JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2024
·Vol. 28
·期 13
·e18527
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IF 4.3
Maomao Miao,Mengying Li,Yunjie Sheng,Peijian Tong,Yang Zhang,Dan Shou
Infected bone defects (IBDs) are the common condition in the clinical practice of orthopaedics. Although surgery and anti-infective medicine are the firstly chosen treatments, in many cases, patients experience a prolonged bone union process after anti-infective treatment. Epimedium-Curculigo herb pair (ECP) has been proved to be effective for bone repair. However, the mechanisms of ECP in IBDs are insufficiency. In this study, Effect of ECP in IBDs was verified by micro-CT and histological examination. Qualitative and quantitative analysis of the main components in ECP containing medicated serum (ECP-CS) were performed. The network pharmacological approaches were then applied to predict potential pathways for ECP associated with bone repair. In addition, the mechanism of ECP regulating LncRNA MALAT1/miRNA-34a-5p/SMAD2 signalling axis was evaluated by molecular biology experiments. In vivo experiments indicated that ECP could significantly promote bone repair. The results of the chemical components analysis and the pathway identification revealed that TGF-β signalling pathway was related to ECP. The results of in vitro experiments indicated that ECP-CS could reverse the damage caused by LPS through inhibiting the expressions of LncRNA MALAT1 and SMAD2, and improving the expressions of miR-34a-5p, ALP, RUNX2 and Collagen type І in osteoblasts significantly. This research showed that ECP could regulate the TGF-β/SMADs signalling pathway to promote bone repair. Meanwhile, ECP could alleviate LPS-induced bone loss by modulating the signalling axis of LncRNA MALAT1/miRNA-34a-5p/ SMAD2 in IBDs.
研究领域:
骨科
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药理学
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分子生物学
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信号转导
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PubMed
高影响因子
Biomaterials Science
·
2020
·Vol. 9
·期 6
·2090-2102
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IF 6.183
Rui Shi,Jingshuang Zhang,Kun Niu,Weiyang Li,Ni Jiang,Jianlin Li,Qingsong Yu,Chengai Wu
Deferoxamine (DFO), an iron chelator regarded as a hypoxic analogue, has been reported to be involved in angiogenesis and osteogenic differentiation. In this study, DFO was loaded into nanospheres, Then, DFO-loaded NPs and free DFO were co-encapsulated in nanofibers through coaxial electrospinning and its effects on cell viability, migration, and osteogenic differentiation, and the potential mechanisms were investigated. The results suggested that DFO maintained cell viability and promoted the migration of human mesenchymal stem cells (hMSCs) and MC3T3-E1 cells. ALP activity, calcium deposition, and expression of osteogenesis-related markers, including collagen, osteocalcin, and osteopontin, were all increased with DFO. Moreover, hypoxia-inducible factor-1α, transforming growth factor-β, and Smad2 were upregulated with DFO, which indicated activation of the TGF-β1/Smad2 signalling pathway. This may contribute to osteogenic differentiation of cells.
研究领域:
生物材料
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组织工程
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再生医学
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细胞生物学
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PubMed
高影响因子
Journal of Advanced Research
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2026
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IF 17.1
Xiao-Fei Zhang,Bo-Wen Zhang,Fan Wu,Zi-Xuan Wang,Wen-Ming Pan,Chu-Yi Cao,Xin-Yu Lv,Tian-Xing Ren,Wei-Hua Xu,Hui Wang,Jin-Xiang Zhang
Introduction Osteoarthritis (OA) is the most prevalent degenerative joint disorder worldwide, characterized by impaired anabolic activity and excessive catabolic responses in chondrocytes. However, the precise mechanisms governing chondrocyte homeostasis during OA progression remain unclear. Objectives This study aimed to elucidate the role of polycomb protein BMI1 in maintaining chondrocyte homeostasis, identify its upstream transcriptional regulator and downstream signaling cascade, and evaluate its therapeutic potential in OA. Methods BMI1 expression was assessed in articular cartilage from OA patients and destabilization of the medial meniscus (DMM) mouse models. Transcriptional regulation of BMI1 by zinc finger and BTB domain–containing protein 17 (ZBTB17) was analyzed using Western blotting, chromatin immunoprecipitation and dual-luciferase reporter assays. In vivo effects of BMI1 were evaluated by intra-articular injection of rAAV6- Bmi1 . In vitro BMI1 overexpression and inhibition were achieved using Bmi1-overexpressing plasmid and PTC209, respectively. The BMI1-SMAD2 interaction was investigated using nuclear–cytoplasmic fractionation, co-immunoprecipitation, ubiquitination assays, cycloheximide chase assays, and immunofluorescence. Therapeutic efficacy of BMI1 was evaluated using a three-dimensional hydrogel-based delivery system in DMM mice. Results BMI1 expression was significantly downregulated in human and murine OA cartilage and negatively correlated with disease severity. ZBTB17 directly activated BMI1 transcription by binding to its promoter. BMI1 overexpression alleviated OA progression by enhancing chondrocyte anabolism and antioxidant capacity through upregulating SMAD2 and promoting its nuclear localization. Mechanistically, BMI1 interacted with SMAD2 to increase its stability by inhibiting SMURF2-mediated K48-linked ubiquitination while facilitating K63-linked ubiquitination at Lys157 to facilitate SMAD2 nuclear translocation. DKK1 was identified as a principal downstream target of the BMI1-SMAD2 axis. Finally, we confirmed that local delivery of BMI1 mdified stromal cells via a three-dimensional hydrogel significantly attenuated cartilage degeneration in vivo . Conclusion Our findings identify a novel ZBTB17–BMI1–SMAD2–DKK1 axis essential for chondrocyte homeostasis and highlight BMI1 as a promising therapeutic target for osteoarthritis.
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高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2025
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IF 2.2
Meng Zhang,Congyao Wang,Ruiqi Zhao,Jiabo Yuan
Background Asthma is a chronic disease characterized by airway remodeling, which results in a progressive decline in lung function. Senkyunolide A is one of the effective components of ligusticum chuanxiong Hort, it shows protective effects on many human diseases. However, the role of Senkyunolide A in asthma remains unclear. Results In our study, we established an asthma mouse model by ovalbumin (OVA) sensitization and challenge, and Senkyunolide A (20 mg/kg and 40 mg/kg) was given by intraperitoneal injection. For in vitro study, lung epithelial BEAS-2B cells were treated with TGF-β1 to induce epithelial mesenchymal transformation. Our study showed that Senkyunolide A (40 mg/kg) alleviated airway injury, inflammatory infiltration and airway remodeling induced by OVA in asthma mice. Meanwhile, Senkyunolide A (40 μM) recovered the high level of cell migration and profibrotic factors expression induced by TGF-β1. Mechanistically, Senkyunolide A abolished the effect of OVA or TGF-β1 on Smad2/3 phosphorylation at site Ser 465/467 /Ser 423/425 in mice or BEAS-2B cells and inhibited the activation of NLRP3 inflammasome induced by OVA. Conclusions In total, our study indicated that Senkyunolide A alleviated airway damage and airway remodeling in asthmatic mice and regulated the progress of asthma by inhibiting the TGF-β/Smad2/3 signaling pathway and NLRP3 activation.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2021
·Vol. 25
·期 24
·11113-11127
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IF 5.31
Ting Liu,Shujia Chen,Xiaoli Xie,Hongqun Liu,Yongjuan Wang,Shengbin Qi,Linping Shi,Xue Zhou,Jiuna Zhang,Shuling Wang,Yijun Wang,Shengxiong Chen,Shiying Dou,Xiaoyu Jiang,Ruolin Cui,Huiqing Jiang
Triggering receptor expressed on myeloid cells-1 (TREM-1) exists in two forms: a transmembrane form and a soluble form (sTREM-1). The levels of sTREM-1 are elevated in supernatants of activated HSCs. However, the role of sTREM-1 in HSC activation and liver fibrosis remains undefined. Previous studies have primarily focused on the transmembrane form of TREM-1; we innovatively observed the function of sTREM-1 as a ligand in liver fibrosis and screened its receptor. Here, recombinant sTREM-1 was used as a stimulator which induced HSC activation and further aggravated liver fibrosis. Then, screening for sTREM-1 interacting membrane receptors was performed using pull-down assay followed by mass spectrometry, and the membrane receptor roundabout guidance receptor 2 (Robo2) was identified as a candidate receptor for sTREM-1. The interaction between sTREM-1 and Robo2 was verified by pull-down and immunofluorescence. The role of Robo2 on sTREM-1-induced HSC activation and its downstream signal pathways was assessed by knockdown of Robo2 in LX-2 cells. Furthermore, HSC-specific knockdown of Robo2 was achieved in a mouse model of liver fibrosis by using a recombinant adeno-associated virus (AAV) vector to confirm the role of the receptor, and we proved that Robo2 knockdown inhibited the activation of HSC and liver fibrosis, which also led to the inactivation of Smad2/3 and PI3K/Akt pathways in sTREM-1-induced HSC activation and liver fibrosis. In conclusion, sTREM-1 acts as a new ligand of Robo2; the binding of sTREM-1 to Robo2 initiates the activation of the downstream Smad2/3 and PI3K/Akt signalling pathways, thereby promoting HSC activation and liver fibrosis.
研究领域:
免疫学
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肝病学
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细胞生物学
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分子生物学
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PubMed
高影响因子
Biomolecules
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2020
·Vol. 10
·期 3
·398
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IF 4.082
Shan Shan Qi,Hong Xing Zheng,Hai Jiang,Li Ping Yuan,Le Chen Dong
Diabetic nephropathy (DN) is one of the most important complications of diabetes, and the leading cause of end-stage renal disease (ESRD). While Chromium picolinate (CrPic) supplementation has been found to be effective in treating diabetes, its effects on diabetic-induced nephropathy have not been studied. Therefore, in this study, CrPic (1 mg kg−1d−1) was administered to a DN rat model by oral gavage for eight weeks to investigate its effects. The results show that CrPic supplementation caused a decrease in levels of blood glucose, serum insulin, blood urea nitrogen (BUN), serum creatinine, and urinary albumin in DN rats. It also reversed renal pathological changes, including renal glomerular sclerosis and interstitial fibrosis. In addition, the oxidative defense system in the kidneys of DN rats was found to be improved; the biological activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) increased; and the content of malondialdehyde (MDA) lowered. Immunohistochemical results reveal that the expression levels of renal transforming growth factor-β1 (TGF-β1), Smad 2, and Smad 3 decreased significantly in the kidneys of rats in the CrPic-treated group. CrPic administration was thus found to ameliorate diabetic nephropathy in SD rats via an antioxidative stress mechanism, as well the ability to inhibit TGF-β1/Smad2/3 expression. This study suggests that CrPic could be a potential renal-protective nutrient against diabetic nephropathy.Keywords:diabetic nephropathy;chromium picolinate;renal fibrosis;antioxidative stress
研究领域:
内分泌学
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肾病学
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药理学
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PubMed
高影响因子
CANCER LETTERS
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2024
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IF 9.1
Erbao Zhang,Qi Sun,Chang Zhang,Huimin Ma,Jing Zhang,Yue Ding,Guoqing Wang,Chen Jin,Chenying Jin,Yating Fu,Caiwang Yan,Meng Zhu,Cheng Wang,Juncheng Dai,Guangfu Jin,Zhibin Hu,Hongbing Shen,Hongxia Ma
Approximately 51 non-small-cell lung cancer (NSCLC) risk loci have been identified by genome-wide association studies (GWASs). We conducted a high throughput RNA-interference (RNAi) screening to identify the candidate causal genes in NSCLC risk loci. KIAA0391 at 14q13.1 had the highest score and could promote proliferation and metastasis of NSCLC in vitro and in vivo . We next prioritized rs3783313 as a causal variant at 14q13.1, by integrating a large-scale population study consisting of 27,120 lung cancer cases and 27,355 controls, functional annotation, and expression quantitative trait locus (eQTL) analysis. Then we found that rs3783313 could facilitate a promoter-enhancer interaction to upregulate KIAA0391 expression by affecting the affinity of transcription factor NFYA. Mechanistically, KIAA0391 knockdown dramatically influenced pyroptosis-related pathways and increased the expression of CASP1. And KIAA0391 transcriptionally repressed CASP1 by binding to SMAD2 and induced an anti-pyroptosis phenotype, promoting tumorigenesis of NSCLC, which provides new insights and potential target for NSCLC.
研究领域:
肿瘤学
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基因组学
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分子生物学
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癌症研究
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PubMed
高影响因子
Science Advances
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2025
·Vol. 11
·期 50
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IF 12.5
Sichen Zhang,Huidong Liu,Tianyue Zhang,Yansong Wang,Mengtong Zhang,Xiao Zhang,Hansong Li,Shuai Huang,Lin Liang,Ke Cheng,Shaowei Wang
Aging in females is characterized by dysfunctional ovaries (DOs). While human umbilical cord mesenchymal stem cell (HucMSC)–derived extracellular vesicles (EVs) have shown promise in ameliorating DO, the mechanisms underlying their effects remain poorly understood. In this study, we investigated the therapeutic potential of growth differentiation factor 9 (GDF-9)–overexpressing EVs (GOEs) on granulosa cells. We identified the activin A receptor type 1B (ACVR1B) as a critical target for the restoration of ovarian function. Genetic modification of HucMSCs to overexpress GDF-9 resulted in the production of GOEs, which, through ACVR1B activation, induced SMAD2 phosphorylation in the nucleus, thereby rescuing ovarian function. These findings provide previously unknown insights into the mechanisms by which EVs mediate ovarian recovery and propose GOEs as a potential therapeutic strategy for the treatment of DO.
研究领域:
生殖医学
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分子生物学
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再生医学
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细胞信号传导
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PubMed
高影响因子
TOXICON
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2021
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IF 3.033
Xiong Zhang,Chen Feng,Yimao Li,Chenlin Su,Shuxin Zhao,Shengdi Su,Feng Yu,Ji LI
Aristolactam I (AL-I) is the main active ingredient in the Aristolochia plant species, which have been associated with severe nephrotoxicity. In order to investigate the mechanism of AL-I induced renal epithelial-mesenchymal transition (EMT), we established an AL-I induced EMT model in human proximal tubular epithelial cells (HK-2 cells). Biochemical analysis experiment including Morphological examination, 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay, and Western blot analysis were performed. The results showed that AL-I accumulates in the cytosol causing cytotoxicity and inhibition of proliferation in a concentration- and time-dependent manner. Morphological examination showed that with the increasing concentration of AL-I, the tendency of HK-2 cells transform form epithelial cell to fibroblast cells was stronger. In the Western blot analysis, the expression of α-Smooth muscle actin (α-SMA) and Transforming Growth Factor β1 (TGF-β1) were significantly up-regulated, the expression of E-cadherin was significantly down-regulated after administrating. The ratio of the expression of P-Smad2/3 and Smad2/3 was significantly up-regulated, suggested that TGF-β/Smad-dependent signaling pathway was activated in this process. With presence of TGF-β receptor inhibitor (LY364947), we found that the expressions of three EMT related proteins (E-cadherin, α-SMA and TGF-β1) were obviously reversed. In conclusion, we acknowledge that AL-I can induce renal EMT process in HK-2 cell, which is triggered by the activation of TGF-β/Smad-dependent signaling pathway.
研究领域:
药理学
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毒理学
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细胞生物学
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分子生物学
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
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IF 5.7
Manman Yuan,Jing Ye,Xiangqiao Sun,Zhiwu Tong,Tingting Wang,Renxiang Tan,Xingxin Wu
Acaudiolide ameliorates liver fibrosis in mice • Acaudiolide inhibits TGF-β1/SMAD signaling in HSCs • Acaudiolide inhibits the nuclear translocation of p-SMAD2/3 • Acaudiolide weakens the interaction between SMAD4 and p-SMAD2/3 • SMAD4 is a candidate covalent target of acaudiolide Hepatic stellate cell (HSC) activation is a central driver of fibrosis progression in metabolic dysfunction-associated steatohepatitis (MASH), yet effective antifibrotic pharmacotherapies remain limited. Here, we identify acaudiolide, a sulfur-bridged symmetric dimeric macrodiolide isolated from the fungus Acaulium sp. H-JQSF, as a natural-product lead that suppresses HSC activation and experimental liver fibrosis. In a Western diet (WD)/CCl 4 murine model of MASH, acaudiolide reduced collagen deposition, alpha-smooth muscle actin (α-SMA) expression and fibrogenic gene expression. Transcriptomic profiling of HSCs showed that acaudiolide antagonized transforming growth factor-β1 (TGF-β1)-driven profibrotic programs. Mechanistically, acaudiolide did not measurably alter SMAD2/3 phosphorylation but markedly reduced the nuclear accumulation of phosphorylated SMAD2/3 (p-SMAD2/3). Integration of Connectivity Map (CMap) analysis with isotopic tandem orthogonal proteolysis-activity-based protein profiling (isoTOP-ABPP) chemical proteomics nominated SMAD4 as a candidate covalent target of acaudiolide. Covalent docking suggested Cys363 as a potential engagement site, and co-immunoprecipitation showed that acaudiolide weakened the association of SMAD4 with p-SMAD2/3. These findings support a model in which acaudiolide interferes with SMAD complex assembly, thereby attenuating TGF-β-dependent profibrotic transcription and HSC activation. Collectively, our data nominate acaudiolide as a preclinical antifibrotic lead and SMAD4 as a potentially tractable downstream node for pharmacological modulation of TGF-β signaling in MASH-related fibrosis. Download: Download high-res image (386KB) Download: Download full-size image
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高影响因子
FASEB JOURNAL
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2024
·Vol. 38
·期 15
·e23495
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IF 4.4
Yuwei Liu,Xiaomei Wang,Zhongfeng Wang,Xiuzhu Gao,Hongqin Xu,Yanhang Gao,Junqi Niu
Hepatic stellate cell (HSC) activation is the essential pathological process of liver fibrosis (LF). The molecular mechanisms regulating HSC activation and LF are incompletely understood. Here, we explored the effect of transcription factor SRY-related high mobility group box 7 (SOX7) on HSC activation and LF, and the underlying molecular mechanism. We found the expression levels of SOX7 were decreased in human and mouse fibrotic livers, particularly at the fibrotic foci. SOX7 was also downregulated in primary activated HSCs and TGF-β1 stimulated LX-2 cells. SOX7 knockdown promoted activation and proliferation of LX-2 cells while inhibiting their apoptosis. On the other hand, overexpression of SOX7 suppressed the activation and proliferation of HSCs. Mechanistically, SOX7 attenuates HSC activation and LF by decreasing the expression of β-catenin and phosphorylation of Smad2 and Smad3 induced by TGF-β1. Furthermore, overexpression of SOX7 using AAV8-SOX7 mouse models ameliorated the extent of LF in response to CCl 4 treatment in vivo. Collectively, SOX7 suppressed HSC activation and LF. Targeting SOX7, therefore, could be a potential novel strategy to protect against LF.
研究领域:
分子生物学
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细胞生物学
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肝病学
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PubMed
高影响因子
Nutrients
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2019
·Vol. 11
·期 2
·483
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IF 4.171
Zhonghua Dong,Yueyue Sun,Guangwei Wei,Siying Li,Zhongxi Zhao
(1) Background: Diabetic nephropathy, a microvascular complication of diabetes, is one of the principal causes of end-stage renal disease worldwide. The aim of this study was to explore the therapeutic effects of ergosterol on diabetic nephropathy. (2) Methods: Streptozotocin (STZ)-induced C57BL/6 diabetic mice were treated with ergosterol (10, 20, 40 mg/kg/day) for 8 weeks by oral gavage. The in vitro study employed rat mesangial cells exposed to 30 mM glucose for 48 h in the presence of 10 or 20 μM ergosterol. (3) Results: Ergosterol treatment improved body weights, ameliorated the majority of biochemical and renal functional parameters and histopathological changes, and reduced extracellular matrix (ECM) deposition in diabetic mice. In vitro, ergosterol suppressed proliferation, reduced the levels of ECM proteins, and increased the expression of matrix metalloproteinase-2 and -9 in high glucose-induced mesangial cells; Furthermore, ergosterol markedly improved transforming growth factor-β1 (TGF-β1) expression, enhanced phosphorylation levels of drosophila mothers against decapentaplegic 2 (Smad2), and regulated the downstream factors in vivo and in vitro. (4) Conclusions: Ergosterol alleviated mesangial cell proliferation and the subsequent ECM deposition by regulating the TGF-β1/Smad2 signaling pathway.Keywords:ergosterol;diabetic nephropathy;mesangial cells;ECM;TGF-β1
研究领域:
药理学
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肾病学
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糖尿病
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PubMed
高影响因子
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