JOURNAL OF ETHNOPHARMACOLOGY
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2025
·
IF 5.4
Liting Zhu,Linjie Mu,Xiaoqiu Ni,Feng Wang,Xinyi Peng,Yujiu Gao,Tingting Wei,Congcong Zeng,Yongheng Bai,Fangyan Wang,Zhengzhong Yuan,Jinguo Cheng
Ethnopharmacological relevance Xin-Zi-Sheng-Wan Decoction (XZSWD), a formulation rooted in the classic Zi-Sheng Pill first recorded in the Qing-dynasty compendium “ Golden Mirror of Medicine ,” is traditionally employed to resolve turbid pathogenic stagnation and restore metabolic equilibrium. Modern ethnopharmacological studies reveal a marked uric acid–lowering effect, although its precise molecular mechanisms have yet to be fully clarified. Aim of the study This study aimed to evaluate the therapeutic efficacy of XZSWD in hyperuricemia (HUA)-induced kidney injury and to elucidate its molecular mechanisms. Methods UPLC-QTOF/MS was used to identify compounds in XZSWD medicated serum. A HUA mouse model was induced by potassium oxonate and hypoxanthine to evaluate the therapeutic effects of XZSWD on renal injury. RNA-Seq, qRT-PCR, Western blot, immunofluorescence, and flow cytometry were applied to investigate immune infiltration and key signaling pathways. A THP-1/HK-2 co-culture system combined with SPP1 overexpression and knockdown was used to explore the molecular mechanisms. Results 99 compounds were identified in XZSWDS. XZSWD improved renal function, reduced serum uric acid levels, and downregulated macrophage-related inflammatory genes while modulating mixed M1/M2 polarization. XZSWD also inhibited the SPP1-CD44 axis and downstream SRC/FAK/β-Catenin signaling to reduce renal extracellular matrix (ECM) deposition. In vitro, SPP1 was identified as a critical target mediating these effects. Conclusions XZSWD alleviates HUA-induced renal injury by suppressing macrophage-mediated inflammation via regulation of the SPP1–CD44 axis and SRC/FAK/β-Catenin signaling, highlighting its therapeutic potential for HUA-related renal dysfunction.
研究领域:
民族药理学
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肾脏病学
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免疫学
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信号转导
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植物化学
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分子生物学
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PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Xiaoyu Zhang,Peiwen Li,Jin Zhou,Ziliang Zhang,Huan Wu,Xinyu Shu,Wang Li,Yi Wu,Yu Du,Dongyuan Lü,Shouqin Lü,Ning Li,Mian Long
Liver sinusoidal endothelial cells (LSECs) are highly specific endothelial cells which play an essential role in the maintenance of liver homeostasis . During the progression of liver fibrosis, matrix stiffening promotes LSEC defenestration, however, the underlying mechanotransduction mechanism remains poorly understood. Here, we applied stiffness-tunable hydrogels to assess the matrix stiffening-induced phenotypic changes in primary mouse LSECs. Results indicated that increased stiffness promoted LSEC defenestration through cytoskeletal reorganization. LSECs sensed the increased matrix stiffness via focal adhesion kinase (FAK), leading to the activation of p38-mitogen activated protein kinase activated protein kinase 2 (MK2) pathway, thereby inducing actin remodeling via LIM Kinase 1 (LIMK1) and Cofilin . Interestingly, inhibition of FAK or p38-MK2 pathway was able to effectively restore the fenestrae to a certain degree in LSECs isolated from early to late stages of liver fibrosis mice. Thus, this study highlights the impact of mechanotransduction in LSEC defenestration, and provides novel insights for potential therapeutic interventions for liver fibrosis.
研究领域:
细胞生物学
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肝病学
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力学生物学
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DOI
PubMed
高影响因子
Acta Biomaterialia
·
2024
·
IF 9.4
Shixin Xu,Miaomiao Zhang,Ruoying Wang,Jinxin Zhang,Chengwei Wang,Li Xie,Wen Zhao
Secretomes from mesenchymal stem cells (MSCs) have significant therapeutic potential and could be the basis for future MSCs treatments. Innovative design of the topology of biomaterials, which mechanically regulate cell behavior and function, can tremendously improve the efficacy of stem cell therapy. However, how spatial dimension cues derived from specific topology command cell mechanotransduction to regulate the paracrine function of MSCs remains unknown. In this study, the three-dimensional (3D) fibrous constructs with box-like pores and precise strand spacing from 150 μm down to only 40 μm were manufactured using melt electrowriting (MEW), which were used to systematically investigate the spatial dimension cues-triggered mechanotransduction of adipose-derived mesenchymal stem cells (Ad-MSCs) and their impact on the paracrine and regeneration function of Ad-MSCs. The results demonstrated that spatial instructions from the 3D fibrous constructs could influence the spatial reorganization of the cytoskeleton, resulting in cell elongation and augmented immunomodulatory and angiogenic paracrine effects of Ad-MSCs, which was most pronounced at a minimum strand spacing of 40 μm. Besides, mechanical activation of the FAK-PI3K/AKT axis significantly enhanced the paracrine function of Ad-MSCs. In vivo experiments demonstrated that the Ad-MSCs trained using well-defined 3D fibrous constructs with a strand spacing of 40 μm significantly promoted skin regeneration via paracrine signals. In conclusion, this study provides a new horizon for deciphering space dimension insights into the interactional mechanisms of mechanotransduction in regulating cell function, which has inspired innovations in biomaterials for improving tissue regeneration. Statement of Significance Designing cell-scale spatial dimension cues in engineered constructs potentiates the paracrine and regenerative functions of Ad-MSCs. FAK-PI3K/AKT signaling serves as the key mechanotransduction checkpoints for spatial dimension cues triggering mechanical activation. Paracrine signals of Ad-MSCs triggered by mechanical activation promotes skin repair and regeneration via the immunomodulation and angiogenesis.
研究领域:
组织工程
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干细胞生物学
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生物材料科学
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力学生物学
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再生医学
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PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2020
·Vol. 24
·期 8
·4480-4493
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IF 4.486
Linhao Xu,Yanli Bi,Yizhou Xu,Zhuocheng Zhang,Wenjie Xu,Sisi Zhang,Jian Chen
Small cell lung cancer (SCLC) is a severe malignant with high morbidity; however, few effective and secure therapeutic strategy is used in current clinical practice. Oridonin is a small molecule from the traditional Chinese herb Rabdosia rubescens. This study mainly aimed to investigate the role of oridonin on inhibiting the process of H1688, a kind of small cell lung cancer cells from human. Oridonin could suppress H1688 cell proliferation and induce their apoptosis in a high dosage treatment (20 μmol/L). Meanwhile, cell migration was suppressed by oridonin (5 and 10 μmol/L) that did not affect cell proliferation and apoptosis. The expression level of E-cadherin was significantly increased, and the expression of vimentin, snail and slug was reduced after administration of oridonin. These expression changes were associated with the suppressed integrin β1, phosphorylation of focal adhesion kinase (FAK) and ERK1/2. In addition, oridonin (5 and 10 mg/kg) inhibited tumour growth in a nude mouse model; however, HE staining revealed a certain degree of cytotoxicity in hepatic tissue after treatment oridonin (10 mg/kg). Furthermore, the concentration of alanine aminotransferase (ALP) was significantly increased and lactate dehydrogenase (LDH) was reduced after oridonin treatment (10 mg/kg). Immunohistochemical analysis further revealed that oridonin increased E-cadherin expression and reduced vimentin and phospho-FAK levels in vivo. These findings indicated that oridonin can inhibit the migration and epithelial-to-mesenchymal transition (EMT) of SCLC cells by suppressing the FAK-ERK1/2 signalling pathway. Thus, oridonin may be a new drug candidate to offer an effect of anti-SCLC with relative safety.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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PubMed
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Cell Communication and Signaling
·
2026
·
IF 11.6
Wu Shuaihui,Wang Kunlei,Tayier Dilinigeer,Cheng Zhixiang,Shi Yang,Cheng Qian,Wei Shujian,Li Xinyin,Wei Qifeng,Wang Huibin,Chen Zhinan,Guo Deliang,Xu Pengfei,Jiang Ping,Liao Bo,Yang Zhiyong
Background Liver fibrosis represents a critical stage in the progression of chronic liver diseases toward cirrhosis and hepatocellular carcinoma. However, there are no targeted therapies specifically designed for the treatment of liver fibrosis. This research aims to identify novel targets for anti-hepatic fibrosis and to provide new insights into therapeutic strategies for addressing this condition. Methods Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) analyses were conducted to assess the modulation of UNC5B gene transcription. Co-immunoprecipitation experiments were performed to investigate the interactions between UNC5B and Src homology phosphotyrosyl phosphatase 2 (SHP2) or Focal adhesion kinase (FAK) proteins. Virtual screening was utilized to identify small-molecule inhibitors of UNC5B. The in vivo effects of Unc5b knockdown in liver fibrosis mouse models were evaluated using an Unc5b inhibitor (D359-0264) and an adeno-associated virus vector of serotype 6 (AAV6) containing short hairpin RNA targeting Unc5b. Results This study demonstrates that the pro-fibrotic pathway TGF-β1/SMAD3 transcriptionally regulates UNC5B expression. Unc5b expression was significantly upregulated in liver fibrosis mouse models. Knocking down Unc5b resulted in reduced hepatocyte damage and decreased fibrosis in these models. Additionally, UNC5B was shown to interact with the PTP domain of SHP2 and the Y397 site of FAK, indicating that UNC5B competitively binds to the Y397 site of FAK, thereby inhibiting FAK dephosphorylation by SHP2 and promoting liver fibrosis. Conclusion This study identifies a novel regulatory axis in liver fibrosis models involving UNC5B, which is regulated by the TGF-β/SMAD signaling pathway. UNC5B facilitates liver fibrosis by competitively binding to the Y397 site of FAK with SHP2, thus enhancing its phosphorylation and activating FAK. Furthermore, the UNC5B inhibitor has demonstrated the therapeutic potential of targeting this molecule for the treatment of liver fibrosis.
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高影响因子
Translational Research
·
2026
·
IF 6.1
Lu Han,Guo-Yuan Lin,Shao-Jie Chen,Qing-Xiu Zhang,Hua-Yue Wu,Tao Huang,Fan Lu,Hong-Fei Pu,Jing-Lin Wang,Tao Ran,Gao-Liang Zou,Jian-Chao Li,Ya Zhang,Xue-Ke Zhao
Liver fibrosis is marked by hepatic stellate cell (HSC) activation and increased glucose consumption. Focal adhesion kinase (FAK) upregulates c-Myc expression in HSCs, promoting aerobic glycolysis. This study explores how FAK promotes HSC activation and glycolysis via TRIM25. Immunohistochemistry (IHC) and Western blotting assessed the expression of FAK, TRIM25, FBXW7, c-Myc, and glycolysis-related proteins in human liver tissues and mouse models. Protein interactions were identified by co-immunoprecipitation (Co-IP) and LC-MS, and FAK and TRIM25 localization was observed by immunofluorescence. FAK inhibition reduced LX-2 cell activation, migration, and glycolysis. Co-IP and immunofluorescence confirmed FAK-TRIM25 interaction. FAK inhibits FBXW7-mediated c-Myc ubiquitination and enhances glycolysis by binding TRIM25’s RING, B-BOX, and SPRY regions. Inhibition of FAK improved liver fibrosis and glycolysis. FAK promotes HSC glycolysis through TRIM25 interaction, and its inhibition mitigates liver fibrosis, suggesting a potential therapeutic target.
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DOI
PubMed
高影响因子
Clinical & Translational Oncology
·
2023
·Vol. 25
·期 6
·1629-1640
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IF 3.4
Zhang Yi-Dan,Zhong Rui,Liu Jin-Quan,Sun Zhen-Xuan,Wang Teng,Liu Jin-Tao
Purpose Breast cancer is one of the leading causes of tumor death worldwide in female, and the five-year overall survival of breast cancer patients remains poor. It is an urgent need to seek novel target for its treatment. Synaptotagmin 13 (SYT13) is a synaptic vesicle transporting protein that regulates the malignant phenotypes of various cancers. However, its role in breast cancer is still unclear. The current study aimed to investigate the effects of SYT13 on the progression of breast cancer. Methods Twenty-five pairs of breast cancer tissues and non-tumor tissues were obtained to assess the expression of SYT13. We manually modified the expression of SYT13 in MCF-7 and MDA-MB-231 cells. CCK-8 assay, EdU staining, and cell cycle analysis were carried out to measure the proliferated ability of cells. Annexin V/PI and TUNEL assays were used to detect the apoptotic ability of cells. Wound healing and transwell assays were employed to evaluate the migrated and invasive ability of breast cancer cells. Results The results revealed that the mRNA and protein levels of SYT13 were higher in breast cancer tissues and cell lines. Knockdown of SYT13 inhibited the cell proliferation and induced cell cycle arrest in G1 phase of MCF-7 cells by downregulating cyclin D1 and CDK4, as well as upregulating p21. The migration and invasion of MCF-7 cells were repressed by the loss of SYT13 via the gain of E-cadherin and the loss of vimentin. Overexpression of SYT13 in MDA-MB-231 cells led to the opposite effects. Silencing of SYT13 induced the apoptosis ability of MCF-7 cells by the upregulation of bax and the downregulation of bcl-2. Moreover, we found that SYT13 depletion suppressed the FAK/AKT signaling pathway. PF573228 (a FAK inhibitor) and MK2206 (an AKT inhibitor) reversed the SYT13 overexpression-induced promotion of proliferation, migration, and invasion of MDA-MB-231 cells. Conclusion The results indicated that SYT13 promoted the malignant phenotypes of breast cancer cells by the activation of FAK/AKT signaling pathway.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症生物学
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 5.9
Lidong Gong,Zichao Liang,Xianling Ning,Jianan He,Junjie Huang,Runtao Li,Yuxin Yin,Ridong Li,Zhiqiang Lin
A series of novel 2,4-diarylaminopyrimidine derivatives incorporating a 3-sulfamoylbenzamide moiety were designed and synthesized as potent focal adhesion kinase (FAK) inhibitors. Three compounds ( 5f, 10b , and 10c ) demonstrated FAK inhibitory activities comparable to the reference inhibitor TAE226 . In cellular assays, most analogues exhibited significant antiproliferative effects against four FAK-overexpressing tumor cell lines (HCT116, HeLa, MDA-MB-231, and A375), with IC 50 values below 1 μM. Notably, compound 10c displayed superior potency, showing IC 50 values ranging from 0.08 to 0.31 μM across the tested cell lines, and exhibited approximately 2-fold enhanced activity over TAE226 in inhibiting HCT116, MDA-MB-231, and A375 cell proliferation. Further mechanistic studies revealed that 10c effectively suppressed colony formation, migration, and adhesion of HCT116 cells, while inducing apoptosis via ROS elevation. Molecular docking analysis suggested that the enhanced activity of 10c may arise from an additional hydrogen bond interaction with the Arg426 residue of FAK, leading to stronger binding affinity compared to TAE226 . In vivo , 10c showed good oral bioavailability and significantly inhibited HCT116 xenograft tumor growth (TGI = 62.22 % at 50 mg/kg), outperforming TAE226 (50.98 %) without inducing weight loss or hepatorenal toxicity. These results highlight 10c as a promising FAK-targeted candidate worthy of further preclinical investigation.
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Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 31
·6912-6924
·
IF 5.344
Lei Liu,Xianling Gao,Xiaoyu Li,Guanglin Zhu,Nanying Li,Xuetao Shi,Yingjun Wang
Bioceramic–biopolymer composites have been used extensively as bone tissue engineering scaffolds due to their bioactive properties. However, composite scaffolds are insufficient in inducing osteogenic differentiation of stem cells. In this study, a strategy for the local delivery of bioactive factors by coating calcium alendronate (ALC) on the surface of composite scaffolds was systematically evaluated for the first time. The coated ALC not only displayed excellent cytocompatibility and cell adhesion properties but also resulted in the significant upregulation of osteogenic related gene expression, osteogenic related protein levels, alkaline phosphatase (ALP) activity and calcium deposition of ADSCs. Furthermore, our results suggested that the molecular mechanism of ADSC osteogenic differentiation induced by the constructed ALC may be related to the integrin binding and the activation of FAK/ERK signalling pathways. These findings suggested that ALC-coated composite scaffolds can serve as bone tissue engineering scaffolds, providing a simple and universal method to improve the osteogenic differentiation of ADSCs by calcium phosphate-containing composite materials.
研究领域:
组织工程
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生物材料
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干细胞生物学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2019
·
IF 8.456
Fei Jia,Suya Lin,Xuzhao He,Jiamin Zhang,Shuxian Shen,Zhiying Wang,Bolin Tang,Cheng Li,Yongjun Wu,Lingqing Dong,Kui Cheng,Wenjian Weng
The surface electric potential of biomaterials has been extensively proven to play a critical role in stem cells’ fate. However, there are ambiguous reports on the relation of stem cells’ osteogenic capacity to surface potential characteristics (potential polarity and intensity). To address this, we adopted a surface with a wide potential range and both positive/negative polarity in a comprehensive view to get insight into surface potential-regulating cellular osteogenic differentiation. TbxDy1–xFe2 alloy/poly(vinylidene fluoride-trifluoroethylene) magnetoelectric films were prepared, and the film could provide controllable surface potential characteristics with positive or negative polarity and potential (ϕME) intensity variation from 0 to ±120 mV as well as keep the surface chemical composition and microstructure unchanged. Cell culture results showed that osteogenic differentiation of mesenchymal stem cells on both positive and negative potential films was obviously upregulated when the /ϕME/ intensities were set from 0–55 mV. Differently, the highest upregulated osteogenic differentiation on the positive potential films corresponded to the /ϕME/ intensity from 35–55 mV and was better than that on the negative potential films whereas the highest on the negative potential films corresponded to the /ϕME/ intensity from 0–35 mV and was better than that on the positive potential films. This fact could illustrate why previous reports appeared ambiguously; i.e., the comparative result in osteogenic differentiation between the positive and negative potential films strongly depends on the selection of surface potential intensity. On the basis of assaying of the exposed functional sites (RGD and PHSRN) of the adsorbed fibronectin (FN) and the expression of cellular integrin α5 and β1 subunits, the difference in the behavior between the positive and negative potential films was attributed to the distinct conformation of adsorbed fibronectin (FN) and the opposite changing trend with /ϕME/ for the two films, which triggers the osteogenesis-related FAK/ERK signaling pathway to a different extent. This study could provide new cognition for the in-depth understanding of the regulation mechanism underlying surface potential characteristics in cell behaviors.
研究领域:
生物材料学
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细胞生物学
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组织工程学
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PubMed
高影响因子
Autophagy
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2026
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IF 18.6
Ming-Yue Wu,Wan Tang,Xiao-Wen Zhang,Meng-Ni Zhang,He-Dan Xu,Si-Rui Yu,Yue Cheng,Ling Li,Ying Chen,Sen Liang,Qiong Pan,Jia-Hong Lu,Jin Chai
Macroautophagy/autophagy represents a promising therapeutic target in oncology, exhibiting context-dependent roles in tumor progression. Kinase inhibitors are a large group of anti-cancer drugs, and elucidating the regulatory effects of different kinase inhibitors on autophagy offers a valuable strategy to advance our understanding of autophagy regulation in cancer and develop innovative anti-cancer therapies. In this study, we developed a drug screening platform and performed high-content screening using a kinase inhibitor library. The screening identified PTK2/FAK (protein tyrosine kinase 2) inhibitors as potent autophagy inducers. Mechanistic investigations revealed that PTK2/FAK inhibition triggers rapid autophagy flux through a non-classical mechanism dependent on PTK2/FAK expression, which is associated with the spatial redistribution of ER exit sites (ERES). Further analysis demonstrated that PTK2/FAK inhibitor (FAKi)-induced ERES-associated autophagy is not contingent upon full PREB/SEC12 and SEC16 expression, but is sensitized to TMED9 expression level. Additionally, we identified AKAP13 as a novel FAKi-responsive protein that undergoes dephosphorylation upon FAKi treatment and contributes to TMED9-mediated ERES-associated autophagy. Given that ERES-associated autophagy is initiated through membrane contact between ERES and the ER-Golgi intermediate compartment (ERGIC), we further observed enhanced TMED9-ERGIC interactions following FAKi treatment. Furthermore, functional studies confirmed that FAKi-induced autophagy promotes pancreatic ductal adenocarcinoma (PDAC) cell survival both in vitro and in vivo. Collectively, our work unveils a previously unrecognized mechanism of FAKi-mediated autophagy induction and provides new insights for developing targeted therapies against PDAC.
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PubMed
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2026
·Vol. 27
·期 3
·1228
·
IF 4.9
Ruifang Guo,Yihang Wang,Aiwen Zhang,Siwanon Jirawatnotai,Chen Chu,Lijun Liu
Beyond their canonical role in promoting G1/S progression, the complexes formed by cyclin D and cyclin-dependent kinase (CDK) 4/6 have emerged as contributors to enhanced cell migration. However, a direct link between this complex and cytoskeletal remodeling during cell motility has remained poorly understood. Here, we show that CDK4/6 inhibition in HeLa cells disrupts lamellipodia formation and subsequent focal adhesion assembly, leading to a reduction in cell migration and invasion. Notably, CDK4, but not CDK6, in complex with cyclin D1/D2, localizes to membrane ruffles to facilitate cytoskeletal reorganization. Mechanistically, proteomic and phosphoproteomic analyses revealed that CDK4 inhibition attenuates the transforming growth factor β (TGFβ) pathway via reduced Smad3 phosphorylation at Thr8, downregulating integrin subunits (α5, α6, and β1). Furthermore, CDK4 inhibition significantly decreased focal adhesion kinase (FAK) phosphorylation at Tyr397 and Rac1-GTP levels. Importantly, the resulting migration defect was largely restored by activation of either Rac1 or FAK. Thus, our data support a model in which cyclin D1/D2–CDK4 promotes phosphorylation of Smad3, leading to upregulation of integrin subunits, activation of FAK and Rac1, and consequent lamellipodia formation and cell migration. These findings provide direct evidence that CDK4 regulates actin cytoskeletal reorganization during cell migration and suggest that CDK4/6 inhibitors may dampen cytoskeleton-dependent tumor invasion, in addition to their antiproliferative effects.
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