Small
·
2023
·
IF 13.3
Yuan Li,Kuo Zhang,Xuezheng Ai,Qingshi Zhang,Lu Jiang,Jiang Long,Huange Xu,Chencheng Feng,Yaqing Zhang,Guoke Tang,Fanli Chong,Lei Wang,Bo Huang
Maintaining quiescence of stem cells is a potential way to decrease cell nutrition demand for restoring the organization. Herein, a biomimetic peptide to maintain quiescence of stem cells through C-X-C motif chemokine ligand 8 (CXCL8)-C-X-C motif chemokine receptor 1 (CXCR1) pathway against intervertebral disc degeneration (IVDD) is developed. First, it is confirmed that quiescence can be induced via inhibiting phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in nucleus pulposus stem cells (NPSCs). Meanwhile, it is well known that CXCR1, a chemokine receptor, can be targeted by CXCL8, resulting in cell proliferation via activating PI3K/Akt/mTOR pathway. Second, a biomimetic peptide (OAFF) that can bind to CXCR1 and form fibrous networks on NPSCs, mimicking extracellular matrix formation is developed. The multivalent effect and long-term binding to CXCR1 on NPSCs of OAFF fibers offer forcefully competitive inhibition with natural CXCL8, which induces NPSCs quiescence and ultimately overcomes obstacle in intradiscal injection therapy. In rat caudal disc puncture model, OAFF nanofibers still maintain at 5 weeks after operation and inhibit degeneration process of intervertebral disc in terms of histopathology and imageology. In situ fibrillogenesis of biomimetic peptide on NPSCs provides promising stem cells for intradiscal injection therapy against IVDD.
研究领域:
生物医学工程
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干细胞生物学
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组织工程
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再生医学
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骨科
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DOI
PubMed
高影响因子
STEROIDS
·
2020
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IF 1.948
Jingwen Xu,Mingmei Zhang,Xiaoying Lin,Yihai Wang,Xiangjiu He
Allium chinense , as a side dish on Asian table, is often used in folk medicine for its health benefits. (25R)-5α-spirostan-3β-yl-3-O-acetyl-O-β- d -glucopyranosyl-(1 → 2)-O-[β- d -glucopyranosyl-(1 → 3)]-O-β- d -glucopyranosyl-(1 → 4)-β- d -galactopyranoside (A-24) is a bioactive steroidal saponin isolated from Allium chinense . Previously, we have shown that A-24 has cytotoxic effects on cancer cells, but not on normal cells. To further explore the underlying mechanisms, in this study, we investigated the anticancer activity of A-24 in human gastric cancer cell lines in terms of cell proliferation, colony formation, cell cycle, induction of apoptosis/autophagy, and PI3K/Akt/mTOR pathway. A-24 showed dose-dependent cytotoxicity in SGC-7901 and AGS cell lines, it induced intrinsic mitochondrial pathway of apoptosis as well as autophagy, G2/M phase arrest and modulation of cyclinB1, p-cdc2, p-wee1 and p-Histone H3 expression. Furthermore, A-24 downregulated the phosphorylation of Akt at Ser473 and mTOR at Ser2448 in PI3K/Akt/mTOR pathway, and its downstream substrates p-p70S6K and p-4EBP1 in a dose-dependent manner. In addition, the pre-treatment of tumor cells with 3-methyladenine (3-MA) and LY294002 increased A-24-induced apoptosis. Collectively, these findings highlight the significance of downregulation of PI3K/Akt/mTOR pathway in A-24-induced apoptosis and autophagy, and the potential application of A-24 as a novel candidate in the treatment of human gastric adenocarcinoma.
研究领域:
药理学
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肿瘤学
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细胞生物学
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分子生物学
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生物化学
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DOI
PubMed
高影响因子
CURRENT CANCER DRUG TARGETS
·
2022
·Vol. 22
·期 1
·86-95
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IF 2.907
Yiyan SongYang,Yang Songyisha,Li Dejia,Li Wen
Background: Non-Small-Cell Lung Cancer (NSCLC) is the most prevalent form of lung cancer, accounting for approximately 85% of all lung cancer cases and resulting in high morbidity and mortality. Previous studies have demonstrated that 1,25-dihydroxy-vitamin-D3 (vitamin D) exhibited
anti-cancer activity against breast and prostate cancer. Objectives: The aim of the current study is to investigate the effect of vitamin D on NSCLC and its underlying mechanism. Methods: The effects of vitamin D on stemness maintenance and the Warburg effect in NSCLC cells were
investigated both in vitro and in vivo. Results and Discussion: In vitro experiments revealed that vitamin D inhibited glycolysis and stemness maintenance in A549 and NCI-H1975 cells. Both in vitro and in vivo experiments indicated that vitamin D attenuated the expression of metabolism-related
enzymes associated with the Warburg effect (GLUT1, LDHA, HK2, and PKM2). In addition, vitamin D down-regulated the expression of stemness-related genes (Oct-4, SOX-2, and Nanog) and the expression of PI3K, AKT, and mTOR. Conclusion: Overall, these findings suggest that vitamin D suppresses
the Warburg effect and stemness maintenance in NSCLC cells via the inactivation of PI3K/AKT/mTOR signaling, thereby inhibiting the progression of NSCLC. The current study indicates that vitamin D is a potential candidate in therapeutic strategies against NSCLC.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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细胞生物学
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DOI
PubMed
高影响因子
AQUATIC TOXICOLOGY
·
2026
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IF 4.6
Zhihui Jiang,Yufei Du,Yilin Zhu,Jingyan Wu,Shengming Ma,Shaoting Weng,Kunpeng Zhang
Dimethyl phthalate (DMP), a widespread environmental pollutant, poses serious risks to aquatic organisms. This study investigated the mechanisms of DMP-induced oxidative stress and autophagy in zebrafish gill tissues, and evaluated the protective effect of 1,8-cineole. Zebrafish models were established for DMP exposure alone, 1,8-cineole treatment alone, and combined exposure. Using histopathology, transmission electron microscopy, fluorescence staining, antioxidant enzyme activity assays, real-time quantitative PCR, and Western blot, we systematically analyzed the impacts of DMP on gill morphology, oxidative stress levels, autophagy-related gene and protein expression, and the PI3K/AKT/mTOR signaling pathway. Results revealed that DMP exposure significantly induced oxidative stress and autophagy in gill tissues and suppressed PI3K/AKT/mTOR pathway activity. In contrast, 1,8-cineole treatment effectively alleviated DMP-induced oxidative damage and autophagy activation, while partially restoring PI3K/AKT/mTOR signaling. This study is the first to demonstrate that 1,8-cineole mitigates DMP-induced autophagy injury in gills by modulating the PI3K/AKT/mTOR pathway, offering a theoretical foundation and a potential green strategy for protecting aquatic organisms from phthalate toxicity.
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产品关联
DOI
PubMed
高影响因子
Oncology Letters
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2020
·Vol. 20
·期 6
·1-1
·
IF 2.311
Hao Zhu,Yuhuan Shi,Xiuxiu Jiao,Gang Yang,Rong Wang,Yongfang Yuan
Cisplatin resistance is an obstacle for the effective treatment of non‑small cell lung cancer (NSCLC). The combined use of two or more chemotherapeutic agents displays advantages for the clinical treatment of drug‑resistant lung cancer. The present study aimed to assess the synergy of the dual PI3K/Akt/mTOR signaling pathway inhibitor NVP‑BEZ235 and cisplatin, a chemotherapeutic agent, on proliferation, apoptosis, cell cycle arrest and protein expression in cisplatin‑resistant NSCLC A549/diamminedichloroplatinum resistance (DDP) cells. Cell proliferation was determined by performing Cell Counting Kit 8 and colony formation assays. Combination index (CI) was used to assess the combinatorial effects of NVP‑BEZ235 and cisplatin. Cellular apoptosis and cell cycle arrest were detected via flow cytometry. Western blotting was performed to evaluate protein expression levels relative to β‑actin. Cisplatin and NVP‑BEZ235 displayed the strongest synergy (CI50=0.23) at the mass ratio of 10:1. The half inhibitory concentrations of cisplatin and NVP‑BEZ235 at 10:1 were 1.53 and 0.15 µg/ml, respectively. Compared with the control group, the combination of cisplatin and NVP‑BEZ235 induced cell apoptosis and inhibited colony formation. Furthermore, compared with the control group, phosphorylation of Akt and p70S6 Kinase was significantly inhibited and cell cycle was arrested at G0G1 phase in the combination treatment group. The expression levels of drug efflux proteins, such as multidrug resistance‑associated protein 1 and ATP‑binding cassette sub‑family G member 2, were significantly decreased when A549/DDP cells were treated with a combination of cisplatin and NVP‑BEZ235 compared with the control group. Collectively, the present study indicated that the combined treatment of cisplatin and NVP‑BEZ235 displayed synergistic antitumor effects on drug‑resistant A549/DDP cells, by which the antiproliferative effects may occur via inhibition of the PI3K/Akt/mTOR signaling pathway and downregulation of drug efflux.
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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产品关联
DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2021
·Vol. 22
·期 5
·1-12
·
IF 2.447
Yiqiang Li,Mingwei Zhu,Xuemei Lin,Jingchun Li,Zhe Yuan,Yanhan Liu,Hongwen Xu
Neurofibromatosis type I (NF1) is an autosomal dominant genetic disease that is caused by mutations in the NF1 gene. Various studies have previously demonstrated that the mTOR complex 1 signaling pathway is essential for the NF1‑modulated osteogenic differentiation of bone mesenchymal stem cells (BMSCs). Additionally, the mTOR signaling pathway plays a notable role in autophagy. The present study hypothesized that NF1 could modulate the osteogenic differentiation of BMSCs by regulating the autophagic activities of BMSCs. In the present study, human BMSCs were cultured in an osteogenic induction medium. The expression of the NF1 gene was either knocked down or overexpressed by transfection with a specific small interfering RNA (siRNA) targeting NF1 or the pcDNA3.0 NF1‑overexpression plasmid, respectively. Autophagic activities of BMSCs (Beclin‑1, P62, LC3B I, and LC3B II) were determined using western blotting, electron microscopy, acridine orange (AO) staining and autophagic flux/lysosomal detection by fluorescence microscopy. In addition, the autophagy activator rapamycin (RAPA) and inhibitor 3‑methyladenine (3‑MA) were used to investigate the effects of autophagy on NF1‑modulated osteogenic differentiation in BMSCs. Inhibiting NF1 with siRNA significantly decreased the expression levels of autophagy markers Beclin‑1 and LC3B‑II, in addition to osteogenic differentiation markers osterix, runt‑related transcription factor 2 and alkaline phosphatase. By contrast, overexpressing NF1 with pcDNA3.0 significantly increased their levels. Transmission electron microscopy, AO staining and autophagic flux/lysosomal detection assays revealed that the extent of autophagosome formation was significantly decreased in the NF1‑siRNA group but significantly increased in the NF1‑pcDNA3.0 group when compared with the NC‑siRNA and pcDNA3.0 groups, respectively. In addition, the activity of the PI3K/AKT/mTOR pathway [phosphorylated (p)‑PI3K, p‑AKT, p‑mTOR and p‑p70S6 kinase] was significantly upregulated in the NF1‑siRNA group compared with the NC‑siRNA group, and significantly inhibited in the NF1‑pcDNA3.0 group, compared with the pcDNA3.0 group. The knockdown effects of NF1‑siRNA on the autophagy and osteogenic differentiation of BMSCs were reversed by the autophagy activator RAPA, while the overexpression effects of NF1‑pcDNA3.0 on the autophagy and osteogenic differentiation of BMSCs were reversed by the autophagy inhibitor 3‑MA. In conclusion, results from the present study suggest at the involvement of autophagy in the NF1‑modulated osteogenic differentiation of BMSCs. Furthermore, NF1 may partially regulate the autophagic activity of BMSCs through the PI3K/AKT/mTOR signaling pathway.
研究领域:
医学遗传学
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细胞生物学
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干细胞研究
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DOI
PubMed
高影响因子
Frontiers in Medicine
·
2025
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IF 3
Xiaohui Gao,Hui Zeng,Fei Sun,Xiaoyan Zhao,Haibing Wu,Minchao Yan,Yuan Li,Qinyan Fu,Gang Zhang
Purpose: This study aimed to evaluate the underlying mechanisms of decitabine (DAC) in inhibiting acute T-acute lymphoblastic leukemia (T-ALL) cell proliferation and promoting apoptosis.Methods: Human T-ALL cells (CCRF-CEM) were treated with varying concentrations of DAC, and cell proliferation was assessed using a CCK-8 assay. Flow cytometry was used to detect apoptosis and cell cycle alterations. The expression levels of apoptosis-related genes, including PI3K and miR-92b-3p, were quantified using real-time PCR (RT-PCR). Western blotting was used to analyze the expression of apoptotic proteins. Furthermore, we evaluated the in vivo antileukemic activity of DAC using a nude mouse xenograft model, monitored the body weight and tumor volume of mice to calculate inhibition rates, and examined tumor morphological changes in histological sections.Results: DAC significantly inhibited the proliferation of CCRF-CEM cells, accelerated apoptosis, and effectively downregulated the expression of PI3K, AKT, 4EBP1, and mTOR while concurrently upregulating PTEN protein expression. Its regulatory efficacy was markedly enhanced by increasing the dosage. Animal experimental results indicated that both DAC and doxorubicin substantially decreased tumor length, width, volume, and mass; however, DAC demonstrated significantly superior efficacy in inhibiting tumor growth compared to doxorubicin.Conclusion: By selectively targeting the regulation of PTEN and 4EBP1, along with their associated downstream signaling pathways, DAC effectively modulated cellular proliferation, facilitated apoptotic processes, and restrained tumor growth, providing a robust theoretical foundation for clinical treatment strategies in T-ALL.
研究领域:
血液学
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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
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2019
·
IF 3.17
Qi Wan,Hui Chen,Guirun Xiong,Rui Jiao,Yun Liu,Xiaolei Li,Yu Sun,Jingcheng Wang,Lianqi Yan
Intraarticular fibrosis following knee surgery is a troublesome complication and remains a challenging problem for clinicians. Artesunate (ART), a classical anti-malarial drug extracted from the Chinese medicinal herb Artemisia annua L, has been associated with some fibrosis-related diseases. However, its effect and underlying mechanism on knee arthrofibrosis are still obscure. In the present study, we found that ART induced cellular autophagy flux and inhibited cell proliferation in fibroblasts. Intriguingly, genetic depletion of Beclin-1 abolished ART-triggered cellular autophagy and further attenuated the inhibitory effect of ART on fibroblasts proliferation. Moreover, at molecular level, our results demonstrated that ART-induced autophagy activation was associated with the inhibition of mTOR signaling through PI3K/AKT/mTOR pathway and AMPK/mTOR pathway. In vivo, ART treatment triggered autophagy activation and alleviated the severity of surgery-induced knee arthrofibrosis. Taken together, we concluded that ART exhibited anti-proliferation efficacy in fibroblasts and alleviated the severity of knee arthrofibrosis in rabbits by inducing Beclin-1-mediated autophagy via inhibition of mTOR signaling. These findings indicated that ART might be a potential therapeutic agent for preventing the progression of surgery-induced intraarticular fibrosis of knee.
研究领域:
药理学
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骨科
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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
Frontiers in Cell and Developmental Biology
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2022
·
IF 6.081
Deng Changping,Hu Fabiao,Zhao Zhangting,Zhou Yiwen,Liu Yuping,Zhang Tong,Li Shihui,Zheng Wenyun,Zhang Wenliang,Wang Tianwen,Ma Xingyuan
Quantitative analysis and regulating gene expression in cancer cells is an innovative method to study key genes in tumors, which conduces to analyze the biological function of the specific gene. In this study, we found the expression levels of Survivin protein (BIRC5) and P-glycoprotein (MDR1) in MCF-7/doxorubicin (DOX) cells (drug-resistant cells) were significantly higher than MCF-7 cells (wild-type cells). In order to explore the specific functions of BIRC5 gene in multi-drug resistance (MDR), a CRISPR/Cas9-mediated knocking-in tetracycline (Tet)-off regulatory system cell line was established, which enabled us to regulate the expression levels of Survivin quantitatively (clone 8 named MCF-7/Survivin was selected for further studies). Subsequently, the determination results of doxycycline-induced DOX efflux in MCF-7/Survivin cells implied that Survivin expression level was opposite to DOX accumulation in the cells. For example, when Survivin expression was down-regulated, DOX accumulation inside the MCF-7/Survivin cells was up-regulated, inducing strong apoptosis of cells (reversal index 118.07) by weakening the release of intracellular drug from MCF-7/Survivin cells. Also, down-regulation of Survivin resulted in reduced phosphorylation of PI3K, Akt, and mTOR in MCF-7/Survivin cells and significantly decreased P-gp expression. Previous studies had shown that PI3K/Akt/mTOR could regulate P-gp expression. Therefore, we speculated that Survivin might affect the expression of P-gp through PI3K/Akt/mTOR pathway. In summary, this quantitative method is not only valuable for studying the gene itself, but also can better analyze the biological phenomena related to it.
研究领域:
癌症生物学
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分子生物学
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基因工程
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药理学
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DOI
PubMed
高影响因子
Journal of Functional Foods
·
2023
·
IF 5.6
Lina Jian,Huixing Wu,Haiyan Zeng,Ting Quan,Fan Xia,Shijian Xiang,Benjie Zhou
The therapeutic and pharmacological potential of isoliquiritigenin has been reported in relieving inflammation and lipid metabolism disorders, particularly in the context of non-alcoholic fatty liver disease (NAFLD). The aim of this study is to investigate the effects of isoliquiritigenin on NAFLD, obesity-associated metabolic symptoms in vivo and in vitro , and explore new mechanisms underlying its effects. Our study revealed that isoliquiritigenin effectively reduced lipid accumulation and suppressed inflammation factors expression in hepatocytes and high fat diet (HFD) mice. Additionally, it prevented body weight gain and liver damage in HFD mice. Importantly, RNA-sequencing results revealed that isoliquiritigenin exerts its anti-NAFLD effect may through the mTOR pathway and autophagy. Rescue experiments further confirmed that it inhibits inflammation by suppressing the PI3K/AKT/mTOR pathway and reduces lipid accumulation by promoting autophagy. Therefore, it holds promise as a novel treatment for NAFLD.
研究领域:
药理学
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肝病学
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代谢学
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分子生物学
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DOI
高影响因子
Cancer Cell International
·
2021
·Vol. 21
·期 1
·1-15
·
IF 5.722
Lv Minchao,Xu Qingxin,Zhang Bei,Yang Zhiqiang,Xie Jun,Guo Jinku,He Feixiong,Wang Wei
Background Osteosarcoma is the third most common cancer in adolescence and the first common primary malignant tumor of bone. The long-term prognosis of osteosarcoma still remains unsatisfactory in the past decades. Therefore, development of novel therapeutic agents which are effective to osteosarcoma and are safe to normal tissue simultaneously is quite essential and urgent. Methods Firstly, MTT assay, cell colony formation assay, cell migration and invasion assays were conducted to evaluate the inhibitory effects of imperatorin towards human osteosarcoma cells. RNA-sequence assay and bioinformatic analysis were then performed to filtrate and assume the potential imperatorin-induced cell death route and signaling pathway. Moreover, quantitative real-time PCR assay, western blot assay and rescue experiments were conducted to confirm the assumptions of bioinformatic analysis. Finally, a subcutaneous tumor-transplanted nude mouse model was established and applied to evaluate the internal effect of imperatorin on osteosarcoma by HE and immunohistochemistry staining. Results Imperatorin triggered time-dependent and dose-dependent inhibition of tumor growth mainly by inducing autophagy promotion and G0/G1 phase arrest in vitro and in vivo. Besides, imperatorin treatment elevated the expression level of PTEN and p21, down-regulated the phosphorylation of AKT and mTOR. In contrast, the inhibition of PTEN using Bpv (HOpic), a potential and selective inhibitor of PTEN, concurrently rescued imperatorin-induced autophagy promotion, cell cycle arrest and inactivation of PTEN-PI3K-AKT-mTOR/p21 pathway. Conclusions This work firstly revealed that imperatorin induced autophagy and cell cycle arrest through PTEN-PI3K-AKT-mTOR/p21 signaling pathway by targeting and up-regulating PTEN in human osteosarcoma cells. Hence, imperatorin is a desirable candidate for clinical treatments of osteosarcoma.
研究领域:
肿瘤学
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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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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Chanling Yuan,Chunguang Zhu,Qingshuang Lv,Jiahui Shi,Jiacheng Wang,Shiqi Gao,Jiayi Qian,Yanhua Chen,Qiong Wu,Wenjie Mei
Developing drugs for treating glioblastoma has been a significant challenge. Herein, a series of arene ruthenium(II) complexes have been synthesized and investigated as potential candidates to suppress the proliferation and metastasis of glioblastoma. It is found that para-substituent-modified molecules, especially 6, exhibit higher antitumor activity than ortho-substituents. Further studies show that 6 can trigger tumor cell autophagy by regulating the PI3K/AKT/mTOR pathway. Moreover, it is also found that 6 can induce DNA damage in glioblastoma cells through binding and stabilizing VEGF G-quadruplex DNA. Furthermore, it is confirmed that 6 can inhibit the proliferation and metastasis of U87-MG glioblastoma cell in situ xenograft in the zebrafish model. Hence, arene ruthenium(II) complexes can be developed as promising therapeutic agents for glioblastoma treatment in the future.
研究领域:
癌症研究
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药理学
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分子生物学
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化疗
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）