Molecular Medicine Reports
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2015
·Vol. 11
·期 6
·4321-4326
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IF 1.554
Lei Lan,Yongsheng Han,Wei Ren,Jielong Jiang,Peng Wang,Zhao Hu
The present study aimed to determine the molecular mechanisms leading to the production of advanced glycation end‑products (AGEs) and their effect on the morphology and function of rat glomerular capillary endothelial cells (GECs). Primary rat GECs were treated with AGE‑modified human serum albumin (AGE‑HSA) and divided into groups according to AGE concentration and treatment time. The structure and distribution of cytoskeletal protein F‑actin and the cortical actin binding protein, cortactin, were analyzed using immunofluorescence and confocal microscopy. As the Ras‑related C3 botulinum toxin substrate 1 (Rac1) signaling pathway was previously identified to be involved in mediating the contraction of endothelial actin‑myosin activity, Rac1 was examined subsequent to treatment of the cells with the Rac1 agonist 2'‑O‑methyladenosine‑3',5'‑cyclic monophosphate (O‑Me‑cAMP) for 1 h using a pull‑down assay. Cell permeability was determined by the leakage rate of a fluorescein isothiocyanate fluorescent marker protein. AGE‑HSA treatment resulted in alterations in the structure and distribution of F‑actin and cortactin in a dose‑ and time‑dependent manner, while no effect was observed with HSA alone. The effect of AGE on the cytoskeleton was inhibited by the addition of O‑Me‑cAMP. AGE‑HSA significantly reduced the level of Rac1 activity (P<0.05); however, no effect was observed on total protein levels. Furthermore, AGE‑HSA treatment led to a significant increase in the permeability of endothelial cells (P<0.01), which was inhibited by O‑Me‑cAMP (P<0.01). The Rac1 signaling pathway is thus suggested to serve an important function in mediating AGE‑induced alterations in GEC morphology and function.
研究领域:
分子生物学
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医学
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细胞生物学
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DOI
PubMed
高影响因子
LANGMUIR
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2020
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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
Nanoscale
·
2020
·Vol. 12
·期 5
·3183-3193
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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
Journal of Ginseng Research
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2022
·
IF 5.735
Ye-ying Jiang,Rong-yun Wei,Kai Tang,Zhen Wang,Ning-hua Tan
Background Mechanisms of synaptic plasticity in retinal ganglion cells (RGCs) are complex and the current knowledge cannot explain. Growth and regeneration of dendrites together with synaptic formation are the most important parameters for evaluating the cellular protective effects of various molecules. The effect of ginsenoside Rg1 (Rg1) on the growth of retinal ganglion cell processes has been poorly understood. Therefore, we investigated the effect of ginsenoside Rg1 on the neurite growth of RGCs. Methods Expression of proteins and mRNA were detected by Western blot and qPCR. cAMP levels were determined by ELISA. In vivo effects of Rg1 on RGCs were evaluated by hematoxylin and eosin, and immunohistochemistry staining. Results This study found that Rg1 promoted the growth and synaptic plasticity of RGCs neurite by activating the cAMP/PKA/CREB pathways. Meanwhile, Rg1 upregulated the expression of GAP43, Rac1 and PAX6, which are closely related to the growth of neurons. Meantime, H89, an antagonist of PKA, could block this effect of Rg1. In addition, we preliminarily explored the effect of Rg1 on enhancing the glycolysis of RGCs, which could be one of the mechanisms for its neuroprotective effects. Conclusion Rg1 promoted neurite growth of RGCs through cAMP/PKA/CREB pathways. This study may lay a foundation for its clinical use of optic nerve diseases in the future.
研究领域:
神经科学
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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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产品关联
DOI
PubMed
高影响因子
Computational and Mathematical Methods in Medicine
·
2022
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IF 2.809
Zhulin Wu,Jianyuan Kang,Wanjun Tan,Chunshan Wei,Li He,Xiaoyan Jiang,Lisheng Peng
Objective. Traditional Chinese medicine (TCM) is an important part of the comprehensive treatment of hepatocellular carcinoma (HCC), and Chinese materia medica formulas with the effect of “Yiqi Jianpi” (replenishing qi and strengthening spleen) or “Jiedu” (removing toxicity) have been proved to be effective in treating HCC. However, mechanisms of these formulas in treating HCC remain unclear. In this paper, our goal is to explore the antitumor activity and its molecular mechanisms of Yiqi Jianpi Jiedu (YQJPJD) formula against HCC. Methods. The bioactive ingredients and targets of YQJPJD formula and HCC targets were screened by five Chinese materia medicas and two disease databases, respectively. The network pharmacology was utilized to construct the relationship network between YQJPJD formula and HCC, and the mechanisms were predicted by the protein-protein interaction (PPI) network, pathway enrichment analysis, bioinformatics, and molecular docking. Numerous in vitro assays were performed to verify the effect of YQJPJD formula on HCC cells, cancer-associated targets, and PI3K/Akt pathway. Results. The network relationship between YQJPJD formula and HCC suggested that YQJPJD formula mainly regulated the potential therapeutic targets of HCC by several key bioactive ingredients (e.g., quercetin, luteolin, baicalein, and wogonin). PPI network, bioinformatics, and molecular docking analyses displayed that YQJPJD formula may play an anti-HCC effect through key targets such as MAPK3, RAC1, and RHOA. Additionally, pathway analysis demonstrated that YQJPJD formula could play an anti-HCC effect via multiple pathways (e.g., PI3K-Akt and hepatitis B). Experimental results showed that YQJPJD formula could effectively inhibit the proliferation, migration, and invasion of HCC cells and promote HCC cell apoptosis in a concentration-dependent manner. Moreover, YQJPJD formula could decrease the mRNA expression of β-catenin, MAPK3, and RHOA and the protein expression of phosphorylated PI3K and Akt. Conclusion. YQJPJD formula mainly exerts its anti-HCC effect through multiple bioactive ingredients represented by quercetin, as well as multiple pathways and targets represented by PI3K/Akt pathway, β-catenin, MAPK3, and RHOA.
研究领域:
药理学
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肿瘤学
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中医药
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分子生物学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
Pharmaceuticals
·
2025
·Vol. 18
·期 7
·1059
·
IF 4.8
Yujin Shen,Xi Ma,Zhenzhen Du,Yang Li,Zhinan Mei,Ling Zhao
Background:Allergic rhinitis (AR) is a prevalent allergic disorder characterized by a complex pathogenesis. Drawing on traditional Chinese medicine theory and contemporary pharmacological principles, this study developed an inhalation-based herbal formulation, ZHW, to explore a novel non-invasive therapeutic approach.Objective:To investigate the therapeutic effects of ZHW on AR and elucidate its underlying mechanisms and potential targets through an integrated analysis of network pharmacology and proteomics.Materials and Methods:The volatile components of ZHW were analyzed by gas chromatography–mass spectrometry (GC-MS). The mouse model of AR was induced by OVA sensitization. The therapeutic efficacy of ZHW was assessed based on nasal symptom scores, histopathological examination, and inflammatory cytokine levels. Furthermore, the underlying mechanisms and potential targets of ZHW were investigated through integrated network pharmacology and proteomics analyses.Results:GC-MS analysis identified 39 bioactive compounds in ZHW. Inhalation treatment with ZHW demonstrated significant anti-allergic effects in OVA-sensitized mice, as evidenced by (1) reduced sneezing frequency and nasal rubbing behaviors; (2) decreased serum levels of IL-4, histamine, and OVA-specific IgE; (3) attenuated IL-4 concentrations in both nasal lavage fluid and lung tissue; (4) diminished nasal mucosal thickening; and (5) suppression of inflammatory cell infiltration. Integrated network pharmacology and proteomics analyses indicated that ZHW’s therapeutic effects were mediated through the modulation of multiple pathways, including the PI3K-Akt signaling pathway, the B cell receptor signaling pathway, oxidative phosphorylation, and the FcεRI signaling pathway. Key molecular targets involved Rac1, MAPK1, and SYK. Molecular docking simulations revealed strong binding affinities between ZHW’s primary bioactive constituents (linalool, levomenthol, linoleic acid, Linoelaidic acid, and n-Valeric acid cis-3-hexenyl ester) and these target proteins.Conclusions:The herbal formulation ZHW demonstrates significant efficacy in alleviating allergic rhinitis symptoms through multi-target modulation of key signaling pathways, including PI3K-Akt- and FcεRI-mediated inflammatory responses. These findings substantiate ZHW’s therapeutic potential as a novel, non-invasive treatment for AR and provide a strong basis for the development of new AR therapies. Future clinical development will require systematic safety evaluation to ensure optimal therapeutic outcomes.
研究领域:
药理学
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免疫学
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药物化学
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呼吸系统疾病
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系统生物学
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药物研发
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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 ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Weilai Yu,Boyang Li,Luxi Chen,Qiu Chen,QingQing Song,Xiaosheng Jin,Yandan Yin,Haibin Tong,Liwei Xue
Ethnopharmacological relevance Dendrobium, recognized as “Shihu” in traditional Chinese medicine, holds a rich history of medicinal utilization documented in the Chinese Pharmacopoeia. Ancient texts like “Shen Nong Ben Cao Jing” extol Dendrobium 's virtues as a superior herbal medicine fortifying “Yin” and invigorating the five viscera. Dendrobium is extensively employed for the treatment of gastrointestinal inflammatory disorders, showcasing significant therapeutic efficacy, particularly against ulcerative colitis (UC), within the realm of Chinese ethnopharmacology. Dendrobium plays crucial pharmacological roles due to its rich content of polysaccharides, alkaloids, phenanthrenes, and bibenzyls. Gigantol, a prominent bibenzyl compound, stands out as one of the most vital active constituents within Dendrobium , the gigantol content of Dendrobium leaves can reach approximately 4.79 μg/g. Its significance lies in being recognized as a noteworthy anti-inflammatory compound derived from Dendrobium . Aim of the study Given the pivotal role of gigantol as a primary active substance in Dendrobium , the therapeutic potential of gigantol for gastrointestinal diseases remains enigmatic. Our present investigation aimed to evaluate the therapeutic effects of gigantol on dextran sulfate sodium (DSS)-induced colitis and reveal its potential mechanism in countering UC activity. Materials and methods The protective efficacy of gigantol against colitis was assessed by examining the histopathological changes and conducting biochemical analyses of colon from DSS-challenged mice. Assessments focused on gigantol's impact on improving the intestinal epithelial barrier and its anti-inflammatory effects in colonic tissues of colitis mice. Investigative techniques included the exploration of the macrophage inflammatory signaling pathway via q PCR and Western blot analyses. In vitro studies scrutinized macrophage adhesion, migration, and chemotaxis utilizing transwell and Zigmond chambers. Furthermore, F-actin and Rac1 activation assays detailed cellular cytoskeletal remodeling. The potential therapeutic target of gigantol was identified and validated through protein binding analysis, competitive enzyme-linked immunosorbent assay (ELISA), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assay. The binding sites between gigantol and its target were predicted via molecular docking. Results Gigantol ameliorated symptoms of DSS-induced colitis, rectified damage to the intestinal barrier, and suppressed the production of pro-inflammatory cytokines in colonic tissues. Intriguingly, gigantol significantly curtailed NF-κB signaling activation in the colons of DSS-induced colitis mice. Notably, gigantol impaired the β2 integrin-dependent adhesion and migratory capacity of RAW264.7 cells. Moreover, gigantol notably influenced the cytoskeleton remodeling of RAW264.7 cells by suppressing Vav1 phosphorylation and Rac1 activation. Mechanistically, gigantol interacted with β2 integrin, subsequently diminishing binding affinity with intercellular adhesion molecule-1 (ICAM-1). Conclusions In conclusion, these findings elucidate that gigantol ameliorates DSS-induced colitis by antagonizing β2 integrin-mediated macrophage adhesion, migration, and chemotaxis, thus it may impede macrophage recruitment and infiltration into colonic tissues. This study suggests that gigantol shows promise as a viable candidate for clinical colitis therapy.
研究领域:
药理学
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免疫学
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炎症性肠病
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传统中药
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分子生物学
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产品关联
DOI
PubMed
高影响因子
RESEARCH IN MICROBIOLOGY
·
2025
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IF 3.4
Haoying Zhang,Qi Zhang,Ting Zuo,Ziqi Wang,Jianmin Liao,Yuanyuan Lu
Candida albicans is an opportunistic pathogen, and the formation of its biofilm makes it resistant to traditional antifungal therapy. Anthraquinones have universal antibacterial activity. We evaluated the inhibitory effects of 2-chloromethyl anthraquinone on C. albicans adhesion, mycelial morphology transformation, and biofilm formation. The results showed that 2-chloromethyl anthraquinone could inhibit C. albicans adhesion, mycelium formation, and biofilm formation in a dose-dependent manner at 2 μg/mL. In addition, 2-chloromethyl anthraquinone significantly inhibited the expression of biofilm formation-related genes in C. albicans , including ALS1 , CPH1 , ECE1, HWP1 , TEC1 , BCR1 , and UME6 . In addition, Ras1-cAMP-Efg1 pathway-related genes ( RAC1 , CYR1 , and TPK2) were also significantly down-regulated, indicating that the inhibitory effect of 2-chloromethyl anthraquinone on C. albicans biofilms may be related to the Ras1-cAMP-Efg1 signaling pathway. In summary, the results of this study confirmed the inhibitory mechanism of 2-chloromethyl anthraquinone on the virulence factors of C. albicans , which laid a theoretical foundation for its use as an anti-biofilm agent against C. albicans .
研究领域:
微生物学
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真菌学
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药理学
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产品关联
DOI
PubMed
高影响因子
CARCINOGENESIS
·
2023
·
IF 4.7
Han Sijia,Jin Xueying,Hu Tianyu,Chi Feng
Downregulation of ARHGAP25 was found in the tumor samples from breast cancer patients and five breast cancer cell lines. However, its precise role and molecular mechanisms in breast cancer remain completely unknown. Herein, we found that knockdown of ARHGAP25 in breast cancer cells promoted proliferation, migration and invasion of breast cancer cells. Mechanistically, ARHGAP25 silence facilitated the activation of the Wnt/β-catenin pathway and the upregulation of its downstream molecules (including c-Myc, Cyclin D1, PCNA, MMP2, MMP9, Snail, and ASCL2) by directly regulating Rac1/PAK1 in breast cancer cells. In vivo xenograft experiments indicated ARHGAP25 silence promoted tumor growth and activated the Wnt/β-catenin pathway. In contrast, overexpression of ARHGAP25 in vitro and in vivo impeded all of the above cancer properties. Intriguingly, ASCL2, a downstream target of the Wnt/β-catenin pathway, transcriptionally repressed the expression of ARHGAP25 and therefore constituted a negative feedback loop. Moreover, bioinformatics analysis indicated that ARHGAP25 is significantly correlated with tumor immune cell infiltration and the survival of patients with different immune cell subgroups in breast cancer. Collectively, our work revealed that ARHGAP25 suppressed tumor progression of breast cancer. It provides a novel insight for the treatment of breast cancer.
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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免疫学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Jiangwei Ni,Ge Li,Ningfeng Dai,Zijiao Quan,Haibin Tong,Yu Liu
Objectives Acute lung injury (ALI) poses a serious threat to human health globally, particularly with the Coronavirus 2019 (COVID-19) pandemic. Excessive recruitment and infiltration of neutrophils is the major etiopathogenesis of ALI. Esculin, also known as 6,7-dihydroxycoumarin, is a remarkable compound derived from traditional Chinese medicine Cortex fraxini . Accumulated evidence indicates that esculin has potent anti-inflammatory effects, but its pharmaceutical effect against ALI and potential mechanisms are still unclear. Methods This study evaluated the protective effect of esculin against ALI by histopathological observation and biochemical analysis of lung tissues and bronchoalveolar lavage fluid (BALF) in lipopolysaccharide (LPS)-challenged ALI mice in vivo . The effects of esculin on N-formyl-met-leu-phe (fMLP)-induced neutrophil migration and chemotaxis were quantitatively assessed using a Transwell assay and an automated cell imaging system equipped with a Zigmond chamber, respectively. The drug affinity responsive target stability (DARTS) assay, in vitro protein binding assay and molecular docking were performed to identify the potential therapeutic target of esculin and the potential binding sites and pattern. Results Esculin significantly attenuated LPS-induced lung pathological injury, reduced the levels of pro-inflammatory cytokines in both BALF and lung, and suppressed the activation of NF-κB signaling. Esculin also significantly reduced the number of total cells and neutrophils as well as myeloperoxidase (MPO) activity in the BALF. Esculin impaired neutrophil migration and chemotaxis as evidenced by the reduced migration distance and velocity. Furthermore, esculin remarkably inhibited Vav1 phosphorylation, suppressed Rac1 activation and the PAK1/LIMK1/cofilin signaling axis. Mechanistically, esculin could interact with β 2 integrin and then diminish its ligand affinity with intercellular adhesion molecule-1 (ICAM-1). Conclusions Esculin inhibits β 2 integrin-dependent neutrophil migration and chemotaxis, blocks the cytoskeletal remodeling process required for neutrophil recruitment, thereby contributing to its protective effect against ALI. This study demonstrates the new therapeutic potential of esculin as a novel lead compound.
研究领域:
药理学
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免疫学
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病理生理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CARCINOGENESIS
·
2024
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IF 3.3
Chen Fangquan,Tang Hu,Lin Junhao,Xiang Limin,Lu Yanjiao,Kang Rui,Tang Daolin,Liu Jiao
Alkaliptosis, a form of regulated cell death, is characterized by lysosomal dysfunction and intracellular pH alkalinization. The pharmacological induction of alkaliptosis using the small molecule compound JTC801 has emerged as a promising anticancer strategy in various types of cancers, particularly pancreatic ductal adenocarcinoma (PDAC). In this study, we investigate a novel mechanism by which macropinocytosis, an endocytic process involving the uptake of extracellular material, promotes resistance to alkaliptosis in human PDAC cells. Through lipid metabolomics analysis and functional studies, we demonstrate that the inhibition of alkaliptosis by fatty acids, such as oleic acid, is not dependent on endogenous synthetic pathways but rather on exogenous uptake facilitated by macropinocytosis. Consequently, targeting macropinocytosis through pharmacological approaches (e.g., using EIPA or EHoP-016) or genetic interventions (e.g., RAC1 knockdown) effectively enhances JTC801-induced alkaliptosis in human PDAC cells. These findings provide compelling evidence that the modulation of macropinocytosis can increase the sensitivity of cancer cells to alkaliptosis inducers.
研究领域:
癌症生物学
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细胞生物学
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药理学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）