COLLOIDS AND SURFACES B-BIOINTERFACES
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2026
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IF 5.9
Chen Guo,Yunqing Xie,Ziyao Lu,Shanshan Chen,Lili Su,Xiaowei Lin,Li Chen,Shaukat Semm Ally Basinda,Yang Sun,Jianyong Liu,Qinying Liu
Hypoxia is a distinctive characteristic of solid tumors, limiting the efficiency of photodynamic therapy (PDT). In this study, transcriptomics was applied to analyze the changes in mRNA levels in mouse tumors treated with multiple photodynamic therapy sessions, revealing that 12 genes in the PI3K/mTOR pathway were significantly upregulated. In order to improve delivery efficiency and enhance the efficacy of PDT photosensitizers, a nitroreductase-responsive BODIPY prodrug (BNP) was designed and employed to encapsulate a PI3K/ mTOR dual inhibitor (BEZ235) to self-assemble into nanoparticles (BNP@BEZ NPs). The fluorescence level of BNP@BEZ NPs in hypoxic cells was 12.20-fold that in normoxic cells because of the responsiveness of nitrobenzyl groups to hypoxia. Such minimized off-target effects also resulted in preferential intratumoral activation of prodrugs. Meanwhile, BEZ co-loading alleviated tumor hypoxia and increased intracellular ROS levels to 155.26% compared to blank prodrug nanoparticles. BNP@BEZ NPs-mediated PI3K/mTOR inhibition and apoptosis of tumor cells exhibited sufficient antitumor efficacy with a tumor inhibition rate of 93.31%. In conclusion, this study confirms that the PI3K/mTOR pathway promotes tumor PDT resistance by enhancing mitochondrial respiration. The hypoxic -responsive photodynamic properties of BNP, combined with BEZ's oxygen consumption-inhibiting capacity, can enhance tumor suppression rates. This strategy of nanomedicine development by capitalizing on the synergistic effect between active ingredients will avoid the low efficacy and adverse effects of monotherapies.
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Frontiers in Oncology
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2025
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IF 3.3
Jing Cheng,Zhihan Liu,Haibo Liu,Chao Fang,Jun Li
Colorectal cancer (CRC) is one of the most prevalent malignant tumors worldwide, with its pathogenesis tightly linked to the regulation of cell death. Ferroptosis plays a pivotal role in the initiation, progression, and treatment of CRC. In our previous studies, we demonstrated that PPP2CA knockdown enhances the malignant phenotype of CRC cells while increasing their susceptibility to ferroptosis, albeit this latter effect frequently mitigates the malignant phenotype. The present study aims to further elucidate the regulatory mechanism underlying the association between PPP2CA and ferroptosis. Lentiviral-mediated PPP2CA knockdown was performed in CRC cell lines HCT116 and SW480 to establish stable PPP2CA-knockdown models, and PPP2CA gene expression in these models was verified. Colony formation assays and scratch wound healing assays were used to assess the proliferative and migratory capacities of CRC cells after PPP2CA knockdown. Additionally, CRC samples from The Cancer Genome Atlas (TCGA) database were analyzed via bioinformatics approaches to identify ferroptosis-related genes closely correlated with PPP2CA, with subsequent validation in model cells. The STRING database was employed to analyze the interaction networks between PPP2CA and target ferroptosis-related genes, predict potential signaling pathways via which PPP2CA regulates cellular ferroptosis, and validate these findings in model cells. Compared with the control group, HCT116 and SW480 cells in the PPP2CA-knockdown group exhibited significantly enhanced proliferative and migratory capacities. Bioinformatics analysis identified the top 10 most significant ferroptosis-related genes associated with PPP2CA. Validation in model cells showed that the expression levels of transferrin receptor (TFRC) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were significantly upregulated. STRING analysis and in-model-cell validation indicated that increased mTOR phosphorylation subsequent to PPP2CA knockdown could upregulate the protein expression levels of transferrin receptor (TfR, encoded by the TFRC gene) and ACSL4, and this effect could be reversed by the mTOR inhibitor rapamycin. Thus, PPP2CA knockdown enhances the malignant phenotype of CRC cells, while potentially upregulating the expression of ferroptosis-related genes TFRC and ACSL4 via the mTOR signaling pathway, thereby increasing ferroptosis sensitivity.
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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癌症研究
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信号转导
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American Journal of Translational Research
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2025
·Vol. 17
·期 10
·7749
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IF 1.6
Xiaowen Li,Ruikang Guo,Lingling Liang,Hao Liang,Guangqi Zhou,Qinglan Lu,Yonghui Huang,Zhen Qi,Xiaojie Li
Objective: Periodontitis, a prevalent oral disease leading to alveolar bone defects, remains a primary cause of tooth loss in adults. The biologic mechanisms driving bone loss in periodontitis are still poorly understood, limiting the development of genetic treatment. This study investigates potential therapeutic targets for alveolar bone loss by analyzing transcriptomic data related to the osteogenic differentiation of induced pluripotent stem cells (iPSCs). Methods: Using in vitro and in vivo models, we examined the role of neuropeptide Y receptor Y1 (NPY1R) and the PI3K-AKT-mTOR (PAM) signaling pathway in osteogenic differentiation and bone loss. A combination of bioinformatics, molecular biology, and histologic techniques was employed to pinpoint key signaling events that influence bone remodeling in periodontitis and to identify potential intervention points. Results: Transcriptomic profiling during iPSC osteogenic differentiation revealed significant upregulation of neuropeptide Y (NPY) and NPY1R. Suppression of NPY1R reduced the osteogenic capacity of iPSCs. Activation of the PAM pathway was observed during osteogenesis, and treatment with LY294002, a PAM pathway inhibitor, led to decreased osteogenic activity. In vivo experiments using a rat periodontitis model confirmed increased expression of NPY1R and activation of the PAM pathway, suggesting a role in bone repair processes. Conclusion: The NPY/NPY1R axis and the PAM signaling pathway appear to regulate bone regeneration and may be involved in preventing alveolar bone loss in periodontitis. These findings provide a new direction for therapy targeting bone defects associated with periodontal disease.
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JOURNAL OF BIOMEDICAL SCIENCE
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2023
·Vol. 30
·期 1
·1-19
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IF 11
Li Peisi,Zhou Dawang,Chen Dongwen,Cheng Yikan,Chen Yuan,Lin Zhensen,Zhang Xi,Huang Zhihong,Cai Jiawei,Huang Wenfeng,Lin Yanyun,Ke Haoxian,Long Jiahui,Zou Yifeng,Ye Shubiao,Lan Ping
Background A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies suggested an important role for tumor-infiltrating cytotoxic T lymphocytes (CTL) in enhancing response to immunotherapy. Here, we aim to identify gene that induce proliferative and cytotoxic states of CD8 + T cells, and to investigate its effect on CAR-T cells against colorectal cancer. Methods Correlation between the expression of IFI35 with the activation and cytotoxicity of CD8 + T cells was assessed with TCGA and proteomic databases. Then we constructed murine colon cancer cells over-expressing IFI35 and tested their effect on anti-tumor immunity in both immunodeficient and immunocompetent mouse models. Flow cytometry and immunohistochemistry were performed to assess the immune microenvironment. Western blot analysis was used to identify the potential down-stream signaling pathway regulated by IFI35. We further investigated the efficacy of the rhIFI35 protein in combination with immunotherapeutic treatment. Results The transcriptional and proteomic analysis of the activation and cytotoxicity of CD8 + T cells in human cancer samples demonstrated that IFI35 expression is correlated with increased CD8 + T cell infiltration and predicted a better outcome in colorectal cancer. The number and cytotoxicity of CD8 + T cells were significantly increased in IFI35-overexpressing tumors. Mechanistically, we identified that the IFNγ-STAT1-IRF7 axis stimulated IFI35 expression, and that IFI35-mediated regulation of CD8 + T cell proliferation and cytotoxicity was dependent on PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, IFI35 protein enhanced the efficacy of CAR-T cells against colorectal cancer cells. Conclusion Our findings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8 + T cells, as well as increase the efficacy of CAR-T cells against colorectal cancer cells. Graphical Abstract
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Evidence-based Complementary and Alternative Medicine
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2022
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IF 2.65
Yihua Shi,Kai Lian,Jiguang Jia
Osteosarcoma (OS) is a prevalent primary malignant bone tumor that commonly occurs in children and adolescents. Apigenin (4′,5,7-trihydroxyflavone) is one of the most researched phenolic compounds that exhibits antitumor effects in several cancers. The aim of the current study was to investigate the effect and underlying mechanisms of apigenin on OS. To address this, OS cells (SOSP-9607) were treated with different concentrations of apigenin. The proliferation, migration, invasion, stem-like properties, and Warburg effect of apigenin-treated OS cells were evaluated. Apigenin was found to suppress the proliferation of SOSP-9607 cells and inhibit epithelial-mesenchymal transition, as indicated by decreased number of migrated and invaded cells, decreased protein expression of vimentin, and increased protein expression of E-cadherin. Additionally, apigenin suppressed tumorsphere formation and reduced the proportion of SOSP-9607 cells with positive expression of the stem cell-related markers Nanog and OCT-4. Apigenin inhibited the Warburg effect in SOSP-9607 cells, as demonstrated by decreased glucose and lactic acid levels, increased citrate and ATP levels, and downregulation of GLUT1, HK1, and LDHA, which are metabolism-related enzymes related to the Warburg effect. Moreover, apigenin inhibited the phosphorylation of PI3K, Akt, and mTOR in SOSP-9607 cells. Collectively, these results indicate that apigenin suppresses the Warburg effect and stem-like properties in SOSP-9607 cells, which may be mediated by PI3K/Akt/mTOR signaling, thus, providing a novel strategy for OS treatment.
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Biomed Research International
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2021
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IF 3.411
Fengqin Wang,Hanzhong Zhang,Zhigang Cheng
EPHA2 is a member of the ephrin receptor tyrosine kinase family and is closely related to the malignant tumor progression. The effect of EPHA2 on OSCC is not clear. This study explored the role of EPHA2 and AKT/mTOR signaling pathways in Cal-27 cell invasion and migration. The expression of EPHA2 and EPHA4 in human OSCC and normal oral tissue was detected by immunohistochemistry. EPHA2-overexpressing and EPHA2-knockdown Cal-27 cells were established, and the cells were treated with an AKT inhibitor (MK2206) and mTOR inhibitor (RAD001). The expression of EPHA2 was detected by qRT-PCR, cell proliferation was evaluated by MTT assay, cell migration and invasion were examined by scratch and Transwell assay, and cell morphology and apoptosis were assessed by Hoechst 33258 staining. Western blot was performed to detect the expression of proteins related to AKT/mTOR signaling, cell cycle, and pseudopod invasion. EPHA2 and EPHA4 were highly expressed in clinical human OSCC. Overexpression of EPHA2 promoted the proliferation, migration, and invasion of Cal-27 cells, inhibited cell cycle blockage and apoptosis, and enhanced the activity of the AKT/mTOR signaling pathway. MK2206 (AKT inhibitor) and RAD001 (mTOR inhibitor) reversed the effect of EPHA2 overexpression on the biological behavior of Cal-27 cells. EPHA2 promotes the invasion and migration of Cal-27 human OSCC cells by enhancing the AKT/mTOR signaling pathway.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2021
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IF 4.932
Xinrui Li,Peiquan Yu,Yinghua Yu,Ting Xu,Jiao Liu,Yuan Cheng,Xia Yang,Xiaoying Cui,Cui Yin,Yi Liu
Hyperglycemia-induced neuroinflammation promotes the progression of diabetic encephalopathy. Hydrogen sulfide (H 2 S) exerts anti-inflammatory and neuroprotective activities against neurodegenerative diseases. However, the effects of H 2 S on hyperglycemia-induced neuroinflammation has not been investigated in neurons. Herein, by using HT-22 neuronal cells, we found that high glucose decreased the levels of endogenous H 2 S and its catalytic enzyme, cystathionine-β-synthase (CBS). The administration of sodium hydrosulfide (NaHS, a H 2 S donor) or S-adenosylmethionine (SAMe, an allosteric activator of CBS) restored high glucose-induced downregulation of CBS and H 2 S levels. Importantly, H 2 S ameliorated high glucose-induced inflammation in HT-22 cells, evidenced by NaHS or SAMe inhibited the pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) expression in HT-22 cells exposed to high glucose. Furthermore, NaHS or SAMe restored the SIRT1 level and the phosphorylation of mTOR and NF-κB p65 disturbed by high glucose in HT-22 cells, suggesting H 2 S reversed high glucose-induced alteration of SIRT1-mTOR/NF-κB signaling pathway. Our results demonstrated that exogenous H 2 S treatment or enhancing endogenous H 2 S synthesis prevents the inflammatory processes in the neurons with the exposure of high glucose. Therefore, increasing the H 2 S level using NaHS or SAMe might shed light on the prophylactic treatment of diabetic encephalopathy.
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Oxidative Medicine and Cellular Longevity
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2019
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IF 4.868
Qiang Chu,Xin Yu,Ruoyi Jia,Yaxuan Wang,Yiru Zhang,Shuang Zhang,Yangyang Liu,Yonglu Li,Wen Chen,Xiang Ye,Xiaodong Zheng
Apios americana Medikus was once widely accepted as staple food in India for a long time, and the tuber of which possesses high nutrients. During the past decades, most of the research has focused on the biological activity in the tubers of Apios americana Medikus whereas the leaves were ignored. In this study, the Apios americana Medikus leaf extract (ALE) was obtained and seven compounds were identified. LPS-induced RAW264.7 cells were used to study the anti-inflammation activity of ALE. As expected, ALE reduced the secretion of nitric oxide (NO) and inflammatory cytokines via inhibition of NF-κB and MAPK signaling together with activation of Nrf2-Keap1 and FOXO pathways, as well as alleviating the oxidative stress and mitochondrial dysfunction. In addition, ALE could activate HMGB1-Beclin1 and Sirt1-FoxO1 pathways and inhibit the Akt-mTOR signaling pathway to activate autophagy, protecting RAW264.7 cells from inflammation. In summary, our results suggested that ALE might help activate the anti-inflammation system, resulting in the prevention of LPS-induced damage in RAW264.7 cells.
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JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
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2018
·Vol. 78
·期 2
·157-171
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IF 3.49
Yan Bing Chun,Wang Jie,Rui Yanggang,Cao Jianwen,Xu Pei,Jiang Dan,Zhu Xiaolu,Won Moo-Ho,Bo Ping,Su Peiqing
Gabapentin (GBP), an analgesic, adjunct antiepileptic, and migraine prophylactic drug, reduces neuronal injury induced by cerebral ischemia reperfusion (IR). However, the underlying biological molecular mechanism of GBP neuroprotection is not clear. In this study, we confirmed that dose-dependent (75 and 150 mg/kg) GBP treatment could significantly reduce IR-induced neuronal death. IR-induced neuronal death was inhibited by pretreatment with 150 mg/kg GBP in a middle cerebral artery occlusion rat model. In addition, 150 mg/kg GBP treatment remarkably promoted the levels of antioxidants and reduced the autophagy of neurons in the infarct penumbra. Moreover, the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway was activated by pretreatment with 150 mg/kg GBP, as detected by Western blot analyses. In vitro, pretreatment of PC12 cells with 450 µM GBP significantly reduced cell death induced by oxygen-glucose deprivation, increased antioxidant function, and reduced the levels of autophagy and reactive oxygen species via activation of the PI3K/Akt/mTOR pathway. This neuroprotection by GBP was inhibited significantly by 10 µM LY294002. In summary, dose-dependent pretreatment with GBP protected against cerebral IR injury via activation of the PI3K/Akt/mTOR pathway, which provided a neuroprotective function to inhibit oxidative stress-related neuronal autophagy.
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JOURNAL OF FOOD AND DRUG ANALYSIS
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2024
·Vol. 32
·期 4
·506
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IF 2.6
Tian-Shuang Xia,Sheng-Yan Xu,Li-Yong Lai,Yi-Ping Jiang,Na-Ni Wang,Hai-Liang Xin
Bitter acids (BA) are main component of Humulus lupulus L. (hops). They are known for beer brewing and have various biological and pharmacological properties, especially the bone-protective effect confirmed by our previous in vivo study. Here we aimed to elucidate the anti-senior osteoporosis (SOP) effect of BA on osteoblasts and explore its underlying mechanism. In vitro SOP model was established by D-galactose (D-gal) injured osteoblasts, and the bone formation markers and apoptosis level were measured. mCherry-EGFP-LC3 adenovirus infection and autophagic markers including beclin1 and LC3 proteins were detected to investigate the autophagy level in osteoblasts. To further verify whether BA play the bone-protective role through regulating autophagy, the autophagy inhibitor 3-MA was used, and the cell proliferation, ALP activity, bone mineralization, apoptosis rate and SA-β-gal staining areas were measured. Finally, the protein expressions of AKT/mTOR signaling pathway were detected by Western blotting, and AKT agonist SC79 and mTOR agonist MHY1485 were used to further study the mechanism of BA on AKT/mTOR-mediated autophagy. The results showed that BA stimulated osteoblastic differentiation and inhibited apoptosis proteins Bcl-2/Bax in D-gal-treated osteoblasts. BA also increased the expression of autophagic markers beclin1 and LC3-II/LC3-I in D-gal-treated osteoblasts. mCherry-EGFP-LC3 autophagic double fluorescent adenovirus showed BA promoted the generation of autolysosomes and autophagosomes in D-gal-injured osteoblasts, indicating that BA might prevent osteoblastic bone loss through activating autophagy. Autophagy inhibitor 3-MA was used to further verify whether BA played the bone-protective role via regulating autophagy. The results revealed the promotion effects of BA on proliferation, ALP activity, and mineralized nodule formation in D-gal-injured osteoblasts were eliminated after autophagy blocking with 3-MA, and the inhibitory effects of BA on apoptosis rate and SA-β-gal staining areas were also eliminated. Moreover, BA reduced the phosphorylation levels of AKT, mTOR, p70S6K, and 4EBP in AKT/mTOR pathway, and the promotion of BA on the autophagic markers was blocked after the activation of AKT and mTOR by SC79 and MHY1485. In conclusion, it was the first time to demonstrate that BA improved cell activities and bone formation in aging osteoblasts, and revealed the mechanism of BA against SOP in osteoblasts was activating AKT/mTOR-mediated autophagy.
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Journal of Functional Foods
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2024
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IF 3.8
Lu Xiu,Rongguang Ge,Siyu Lu,Linwei Li,Wenqi Huang,Guojun Du,Zengli Zhang,Jie Zhang,Zhongxiao Wan,Jie Chang
Diabetes, a ruthless chronic metabolic disorder, is increasingly considered to jeopardize global well-being over the decades. Royal jelly (RJ) is a complex natural product secreted by worker bees containing a unique fatty acid known as 10-hydroxy-2-decenoic acid (10-HDA). This study aimed to verify the protective effect on cognitive function of RJ and 10-HDA in diabetic mice and explore the underlying mechanism. Briefly, our animal experiment results suggested that 10-HDA had a significant hypoglycemic effect and improved cognitive performance. Through western blotting, RJ and 10-HDA intervention notably increased Atg7, Atg16L1, Beclin-1, Atg5, Atg12, Atg3, and LC3-II expression and decreased p62 expression. Meanwhile, decreased mTOR expression and increased ULK1 expression were also observed in the 10-HDA intervention group. In conclusion, 10-HDA can regulate mTOR/ULK1 pathway to activate autophagy to alleviate hippocampal damage, thereby improving cognitive function in mice with diabetes, which may provide a new option for real-world cognitive impairment management.
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FASEB JOURNAL
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2025
·Vol. 39
·期 16
·e70901
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IF 4.2
Yanping Dai,Xiaoqin Gao
Aging-related decline in male fertility is closely associated with impaired sperm quality and dysregulated autophagy/apoptosis in reproductive tissues. This study elucidates the protective role of the AKT2/mTOR/VEGF axis in mitigating age-induced epididymal dysfunction and sperm deterioration. Utilizing iTRAQ proteomics and transcriptome sequencing in young (6-month) versus aged (18-month) rat models, we identified AKT2 and VEGF as key regulators of reproductive aging. Functional validation revealed that AKT2/mTOR/VEGF activation suppressed oxidative stress, preserved mitochondrial membrane potential, and inhibited autophagy/apoptosis in rat epididymal epithelial cells (REECs, cells lining the epididymis involved in sperm maturation and transport) through downstream targets including Bcl-2, Bax, and LC3-II. Notably, extracellular vesicles (EVs) derived from AKT2-activated REECs enhanced sperm motility and reduced sperm DNA fragmentation through reactive oxygen species (ROS) scavenging and autophagy modulation. Pharmacological inhibition of VEGF or AKT2 exacerbated cellular stress responses, while lentivirus-mediated AKT2 overexpression reversed age-related epididymal damage in vivo. Mechanistically, the pathway crosstalk between mTOR-driven VEGF secretion and EV-mediated intercellular communication emerged as a critical mechanism for maintaining sperm viability. These findings establish AKT2/mTOR/VEGF signaling as a central coordinator of epididymal homeostasis and propose EV-based therapies as promising strategies to counteract male reproductive aging. Graphical The AKT2/mTOR/VEGF axis inhibits oxidative stress in REECs, alleviating autophagy and apoptosis. It promotes sperm activity and motility by secreting EVs, reducing sperm autophagy and apoptosis, and thereby increasing the IVF rate.
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