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    Deficiency of sorting nexin 10 prevents bone erosion in collagen-induced mouse arthritis through promoting NFATc1 degradation. Zhou Chun,You Yan,Shen Weixing,Zhu Yi-Zhun,Peng Jing,Feng Hao-Tian,Wang Ying,Li Dong,Shao Wei-Wei,Li Cui-Xian,Li Wan-Zhen,Xu Jiake,Shen Xiaoyan Annals of the rheumatic diseases OBJECTIVE:Periarticular and subchondral bone erosion in rheumatoid arthritis caused by osteoclast differentiation and activation is a critical index for diagnosis, therapy and monitoring of the disease. Sorting nexin (SNX) 10, a member of the SNX family which functions in regulation of endosomal sorting, has been implicated to play an important clinical role in malignant osteopetrosis. Here we studied the roles and precise mechanisms of SNX10 in the bone destruction of collagen-induced arthritis (CIA) mice. METHODS:The role of SNX10 in bone destruction was evaluated by a CIA mice model which was induced in male SNX10(-/-) mice and wild type littermates. The mechanism was explored in osteoclasts induced by receptor activator of nuclear factor κB ligand from bone marrow mononuclear cells of wild type and SNX10(-/-) mice. RESULTS:SNX10 knockout prevented bone loss and joint destruction in CIA mice with reduced serum levels of TNF-α, interleukin 1β and anticollagen IgG 2α antibody. SNX10 deficiency did not block osteoclastogenesis, but significantly impaired osteoclast maturation and bone-resorption function by disturbing the formation of actin belt. The production of TRAP, CtsK and MMP9 in SNX10(-/-) osteoclasts was significantly inhibited, and partially restored by SNX10 overexpression. We further demonstrated that the degradation of NFATc1 was accelerated in SNX10(-/-) osteoclasts causing an inhibition of integrin β3-Src-PYK2 signalling. CONCLUSIONS:Our study discloses a crucial role and novel mechanism for SNX10 in osteoclast function, and provides evidence for SNX10 as a promising novel therapeutic target for suppression of immune inflammation and bone erosion in rheumatoid arthritis. 10.1136/annrheumdis-2014-207134
    Sorting nexin 10 acting as a novel regulator of macrophage polarization mediates inflammatory response in experimental mouse colitis. You Yan,Zhou Chun,Li Dong,Cao Zhong-Lian,Shen Weixing,Li Wan-Zhen,Zhang Sulin,Hu Bin,Shen Xiaoyan Scientific reports In response to changes in microenvironment, macrophages polarize into functionally distinct phenotypes, playing a crucial role in the pathogenesis of inflammatory bowel disease (IBD). Here, we investigated the effects of sorting nexin 10 (SNX10), a protein involved in endosomal trafficking and osteoclast maturation, on regulation of macrophage polarization and progression of mouse colitis. Our results revealed that SNX10 deficiency increased the population of M2-type monocytes/macrophages, and protected against colonic inflammation and pathological damage induced by dextran sulfate sodium (DSS). By in vitro study, we showed that deficiency of SNX10 polarized macrophages derived from mouse bone marrow or human peripheral blood mononuclear cells (PBMCs) towards an anti-inflammatory M2 phenotype, which partially reversed by SNX10 plasmid transfection. Adoptive transfer of SNX10(-/-) macrophages ameliorated colitis in WT mice. However, transfer of WT macrophages exacerbated colitis in SNX10(-/-) mice. Our data disclose a crucial role and novel function for SNX10 in macrophage polarization. Loss of SNX10 function may be a potential promising therapeutic strategy for IBD. 10.1038/srep20630
    Sorting nexin 10 acts as a tumor suppressor in tumorigenesis and progression of colorectal cancer through regulating chaperone mediated autophagy degradation of p21. Zhang Sulin,Hu Bin,You Yan,Yang Zhiwen,Liu Lixin,Tang Huanhuan,Bao Weilian,Guan Yunyun,Shen Xiaoyan Cancer letters Chaperone-mediated autophagy (CMA) characterized by the selective degradation of target proteins has been linked with tumorigenesis in recent years. Here, we explored the function of sorting nexin 10 (SNX10), a protein involved in maintaining endosome/lysosome homeostasis, in mediating CMA activity and its impact on the progression of mouse inflammation-driven colorectal cancer. Our results revealed that SNX10 deficiency increased the activation of CMA by preventing the degradation of lysosomal LAMP-2A. In SNX10 KO cells, we disclosed that p21, a master effector in various tumor suppressor pathways, is a substrate of CMA, and decrease of p21 caused by SNX10-mediated CMA activation contributes to HCT116 cell proliferation and survival. Moreover, we found that SNX10 KO promoted tumorigenesis in the mouse colorectum which could be restored by SNX10 over-expression. Furthermore, SNX10 was remarkably down-regulated in human CRC tissues which showed the increased activity of CMA and decreased expression of p21. These findings suggest that SNX10 acts as a tumor suppressor in the mouse colorectum and drives inflammation-associated colorectal cancer by a chaperone-mediated autophagy mechanism. 10.1016/j.canlet.2018.01.045
    SNX10 mediates alcohol-induced liver injury and steatosis by regulating the activation of chaperone-mediated autophagy. You Yan,Li Wan-Zhen,Zhang Sulin,Hu Bin,Li Yue-Xuan,Li Hai-Dong,Tang Huan-Huan,Li Qian-Wen,Guan Yun-Yun,Liu Li-Xin,Bao Wei-Lian,Shen Xiaoyan Journal of hepatology BACKGROUND & AIMS:Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. However, the cellular defense mechanisms underlying ALD are not well understood. Recent studies highlighted the involvement of chaperone-mediated autophagy (CMA) in regulating hepatic lipid metabolism. Sorting nexin (SNX)-10 has a regulatory function in endolysosomal trafficking and stabilisation. Here, we investigated the roles of SNX10 in CMA activation and in the pathogenesis of alcohol-induced liver injury and steatosis. METHODS:Snx10 knockout (Snx10 KO) mice and their wild-type (WT) littermates fed either the Lieber-DeCarli liquid alcohol diet or a control liquid diet, and primary cultured WT and Snx10 KO hepatocytes stimulated with ethanol, were used as in vivo and in vitro ALD models, respectively. Activation of CMA, liver injury parameters, inflammatory cytokines, oxidative stress and lipid metabolism were measured. RESULTS:Compared with WT littermates, Snx10 KO mice exhibited a significant amelioration in ethanol-induced liver injury and hepatic steatosis. Both in vivo and in vitro studies showed that SNX10 deficiency upregulated lysosome-associated membrane protein type 2A (LAMP-2A) expression and CMA activation, which could be reversed by SNX10 overexpression in vitro. LAMP-2A interference confirmed that the upregulation of Nrf2 and AMPK signalling pathways induced by SNX10 deficiency relied on CMA activation. Pull-down assays revealed an interaction between SNX10 and cathepsin A (CTSA), a key enzyme involved in LAMP-2A degradation. Deficiency in SNX10 inhibited CTSA maturation and increased the stability of LAMP-2A, resulting in an increase in CMA activity. CONCLUSIONS:SNX10 controls CMA activity by mediating CTSA maturation, and, thus, has an essential role in alcohol-induced liver injury and steatosis. Our results provide evidence for SNX10 as a potential promising therapeutic target for preventing or ameliorating liver injury in ALD. LAY SUMMARY:Alcoholic liver disease is a major cause of morbidity and mortality worldwide. Recent studies highlight the involvement of chaperone-mediated autophagy (CMA) in regulating hepatic lipid metabolism. Our study reveals that deficiency of sorting nexin (SNX) 10 increases the stability of LAMP-2A by inhibiting cathepsin A maturation, resulting in the increase of CMA activity and, thus, alleviates alcohol-induced liver injury and steatosis. 10.1016/j.jhep.2018.01.038
    Sorting nexin 10 controls mTOR activation through regulating amino-acid metabolism in colorectal cancer. Le Yunchen,Zhang Sulin,Ni Jiahui,You Yan,Luo Kejing,Yu Yunqiu,Shen Xiaoyan Cell death & disease Amino-acid metabolism plays a vital role in mammalian target of rapamycin (mTOR) signaling, which is the pivot in colorectal cancer (CRC). Upregulated chaperone-mediated autophagy (CMA) activity contributes to the regulation of metabolism in cancer cells. Previously, we found that sorting nexin 10 (SNX10) is a critical regulator in CMA activation. Here we investigated the role of SNX10 in regulating amino-acid metabolism and mTOR signaling pathway activation, as well as the impact on the tumor progression of mouse CRC. Our results showed that SNX10 deficiency promoted colorectal tumorigenesis in male FVB mice and CRC cell proliferation and survival. Metabolic pathway analysis of gas chromatography-mass spectrometry (GC-MS) data revealed unique changes of amino-acid metabolism by SNX10 deficiency. In HCT116 cells, SNX10 knockout resulted in the increase of CMA and mTOR activation, which could be abolished by chloroquine treatment or reversed by SNX10 overexpression. By small RNA interference (siRNA), we found that the activation of mTOR was dependent on lysosomal-associated membrane protein type-2A (LAMP-2A), which is a limiting factor of CMA. Similar results were also found in Caco-2 and SW480 cells. Ultra-high-performance liquid chromatography-quadrupole time of flight (UHPLC-QTOF) and GC-MS-based untargeted metabolomics revealed that 10 amino-acid metabolism in SNX10-deficient cells were significantly upregulated, which could be restored by LAMP-2A siRNA. All of these amino acids were previously reported to be involved in mTOR activation. In conclusion, this work revealed that SNX10 controls mTOR activation through regulating CMA-dependent amino-acid metabolism, which provides potential target and strategy for treating CRC. 10.1038/s41419-018-0719-2
    SNX10 (sorting nexin 10) inhibits colorectal cancer initiation and progression by controlling autophagic degradation of SRC. Zhang Sulin,Yang Zhiwen,Bao Weilian,Liu Lixin,You Yan,Wang Xu,Shao Liming,Fu Wei,Kou Xinhui,Shen Weixing,Yuan Congmin,Hu Bin,Dang Wenzhen,Nandakumar Kutty Selva,Jiang Hualiang,Zheng Mingyue,Shen Xiaoyan Autophagy The non-receptor tyrosine kinase SRC is a key mediator of cellular protumorigenic signals. SRC is aberrantly over-expressed and activated in more than 80% of colorectal cancer (CRC) patients, therefore regulation of its stability and activity is essential. Here, we report a significant down regulation of SNX10 (sorting nexin 10) in human CRC tissues, which is closely related to tumor differentiation, TNM stage, lymph node metastasis and survival period. SNX10 deficiency in normal and neoplastic colorectal epithelial cells promotes initiation and progression of CRC in mice. SNX10 controls SRC levels by mediating autophagosome-lysosome fusion and SRC recruitment for autophagic degradation. These mechanisms ensure proper controlling of the activities of SRC-STAT3 and SRC-CTNNB1 signaling pathways by up-regulating SNX10 expression under stress conditions. These findings suggest that SNX10 acts as a tumor suppressor in CRC and it could be a potential therapeutic target for future development.: ACTB: actin beta; ATG5: autophagy related 5; ATG12: autophagy related 12; CQ: chloroquine; CRC: colorectal cancer; CTNNB1: catenin beta 1; EBSS: Earle's balanced salt solution; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; MAP1LC3: microtubule associated protein 1 light chain 3; MKI67: marker of proliferation Ki-67; mRNA: messenger RNA; PX: phox homology; RT-qPCR: real time quantitative polymerase chain reaction; siRNA: small interfering RNA; SNX10: sorting nexin 10; SQSTM1: sequestosome 1; SRC: SRC proto-oncogene, non-receptor tyrosine kinase; STAT3: signal transducer and activator of transcription 3; WT: wild type. 10.1080/15548627.2019.1632122
    SNX10 deficiency restricts foam cell formation and protects against atherosclerosis by suppressing CD36-Lyn axis. Fan Yujuan,Yang Jialin,Li Hui,Li HaiDong,Zhang Sulin,Li Xuesong,Song Yuping,Dang Wenzhen,Liu Lixin,Cao Xinyue,Wang Xu,Nandakumar Kutty Selva,Shen Xiaoyan,You Yan The Canadian journal of cardiology BACKGROUND:Atherosclerosis-related cardiovascular diseases are among the leading causes of mortality worldwide. Uptake of modified lipoproteins by monocyte-derived macrophages leads to the formation of foam cells, which by secreting pro-inflammatory cytokines accelerate plaque development. Sorting Nexin 10 (SNX10) plays a critical role in the regulation of macrophage functions as well as in the lipid metabolism. This study aims to explore the precise effects and the underlying molecular mechanisms of SNX10 mediated processes in atherosclerotic diseases. METHODS:SNX10 knockout mice were generated and bone marrow-derived macrophages (BMDMs) were studied in vitro. Mice were crossed with apolipoprotein E-deficient (ApoE) mice and atherogenesis was monitored for 16 weeks. RESULTS:Expression of SNX10 was increased in atherosclerotic plaques from both humans and ApoE mice. SNX10 deficiency decreased foam cell abundance and alleviated atherosclerotic plaque progression in ApoE mice. In addition, high fat, high cholesterol diet fed ApoE mice contained more Ly6CCX3CR1 monocytes than ApoE SNX10 (DKO) littermates. ApoE mice showed a higher level of inflammatory macrophages infiltrating into atherosclerotic lesions. SNX10 deficiency reduced the interactions between CD36 and Lyn, thus inhibiting CD36-mediated lipoprotein uptake and foam cell formation. CONCLUSIONS:Our findings demonstrate CD36-Lyn dependent non-redundant atherogenic role for SNX10 in diet-induced atherogenesis. We propose SNX10 as a potential therapeutic target for the prevention and treatment of atherosclerosis. 10.1016/j.cjca.2020.05.010
    Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway. You Yan,Bao Wei-Lian,Zhang Su-Lin,Li Hai-Dong,Li Hui,Dang Wen-Zhen,Zou Si-Li,Cao Xin-Yue,Wang Xu,Liu Li-Xin,Jiang Hualiang,Qu Le-Feng,Zheng Mingyue,Shen Xiaoyan Circulation research RATIONALE:SNX10 (sorting nexin 10) has been reported to play a critical role in regulating macrophage function and lipid metabolism. OBJECTIVE:To investigate the precise role of SNX10 in atherosclerotic diseases and the underlying mechanisms. METHODS AND RESULTS:SNX10 expression was compared between human healthy vessels and carotid atherosclerotic plaques. Myeloid cell-specific SNX10 knockdown mice were crossed onto the APOE (apolipoprotein E) background and atherogenesis (high-cholesterol diet-induced) was monitored for 16 weeks. We found that SNX10 expression was increased in atherosclerotic lesions of aortic specimens from humans and APOE mice. Myeloid cell-specific SNX10 deficiency (Δ knockout [KO]) attenuated atherosclerosis progression in APOE mice. The population of anti-inflammatory monocytes/macrophages was increased in the peripheral blood and atherosclerotic lesions of ΔKO mice. In vitro experiments showed that SNX10 deficiency-inhibited foam cell formation through interrupting the internalization of CD36, which requires the interaction of SNX10 and Lyn-AKT (protein kinase B). The reduced Lyn-AKT activation by SNX10 deficiency promoted the nuclear translocation of TFEB (transcription factor EB), thereby enhanced lysosomal biogenesis and LAL (lysosomal acid lipase) activity, resulting in an increase of free fatty acids to fuel mitochondrial fatty acid oxidation. This further promoted the reprogramming of macrophages and shifted toward the anti-inflammatory phenotype. CONCLUSIONS:Our data demonstrate for the first time that SNX10 plays a crucial role in diet-induced atherogenesis via the previously unknown link between the Lyn-Akt-TFEB signaling pathway and macrophage reprogramming, suggest that SNX10 may be a potentially promising therapeutic target for atherosclerosis treatment. 10.1161/CIRCRESAHA.119.315516
    Allicin inhibits mouse colorectal tumorigenesis through suppressing the activation of STAT3 signaling pathway. Li Xiang,Ni Jiahui,Tang Yixin,Wang Xu,Tang Huanhuan,Li Haidong,Zhang Sulin,Shen Xiaoyan Natural product research Allicin is the major biologically active compounds of freshly crushed garlic. It has been reported to inhibit the proliferation and promote the apoptosis of multiple colorectal cancer cells. However, the anti-colorectal cancer effect of Allicin has not been verified by studies. In the present study, we investigated the effect of Allicin on azoxymethane/dextran sodium sulfate (AOM/DSS) colorectal cancer mouse model and explore the underlying possible mechanism. Our result showed that Allicin could inhibit colonic tumorigenesis of AOM/DSS mice . In vitro study showed that Allicin promoted the apoptosis and suppressed the survival and proliferation of HCT116 cells. The molecular mechanism is related to the suppression of STAT3 signaling activation. Thus, our data provide further support for Allicin as a potential favorable supplement for human colorectal cancer. 10.1080/14786419.2018.1465425
    Oral Nanoparticles of SNX10-shRNA Plasmids Ameliorate Mouse Colitis. Bao Wei-Lian,Wu Qibiao,Hu Bin,Sun Dongdong,Zhao Shengnan,Shen Xiaoyan,Cheng Haibo,Shen Weixing International journal of nanomedicine Background:Our previous study found that deletion of Sorting nexin 10 (SNX10) can protect against colonic inflammation and pathological damage induced by dextran sulfate sodium (DSS). This inspired us that modulation of SNX10 expression in colonic epithelial cells might represent a promising therapeutic strategy for inflammatory bowel disease (IBD). Methods:Effective delivery of siRNA/shRNA to silence genes is a highly sought-after means in the treatment of multiple diseases. Here, we encapsulated SNX10-shRNA plasmids (SRP) with polylactide-polyglycolide (PLGA) to make oral nanoparticles (NPs), and then applied them to acute and chronic IBD mice model, respectively. The characteristics of the nanoparticles were assayed and the effects of SRP-NPs on mouse IBD were evaluated. Results:High-efficiency SNX10-shRNA plasmids were successfully constructed and coated with PLGA to obtain nanoparticles, with a particle size of 275.2 ± 11.4mm, uniform PDI distribution, entrapment efficiency of 87.6 ± 2.5%, and drug loading of 13.11 ± 1.38%, displayed dominant efficiency of SNX10 RNA interference in the colon. In both acute and chronic IBD models, SRP-NPs could effectively reduce the loss of mice body weight, relieve the intestinal mucosal damage and inflammatory infiltration, inhibit the expression of inflammatory cytokines IL-1β, IL-23, TNF-α, and down-regulate the expression of toll-like receptors (TLRs) 2 and 4. Conclusion:Oral nanoparticles of SNX10-shRNA plasmid displayed dominant efficiency of SNX10 RNA interference in the colon and ameliorate mouse colitis via TLR signaling pathway. SNX10 is a new target for IBD treatment and nanoparticles of SNX10-shRNA plasmid might be a promising treatment option for IBD. 10.2147/IJN.S286392
    BIG1 controls macrophage pro-inflammatory responses through ARF3-mediated PI(4,5)P2 synthesis. Liu Lixin,Zhang Sulin,Wang Yirui,Bao Weilian,Zhou Yile,Dang Wenzhen,Wang Xu,Li Haidong,Cao Xinyue,You Yan,Fang Hao,Shen Xiaoyan Cell death & disease Sepsis is caused by a dysregulated host inflammatory response to serious infections resulting in life-threatening organ dysfunction. The high morbidity and mortality make sepsis still a major clinical problem. Here, we investigated the roles of Brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1) in the pathogenesis process of sepsis and the underlying mechanisms. We found myeloid cell-specific BIG1 knockout (BIG1 cKO) significantly reduced the mortality and organ damage in LPS-induced and CLP-induced polymicrobial sepsis mouse model. The serum concentration and mRNA expression of pro-inflammatory cytokines including TNF-α, IL-6, IL-1β, and IL-12 were obviously decreased in BIG1 cKO mice. In bone marrow-derived macrophages or THP-1 cells, BIG1 deficiency caused an inhibited ARF3 activation, which reduced PI(4,5)P2 synthesis and the recruitment of TIRAP to the plasma membrane through inhibiting the activation of PIP5K induced by LPS, and eventually resulted in the inhibitory activity of TLR4-MyD88 signaling pathway. These results reveal a crucial new role of BIG1 in regulating macrophage inflammation responses, and provide evidence for BIG1 as a potential promising therapeutic target in sepsis. 10.1038/s41419-020-2590-1
    Targeting sorting nexin 10 improves mouse colitis via inhibiting PIKfyve-mediated TBK1/c-Rel signaling activation. Bao Weilian,Liu Xiaohong,You Yan,Hou Hui,Wang Xu,Zhang Sulin,Li Haidong,Feng Guize,Cao Xinyu,Jiang Hualiang,Zheng Mingyue,Shen Xiaoyan Pharmacological research Sorting nexin 10 (SNX10) has been reported as a critical regulator in macrophage function, and germline SNX10 knockout effectively alleviated mouse colitis. Here, we investigated the precise role of SNX10 in inflammatory responses in macrophages in mouse colitis, and explored the druggability of SNX10 as a therapeutic target for inflammatory bowel disease (IBD). Our results revealed that myeloid-specific SNX10 deletion alleviated inflammation and pathological damage induced by dextran sulfate sodium (DSS). In vitro experiments showed that SNX10 deletion contributed to inflammation elimination by inhibiting PIKfyve-mediated TANK-binding kinase 1 (TBK1) /c-Rel signaling activation. Further study provided rational mechanism that SNX10 was required for the recruitment of PIKfyve to the TRIF-positive endosomes, through which PIKfyve activated TBK1/c-Rel for LPS-induced inflammation response. Based on the structure of SNX10, we discovered a new small-molecule inhibitor DC-SX029, which targeted SNX10 to block the SNX10-PIKfyve interaction, thereby decreased the TBK1/c-Rel signaling activation. Additionally, therapeutic efficiency of DC-SX029 was evaluated in both DSS-induced and IL10-deficient mouse colitis models. Our data demonstrate a new mechanism by which SNX10-PIKfyve interaction regulates LPS-induced inflammation response in macrophages via the TBK1/c-Rel signaling pathway. In vivo and in vitro pharmacological studies of SNX10 protein-protein interaction (PPI) inhibitor DC-SX029 demonstrate the feasibility of targeting SNX10 in IBD treatment. 10.1016/j.phrs.2021.105679
    Wang-Bi Tablet Ameliorates DMM-Induced Knee Osteoarthritis through Suppressing the Activation of p38-MAPK and NF-B Signaling Pathways in Mice. Li Hui,You Yan,Jiang Bing,Li Haidong,Li Xiang,Wu Wei,Cao Hong,Shen Xiaoyan,Zou Jun Evidence-based complementary and alternative medicine : eCAM Background:Traditional Chinese medicine (TCM) exhibits outstanding therapeutic effects on the treatment of osteoarthritis (OA). Wang-Bi tablets (WBTs) have been used in clinics to treat knee osteoarthritis (KOA) by alleviating joint swelling and paining, and thus, the quality of life in patients with KOA was improved. However, its underlying molecular mechanism of anti-inflammatory response remains unclear. Therefore, further investigation is required. Purpose:This study aimed to explore the function of WBT in KOA mice and uncover the possible molecular mechanisms. . A KOA model was constructed by destabilizing the medial meniscus (DMM). IL-1-treated chondrocytes were used to investigate the precise mechanism in vitro. Methods:(1) C57BL/6 male mice (8-week-old) were divided into Model, Sham, WBT-L, WBT-M, and WBT-H groups. After intragastric administration of 0.5% CMC-Na or WBT for 4 weeks, inflammation and pathological change were analyzed by ELISA, RT-qPCR, hematoxylin and eosin (H & E) and safranine O staining. (2) Isolated chondrocytes were stimulated with IL-1 followed by WBT-containing serum treatment, and then, the expression of inflammatory cytokines was analyzed by ELISA and RT-qPCR. (3) The effects of WBT on inflammatory signaling cascades in mice knee joint and chondrocytes were detected by WB. Results:The results indicated that WBT could alleviate inflammation and prevent cartilage injury in KOA mice. Compared with 0.5% CMC-Na-treated mice, the serum glycosaminoglycans (GAG) level in WBT-treated mice was notably increased, while the proinflammatory cytokine interleukin- (IL-) 6 level was decreased. In addition, WBT treatment suppressed the activation of NF-B and p38 signaling pathways both in vivo and in vitro. Conclusion:WBT can effectively inhibit articular cartilage injury and inflammatory response in KOA mice. The protective role of WBT in mice KOA was a result of the downregulation of NF-B and p38-MAPK signal pathways. 10.1155/2021/3930826