Cancer Management and Research
·
2024
·
IF 2.5
Yantao Yu,Chenkai Zhang,Qiannan Sun,Shantanu Baral,Jianyue Ding,Fanyu Zhao,Qing Yao,Shuyang Gao,Bin Liu,Daorong Wang
Background Gastric cancer (GC) is a highly phenotypically heterogeneous disease and is caused by a combination of factors. Retinol binding protein 4 (RBP4) is a member of a family of lipid transport proteins that are involved in the transport of substances between cells and play a crucial role in a variety of cancers. However, the expression and role of RBP4 in GC remain unknown.Methods In this study, we explored the expression, prognostic significance, immune microenvironment, drug responsiveness and function of associated signaling pathways of RBP4 in GC using web-based bioinformatics tools. Immunohistochemistry and real-time quantitative PCR were utilized to analyze the tissue and cell expression levels of RBP4. CCK-8, colony formation, EDU incorporation, wound healing and transwell assays were applied to demonstrate the effect of RBP4 on GC cell function. Flow cytometric detection of apoptosis after RBP4 knockdown. Nude mice xenograft model elucidates the role of RBP4 for GC in vivo. Related proteins of the RAS signaling pathway were analyzed by employing Western blot assays.Results RBP4 is highly expressed in GC. RBP4 is closely associated with patient survival and sensitivity to a wide range of antitumor agents. Knockdown of RBP4 promoted apoptosis and inhibited cell proliferation, invasion and migration. RBP4 promotes GC tumorigenesis in vivo. Finally, RBP4 modulates the RAS/RAF/ERK axis.Conclusion RBP4 may promote gastric carcinogenesis and development through the RAS/RAF/ERK axis and is expected to be a novel target for GC treatment.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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生物信息学
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DOI
PubMed
高影响因子
MICROVASCULAR RESEARCH
·
2025
·
IF 2.7
Jiang Hugang,Liu Ai,Guo Zeao,Ren Chunzhen,Lin Wenyan,Liu Kai,Zhao Xinke,Li Yingdong
Background Coronary Microvascular Dysfunction (CMVD), a prevalent comorbidity of various cardiovascular diseases, may contribute to myocardial cell ischemic necrosis. The loss of microvessels—driven by endothelial cells (ECs) apoptosis—is the core pathological hallmarks of CMVD. Our previous studies have established that RAS-RH ( Angelica sinensis and Astragalus membranaceus ultrafiltrate) promotes angiogenesis and improves cardiac perfusion. However, its underlying molecular mechanisms remain incompletely understood. Purpose This study aimed to elucidate the key mechanism by which quercetin, the primary active component of RAS-RH, modulates radiation-induced ECs apoptosis. Methods Through the integration of network pharmacology and transcriptomics, we identified potential active components of RAS-RH and their key targets involved in regulating the telocytes-endothelial cell (TCs-ECs) crosstalk pathway underlying CMVD. These predictions were further validated using in vitro cellular models via flow cytometry, western blot, wound-healing assays, in situ hybridization, immunofluorescence staining, and EdU proliferation assays. Results Consistent with our predictions, experimental results demonstrated that quercetin (the primary active component of RAS-RH) significantly upregulated the expression of HIF-1α and miRNA-126 in TCs ( P < 0.01) and enhanced miRNA-126 paracrine secretion. Through this paracrine mechanism, quercetin downregulated the expression of Cypd, ANT, F1F0-ATPase, and VDAC in ECs ( P < 0.01), inhibited the reduction of mitochondrial membrane potential (ΔΨm) and ECs apoptosis induced by excessive mPTP opening. Collectively, these effects enhanced ECs proliferation, migration, and tube formation capacity, ultimately promoting angiogenesis. Conclusion These results collectively demonstrate that quercetin, the primary active component of RAS-RH, suppresses excessive mPTP activation and apoptosis while stimulating ECs migration and tube formation. This occurs via upregulating HIF-1α and miRNA-126 expression in TCs and enhancing miRNA-126 paracrine to ECs, positioning the TCs-ECs crosstalk mechanism as a promising novel therapeutic target for intervening in coronary microcirculation dysfunction.
研究领域:
心血管药理学
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分子生物学
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辐射生物学
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网络药理学
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转录组学
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血管生成研究
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DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2015
·Vol. 11
·期 6
·4321-4326
·
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
Theranostics
·
2024
·
IF 12.4
Maojiao Li,Qi Tang,Chengcheng Liao,Zhuo Wang,Siyuan Zhang,Qingqing Liang,Cheng Liang,Xiaodong Liu,Jingyi Zhang,Weidong Tian,Li Liao
Rationale: Mesenchymal stromal cells (MSCs) are considered a promising resource for cell therapy, exhibiting efficacy in ameliorating diverse bone diseases. However, most MSCs undergo apoptosis shortly after transplantation and produce apoptotic extracellular vesicles (ApoEVs). This study aims to clarify the potential role of ApoEVs from apoptotic MSCs in ameliorating osteoporosis and molecular mechanism. Methods: In this study, Dio-labeled bone marrow mesenchymal stem cells (BMSCs) were injected into mice to track BMSCs apoptosis and ApoEVs production. ApoEVs were isolated from BMSCs after inducing apoptosis, the morphology, size distribution, marker proteins expression of ApoEVs were characterized. Protein mass spectrometry analysis revealed functional differences in proteins between ApoEVs and BMSCs. BMSCs were adopted to test the cellular response to ApoEVs. Ovariectomy mice were used to further compare the ability of ApoEVs in promoting bone formation. SiRNA and lentivirus were used for gain and loss-of-function assay. Results: The results showed that BMSCs underwent apoptosis within 2 days after being injected into mice and produce a substantial quantity of ApoEVs. Proteomic analysis revealed that ApoEVs carried a diverse functional array of proteins, and easily traversed the circulation to reach the bone. After being phagocytized by endogenous BMSCs, ApoEVs efficiently promoted the proliferation, migration, and osteogenic differentiation of BMSCs. In an osteoporosis mouse model, treatment of ApoEVs alleviated bone loss and promoted bone formation. Mechanistically, ApoEVs carried Ras protein and activated the Ras/Raf1/Mek/Erk pathway to promote osteogenesis and bone formation in vitro and in vivo . Conclusion: Given that BMSC-derived ApoEVs are high-yield and easily obtained, our data underscore the substantive role of ApoEVs from dying BMSCs to treat bone loss, presenting broad implications for cell-free therapeutic modalities.
研究领域:
干细胞生物学
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骨生物学
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再生医学
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分子生物学
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DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Yang Chen,Wenzhe Xu,Hao Jin,Mengsi Zhang,Shuwei Liu,Yi Liu,Hao Zhang
Heterogeneous reprogrammed nutrient metabolic networks formed by oncogenes exhibit the potential for exploring novel druggable targets and developing innovative anticancer therapeutics. Herein, based on the heterogeneous metabolic characteristics of glutamine (Gln) addiction in pancreatic cancer cells, an iron-delivery system (IDS) with enhanced endocytosis is designed for efficient ferroptosis therapy. The IDS is characterized by Gln modification and can be recognized as a source of Gln nutrients for efficient endocytic uptake by pancreatic tumor cells. Because the IDS is flexible to combine with amino acid-like components, the IDS with enhanced endocytosis is further produced by loading the Gln transporter inhibitor of V9302. V9302 is capable of suppressing molecular Gln uptake via transporter ASCT2, which generates Gln deprivation to direct metabolic reprogramming of cancer cells and enhances cellular uptake of Gln-modified IDS via RAS-stimulated macropinocytosis. The enhanced endocytosis and high iron content of IDS facilitate ferroptosis in mice pancreatic tumor models; thus, an amino acid-like ferroptosis inducer of l-buthionine sulfoximine (BSO) is further combined. The enhanced endocytosis resulting from the synergism of Gln and V9302 enables the efficient delivery of iron and BSO for ferroptosis tumor therapy. This work provides an alternative approach for enhancing intracellular drug delivery of the tumors with heterogeneous nutrient metabolism by virtue of combining nutrient-modified nanodrugs with the corresponding nutrient transporter inhibitors.
研究领域:
肿瘤学
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药学
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生物医学工程
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癌症代谢
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
·
2022
·
IF 3.784
Xiaomei Wu,Zhumei Wei,Hui Feng,Hongli Chen,Jiaxiu Xie,Yupeng Huang,Mengyao Wang,Chanjuan Yao,Jianchun Huang
Betulinic acid (BA) is a natural pentacyclic triterpenoid with broad-spectrum anticancer activity, which has great development potential as an anti-cancer drug. In this study, a novel hyaluronic acid (HA)-modified BA liposome (BA-L) was developed for use in targeted liver cancer therapy. The size, polymer dispersity index (PDI), zeta potential , and entrapment efficiency were measured. Cell viability, cell migration and clonogenicity, cellular uptake, immunohistochemistry of CD44, and protein expression of ROCK1/IP3/RAS were also investigated. BA, BA-L, and HA-BA-L had no inhibitory effect on the activity of LO2 normal hepatocytes, but they inhibited the proliferation of HepG2 and SMMC-7721 cells in a dose- and time-dependent manner, with HA-BA-L exhibiting the most prominent inhibitory effect. Compared with the BA-L group, the expression of CD44 in HepG2 cells in the HA-BA-L group was decreased. The results of WB showed that BA, BA-L, and HA-BA-L downregulated the expression of ROCK1, IP3, and RAS in HepG2 cells, and the expression level in the HA-BA-L group was significantly decreased. The easily prepared HA-BA-L was demonstrated to be an excellent CD44-mediated intracellular delivery system capable of targeting effects. Further mechanistic research revealed that the inhibition of HA-BA-L on HepG2 cells may be mediated by blocking the ROCK1/IP3/RAS signaling pathways.
研究领域:
药理学
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肿瘤学
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生物技术
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细胞生物学
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DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2021
·
IF 4.749
Chuanchuan Lin,Ye He,Kun Xu,Qian Feng,Xuan Li,Songyue Zhang,Ke Li,Ruqing Bai,Hong Jiang,Kaiyong Cai
The mechanical properties of the natural extracellular matrix (ECM) change extensively, but these specific properties provide a relatively stable environment for resident cells. Although the effect of matrix stiffness on cell functions has been widely studied, the molecular mechanism was still not fully understood. Matrix stiffening is a common phenomenon in tissue damaging processes. To explore the effect of the increase in local matrix stiffness on cell behaviors, a three-dimensional (3D) cell culture system with a tunable modulus but constant other physical parameters was constructed by the alginate hydrogel with different molecular weights and cross-linking degrees. By using this culture system, the transcriptome response of mesenchymal stem cells (MSCs) to matrix stiffness was explored. Furthermore, a finite element model was developed to simulate the interaction between cells and the matrix. Results revealed that the increased matrix stiffness promoted the proliferation-related signaling of MSCs, and this process depended on the increased cortex tension caused by the activation of RAS and myosin II.
研究领域:
细胞生物学
·
生物力学
·
组织工程
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产品关联
DOI
PubMed
高影响因子
Heliyon
·
2024
·
IF 3.4
Min Cai,Yangchen Mao,Wenjing Gao,Zhenzhen Wang,Jianwei Mao,Ruyi Sha
Inflammatory bowel disease (IBD) is a growing global health problem. IBD is commonly prevalent in Europe and America and the incidence rate in Asia is on the rise due to altered dietary structure. Diosgenin is a natural steroidal saponin derived from Dioscorea plants. Diosgenin is the main active ingredient of some Chinese medicines which are mainly used to treat coronary heart disease, angina and hyperlipidemia. Recently, growing evidence has exhibited a crucial role of diosgenin and dioscin in alleviating IBD in multiple ways. However, the precise mechanism of diosgenin against IBD needs further exploration. In this study, network pharmacological and systematic bioinformatic analyses were performed to investigate the diosgenin's targets against IBD. 71 targets such as SRC, TNF and STAT3 were identified as overlapped genes between diosgenin and IBD. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis exhibited their involvement in the tyrosine kinase signaling pathway and its membrane receptors. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance and its downstream Ras-MAPK pathway and PI3K-Akt pathway might become the mechanism of diosgenin against IBD. In addition, molecular docking analysis showed that diosgenin has the massive potential of direct binding to tyrosine kinase and its receptors such as SRC, EGFR, FGFR1 and VEGFR. The results above collectively provided evidence that diosgenin is a promising nutraceutical food against IBD.
研究领域:
药理学
·
分子生物学
·
生物信息学
·
功能性食品
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DOI
PubMed
高影响因子
ACS Nano
·
2020
·
IF 14.588
Xuliang Guo,Fang Liu,Jian Deng,Peipei Dai,Yan Qin,Zhi Li,Bingbing Wang,Aiping Fan,Zheng Wang,Yanjun Zhao
Ferroptotic antitumor therapy has been compromised by various intracellular antioxidants, particularly glutathione and thioredoxin. Both are cofactors of glutathione peroxide 4 (GPX4) that act against oxidative stress via catalyzing the reduction of lipid peroxides. It was postulated that tailored polymer micelles could enhance ferroptotic antitumor efficacy via diminishing glutathione and thioredoxin under hypoxia. The aim was to engineer hypoxia-responsive micelles for selective enhancement of ferroptotic cell death in solid tumor. The polymer contains hydrophilic poly(ethylene glycol) (PEG) that is linked by azobenzene linker with nitroimidazole-conjugated polypeptide. The tailored polymer could self-assemble into nanoscale micelles to encapsulate RAS-selective lethal small molecule 3, a covalent GPX4 inhibitor. Under hypoxia, the azobenzene moiety enabled PEG shedding and enhanced micelles uptake in 4T1 cells. Likewise, the nitroimidazole moiety was reduced by the overexpressed nitroreductase with reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the cofactor, resulting in transient depletion of NADPH. This impaired both the glutathione and thioredoxin redox cycle, leading to diminished intracellular glutathione and thioredoxin. The selective potency of ferroptotic micelles in depleting NADPH, glutathione and thioredoxin was further verified in vivo in the 4T1 tumor xenograft mice model. This work highlights the role of hypoxia-responsive polymers in enhancing the potency of ferroptotic inducers against solid tumors without additional side effects to healthy organs.
研究领域:
肿瘤学
·
药学
·
生物医学工程
·
癌症生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Lifang Zou,Xia Yu,Kezhou Cai,Baocai Xu,Conggui Chen,Guiran Xiao
Consuming a high‑sodium diet carries serious health risks and significantly influences the activation state of the renin-angiotensin system (RAS). This study evaluates the protective effect of angiotensin-converting enzyme (ACE) inhibitory peptide IVGFPAYGH on a high‑sodium diet–induced liver injury. IVGFPAYGH supplementation increased the activities of liver antioxidase and decreased the levels of liver inflammatory factor in mice fed a high‑sodium diet (8 % NaCl). IVGFPAYGH supplementation also reduced liver fatty acid synthesis and promoted fatty acid oxidation, increased the expression of low-density lipoprotein receptor, and improved liver dyslipidemia. Furthermore, IVGFPAYGH supplementation inhibited the activation of the liver RAS via inhibiting ACE activity and reducing angiotensin II levels in mice fed a high‑sodium diet. Moreover, IVGFPAYGH supplementation could alter the gut microbiota composition toward a normal gut microbiota composition and increase the abundance of the Lactobacillus genus. IVGFPAYGH supplementation also increased the expression levels of small intestinal tight junction protein and cecum short-chain fatty acids. Thus, IVGFPAYGH supplementation may maintain intestinal homeostasis and improve high‑sodium diet–induced liver injury by altering the gut microbiota composition and inhibiting the RAS. IVGFPAYGH is a promising functional ingredient for protecting liver damage caused by a high‑sodium diet.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2018
·
IF 7.877
Xiaopeng Mo,Zening Zheng,Yang He,Huihai Zhong,Xuejia Kang,Mingjie Shi,Tuanbing Liu,Zheng Jiao,Yongzhuo Huang
Effective treatment of malignant glioma still remains a formidable challenge due to lack of the effective BBB-permeable drugs and efficient brain delivery methods, and the pharmacotherapy options are very limited. Therefore, to develop an effective therapeutic strategy is a pressing need. In this work, a noncytotoxic drug combination (i.e., simvastatin and fenretinide) was revealed to be potent for treating glioma, which was co-encapsulated into a TPGS-TAT-embedded lactoferrin nanoparticle system for achieving brain-targeted biomimetic delivery via the LRP-1 receptor. It was shown that the lactoferrin nanoparticle repolarized the tumor-associated macrophages from the M2 phenotype to M1 via regulating the STAT6 pathway, as well as induced the ROS-mediated mitochondrial apoptosis by inhibiting the Ras/Raf/p-Erk pathway in the glioma cells. The antiglioma efficacy was further demonstrated in both the subcutaneous and orthotopic glioma models. The repolarization of tumor-associated macrophages not only prompted the ROS generation but also induced the innate immunity (e.g., antitumor cytokine release). This delivery and therapeutic strategy provides a novel modality for the glioma treatment.
研究领域:
神经肿瘤学
·
药理学
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纳米医学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
Human Cell
·
2025
·Vol. 39
·期 1
·19
·
IF 3.1
Zhu Linwen,Li Ni,Shi Huoshun,Song Jie,Fang Zhongjie,Shen Qinbo,Zhu Xiuying,Dan Yanggang,Shao Guofeng,Sun Lebo
Circular RNAs (circRNAs) are involved in cardiovascular disease development and progression. We identified has_circ_0000437 from three pairs of clinical samples using a circRNA microarray and predicted the has_circ_0000437 sponge let-7f-5p using bioinformatics. We expanded the sample to confirm the expression, correlation, and diagnostic value of has_circ_0000437, let-7f-5p and RAS-like proto-oncogene B (RALB) in rheumatic valvular heart disease (RVHD). The effects of has_circ_0000437 and let-7f-5p on biological function were observed in hVICs cells. To explore the molecular pathogenesis of has_circ_0000437 in the RVHD process, the target binding protein RAS-like proto-oncogene B (RALB) of has_circ_0000437 was obtained using label-free mass spectrometry and parallel reaction monitoring. The influence of the has_circ_0000437/let-7f-5p/RALB axis on the expression of mitogen-activated protein kinase (MAPK)-related proteins in the inflammatory signaling pathway predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) during RVHD was measured using Western blotting. We found that let-7f-5p was at low expression and negatively correlated with has_circ_0000437, which had a diagnostic value with an area under the curve of 0.998 after the combined diagnosis. Has_circ_0000437 and let-7f-5p had binding sites, and let-7f-5p alleviated the effect of has_circ_0000437 on the proliferation, migration, and cycle progression of hVICs. The inhibitory effect of has_circ_0000437 on hVICs apoptosis was diminished. Mechanism studies showed that has_circ_0000437 promotes the MAPK pathway through has_circ_0000437/let-7f-5p/RALB axis. These findings suggest that the has_circ_0000437/let-7f-5p/RALB axis promotes the MAPK pathway, proliferation, migration, and cycle progression in RVHD, inhibiting the apoptosis process, thereby promoting RVHD development. This pathway may suggest a target for RVHD diagnosis and treatment.
研究领域:
心血管疾病
·
分子生物学
·
非编码RNA研究
·
信号转导
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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）