Frontiers in Medicine
·
2024
·
IF 3.1
Liu Yan,Ge Ri-Li,Shan Zhen-Zhen,Wang Yan-Jun,Yang Yan-Yan,Sun Xue,Luo Peng-Li
Podocytopathies encompass kidney diseases where direct or indirect podocyte injury leads to proteinuria or nephrotic syndrome. Although Semaphorin3A (Sema3A) is expressed in podocytes and tubular cells in adult mammalian kidneys and has a common effect on the progression of podocyte injury, its mechanism remains unclear. Previous studies have shown increased Sema3A expression in various glomerulopathies, indicating a gap in understanding its role. In this study, analysis of human data revealed a positive correlation between the levels of urinary Sema3A and Podocalyxin (PCX), suggesting a close relationship between Sema3A and podocyte loss. Furthermore, the impact of Adriamycin on podocytes was investigated. Adriamycin induced podocyte migration and apoptosis, along with an increase in Sema3A expression, all of which were ameliorated by the inhibition of Sema3A. Importantly, TRPC5 was found to increase the overexpression of Sema3A in podocytes. A TRPC5 inhibitor, AC1903, alleviated podocyte migration and apoptosis, inhibiting the formation of lamellar pseudopodia in the podocyte cytoskeleton by lowering the expression of Rac1. Furthermore, AC1903 relieved massive albuminuria and foot process effacement in the kidneys of Adriamycin-treated mice in vivo. In conclusion, our findings suggest that Sema3A may impact the cytoskeletal stability of podocytes through TRPC5 ion channels, mediated by Rac1, ultimately leading to foot process effacement. Notably, AC1903 demonstrates the potential to reverse Adriamycin-induced foot process fusion and urine protein. These results contribute to a deeper understanding of the mechanisms involved in podocytopathies and highlight the therapeutic potential of targeting the Sema3A-TRPC5 pathway.
研究领域:
肾脏病学
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分子生物学
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DOI
PubMed
高影响因子
Communications Biology
·
2023
·Vol. 6
·期 1
·1-14
·
IF 5.9
Zhu Haixia,Wen Zongzhuang,Zhang Aizhen,Liu Dongyue,Wang Hongxiang,Cheng Yin,Yang Xing,Xiao Yu,Li Jianyuan,Sun Daqing,Wu Bin,Gao Jiangang
Spermatogenesis is an extremely complex process, and any obstruction can cause male infertility. RhoGDIα has been identified as a risk of male sterility. In this study, we generate RhoGDIα knockout mice, and find that the males have severely low fertility. The testes from RhoGDIα −/− mice are smaller than that in WT mice. The numbers of spermatogonia and spermatocytes are decreased in RhoGDIα −/− testis. Spermatogenesis is compromised, and spermatocyte meiosis is arrested at zygotene stage in RhoGDIα −/− mice. Acrosome dysplasia is also observed in sperms of the mutant mice. At the molecular level, RhoGDIα deficiency activate the LIMK/cofilin signaling pathway, inhibiting F-actin depolymerization, impairing testis and inducing low fertility in mouse. In addition, the treatment of RhoGDIα −/− mice with Rac1 inhibitor NSC23766 alleviate testis injury and improve sperm quality by inhibiting the LIMK/cofilin/F-actin pathway during spermatogenesis. Together, these findings reveal a previously unrecognized RhoGDIα/Rac1/F-actin-dependent mechanism involved in spermatogenesis and male fertility.
研究领域:
生殖生物学
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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
JOURNAL OF MOLECULAR MEDICINE-JMM
·
2023
·
IF 4.7
Chen Yinghui,Wu Yizhuo,Feng Weiqi,Luo Xueyang,Xiao Bing,Ding Xiaowei,Gu Yongjia,Lu Yanan,Yu Yu
Abstract The ductus arteriosus (DA), bridging the aorta and pulmonary artery, immediately starts closing after birth. Remodeling of DA leads to anatomic obstruction to prevent repatency. Several histological changes, especially extracellular matrices (ECMs) deposition and smooth muscle cells (SMCs) migration bring to anatomic closure. The genetic etiology and mechanism of DA closure remain elusive. We have previously reported a novel copy number variant containing Vav2 in patent ductus arteriosus (PDA) patients, but its specific role in DA closure remains unknown. The present study revealed that the expression of Vav2 was reduced in human patent DA, and it was less enrichment in the adjacent aorta. Matrigel experiments demonstrated that Vav2 could promote SMC migration from PDA patient explants. Smooth muscle cells with Vav2 overexpression also presented an increased capacity in migration and downregulated contractile-related proteins. Meanwhile, SMCs with Vav2 overexpression exhibited higher expression of collagen III and lessened protein abundance of lysyl oxidase, and both changes are beneficial to DA remodeling. Overexpression of Vav2 resulted in increased activity of Rac1, Cdc42, and RhoA in SMCs. Further investigation noteworthily found that the above alterations caused by Vav2 overexpression were particularly reversed by Rac1 inhibitor. A heterozygous, rare Vav2 variant was identified in PDA patients. Compared with the wild type, this variant attenuated Vav2 protein expression and weakened the activation of downstream Rac1, further impairing its functions in SMCs. In conclusion, Vav2 functions as an activator for Rac1 in SMCs to promote SMCs migration, dedifferentiation, and ECMs production. Deleterious variant potentially induces Vav2 loss of function, further providing possible molecular mechanisms about Vav2 in PDA pathogenesis. These findings enriched the current genetic etiology of PDA, which may provide a novel target for prenatal diagnosis and treatment. Key messages
Although we have proposed the potential association between Vav2 and PDA incidence through whole exome sequencing, the molecular mechanisms underlying Vav2 in PDA have never been reported. This work, for the first time, demonstrated that Vav2 was exclusively expressed in closed DAs.
Moreover, we found that Vav2 participated in the process of anatomic closure by mediating SMCs migration, dedifferentiation, and ECMs deposition through Rac1 activation.
Our findings first identified a deleterious Vav2 c.701C>T variant that affected its function in SMCs by impairing Rac1 activation, which may lead to PDA defect. Vav2 may become an early diagnosis and an effective intervention target for PDA clinical therapy.
研究领域:
心血管生物学
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遗传学
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分子生物学
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发育生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 3.8
Chuanfu Huo,Yuanyuan Zhao,Meng Song,Yuzhe Guo,Shihao Li,Wensong Tan,Yan Zhou
Exosomes are nanoscale vesicles containing a variety of bioactive factors, showing significant potential as cell-free therapeutic agents. However, the large clinical doses required for exosome administration highlight the need for a scalable serum-free production system to increase exosome yield. In this study, human umbilical cord-derived mesenchymal stem cells (hUCMSCs) were cultured in three-dimensional (3D) environments using polyethylene terephthalate (PET) fiber membranes. Two key pathways promoting exosome secretion and biogenesis through 3D culture were identified. Specifically, 3D culture reduced the expression of Integrin β1, leading to the decondensation of cortical actin, and increased the expression of RAC1, which promoted actin aggregation on the membranes of multivesicular bodies (MVBs). Building on this mechanistic understanding, we simulated the depolymerization/aggregation of the cytoskeleton in 3D culture and designed a serum-free medium optimized for exosome production. For large-scale exosome production, hUCMSCs were cultured in a fixed-bed bioreactor using PET fiber rolls as the fixed-bed layer with the developed serum-free medium. This setup increased exosome production per cell by 16-fold compared to 2D culture, yielding 2.6 × 10^14 exosome particles. The exosome products demonstrated enhanced in vitro angiogenesis, immunomodulation, and in vivo wound healing capabilities. This study provides valuable insights and strategic guidance for the serum-free, large-scale production of exosomes using bioreactors, with significant implications for therapeutic applications.
研究领域:
细胞生物学
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再生医学
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生物工程
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高影响因子
Cell Communication and Signaling
·
2023
·Vol. 21
·期 1
·1-18
·
IF 8.4
Liao Zhaohong,Lan Haiqiang,Jian Xiaoting,Huang Jingwen,Wang Han,Hu Jijie,Liao Hua
Background To explore the role of skeletal muscle specific TGF-β signaling on macrophages efferocytosis in inflamed muscle caused by Cardiotoxin (CTX) injection. Methods CTX myoinjury was manipulated in TGF-βr2 flox/flox (control) mice or transgenic mice with TGF-β receptor 2 (TGF-βr2) being specifically deleted in skeletal muscle (SM TGF-βr2 −/− ). Gene levels of TGF-β signal molecules, special inflammatory mediators in damaged muscle or in cultured and differentiated myogenic precursor cells (MPC-myotubes) were monitored by transcriptome microarray or qRT-PCR. TGF-β pathway molecules, myokines and embryonic myosin heavy chain in regenerating myofibers, the phenotype and efferocytosis of macrophages were evaluated by immunofluorescence, immunoblotting, Luminex, or FACS analysis. In vitro apoptotic cells were prepared by UV-irradiation. Results In control mice, TGF-β-Smad2/3 signaling were significantly up-regulated in regenerating centronuclear myofibers after CTX-myoinjury. More severe muscle inflammation was caused by the deficiency of muscle TGF-β signaling, with the increased number of M1, but the decreased number of M2 macrophages. Notably, the deficiency of TGF-β signaling in myofibers dramatically affected on the ability of macrophages to conduct efferocytosis, marked by the decreased number of Annexin-V − F4/80 + Tunel + macrophages in inflamed muscle, and the impaired uptake of macrophages to PKH67 + apoptotic cells transferred into damaged muscle. Further, our study suggested that, the intrinsic TGF-β signaling directed IL-10-Vav1-Rac1 efferocytosis signaling in muscle macrophages. Conclusions Our data demonstrate that muscle inflammation can be suppressed potentially by activating the intrinsic TGF-β signaling in myofibers to promote IL-10 dependent-macrophages efferocytosis.
Video Abstract
研究领域:
免疫学
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肌肉生物学
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细胞信号传导
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炎症
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DOI
PubMed
高影响因子
RARE METALS
·
2024
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IF 9.6
Zhou Xiao-He,Mo Min-Hua,Chen Zi-Wei,Liu Wen-Jing,Zhang Yan-Li,Pathak Janak L.,Wang Li-Jing,Liu Chang,Shao Long-Quan,Chen Liang-Jiao
Promotion of angiogenesis is crucial for bone tissue repair, and the poor activity of angiogenic cells and growth factors is the main problem in angiogenesis. New proangiogenic nanomaterials are urgently needed to be a promising strategy for this issue. Nb promotes bone formation and fracture healing, possibly by increasing vascular endothelial growth factor (VEGF) production. Nanoniobium particles (nNb) may promote angiogenesis. However, the effect of nNb on angiogenesis is unclear, limiting its application. This study confirmed that nNb significantly promoted angiogenesis. nNb increased and Ras-related C3 botulinum toxin substrate (Rac) family small guanosine triphosphatase (GTPase) 1 (Rac1) expression, inducing F-actin aggregation at the front edge of cells and the formation of pseudopodia to mediate cell migration, further promoting angiogenesis. We discovered that cyclin-dependent kinase-like 5 (CDKL5) is a new signaling molecule that activates Rac1. V-ets erythroblastosis virus E26 oncogene homolog (ETS) domain-containing protein (ELK1), regulating CDKL5 and Rac1, plays an upstream regulatory role. When ELK1 was inhibited, CDKL5 and Rac1 levels were decreased. ELK1, CDKL5 or Rac1 are effective regulatory targets of angiogenesis. Inhibiting expression of ELK1, CDKL5 or Rac1 decreased angiogenesis. Thus, nNb has good angiogenic effects. The ELK1-CDKL5-Rac1 signaling pathway regulates the migration of endothelial cells to promote angiogenesis. nNb can be used in bone tissue engineering as a new nanomaterial, and it will promote the development of a new strategy for tissue engineering. Graphical abstract
研究领域:
材料科学
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生物医学工程
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细胞生物学
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组织工程
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DOI
高影响因子
Human Cell
·
2024
·
IF 3.4
Guo Xiaoli,Cao Yijuan,He Qing,Chen Linna,Wang Qing,Zhang Jingbo,Lv Wenqiang,Zhang Bei,Zhou Xueyan
Polycystic ovary syndrome (PCOS) is a complex gynaecological endocrine disease that occurs in women of childbearing age. The pathogenesis of PCOS is still unclear and further exploration is needed. Here, proteomic analysis indicated that the expression of farnesyl diphosphate synthase (FDPS) protein in ovarian tissue of PCOS mice was significantly decreased. The purpose of this study is to investigate the relationship between potential biomarkers of PCOS and granulosa cells (GCs) function. The mechanisms by which FDPS affected the proliferation of granulosa cells were also explored both in vitro and in vivo. We found that knockdown of FDPS inhibited the proliferation of KGN (human ovarian granulosa cell line), while overexpression of FDPS had the opposite effect. FDPS activated Rac1 (Rac Family Small GTPase 1) activity and regulated MAPK/ERK signalling pathway, which affecting the proliferation of KGN cells significantly. In addition, treatment with the adeno-associated virus (AAV)-FDPS reverses the dehydroepiandrosterone (DHEA)-induced PCOS-phenotype in mice. Our data indicated that FDPS could regulate the proliferation of ovarian GCs by modulating MAPK/ERK (mitogen-activated protein kinase/extracellular regulated protein kinases) pathway via activating Rac1 activity. These findings suggest that FDPS could be of great value for the regulation of ovarian granulosa cell function and the treatment of PCOS.
研究领域:
妇科学
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内分泌学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Chinese Herbal Medicines
·
2024
·
IF 4.7
Xin Wu,Cuiwei Chen,Hongyan Zhang,Keda Lu,Gang Cao
Objective This study is mainly to elucidate the characteristic components, hepatoprotective effect, and the underlying anti-hepatic fibrosis molecular mechanism of the total flavonoids of Tetrastigma hemsleyanum Diels & Gilg (SYQTF). Methods The components of SYQTF were confirmed based on global natural products social molecular networking (GNPS) as well as the hepatoprotective effect on CCl 4 -induced acute liver injury. Cell toxicity and viability, cell cycle, and apoptosis analyses were then performed to determine the effects of SYQTF in transforming growth factor-β1 (TGF-β1) (10 ng/mL)-induced HSC-T6 hepatic fibrosis cell model. Finally, the lentiviral particles to package recombinant Ras-related C3 botulinum toxin substrate 1 (Rac1) over-expression and Rac1 knockdown plasmids were transfected into TGF-β1-induced HSC-T6 cells to elucidate the mechanism of anti-hepatic fibrosis of SYQTF targeting Rac1, respectively. Results Our findings demonstrated that 86 components in SYQTF were identified in MS E and FastDDA mode with the aid of GNPS. Moreover, S 15 -ZJ, the genuine functional food and medicinal materials of T. hemsleyanum , was significantly different from other regions by multivariate statistical methods based on progenesis QI. Remarkably, kaempferol-3- O -furananose7- O -rhamnosyl-glucoside, the highest response intensity in S 15 -ZJ, may act as the potential Q-marker of genuine functional food and medicinal materials of T. hemsleyanum in Zhejiang Province distinguished from other areas. In addition, the in vivo experiments revealed that SYQTF greatly alleviated CCl 4 -induced acute liver injury. Furthermore, SYQTF can reversible the activation and proliferation of HSC-T6 cells, block the cell cycle in the G 0 /G 1 phase, and promote cell apoptosis. Remarkably, the study is the first to reveal that SYQTF exhibited the anti-hepatic fibrosis effect through targeting Rac1 in the hedgehog signaling pathway. Conclusion Rac1 is an important signaling molecule for the activation of the hedgehog pathway in HSC-T6. Importantly, SYQTF exerted its anti-hepatic fibrosis effect by inhibiting the Rac1-hedgehog signaling pathway. Furthermore, kaempferol-3- O -furananose7- O -rhamnosyl-glucoside could be a potential Q-marker of T. hemsleyanum in Zhejiang Province distinguished from other areas.
研究领域:
药理学
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分子生物学
·
肝病学
·
天然产物化学
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DOI
高影响因子
Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-11
·
IF 7
Mao Jianyu,Lu Jiajia,Wang Sheng,Jiang Xin,Li Jing,Fu Qiang,Lu Nan,Zhu Lei,Chen Aimin,Ma Jun
Pyroptosis, a form of lytic and inflammatory programmed cell death mediated by gasdermin proteins, contributes to progressive spinal cord neurodegeneration following neural trauma. Nevertheless, the regulatory mechanisms governing this process remain inadequately characterized. In this investigation, hydrogen sulfide (H₂S) was identified as an endogenous inhibitor of neuronal pyroptosis, functioning through Rac1-dependent NLRP3 inflammasome signaling. In a rat model of lumbosacral plexus nerve injury, H₂S treatment significantly decreased pyroptosis-associated markers (NLRP3, caspase-1, GSDMD) and enhanced neuronal survival. In vitro, the administration of H₂S effectively mitigated hypoxia-induced neuronal pyroptosis by inhibiting the assembly of the NLRP3 inflammasome. Mechanistically, our findings indicate that H₂S selectively persulfidates Rac1, inhibiting its GTPase activity and reducing reactive oxygen species (ROS) production, both of which are critical for inflammasome priming. Molecular dynamics simulations and site-directed mutagenesis further confirmed that H₂S persulfidation of Rac1 at Cys178 alters its conformation, thereby suppressing NLRP3 inflammasome activation. Taken together, our findings reveal a novel post-translational regulatory mechanism by which H₂S mitigates pyroptotic neuronal death through Rac1 persulfidation, highlighting the H₂S-Rac1 axis as a promising therapeutic target for neuroprotection in pyroptosis-related neurodegeneration.
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DOI
PubMed
高影响因子
MEDICAL SCIENCE MONITOR
·
2019
·
IF 1.98
Guomin Li,Lirong Zeng,Haiyan Cheng,Jingxian Han,Xuezhu Zhang,Hui Xie
Background Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder. This study aimed to investigate effects of acupuncture administration on cognitive function and associated mechanisms. Material/Methods Senescence-accelerated prone 8 (SAM-P8) mice were randomly divided into 3 groups: the SAM-P8 group (P8-CN), the SAM-P8 administrating with acupuncture (P8-Acup) group, and the SAM-P8 administrating without acupuncture (P8-Sham) group. Morris water maze test was conducted to evaluate cognitive functions (memory and learning ability). PDK1, nPKC, and Rac1 inhibitors were used to treat SAM-P8 mice. Transmission electron microscope analysis was used to examine nuclear damage hippocampal tissues. Hematoxylin and eosin (H&E) staining was employed to evaluate inflammation. Western blot was used to detect PI3K, PDK1, nPKC, and Rac 1 expression in hippocampal tissues. Results Acupuncture administration significantly reduced PI3K, PDK1, nPKC, and Rac 1 levels compared to P8-CN group ( P <0.05). Both acupuncture and enzyme inhibitors (NSC23766, Rottlerin, {"type":"entrez-protein","attrs":{"text":"OSU03012","term_id":"1188654652","term_text":"OSU03012"}} OSU03012 ) significantly improved cognitive functions, reduced inflammation, and alleviated nuclear damages of SAM-P8 mice compared to P8-CN group ( P <0.05). Acupuncture significantly enhanced effects of inhibitors on inflammation and nuclear damages compared to inhibitor treatment single ( P <0.05). Acupuncture significantly enhanced down-regulative effects of {"type":"entrez-protein","attrs":{"text":"OSU03012","term_id":"1188654652","term_text":"OSU03012"}} OSU03012 on PI3K and PDK1 levels, increased down-regulative effects of Rottlerin on nPKC and Rac 1 levels and enhanced effects of Rottlerin on Rac 1 compared to P8-CN group ( P <0.05). Conclusions Acupuncture administration improved cognitive functions and alleviated inflammatory response and nuclear damage of SAM-P8 mice, by downregulating PI3K/PDK1/nPKC/Rac 1 signaling pathway. This study could provide potential insight for treating cognitive dysfunction and aging of AD patients.
研究领域:
神经生物学
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老年医学
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中医药学
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DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2018
·
IF 3.487
Zhengying Su,Zhaoquan Li,Chunmiao Wang,Wei Tian,Fu Lan,Dandan Liang,Junying Li,Danrong Li,Huaxin Hou
Radiation resistance and recurrent have become the major factors resulting in poor prognosis in the clinical treatment of patients with nasopharyngeal carcinoma (NPC). New strategies to enhance the efficacy of radiotherapy have been focused on the development of radiosensitizers and searching for directly targets that modulated tumor radiosensitivity. A novel potential radiosensitizer 1,8-Dihydroxy −3-(2′-(4″-methylpiperazin-1″-yl) ethyl-9,10-anthraquinone −3-carboxylate (RP-4) was designed and synthesized based on molecular docking technology, which was expected to regulate the radiosensitivity of tumor cells through targeting Rac1. In order to assess the radiosensitization activity of RP-4 on NPC cells, the highly differentiated CNE1 and poorly differentiated CNE2 cells NPC lines were employed. According to the results, RP-4 showed higher binding affinity toward the interaction with Rac1 than lead compounds. We found that RP-4 could inhibit cell viability and proliferation in CNE1 and CNE2 cells and significantly induced apoptosis after non-toxic concentration of RP-4 combined with 2Gy irradiation. RP-4 could effectively modulated the radiosensitivity both CNE1 cells and CNE2 cells through activating Rac1/NADPH signaling pathway and its downstream JNK/AP-1 pathway. What's more, Rac1/NADPH signaling pathway were significantly activated in Rac1-overexpressed CNE1 and CNE2 cells after treated with RP-4. Taken together, Rac1 and its downstream pathway may probably be the direct targets of RP-4 in regulating radiosensitivity of NPC cells, our finding provided a novel strategy for the development of therapeutic agents in response to tumorous radiation resistance.
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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放射生物学
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DOI
PubMed
高影响因子
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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高影响因子
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