CELL PROLIFERATION
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2021
·Vol. 55
·期 1
·e13173
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IF 6.831
Jinping Huang,Xiao Sheng,Zhangpeng Zhuo,Danqing Xiao,Kun Wu,Gang Wan,Haiyang Chen
Objectives Adult stem cells uphold a delicate balance between quiescent and active states, which is crucial for tissue homeostasis. Whereas many signalling pathways that regulate epithelial stem cells have been reported, many regulators remain unidentified. Materials and Methods Flies were used to generate tissue-specific gene knockdown and gene knockout. qRT-PCR was used to assess the relative mRNA levels. Immunofluorescence was used to determine protein localization and expression patterns. Clonal analyses were used to observe the phenotype. RNA-seq was used to screen downstream mechanisms. Results Here, we report a member of the chloride channel family, ClC - c , which is specifically expressed in Drosophila intestinal stem/progenitor cells and regulates intestinal stem cell (ISC) proliferation under physiological conditions and upon tissue damage. Mechanistically, we found that the ISC loss induced by the depletion of ClC - c in intestinal stem/progenitor cells is due to inhibition of the EGFR signalling pathway. Conclusion Our findings reveal an ISC-specific function of ClC - c in regulating stem cell maintenance and proliferation, thereby providing new insights into the functional links among the chloride channel family, ISC proliferation and tissue homeostasis.
研究领域:
细胞生物学
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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
EMBO JOURNAL
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2020
·Vol. 39
·期 5
·e101679
·
IF 9.889
Jun Wu,Wen-Jia Tian,Yang Liu,Huanhuan J Wang,Jiangli Zheng,Xin Wang,Han Pan,Ji Li,Junyu Luo,Xuerui Yang,Lester F Lau,H Troy Ghashghaei,Qin Shen
Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular–subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.
研究领域:
神经科学
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干细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2017
·
IF 2.981
Guan Huang,Yanli Tong,Qidi He,Jie Wang,Zuanguang Chen
Ethnopharmacological relevance Aucklandia lappa DC. is a widely used medicinal plant in China, India and Pakistan for a long time. Previously, a number of different pharmacological experiments in vitro and in vivo have convincingly demonstrated the abilities of it to exhibit anticancer activities. Reynoutria japonica Houtt. has also been widely used as traditional Chinese medicinal plant. Previous studies have demonstrated that it is bioactive to exhibit anticancer activities. Aim of the study This study aims to investigate whether the extracts of Aucklandia lappa DC. and Reynoutria japonica Houtt. are capable of treating drug-resistant non-small cell lung cancer (NSCLC), providing support for novel usage beyond traditional uses. Materials and methods Extracts combined with gefitinib have been tested taking the vulval development of transgenic C. elegans ( jgIs25 ) as an effective and simple in vivo model system, evaluating their efficacy against acquired NSCLC. Synchronous larval 1 (L1) larvae were treated with extracts plus gefitinib and cultured to obtain mainly L4 larvae. The multivulva (Muv) phenotype was recorded at the adult stage. Results Our data showed that Aucklandia lappa DC. extract could significantly enhance the efficacy of gefitinib, suppressing the Muv phenotype of jgIs25. Meanwhile, it could also down-regulate the mRNA and protein expression of EGFR in jgIs25. Collectively, our results verified that the capability of Aucklandia lappa DC. to inhibit Muv phenotype may be based on the EGFR signaling pathway inhibition. Conclusion We demonstrated that the co-administration of Aucklandia lappa DC. with gefitinib may provide an effective strategy for the therapy of EGFR inhibitor resistant NSCLCs.
研究领域:
民族药理学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
RESPIRATORY RESEARCH
·
2024
·Vol. 25
·期 1
·1-16
·
IF 4.7
Wang Han,Du Xiaohui,Liu Wenwen,Zhang Congcong,Li Ying,Hou Jingwen,Yu Yi,Li Guiru,Wang Qi
BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs.MethodsWe established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment.ResultsBetulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts.ConclusionsBA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers.Graphical abstract
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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DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2018
·Vol. 28
·期 22
·1800692
·
IF 13.325
Bowen Li,Xin Xie,Zelin Chen,Chenyue Zhan,Fang Zeng,Shuizhu Wu
Comprehensive understanding of signaling pathways regulating cancer progression has led to tremendous advances of molecularly targeted therapies. The epidermal growth factor receptor (EGFR) pathway is an attractive target for cancer therapy, and targeting multiple key elements in the pathway may further facilitate therapeutic efficacy. Here, an EGFR-targeted nanoprodrug is demonstrated for in vivo imaging and tumor inhibition, which is assembled by a disulfide-bridged quercetin (QSSQ) and an EGFR inhibitor erlotinib. QSSQ is synthesized via chemical manipulation of multiple phenolic hydroxyl groups on quercetin; and the nanoprodrug is then fabricated through the disulfide-facilitated assembly of QSSQ and erlotinib. The nanoprodrug is of high drug loading (87.3%) since its only inert component is the disulfide linker. The nanoprodrug is stable in physiological environment, whereas overexpressed glutathione in tumor tissue breaks the disulfide bridge, thereby disrupting the nanostructure and releasing active drugs quercetin and erlotinib. Upon release, erlotinib serves as an active drug blocking the EGFR tyrosine kinase, and quercetin generates strong aggregation-induced emission of fluorescence for imaging drug release and acts as another drug inhibiting the downstream EFGR signaling, as evidenced by Western blotting analyses. The combined action thereof results in remarkable antitumor efficacy toward xenograft tumor-bearing mice.
研究领域:
癌症治疗
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药学
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纳米技术
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分子生物学
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DOI
高影响因子
LIFE SCIENCES
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2024
·
IF 5.2
Chao Sun,Qiushuang Ma,Liya Feng,Jianbo Ji,Dandan Du,Pengfei Shang,Xiuli Guo
Aims This study aims to investigate the role of SOD3 in gastric cancer (GC) progression and its impact on chemotherapy efficacy and toxicity. It further seeks to evaluate the therapeutic potential of MCP in enhancing SOD3 activity to improve treatment outcomes and reduce chemotherapy-induced peripheral neurotoxicity (CIPN). Materials and methods We used overexpression plasmids and small interfering RNAs (siRNAs) to modulate the expression of SOD3 and Desmocollin2 (DSC2) in gastric cancer cells. Molecular biology experiments were performed to analyze pathway-related protein expression and molecular interactions. In vitro and in vivo experiments were conducted to evaluate the effects of modified citrus pectin (MCP) and oxaliplatin (OXA), individually and in combination, on gastric cancer progression and CIPN. Key findings SOD3 inhibited the proliferation, migration, and invasion of GC cells via SOD3/EGFR/PKP3/DSC2 axis. MCP selectively increased SOD3 levels and enhanced its anti-tumor effects. Combined treatment with MCP and OXA synergistically inhibited GC progression in vitro and in vivo, while MCP alleviated CIPN, enabling OXA dose reduction without compromising efficacy. Significance The findings revealed that SOD3 played a critical tumor-suppressive role in gastric cancer by modulating the SOD3/EGFR/PKP3/DSC2 axis. MCP, a natural compound that selectively boosted SOD3 levels, enhanced chemotherapy efficacy while reducing peripheral neurotoxicity, providing a promising strategy to improve gastric cancer treatment and mitigate chemotherapy-related side effects.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Tiantian An,Zhaoyu Xu,Yang Yang,Xinhui Li,Shuaidong Chen,Xingmei Yang,Yi Man,Chen Hu,Yili Qu
This study investigates the role of γδ T cells in wound healing facilitated by an EGCG (Epigallocatechin gallate)-releasing nanofibrous scaffold with aligned topography (APEMS). Incorporating core-shell microcapsules for sustained EGCG release over 11 days, the biocompatible scaffold enhances γδ T cell activity to promote advanced wound repair. In a splinted wound excisional model in 6-8 weeks-old male C57BL/6J mice, APEMS significantly improved re-epithelialization and wound closure compared to a control scaffold (APS). Single-cell RNA sequencing revealed a marked increase in γδ T cell in the APEMS group, where γδ T cells accounted for 66.2% of the T cell population, compared to 33.8% in the APS group. Cellchat analysis identified the AREG-EGFR signaling axis as pivotal to γδ T cell-mediated wound repair. APEMS-induced γδ T cells secreted amphiregulin (AREG), which acted on keratinocytes and fibroblasts to enhance keratinocyte proliferation, migration, and fibroblast-driven extracellular matrix remodeling. In immunodeficient mice lacking mature γδ T cells (TCRδ-/-), wound healing was significantly impaired, characterized by delayed re-epithelialization, reduced neo-dermal thickness, and increased inflammation. Inhibition of AREG and EGFR function via monoclonal antibodies against AREG and EGFR antagonist Gefitinib similarly delayed wound healing, the therapeutic advantage of APEMS over APS was abolished, emphasizing its critical role in the process. These findings provide a framework for developing advanced wound management materials and highlight the therapeutic potential of targeting γδ T cells and AREG-EGFR signaling to enhance tissue regeneration.
研究领域:
生物材料
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免疫学
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组织工程
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再生医学
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药学
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细胞生物学
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皮肤科学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2017
·
IF 3.671
Yang Chunhui,Cai Wenjun,Wen Hui,Sha Liquan,Zhao Changwei,Zhang Tianzhu,Zhao Wenhai
Epidermal growth factor (EGF)/EFG receptor (EGFR) signaling plays an important role in the osteoblastogenesis. The potential effects of pilose antler peptide (PAP) on osteoblast cell damages was investigated in our present study through EGF/EGFR signaling. In MC3T3-E1 osteoblastic cells, PAP treatment significantly inhibited the production of inflammatory cytokines by decreasing the levels of serum proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). PAP treatment also alleviated the oxidative responses as indicated by increased activities of catalase (SOD) and decreased levels of malondialdehyde (MDA). EGF inhibition, by siRNA knockdown, almost abolished PAP-induced osteoblast cytoprotection against inflammation and oxidant stress. Further, our results showed that PAP stimulated the nuclear erythroid factor 2-related factor 2 (Nrf2)2/heme oxygenase-1(HO-1) signaling, and inhibited the activation of uclear factor kappa B (NF-κB) pathway in MC3T3-E1 cells. On the other hand, EGF siRNA knockdown inhibited PAP-induced cytoprotection, which decreased the expression of Nrf-2, HO-1 and increased the level of p -NF-κBp65, p -IκBα in MC3T3-E1 cells. Thus, our research demonstrated that PAP protects osteoblasts from inflammatory and oxidative injury through EGF/EGFR signaling.
研究领域:
药理学
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细胞生物学
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分子生物学
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骨骼生物学
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产品关联
DOI
PubMed
高影响因子
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