JOURNAL OF PATHOLOGY
·
2019
·Vol. 249
·期 4
·461-471
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IF 5.942
Zehua Li,Ji Wu,Xiuli Zhang,Caiwen Ou,Xinglong Zhong,Yanting Chen,Lihe Lu,Hailin Liu,Yining Li,Xiaoyu Liu,Bo Wu,Yuxi Wang,Pingzhen Yang,Jianyun Yan,Minsheng Chen
Vascular calcification is prevalent in patients with chronic kidney disease (CKD) and a major risk factor of cardiovascular disease. Vascular calcification is now recognised as a biological process similar to bone formation involving osteogenic differentiation of vascular smooth muscle cells (VSMCs). Cell division cycle 42 (CDC42), a Rac1 family member GTPase, is essential for cartilage development during endochondral bone formation. However, whether CDC42 affects osteogenic differentiation of VSMCs and vascular calcification remains unknown. In the present study, we observed a significant increase in the expression of CDC42 both in rat VSMCs and in calcified arteries during vascular calcification. Alizarin red staining and calcium content assay revealed that adenovirus-mediated CDC42 overexpression led to an apparent VSMC calcification in the presence of calcifying medium, accompanied with up-regulation of bone-related molecules including RUNX2 and BMP2. By contrast, inhibition of CDC42 by ML141 significantly blocked calcification of VSMCs in vitro and aortic rings ex vivo . Moreover, ML141 markedly attenuated vascular calcification in rats with CKD. Furthermore, pharmacological inhibition of AKT signal was shown to block CDC42-induced VSMC calcification. These findings demonstrate for the first time that CDC42 contributes to vascular calcification through a mechanism involving AKT signalling; this uncovered a new function of CDC42 in regulating vascular calcification. This may provide a potential therapeutic target for the treatment of vascular calcification in the context of CKD. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
研究领域:
心血管疾病
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肾病学
·
细胞生物学
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DOI
PubMed
高影响因子
EMBO REPORTS
·
2025
·
IF 6.2
Shuzhi Cui,Wei Gao,Yuxin Chen,Yi Xu,Zhifang Li,Yu Wei,Yaming Jiu
CDC42 is a member of Rho GTPase family that regulates various biological processes and its activity can be hijacked by invading pathogens. Here, we discovered that the level of active CDC42 in hepatocytes positively correlates with the entry capacity of hepatitis B virus (HBV). Mechanistically, CDC42 activation effectively promotes the transport of the viral receptor sodium taurocholate co-transporting polypeptide (NTCP) to the plasma membrane via Rab11 dependent recycling endosomal pathway. NTCP interacts with Rab11 and activation of CDC42 signaling reinforces the interaction between NTCP and Rab11. We further show that clathrin mediated endocytosis (CME), the known HBV entry pathway, is independent of CDC42 activity. Intriguingly, we reveal that CDC42 dependent macropinocytosis is a route for HBV entry, which is equally essential for viral infection as CME. Together, our findings uncover new mechanisms for HBV entry that involve unrecognized functions of CDC42 and suggest that Rho GTPase signaling might represent a potential target for antiviral therapy.
研究领域:
病毒学
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分子生物学
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细胞生物学
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感染性疾病
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肝脏病学
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信号转导
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药理学
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转化医学
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产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2024
·Vol. 38
·期 17
·e70019
·
IF 4.4
Yuxue Xu,Yue Peng,Xiaojun Wu,Feixue Ni,Daxi Sun,Pengfei Zhang,Yang Yang,Miao Yan,Jia Mi,Geng Tian
Non-proliferative diabetic retinopathy (NPDR) is the early stage of diabetic retinopathy (DR) and is a chronic oxidative stress-related ocular disease. Few treatments are approved for early DR. This study aimed to investigate the pathogenic mechanisms underlying the retinal micro-vasculopathy induced by diabetes and to explore an early potential for treating early DR in a mouse model. The mouse model of type 1 diabetes was established by intraperitoneal injection of streptozotocin (STZ, 180 mg/kg), which was used as the early DR model. The body weight and blood glucose mice were measured regularly; The retinal vascular leakage in the early DR mice was determined by whole-mount staining; Label-free quantitative proteomic analysis and bioinformatics were used to explore the target proteins and signaling pathways associated with the retinal tissues of early DR mice; To detect the effects of target protein on endothelial cell proliferation, migration, and tube formation, knockdown and overexpression of VEGF-B were performed in human retinal vascular endothelial cells (HRECs); Western blotting was used to detect the expression of target proteins in vitro and in vivo; Meanwhile, the therapeutic effect of VEGF-B on vascular leakage has also been evaluated in vitro and in vivo. The protein expressions of vascular endothelial growth factor (VEGF)-B and the Rho GTPases family member CDC42 were reduced in the retinal tissues of early DR. VEGF-B upregulated the expression of CDC42/ZO1/VE-cadherin and prevented hyperglycemia-induced vascular leakage in HRECs. Standard intravitreal VEGF-B injections improved the retinal vascular leakage and neurovascular response in early DR mice. Our findings demonstrated, for the first time, that in diabetes, the retinal vessels are damaged due to decreased VEGF-B expression through downregulation of CDC42/ZO1/VE-cadherin expression. Therefore, VEGF-B could be used as a novel therapy for early DR.
研究领域:
糖尿病
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眼科学
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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
JOURNAL OF ALZHEIMERS DISEASE
·
2025
·
IF 3.1
Wenqiang Zhang,Fei Teng,Xifa Lan,Peihui Liu,Aiming Wang,Fan Zhang,Zhiqiang Cui,Jingwei Guan,Xiaohong Sun
BackgroundThe involvement of microglia is likely to be pivotal in the pathogenesis of Alzheimer's disease (AD) by modulating the deposition of amyloid-β (Aβ) plaques. The deletion of Dedicator of cytokinesis 8 (DOCK8) has a protective effect in mouse with neurodegenerative diseases.ObjectiveTo explore the underlying mechanism of DOCK8 in AD.MethodsIn present study, we first the detected the expression of DOCK8 in the hippocampal tissue of APP/PS1 mice. Then, the expression of DOCK8 was knocked down in the hippocampal tissue of APP/PS1 mice, and the effects of DOCK8 down-regulation on cognitive function, the microglia migration around Aβ plaques, and the cell division cycle 42 (Cdc42)/p38 mitogen-activated protein kinase (MAPK) signaling pathway were detected. Next, the effects of DOCK8 knockdown on Aβ-induced migration and activation of BV-2 cells as well as the MAPK signaling pathway were detected. Finally, the transcriptional regulation of DOCK by transcription factor 3 (ATF3) was detected by a dual luciferase reporter assay.ResultsDOCK8 expression exerts a significant upregulation in the hippocampus of APP/PS1 mice. However, following the DOCK8 knockdown, there was a significant recovery in the results of the behavioral tests and a notable reduction in microglial expression. Moreover, the high expression of DOCK8 mediated by ATF3 successfully triggered the Cdc42/p38 MAPK signaling pathway, thereby enhancing the migration and recruitment of microglia towards senile plaques, accelerating the production of Aβ plaques.ConclusionsATF3-mediated high expression of DOCK8 accelerates the production of Aβ plaques, and participates in the pathogenesis of AD.
研究领域:
神经科学
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分子生物学
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遗传学
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细胞生物学
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病理学
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DOI
PubMed
高影响因子
LANGMUIR
·
2020
·
IF 3.557
Yiqun Wang,Yuan Yao
In natural tissue, nanofibrils in extracellular matrix (ECM), such as collagen fibrils, direct cell migration through contacting guidance. The contacting nanofibers on cell-ECM interface are reorganized from curl fibers to straightened fibers. However, how these nanofibers regulate single cell migration remains obscure. To investigate this issue, we fabricated collagen/polymer based biomimetic nanofiber sheets of varying topography. And we selected tumorigenic cell KGN and nontumorigenic cell 293T for comparison. We found KGN showed higher sensitivity to the nanofiber alignment rather than the nontumorigenic cell 293T, in morphological change, trajectory adaptation, and velocity variation. We also found aligned nanofibers shaped both KGN and 293T into elongated spindle morphology. Comparatively, KGN had greater perimeter and lower roundness than 293T. To study the dynamics of single cell migration of KGN and 293T, we conducted trajectory tracking and siRNA validation on regulatory proteins. We found nanofibers of varying topography regulated the patterns of single cell migration differently. For KGN cell, β-catenin, Rac1, and Cdc42 participated in its directional migration, but it was impervious to vimentin. Comparatively, epithelial cell 293T involved vimentin in its directional migration.
研究领域:
生物材料
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细胞生物学
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组织工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-19
·
IF 10.6
Luo Yuxiao,Zheng Yifan,Chen Ziwei,Mo Minhua,Xie Jiling,Zhou Xiaohe,Wu Yupeng,Yang Qiyuan,Zheng Manjia,Hu Xiaowen,Chen Liangjiao,Lan Zedong
Background Early angiogenesis provides nutrient supply for bone tissue repair, and insufficient angiogenesis will lead tissue engineering failure. Lanthanide metal nanoparticles (LM NPs) are the preferred materials for tissue engineering and can effectively promote angiogenesis. Holmium oxide nanoparticles (HNPs) are LM NPs with the function of bone tissue “tracking” labelling. Preliminary studies have shown that HNPs has potential of promote angiogenesis, but the specific role and mechanism remain unclear. This limits the biological application of HNPs. Results In this study, we confirmed that HNPs promoted early vessel formation, especially that of H-type vessels in vivo, thereby accelerating bone tissue repair. Moreover, HNPs promoted angiogenesis by increasing cell migration, which was mediated by filopodia extension in vitro. At the molecular level, HNPs interact with the membrane protein EphrinB2 in human umbilical vein endothelial cells (HUVECs), and phosphorylated EphrinB2 can bind and activate VAV2, which is an activator of the filopodia regulatory protein CDC42. When these three molecules were inhibited separately, angiogenesis was reduced. Conclusion Overall, our study confirmed that HNPs increased cell migration to promote angiogenesis for the first time, which is beneficial for bone repair. The EphrinB2/VAV2/CDC42 signalling pathway regulates cell migration, which is an important target of angiogenesis. Thus, HNPs are a new candidate biomaterial for tissue engineering, providing new insights into their biological application.
研究领域:
生物医学工程
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组织工程
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纳米技术
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2020
·Vol. 12
·期 5
·3183-3193
·
IF 6.895
Yiqun Wang,Jinkang Gong,Yuan Yao
Extracellular matrix anisotropy tunes the organization and movement of surrounding cells. The primary mediators of the extracellular matrix are fiber-based materials. Natural collagen fibers reorganize from curled and isotropic fibers to straightened and anisotropic fibers during tumorigenesis, yet how the cytoskeleton is involved in the directional migration in response to the topography is unknown. To investigate this, we fabricated random, orthogonal, and aligned nanofibers to deconstruct the basic mechanisms for the migration of the human pancreatic cancer cells PANC-1 on different substrates. We found that the extracellular matrix orchestrated actin reorganization by templating the surface topography as an irregular pattern on random fibers, crossover feature on orthogonal fibers, and parallel characteristics on aligned fibers. The intermediate filament as vimentin was upregulated to form a perinuclear shape on orthogonal or aligned surfaces. We also found that the nanofiber topography mediated the directional migration via different mechanisms. The directionality ratio and velocity were statistically analyzed to unveil the pattern of directional migration. Cells on aligned nanofibers yielded a greater velocity. Rac1 and Cdc42 were involved in cell migration through regulating actin polymerization and membrane protrusions. Thus, our findings elucidate that nanofiber alignment orchestrates cytoskeletal reorganization and mediates the directional migration of cancer cells.
研究领域:
细胞生物学
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癌症生物学
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生物物理学
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组织工程
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Dongping Li,Rongjuan Wei,Xianglong Zhang,Shenhai Gong,Meijuan Wan,Fangzhao Wang,Jiaxin Li,Meiling Chen,Ruofan Liu,Yantong Wan,Yinghao Hong,Zhenhua Zeng,Peng Gu,Zhang Wang,Kutty Selva Nandakumar,Yong Jiang,Hongwei Zhou,Peng Chen
Sepsis progression is significantly associated with the disruption of gut eubiosis. However, the modulatory mechanisms of gut microbiota operating during sepsis are still unclear. Herein, we investigated how gut commensals impact sepsis development in a pre-clinical model. Cecal ligation and puncture (CLP) surgery was used to establish polymicrobial sepsis in mice. Mice depleted of gut microbiota by an antibiotic cocktail (ABX) exhibited a significantly higher level of mortality than controls. As determined by metabolomics analysis, ABX treatment has depleted many metabolites, and subsequent supplementation with L-rhamnose (rhamnose, Rha), a bacterial carbohydrate metabolite, exerted profound immunomodulatory properties with a significant enhancement in macrophage phagocytosis, which in turn improved organ damage and mortality. Mechanistically, rhamnose binds directly to and activates the solute carrier family 12 (potassium-chloride symporter), member 4 (SLC12A4) in macrophages and promotes phagocytosis by activating the small G-proteins, Ras-related C3 botulinum toxin substrate1 (Rac1) and cell division control protein 42 homolog (Cdc42). Interestingly, rhamnose has enhanced the phagocytosis capacity of macrophages from sepsis patients. In conclusion, by identifying SLC12A4 as the host interacting protein, we disclosed that the gut commensal metabolite rhamnose is a functional molecular that could promote the phagocytosis capacity of macrophages and protect the host against sepsis.
研究领域:
免疫学
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微生物学
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药理学
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2024
·
IF 3.8
Xi-you Li,Xiao-yuan Gu,Bai-ling Zhou,Bun Tsoi,Wei-xi Li
Eye deformity, a noteworthy embryopathy, is intricately linked with maternal diabetes, frequently resulting in embryonic malformation or even death. In this investigation, a hyperglycemic chick embryo model was established to delve into the protective potential of tamarind shell extract (TSE) on eye development. Chick embryos were administered with TSE (at dosages of 1, 2, and 4 µg/egg) through air sac injection on embryo development day 0 (EDD0) and later exposed to D-glucose (0.4 mmol/egg) on EDD1. To validate our findings, we replicated hyperglycemic environment using D-glucose in ARPE-19 cell model. Our research unveiled that TSE proficiently counters O-GlcNAcylation of proteins in the presence of D-glucose, thereby reinstating levels of key proteins involved in eye development, including Pax6, Daam1, mTOR, and Cdc42. Furthermore, TSE was pinpointed to curtail the D-glucose concentration within the embryo eye, considerably decreasing the accumulation of reactive oxygen species and malondialdehyde accumulation in both the ARPE-19 cells and chick embryos. Beyond its fundamental role in boosting the cellular antioxidative activity, the improved expression of apoptosis-related proteins like Caspase-3, BAX, BCL-2 and other like PI3K and AKT were observed. This suggests a probable activation of the PI3K-AKT-mTOR pathway on ARPE-19 cells by TSE, thereby downregulating apoptotic proteins in ARPE-19 cells during oxidative stress. TSE may become a potent natural countermeasure against D-glucose-induced eye malformation.
研究领域:
发育生物学
·
药理学
·
细胞生物学
·
胚胎学
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产品关联
DOI
高影响因子
Advanced Science
·
2023
·
IF 15.1
Wenjie Xu,Yu Xiao,Minzhi Zhao,Jiahui Zhu,Yu Wang,Wenbin Wang,Peng Wang,Huan Meng
A nano-enabled drug delivery acupuncture technology ( nd -Acu) is developed that is based on traditional acupuncture needles where the stainless-steel surface is designed to deliver various payload molecules. To create the nd -Acu platform, an electrochemistry procedure is used to attach methyl salicylate-modified cyclodextrin in which the sugar rings allow the encapsulation of structurally defined single or multiple payload molecules via an inclusion complexation process. Drug loading and release profile are first studied using fluorescent dyes abiotically and at intact animal level. nd -Acu allows more efficient dye loading and time-dependent release compared to pristine needles without cyclodextrin modification. Subsequently, a proof-of-principle efficacy study is conducted using the platform to load a local anesthetic, lidocaine, for the treatment of knee osteoarthritis (KOA) in mice. It is demonstrated that lidocaine-laden nd -Acu can effectively alleviate pain, reduce inflammation, and slow down KOA development biochemically and histologically. Hypothesis-driven and proteomic approaches are utilized to investigate the working mechanisms of lidocaine nd -Acu, indicating that the therapeutic outcome is attributed to the in vivo modulation of the HMGB1/TLR4 signaling pathway. The study also obtained preliminary evidence suggesting the involvement of mitochondria as well as small GTPase such as cdc42 during the treatment by lidocaine nd -Acu.
研究领域:
纳米技术
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药学
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生物医学工程
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骨科
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疼痛管理
·
炎症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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