PLoS One
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2019
·Vol. 14
·期 10
·e0223760
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IF 2.776
Pan Zhang,Dan He,Erqun Song,Mingdong Jiang,Yang Song
The current study aimed to identify the radiosensitizing effect of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in combination with radiotherapy in non-small-cell lung cancer (NSCLC) cells. The combination of celecoxib potentiated radiation-induced apoptosis; however, no changes in cell cycle distribution and number of phosphorylated histone H2AX foci were detected, indicating a DNA damage-independent mechanism. In an in vivo mouse model, the tumor size was significantly decreased in the group combining celecoxib with radiation compared with the radiation only group. Phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR), as well as expression of COX-2 were significantly downregulated in cells treated with the combination of celecoxib and radiation compared with the radiation only group. The result indicated that celecoxib exhibits radiosensitizing effects through COX-2 and Akt/mTOR-dependent mechanisms. Induction the Akt/mTOR signaling pathway promotes radioresistance in various cancers, including NSCLC. Therefore, the current study suggested the therapeutic potential of combination therapy of celecoxib and radiation in the prevention of radioresistance.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2017
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IF 2.466
Menglu Zhou,Shuying Shen,Xin Zhao,Xingguo Gong
Autophagy has attracted a great deal of interest in tumour therapy research in recent years. However, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, on autophagy remains poorly understood in human lung cells. In the present study, we have investigated the anticancer effects of luteoloside on non-small cell lung cancer (NSCLC) cells and demonstrated that luteoloside effectively inhibited cancer cell proliferation , inducing G 0 /G 1 phase arrest associated with reduced expression of CyclinE, CyclinD1 and CDK4; we further found that treatment with luteoloside did not strongly result in apoptotic cell death in NSCLC (A549 and H292) cells. Interestingly, luteoloside induced autophagy in lung cancer cells, which was correlated with the formation of autophagic vacuoles, breakdown of p62, and the overexpression of Beclin-1 and LC3-II, but not in a human bronchial epithelial cell line (BEAS-2B). Notably, pretreatment of cancer cells with 3-MA, an autophagy inhibitor, protected against autophagy and promoted cell viability but not apoptosis. To further clarify whether luteoloside-induced autophagy depended on the PI3K/AKT/mTOR/p70S6K signalling pathway , a major autophagy-suppressive cascade, cells were treated with a combination of AKT inhibitor (LY294002) and mTOR inhibitor (Rap). These results demonstrated that luteoloside induced autophagy in lung cancer cell lines by inhibiting the pathway at p -Akt (Ser473), p -mTOR and p-p70S6K (Thr389). Moreover, we observed that luteoloside-induced cell autophagy was correlated with production of reactive oxygen species (ROS). NAC-mediated protection against ROS clearly implicated ROS in the activation of autophagy and cell death. In addition, the results showed that ROS served as an upstream effector of the PI3K/AKT/mTOR/p70S6K pathway. Taken together, the present study provides new insights into the molecular mechanisms underlying luteoloside-mediated cell death in NSCLC cells and supports luteoloside as a potential anti-cancer agent for targeting NSCLC through the induction of autophagy, inhibition of proliferation and PI3K/AKT/mTOR/p70S6K signalling.
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Applied Materials Today
·
2024
·
IF 7.2
Yaru Yue,Zhengquan Liao,Yingqian Zhou,Yongteng Zhang,Zeshu Wang,Shengtao Wang,Xianglong Hu,Quan Zhou
Rheumatoid arthritis (RA) is a common autoimmune disease, and the abnormal proliferation of fibroblast-like synoviocytes (FLSs) in inflamed joints plays a key role in the pathogenesis of RA, which has become an important therapeutic target for RA treatment. This work reported a facilely formulated nanoparticle from saponin (Sap) and dexamethasone (Dex) in precise ratio, affording the resultant Dex@Sap nanoparticles. Benefiting from the enlargement of vascular endothelial cell gap at the inflammation site and intra-articular injection, Dex@Sap could accumulate at the inflamed joints to inhibit excessive proliferation of FLSs and mediate cell apoptosis, achieving symptomatic relief and efficient RA treatment, while reducing the amount of drug needed as well as the occurrence of adverse reactions. Typical AKT (also known as protein kinase B, PKB)/mTOR (mammalian target of rapamycin) pathway was observed to be inhibited, and the mitochondria-mediated intracellular reactive oxygen species (ROS) level was also upregulated by Dex@Sap. Further in vivo evaluations demonstrated that Dex@Sap could significantly alleviate RA-induced inflammatory response and the expression of pro-inflammatory cytokines to cure joint damage in collagen-induced arthritis mice and rats. This work provides a clinically promising nanomedicine to synergistically treat RA.
研究领域:
药理学
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免疫学
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纳米技术
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风湿病学
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BRAIN RESEARCH BULLETIN
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2024
·
IF 3.5
Chenchen Zhao,Liang Sun,Yuxin Zhang,Xin Shu,Yujie Hu,Duo Chen,Zhi Zhang,Shengnan Xia,Haiyan Yang,Xinyu Bao,Jingwei Li,Yun Xu
Background Microglia-mediated inflammation is a critical factor in the progression of ischemic stroke. Consequently, mitigating excessive microglial activation represents a potential therapeutic strategy for ischemic injury. Thymol, a monophenol derived from plant essential oils, exhibits diverse beneficial biological activities, including anti-inflammatory and antioxidant properties, with demonstrated protective effects in various disease models. However, its specific effects on ischemic stroke and microglial inflammation remain unexplored. Methods Rodent transient middle cerebral artery occlusion (tMCAO) model was established to simulate ischemic stroke. TTC staining, modified neurological function score (mNSS), and behavioral tests were used to assess the severity of neurological damage. Then immunofluorescence staining and cytoskeleton analysis were used to determine activation of microglia. Lipopolysaccharide (LPS) was utilized to induce the inflammatory response of primary microglia in vitro . Quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and enzyme-linked immunosorbent assay (ELISA) were performed to exam the expression of inflammatory cytokines. And western blot was used to investigate the mechanism of the anti-inflammatory effect of thymol. Results In this study, we found that thymol treatment could ameliorate post-stroke neurological impairment and reduce infarct volume by mitigating microglial activation and pro-inflammatory response (IL-1β, IL-6, and TNF-α). Mechanically, thymol could inhibit the phosphorylation of phosphatidylinositol-3-kinase (PI3K), sink serine/threonine kinase (Akt), and mammalian target of rapamycin (mTOR), thereby suppressing the activation of nuclear factor-κB (NF-κB). Conclusions Our study demonstrated that thymol could reduce the microglial inflammation by targeting PI3K/Akt/mTOR/NF-κB signaling pathway, ultimately alleviating ischemic brain injury. These findings suggest that thymol is a promising candidate as a neuroprotective agent against ischemic stroke.
研究领域:
神经科学
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药理学
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炎症
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中风
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Neurotherapeutics
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2025
·
IF 6.9
Yue Zhang,Lan Deng,Jing Wei,Lufen Huang,Fei Gao,Lu Yu,Fengdan Zhu,Jianing Mi,Jianming Wu,Fang Ren,Minsong Guo,Xiaogang Zhou,Dalian Qin,Ting Chen,Anguo Wu
Alzheimer's disease (AD) pathology involves amyloid-beta (Aβ) accumulation and neuronal toxicity, highlighting the need for therapeutic strategies that can both inhibit Aβ aggregation and promote pathogenic protein clearance. In this study, we identified Gaultheria leucocarpa as a medicinal plant with promising neuroprotective potential. Thioflavin T (ThT) fluorescence screening revealed that extracts from G. leucocarpa (GE), particularly the petroleum ether fraction of G. leucocarpa extract (GPF), effectively inhibited Aβ fibril formation in vitro . In cell-based assays, GPF significantly improved the viability of PC-12 cells exposed to Aβ peptides and fibrils, indicating protection against Aβ-induced cytotoxicity. Furthermore, GPF enhanced mitophagic activity, as demonstrated by increased GFP-LC3 puncta, elevated LC3-II/I ratio, and colocalization of GFP-LC3 with MitoTracker Red. Mechanistic investigations showed that GPF activates mitophagy via the AMPK/ULK1 pathway and inhibits the PI3K/AKT/mTOR pathway, resulting in enhanced degradation of APP and Tau proteins. In Caenorhabditis elegans models relevant to AD, GPF administration led to reduced Aβ deposits, delayed paralysis onset, improved food perception, and decreased oxidative stress. Collectively, these findings demonstrate that GPF exerts dual actions by inhibiting Aβ fibrillization and promoting mitophagy-mediated degradation of pathogenic proteins. The active ingredients identified from GPF extracts represent promising leads for the development of novel neuroprotective agents targeting AD-related pathological mechanisms.
研究领域:
神经科学
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药理学
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生物化学
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细胞生物学
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药物化学
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神经退行性疾病
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Anquan Ma,Ziqing Yang,Qixuan He,Wenhao Wang,Huiping Ren,Chuanyao Zhai,Jing Lan
Environmental glyphosate exposure has been linked to glioblastoma (GBM), yet its molecular basis remains unclear. Integrating network-toxicology and druggable Mendelian randomization screens, we identified the Src-family kinase FYN as the principal glyphosate target. Molecular-dynamics simulations, surface-plasmon resonance (KD = 1.54 μM) and pull-down assays confirmed high-affinity binding and highlighted ASP353 as a dominant contact residue. Multi-omics profiling showed FYN over-expression and promoter hypomethylation in GBM, correlating with diminished immune infiltration. In U87 cells, sub-toxic glyphosate (0.1 mg/L, 12 h) up-regulated FYN, activated PI3K–AKT–mTOR signaling, increased GLUT1, LDHA and PKM2, and accelerated proliferation, migration and invasion; lentiviral sh-FYN reversed these effects and curtailed glycolytic flux. Orthotopic mouse studies mirrored the in-vitro findings, with FYN knock-down suppressing glyphosate-driven tumor growth. Exosomes derived from sh-FYN glioma cells weakened macrophage M2 polarization and reduced CXCL1, IL-10 and TGF-β secretion, revealing an immunometabolism axis. Collectively, these results establish FYN as the mechanistic conduit between glyphosate and GBM and demonstrate that targeting FYN—directly or via exosome delivery—reprograms tumor glycolysis and immunity, offering a tractable strategy against glyphosate-associated malignancy.
研究领域:
毒理学
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肿瘤学
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分子生物学
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生物信息学
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神经肿瘤学
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药理学
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免疫学
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2019
·
IF 4.784
Qiang Chu,Shuang Zhang,Lushuang Yu,Yonglu Li,Yangyang Liu,Xiang Ye,Xiaodong Zheng
The tubers of Apios americana Medikus possess high nutritional value and have been used as food in many countries for a long time. However, few researches have focused on the tuber polysaccharides. In the present study, a purified polysaccharide (ATP-1) was isolated with the average molecular weights of 12.16 kDa. ATP-1 significantly suppressed the release of nitric oxide (NO) and inflammatory cytokines from LPS-induced RAW 264.7 cells, as well as oxidative stress and mitochondrial dysfunction. Meanwhile, ATP-1 reduced oxidative damage via the NF-κB, MAPKs and Nrf2-Keap1 signaling pathways in RAW264.7 macrophages. Furthermore, autophagy was activated by HMGB1-Beclin1, Sirt1-FoxO1 and Akt-mTOR signaling pathways, leading to a relief of oxidative stress, mitochondrial dysfunction, inflammation and an expression enhancement of autophagy-related proteins, such as LC3, Beclin1, Atg4, Atg5, and Atg7. In summary, our results suggested that ATP-1 might help to activate the anti-inflammation system，resulting in prevention of LPS-induced damage in RAW264.7 cells.
研究领域:
药理学
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免疫学
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细胞生物学
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生物化学
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Bioengineered
·
2021
·
IF 3.269
Xinyue Zhou,Zhenyu Chen,Lipeng Pei,Jingli Sun
Emerging evidence has exhibited an obvious decreased expression of miR-106a-5p in the ectopic endometrial tissue of endometriosis (EMS) patients. Thus far, the pathophysiological function of miR-106a-5p in EMS is unknown. A previous study showed an increased FOXC1 expression in the ectopic endometrial tissue of patients with EMS. Moreover, we found that there was a binding site of miR-106a-5p on the 3ʹUTR of FOXC1 through bioinformatics predictions. Hence, we speculated that miR-106a-5p might affect the development of EMS via targeting FOXC1. We first showed a decreased level of miR-106a-5p and an increased level of FOXC1 mRNA in ectopic endometrial tissues compared with normal tissues. Functionally, we transfected ectopic endometrial stromal cells (ESCs) with miR-106a-5p mimics or NC mimics and indicated an inhibitory role of miR-106a-5p on ESC proliferation, invasion, and migration. Mechanistically, FOXC1 was found to be a target gene of miR-106a-5p. To confirm whether miR-106a-5p exerted an inhibitory activity in ESCs via targeting FOXC1, miR-106a-5p mimic was co-transfected into ESCs with the FOXC1-plasmid or vector. We found that FOXC1 overexpression evidently reversed the results caused by a miR-106a-5p mimic in ESCs. Additionally, our results demonstrated that miR-106a-5p mimic inhibited the expression of p-Akt and p-PI3K. Collectively, these results revealed that miR-106a-5p inhibited the proliferative, migratory, and invasive ability of ESCs via directly binding to FOXC1, likely through the suppression of the PI3K and its downstream signaling pathway, which offered a potential and novel therapeutic strategy for EMS treatment.
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Experimental and Therapeutic Medicine
·
2020
·Vol. 20
·期 5
·1-1
·
IF 1.785
Miao Liu,Wenjie Xie,Xinyue Wan,Tao Deng
Clostridium butyricum (CB), a probiotic, is a gram-positive obligate anaerobic bacillus with acid and heat resistant properties. Previous studies have reported that CB has beneficial effects in intestinal diseases and regulates intestinal function. The aim of the present study was to investigate the protective effects and mechanisms of CB on the intestinal barrier function. Mice were randomly divided into three experimental groups (n=15 mice/group), including control, dextran sodium sulfate (DSS) and DSS + CB. In the DSS and DSS + CB groups colitis was induced with 3% DSS dissolved in drinking water for 7 days. DSS + CB group mice were co-treated daily with 200 µl (2x108 CFU) CB solution via gavage. The intestinal mucosal barrier function in mice was assessed by measuring FITC-labeled 4-kDa dextran (molecular weight, 4,000 Da) flux and by analyzing the expression of tight junction (TJ)-related proteins using western blot analysis. In addition, the secretion levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-10 and IL-13, and the concentration of malondialdehyde, glutathione and superoxide dismutase were detected using ELISAs to determine inflammation and oxidative stress, respectively. The activation status of the Akt/mTOR signaling pathway was also investigated using western blot analysis. The results demonstrated that, in mice with DSS-induced colitis treatment, co-treatment with CB attenuated colitis symptoms and intestinal permeability, increased the expression levels of TJ-related proteins, decreased TNF-α, IL-1β and IL-13 secretion levels but increased those of IL-10, and reduced oxidative stress. Additionally, CB elevated the phosphorylation of Akt, mTOR and p70 ribosomal protein S6 kinase. Collectively, the present results indicated that CB protected intestinal barrier function and decreased intestinal mucosal permeability via upregulating the expression levels of TJ-related proteins in a mouse model of DSS-induced colitis. Moreover, the results suggested that the effects of CB could be mediated by the Akt/mTOR signaling pathway.
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MOLECULAR IMMUNOLOGY
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2024
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IF 3.2
Chaonan Zhu,Zhiquan Chen,Shuai Wang,Junmei Cao,Yuan Cheng,Maogen Zheng
Lung adenocarcinoma (LUAD) is a highly heterogeneous disease that threaten human life with serious incidence and high mortality. High heterogeneity of tumor microenvironment (TME) was reported in multiple studies. However, the factor of controlling the tumor migration progression between eary and late-stage LUAD is still not fully understood. In this study, we conducted a comprehensive analysis of single-cell RNA sequencing (scRNA-seq) data of LUAD obtained from the GEO database. The identification of cell clusters revealed significant expansion of epithelial cells in late-stage patients. Interpretation of the cell-cell communication results between early-stage and late-stage patient samples indicated that early tumor cells may interact with epithelial cells through the TGF-β pathway to promote tumor progression. The cell cycle analysis demonstrated a significant increase in the number of cells in the G2 and M phases in late-stage lung cancer. Further analysis using Non-negative Matrix Factorization (NMF) revealed early-stage cell-specific gene features involved in cell adhesion-related biological processes. Among these, the Tensin (TNS) gene family, particularly TNS1, showed high expression in epithelial cells and fibroblasts of early-stage samples, specifically associated with cell adhesion. Survival analysis using TCGA database for LUAD demonstrated that patients with high expression of TNS1 exhibited significantly higher overall survival rates compared to those with low expression. Immunofluorescence experiments have demonstrated co-expression of TNS1 with fibroblast and tumor cell markers (α-SMA and EPCAM). Immunohistochemistry experiments further validated the significantly higher expression levels of TNS1 in early-stage LUAD tissues compared to late-stage lung cancer tissues (P<0.05). Pathway experiments have shown that early-stage tumor patients with high expression of TNS1 exhibit stronger phosphorylation levels of Akt and mTOR, indicating a more potent activation of the Akt/mTOR signaling pathway. In conclusion, the results of this study demonstrate that TNS1 is an adhesive molecule in the immune microenvironment of early-stage tumor cells, and it may serve as a novel prognostic marker for lug cancer.
研究领域:
肿瘤学
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分子生物学
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基因组学
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细胞生物学
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癌症生物学
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BIOMACROMOLECULES
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2025
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IF 5.4
Yuxin Huang,Wenya Zhu,Jiaxin Zhang,Yichen Zhang,Yuxin Liu,Guowei Wang,Wuli Yang
Triple-negative breast cancer (TNBC) remains a formidable clinical challenge due to its aggressive behavior, lack of therapeutic targets, and poor prognosis. The PI3K/AKT/mTOR pathway is highly activated in TNBC, making it a promising therapeutic target. Conventional PEGylated nanocarriers often face challenges, such as accelerated blood clearance and lysosomal trapping. To overcome these limitations, we developed a zwitterionic block copolymer, poly(2-(N-oxide-dimethylamino)ethyl methacrylate)-block-poly(ε-caprolactone) (OPDMA-PCL), via one-pot living anionic polymerization followed by postmodification. Compared with poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) micelles, the OPDMA-PCL micelles exhibited prolonged systemic circulation, improved tumor targeting, and negligible immunogenicity. OPDMA-PCL micelles exhibited mitochondria-targeting properties in vitro. Loaded with gambogenic acid (GNA), OPDMA-PCL-GNA induces apoptosis in MDA-MB-231 cells by inhibiting the PI3K/AKT/mTOR pathway. In vivo, OPDMA-PCL-GNA achieved 91.2% tumor growth inhibition in xenograft models without systemic toxicity. This work establishes zwitterionic OPDMA-PCL micelles as a promising platform for TNBC therapy, overcoming key limitations of PEGylated systems while enabling organelle-specific drug delivery.
研究领域:
生物医学工程
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药学
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肿瘤学
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聚合物化学
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纳米技术
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细胞生物学
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2017
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IF 3.671
Wenjie Jiang,Yanna Cheng,Na Zhao,Lian Li,Yikang Shi,Aizhen Zong,Fengshan Wang
Previous studies demonstrated that SIP-SII, a sulfated derivative of SIP that is isolated from the ink of Sepiella maindroni , showed significant inhibition of tumor growth and metastasis. In this study, the effects of SIP-SII on the migration, invasion and molecular mechanism in ovarian cancer cell line, SKOV-3 cells, were investigated. The flow cytometry, confocal microscope observation, western blot and RT-PCR results indicated that SIP-SII located on cell membrane and inhibited the expression and activation of epidermal growth factor receptor (EGFR). Moreover, the binding capacity of SIP-SII with EGFR was confirmed by surface plasmon resonance (SPR) analysis and co-localization of EGFR and SIP-SII. Accordingly, SIP-SII was proved to attenuate the EGF-induced EGFR phosphorylation and migration by western blot and wound healing assay, respectively. Additionally, SIP-SII inhibited p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells significantly. What is more, SIP-SII showed amplified inhibitory activity on migration, invasion, and MMP-2 expression in combination with p38-specific inhibitor, PI3K-specific inhibitor or mTOR-specific inhibitor in SKOV-3 cells. Therefore, the mechanism that SIP-SII suppressed EGFR-mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways to inhibit migration and invasion of SKOV-3 cells was demonstrated. These findings suggested that SIP-SII might be used as a potential inhibitor against tumor metastasis.
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