRAF6 relies on the presence of the importin complex. Src regulates the nuclear entry of TRAF6 by mediating the interaction between TRAF6 and importin β1. Ubiquitinated AKT translocates to the plasma membrane where it associates with Mdm2 to phosphorylate it at the S166 and S186 residues. Thereafter, phosphorylated Mdm2 is recruited to the nucleus, resulting in the deubiquitination of β-Arr2. The deubiquitinated β-Arr2 then forms a complex with Gβγ, which serves as a biomarker for GPCRs desensitization. Like in D 3 R, ubiquitination of AKT is also involved in the desensitization of β 2 adrenoceptors. Conclusion Our study proposed that the property of a receptor that causes a change in the subcellular localization of TRAF6 from the cytoplasm to the nucleus to mediate AKT ubiquitination could initiate the desensitization of GPCRs.
研究领域:
细胞生物学
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分子生物学
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药理学
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信号转导
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR HISTOLOGY
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2026
·Vol. 57
·期 3
·142
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IF 2.6
Ye Chunhua,Liu Hua,Ming Zhu,Yi Qinjun,Xiang Rong,Chen Yifu
This study investigated the role of TNF receptor associated factor 6 (TRAF6) in glomerular podocyte pyroptosis. An in vitro LN cell model was established by treating mouse glomerular podocyte MPC5 cells with 100 ng/ml LPS for 12 h. Concurrently, LN cells were treated with TRAF6 knockdown and TXNIP overexpression or NLRP3 activation (Nigericin). MRL/lpr mice were treated with adenovirus vector expressing sh-TRAF6 for in vivo validation. LPS treatment decreased cell viability, increased cell death, elevated Desmin mRNA, malondialdehyde, TRAF6, TXNIP, interleukin (IL)-1β, and IL-18, reduced Nephrin and Podocin mRNA (podocyte markers), superoxide dismutase, and glutathione levels, enhanced cell pyroptosis and lactate dehydrogenase concentration, and activated the NLRP3 inflammasome pathway. TRAF6 knockdown suppressed LPS-stimulated podocyte damage, oxidative stress, and pyroptosis. TRAF6 interacted with TXNIP at the protein level, and TRAF6 increased TXNIP protein expression. The protective functions of TRAF6 silencing on MPC5 cells were counteracted upon TXNIP overexpression or NLRP3 activation. In vivo, TRAF6 knockdown regulated the TXNIP/NLRP3 inflammasome pathway to alleviate renal tissue pathological changes and fibrosis in LN mice. In conclusion, TRAF6 activates the NLRP3 inflammasome pathway through regulating TXNIP, thereby accelerating LPS-induced oxidative stress, pyroptosis, and damage to glomerular podocytes. Hence, TRAF6 may be a promising therapeutic target for LN. Graphical abstract The alternative text for this image may have been generated using AI.
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2025
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IF 5.1
Fangdi Wang,Li Hu,Xingyue Zeng,Wenbin You,Huijun Li,Bing Liu,Xiaohan Zhang
AKT is a pivotal kinase involved in diverse cellular processes, including tumorigenesis and glycogen metabolism. Ubiquitination modification of AKT has been reported as a critical cellular event that regulates its kinase activity and membrane translocation; however, the molecular mechanisms involved in AKT ubiquitination remain elusive. Here, we employed loss-of-function approaches and mutants of PDK1 with altered phosphorylation and modified nucleocytoplasmic shuttling behaviors to identify the functional roles of PDK1 on the ubiquitination of AKT. Our findings reveal that the nuclear entry of PDK1 in an importin7-dependent manner is required for insulin-induced TRAF6-mediated ubiquitination of AKT, which has been previously shown to occur in the nucleus. Moreover, the phosphorylation of PDK1 at S241 and the PI3K-mediated phosphorylation of PDK1 at S396 both regulate AKT ubiquitination by controlling nuclear entry of PDK1. These results provide new insights into the control of AKT signaling and suggest potential avenues for developing targeted AKT-modulating therapeutics.
研究领域:
分子生物学
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细胞信号传导
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生物化学
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内分泌学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
Small
·
2026
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IF 11.8
Junyan Liu,He Ke,Lingyu Su,Zhirou Lin,Chong Liu,Shilong Jiang,Hong Huang,Chengxian Guo,Qinghua Zhang,Huifang Tang,Zhaoqian Liu,Wenhu Zhou,Qi Pei,Qianfei Cui
Osteoarthritis (OA) is a degenerative joint disease, for which effective disease-modifying therapies remain lacking. Here, we report yam-derived nanovesicles (YDNVs) as a plant-derived exosome-like nanoplatform with intrinsic therapeutic activity for OA treatment. YDNVs exhibited typical nanoscale vesicular characteristics and were efficiently internalized by chondrocytes via clathrin-mediated endocytosis. Through enzymatic pretreatment and multi-omics analyses, RNA-particularly microRNAs (miRNAs)-was identified as the primary bioactive component mediating their anti-inflammatory effects. Mechanistic studies further confirmed that aof-miR168a directly binds to the 3′ untranslated regions of TLR4 and TRAF6, thereby suppressing downstream inflammatory signaling. To enhance targeting and therapeutic efficacy, a cartilage-targeting peptide-modified system (YDNVs-CAP) was engineered via membrane insertion of a cholesterol-anchored conjugate. This modification significantly improved cellular uptake, cartilage targeting, and intra-articular retention. Functionally, YDNVs-CAP effectively alleviated inflammation, oxidative stress, and extracellular matrix degradation in vitro, and markedly attenuated OA progression in a destabilization of the medial meniscus (DMM) mouse model. Collectively, this study establishes an RNA-mediated therapeutic mechanism for plant-derived nanovesicles and highlights YDNVs-CAP as a promising biomimetic nanoplatform for disease-modifying OA therapy.
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DOI
高影响因子
Journal of Advanced Research
·
2025
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IF 13
Yajing Li,Runping Liu,Jianan Li,Feng Gao,Zhi Ma,Kaihong Xie,Fanghong Li,Bing Xu,Qi Zheng,Yajie Cai,Jiaorong Qu,Xiaoyong Xue,Kexin Jia,Xiaojiaoyang Li
Introduction Cholestatic liver diseases are highly prevalent and lack effective treatment, ultimately progressing to end-stage liver diseases. Our recent study indicates that the interplay between c-MYC and lncRNA H19 exacerbates the ductular reaction during cholestasis. Objective: This study aims to unveil the underlying mechanisms of the protective effects of senkyunolide A (SenA) on cholangiocyte overproliferation in cholestatic liver diseases. Methods : Through comprehensive characterization using RNA sequencing, CHIP analysis, protein truncation, amino acid mutation or deletion, and the development of SenA derivatives, we explored the effects and mechanisms of SenA in vivo in bile duct ligation mice and in vitro in primary cholangiocytes. Results : We demonstrated that SenA effectively mitigates cholangiocyte hyperproliferation by epigenetically suppressing c-MYC expression and disrupting the downstream H19, Let-7a and Lin28a. Mechanically, we identified a potential interaction between the carbonyl group in SenA and Arg483 in TRAF6, disrupting the TRAF6-HDAC3 complex. This dissociation facilitates the binding of HDAC3 to the MYC promoter region, resulting in enhanced histone deacetylation and transcriptional suppression. Conclusion : We highlight the therapeutic potential of SenA in cholestatic liver diseases by elucidating its role in epigenetic regulation.
研究领域:
医学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Hepatology International
·
2025
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IF 6.1
Yang Yanfang,Wang Tao,Fu Yuyin,Li Xukui,Yu Fuxun
Background Hepatitis B virus (HBV) is a pathogen that poses a serious threat to human health. The interaction between HBV and host has made great progress in recent years. SUMOylation is involved in virus-related cancer progression, but there are fewer studies on the mechanism of SUMOylation on HBV replication and antiviral defense. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a critical adaptor of the NF-κB pathways. Here, we focus on the roles of TRIM28 in regulating TRAF6 SUMOylation in HBV-replicating cells. Methods The SUMO1-modified TRAF6 proteins were enriched from total cellular proteins by immunoprecipitation with anti-SUMO1 antibody, then the SUMOylated TRAF6 was detected by western blot using an anti-TRAF6 antibody. The interaction between TRAF6 and TRIM28 was identified by immunoprecipitation and LC–MS/MS. The modification sites of TRAF6 SUMOylation were identified by amino acid site mutation. Expression and localization of TRAF6 and TRIM28 were assessed by immunohistochemistry and immunofluorescence. The hydrodynamic injection HBV mouse model was used to determine the function of TRIM28-mediated TRAF6 SUMOylation in vivo. Results The results show that the levels of SUMO1-modified TRAF6 are elevated in HBV-replicating cells. Lys453 is a major SUMO1 modification site of TRAF6. There is an antagonistic interaction between SUMOylation and ubiquitination of TRAF6 protein. The SUMO ligase TRIM28 is responsible for catalyzing TRAF6 SUMOylation. Compared to the wild-type TRAF6, its SUMO site mutant TRAF6 K453R promotes NF-κB activation. Moreover, TRIM28 overexpression attenuates TRAF6-mediated NF-κB activation, thereby inhibiting HBV replication in vivo. Conclusions Our findings demonstrate that SUMO ligase TRIM28 affects the ability of TRAF6 on NF-κB activation, nucleocytoplasmic shuttling and HBV replication-related indicators. Our data reveal that TRIM28-mediated SUMOylation of TRAF6 is a novel mechanism to regulate the inflammatory response, which may pave the way for new strategies to control anti-HBV.
研究领域:
病毒学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
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IF 5.6
Huang Yaxian,Wu Jinyan,Zhan Chi,Liu Rong,Zhou Zhaocai,Huang Xin,Tian Yaguang,Lin Zhengmei,Song Zhi
The enhanced osteoclastogenesis contributes to alveolar bone resorption in periodontitis, which increases the risk of tooth loss. To reduce bone destruction, the inhibition of osteoclast development is proposed as a feasible treatment. CD40L-CD40-TRAF6 signal transduction plays a crucial role in inflammation, but how it regulates osteoclast activity in periodontitis has not been elucidated. In this study, we showed the potential role of CD40L-CD40-TRAF6 signaling in periodontitis. CD40L obviously promoted osteoclast formation and bone resorption capacity in vitro. Mechanistically, we found that osteoclastogenesis was enhanced by the overexpression of NFATc1 and NF-κB activation. Importantly, osteoclast activity was effectively suppressed by TRAF-STOP, a small molecular inhibitor of TRAF6. Furthermore, local injection of TRAF-STOP-loaded injectable PLGA-PEG-PLGA hydrogel could alleviate ligation-induced periodontitis in vivo. Taken together, TRAF-STOP shows promising clinical efficacy in periodontitis through alleviating osteoclastogenesis.
研究领域:
牙科学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
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