BIOLOGICAL & PHARMACEUTICAL BULLETIN
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2019
·Vol. 42
·期 6
·886-891
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IF 1.54
Yangbiao He,Xujun Lang,Dong Cheng,Zhihao Yang
Previous studies implicated the mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway in renal fibrosis and found that curcumin could suppress the expression of mTOR. Therefore, the aim of the present study was to investigate the therapeutic effects of curcumin against chronic renal failure (CRF) in a rat model induced by 5/6 nephrectomy through inhibition of mTOR/HIF-1α/VEGF signaling. A total of 70 male Sprague–Dawley rats were divided into seven groups: a sham group, a CRF group, and five treatment groups. Except for the sham rats, all rats underwent 5/6 nephrectomy to induce CRF. The 5/6 nephrectomized rats received treatment with curcumin vehicle, everolimus vehicle, curcumin, everolimus, or the combination of curcumin and everolimus. Everolimus, a specific inhibitor of mTOR, was used as a positive control. At the end of treatment, blood biochemical indexes, proteinuria and the kidney index were detected. Moreover, histological change was examined by hematoxylin and eosin staining, and protein expression levels were detected by Western blotting. The blood biochemical indexes, proteinuria, and kidney index were increased in the CRF group as compared to the sham group, which was accompanied by marked activation of the mTOR/HIF-1α/VEGF pathway. However, curcumin, as well as everolimus, restored or ameliorated these changes. These results indicate that activation of the mTOR/HIF-1α/VEGF signaling pathway plays an important role in the occurrence and development of CRF, and that curcumin has renoprotective effects by blocking activation of this pathway.
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ACTA BIOCHIMICA ET BIOPHYSICA SINICA
·
2018
·Vol. 50
·期 6
·567-578
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IF 2.224
Zhang Yingying,Cong Linhai,He Jiayan,Wang Yu,Zou Yingying,Yang Zhihong,Hu Yuexin,Zhang Shiwen,He Xiaoguang
Hypopharyngeal carcinoma (HC) is one of the most malignant tumors in the upper aerodigestive tract. Currently, there are no effective treatments for HC. Gold nanoparticles (AuNPs) are a promising tool that can be used for plasmonic photothermal therapy (PPTT), which refers to the use of electromagnetic radiation, most often in near infrared (NIR) region, for the treatment of various medical conditions including cancer. AuNPs have been proved to be a promising tool for NIR spectroscopy-mediated photothermal therapies. In this study, we chemically conjugated AuNPs with a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR), a cell-surface receptor that is overexpressed in many cancers. We then assessed the effect of NIR photothermal treatment with the EGFRmAb–AuNPs in FaDu HC cells. Our data showed that nanoparticle conjugation with the EGFRmAb improved the specific targeting towards FaDu cells and reduced cytotoxicity towards normal (293 T) cells which do not overexpress the EGFR. A significant amount of our EGFRmAb-conjugated AuNPs could enter the nucleus. Moreover, the expression levels of double strand DNA break repair proteins, including p-ATR, p-CHK1, and p-CHK2 were increased following AuNPs treatment, indicating the presence of DNA damage. These findings suggest that the AuNPs can potentially disrupt genome integrity and induce apoptosis. In addition, EGFRmAb–AuNPs+NIR could induce FaDu cell apoptosis, accompanied by the inhibition of the PI3K/AKT/mTOR pathway and stimulation of DNA damage response. Based on these data, PPTT using the EGFRmAb–AuNPs could be a new promising treatment for HC.
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Materials Today Bio
·
2022
·
IF 10.761
Lili Liu,Xianjing Li,Wenhuan Bu,Nianqiang Jin,Yuan Meng,Yi Wang,Duan Wang,Xiaowei Xu,Ding Zhou,Hongchen Sun
Pulp injury is one of the most common clinical diseases, and severe cases are usually associated with the functional loss of the tooth, while the current clinical treatment modality is only a cavity filling procedure without the regeneration of the dentin-pulp complex, thus leading to a devitalized and brittle tooth. In this study, carbon dots (CDots) with excellent biocompatibility are prepared from ascorbic acid and polyethyleneimine via a hydrothermal method. The as-prepared CDots can enhance extracellular matrix (ECM) secretion of human dental pulp stem cells (DPSCs), giving rise to increased cell adhesion on ECM and a stronger osteogenic/odontogenic differentiation capacity of DPSCs. Further, the mechanism underlying CDots-enhanced ECM secretion is revealed by the transcriptome analysis, Western blot assay and molecular dynamics simulation, identifying that the pharmacological activities of CDots are originated from a reasonable activation of the autophagy, which is mediated by regulating phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Based on the abundant CDots-induced ECM and thereby the reinforcement of the cell-ECM adhesion, an intact dental pulp stem cell sheet can be achieved, which in return promote in vivo the efficient regeneration of dentin-pulp complex as well as blood vessels.
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JOURNAL OF NANOBIOTECHNOLOGY
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2021
·Vol. 19
·期 1
·1-18
·
IF 10.435
Wang Xueqin,Xiong Tiandi,Cui Miao,Li Na,Li Qin,Zhu Li,Duan Shaofeng,Wang Yunlong,Guo Yuqi
Background Multidrug resistance (MDR) is the main challenge of successful chemotherapy for ovarian cancer patients, with 50% to 75% of ovarian cancer patients eventually relapsed due to it. One of the effective strategies for treating MDR and improving therapeutic efficiency of ovarian cancer is to use nanotechnology-based targeted drug delivery systems. In this study, a novel nano targeted co-delivery system modified by hyaluronic acid (HA) was developed by using gold nanorods coated with functionalized mesoporous silica nanoparticles (HA-PTX/let-7a-GNR@MSN) for combined delivery of hydrophobic chemotherapy drug Paclitaxel (PTX) and lethal-7a (let-7a), a microRNA (miR), to overcome MDR in ovarian cancer. Furthermore, we also analyzed the molecular mechanism of this nanotherapeutic system in the treatment of ovarian cancer.Results HA-modified nanocomplexes can specifically bind to the CD44 receptor, which is highly expressed in SKOV3/SKOV3TR cells, achieving effective cell uptake and 150% enhancement of tumor site permeability. The nanosystem realized the stable combination and protective transportation of PTX and miRs. Analysis of drug-resistant SKOV3TR cells and an SKOV3TR xenograft model in BALB/c-nude mice showed significant downregulation of P-glycoprotein in heterogeneous tumor sites, PTX release, and subsequent induction of apoptosis. More importantly, this nanosystem could synergistically inhibit the growth of ovarian tumors. Further studies suggest that mTOR-mediated signaling pathways play an important role in reversing drug resistance and inducing apoptosis.Conclusion sTo sum up, these data provide a model for overcoming PTX resistance in ovarian cancer.Graphical Abstract
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MOLECULAR MEDICINE
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2021
·Vol. 27
·期 1
·1-16
·
IF 6.354
Cui Jing,Guo Yao,Wu Heshui,Xiong Jiongxin,Peng Tao
Background Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. Methods The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEM sen ) and GEM-resistant (GEM res ) pancreatic cancer cells. Results We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEM sen and GEM res cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEM res cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEM res cells than that in GEM sen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEM res tumors, Evr significantly decreased the volume of GEM res tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. Conclusions Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.
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Frontiers in Oncology
·
2021
·
IF 6.244
Heng Yongqing,Liang Yupei,Zhang Junqian,Li Lihui,Zhang Wenjuan,Jiang Yanyu,Wang Shiwen,Jia Lijun
The neddylation pathway is overactivated in esophageal cancer. Our previous studies indicated that inactivation of neddylation by the NAE inhibitor induced apoptosis and autophagy in cancer cells. Camptothecin (CPT), a well-known anticancer agent, could induce apoptosis and autophagy in cancer cells. However, whether CPT could affect the neddylation pathway and the molecular mechanisms of CPT-induced autophagy in esophageal cancer remains elusive. We found that CPT induced apoptosis and autophagy in esophageal cancer. Mechanistically, CPT inhibited the activity of neddylation and induced the accumulation of p-IkBa to block NF-κB pathway. Furthermore, CPT induced the generation of ROS to modulate the AMPK/mTOR/ULK1 axis to finally promote protective autophagy. In our study, we elucidate a novel mechanism of the NF-κB/AMPK/mTOR/ULK1 pathway in CPT-induced protective autophagy in esophageal cancer cells, which provides a sound rationale for combinational anti-ESCC therapy with CPT and inhibition AMPK/ULK1 pathway.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2020
·Vol. 25
·期 2
·1140-1150
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IF 4.486
Jie Xu,Dazhi Chen,Lanling Jin,Zhengkang Chen,Yulu Tu,Xiaozhe Huang,Feiben Xue,Jialu Xu,Mingzhuan Chen,Xiaodong Wang,Yongping Chen
Inflammation and fibrosis are major consequences of autoimmune hepatitis, however, the therapeutic mechanism remains to be investigated. USP4 is a deubiquitinating enzyme and plays an important role in tissue fibrosis and immune disease. Vialinin A is an extract from mushroom and is a specific USP4 inhibitor. However, there is lack of evidences that Vialinin A plays a role in autoimmune hepatitis. By employing S100-induced autoimmune hepatitis in mice and AML12 cell line, therapeutic mechanism of Vialinin A was examined. Inflammation was documented by liver histological staining and inflammatory cytokines. Fibrosis was demonstrated by Masson, Sirius red staining and fibrotic cytokines with western blot and real-time RT-PCR. In experimental animal, there were increases in inflammation and fibrosis as well as USP4, and which were reduced after treatment of Vialinin A. Vialinin A also reduced Rheb and phosphorylated mTOR. Moreover, in LPS-treated AML12 cells, LPS-induced USP4, inflammatory and fibrotic cytokines, phosphorylated mTOR and Rheb. Specific inhibitory siRNA of USP4 reduced USP4 level and the parameters mentioned above. In conclusion, USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver. The mechanism may be related to regulation of Rheb/mTOR signalling.
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JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
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2020
·Vol. 75
·期 4
·321
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IF 2.598
Cao Qian,Du Hongjiao,Fu Xi,Duan Na,Liu Changhe,Li Xiaodong
Artemisinin is an endoperoxide sesquiterpene lactone from Artemisia annua L with multiple beneficial effects, including anti-inflammation, antioxidant, and vascular protection. Recent studies have found that inflammation along with autophagy deficiency in macrophages is the possible reason for foam cell accumulation in the intima, which leads to atherosclerotic plaque formation. The primary aims of this study were to explore the inhibiting effect of artemisinin on atherosclerosis in high-fat diet–fed ApoE −/− mice and investigate the probable mechanism. Artemisinin (50 and 100 mg/kg, intragastric administration) treatment effectively inhibited foamy macrophage transformation and decreased atherosclerotic plaque formation in atherosclerotic mice. Moreover, artemisinin promoted AMP-activated protein kinase (AMPK) activation, inhibited mammalian target of rapamycin (mTOR) and uncoordinated-51-like kinase 1 (ULK1) phosphorylation, and increased LC-3II accumulation and P62 degradation, thereby enhancing macrophage autophagy . Besides, the inhibiting effect of artemisinin on mTOR and ULK1 phosphorylation could be abrogated by AMPK knockdown, suggesting AMPK was the essential target of artemisinin on promoting macrophage autophagy . Our study indicated that artemisinin alleviated atherosclerotic lesions by accelerating macrophage autophagy through the AMPK/mTOR/ULK1 pathway.
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AGING CLINICAL AND EXPERIMENTAL RESEARCH
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2017
·Vol. 30
·期 7
·737-743
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IF 1.394
Yan Bing Chun,Jiang Dan,Wang Jie,Zhang Yuanyuan,Zhu Xiaolu,Xu Pei,Yu Xing,Won Moo-Ho,Su Pei Qing
Background Aging is an inevitable process which results in many changes. These changes are closely related to the hippocampus which is in charge of long-term learning and episodic memory. Aim This study was to investigate age-related changes of the cell proliferation, neuroblast differentiation and Akt/mTOR signaling in the hippocampal alveus of aged mice. Methods In the present study, we compared the differences of neurogenesis in the hippocampal alveus between adult (postnatal month 6) and aged (postnatal month 24) mice using immunohistochemistry and western blot analysis. Results The cell proliferation, neuroblast differentiation, and the increased astrocyte activation in the hippocampal alveus of mice were decreased in an age-dependent manner. In addition, during normal aging, the protein level of AKT, mTOR and the phosphorylation of mTOR were all decreased. However, the protein level of AKT was increased. Discussion These results indicate the neurogenesis in the immature neurons in the hippocampal alveus of aged mice was closely related to the normal aging process. In addition, during normal aging, the increased AKT phosphorylation and decreased mTOR phosphorylation in the hippocampus may play a role in aging development. Conclusion The result indicates that increased activation of astrocyte, increased phosphorylation of AKT and decreased phosphorylation of mTOR may be involved in the decreased cell proliferation and neuroblast differentiation in the alveus of hippocampus of aged mice.
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TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE
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2025
·
IF 1.6
Shaohao Luo,Yunfei Bai,Boqian Wang,Haixia Xu,Shu Zhang,Gang Guo,Xin Li,Hongyang Sun,Xiaobo Cui
Homeobox A1 (HOXA1) is implicated in the progression of various cancers, but its biological function in laryngeal cancer (LC) remains undefined, which is the foothold of our study. Bioinformatics analysis and survival analysis were performed to predict HOXA1 expression in LC tissues, and the prognostic relationship between high HOXA1 expression and LC. Whether high HOXA1 expression correlated with the clinical characteristics and prognosis of LC patients was analyzed. LC cell viability and sensitivity to cisplatin were determined by Methyl thiazolyl tetrazolium assay. The cell migration, invasion, and cell cycle after transfection were examined by Wound healing, Transwell, and flow cytometry assays, respectively. The corresponding mRNA and protein expressions were measured by quantitative real-time PCR or Western blot. A higher expression of HOXA1 was detected in LC tissues, which was found to be relevant to poor prognosis of LC patients. The association of high expression of HOXA1 with lymph node and clinical stage was also confirmed. Silencing of HOXA1 in LC cells enhanced the cell sensitivity to cisplatin, inhibited viability, migration, invasion and cell cycle, and reduced N-Cadherin, Vimentin, PCNA, p-AKT and p-mTOR expressions, while overexpression of HOXA1 had the opposite effects. Collectively, HOXA1 boosts migration, invasion and cell cycle, while suppressing cisplatin sensitivity of LC cells by mediating AKT/mTOR pathway, hinting that HOXA1 is a promising biomarker for diagnosis and prognosis of LC in clinical practice.
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PeerJ
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2025
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IF 2.4
Jia Song,Jinyu Qiao,Mingxue Chen,Jiahui Li,Jixia Wang,Dayong Yu,Huachuan Zheng,Liying Shi
Chaetoglobosin A (ChA) is an antitumor compound produced by Chaetomium globosum . However, the mechanism of its antitumor effect has been rarely reported. In this study, we evaluated the anti-proliferative effect of ChA on T-24 human bladder cancer cells and explored its mechanism of action. ChA was found to have a good inhibitory effect on T-24 cells by MTT assay with an IC50 value of 48.14 ± 10.25 μΜ. Moreover, it was found to have a migration inhibitory ability and a sustained proliferation inhibitory effect on tumor cells by cell aggregation assay and cell migration assay. The cells morphological changes were determined by Hoechst33342 assay. While Annexin V-FITC/PI double-staining assay also demonstrated that the number of apoptotic cells increased with the increase of drug concentration. Flow cytometry results showed that ChA treatment increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP) in T-24 cells and inhibited cell mitosis, resulting in an increase in the number of sub-G1 phase cells. Further western blot experiments demonstrated that MAPK and PI3K-AKT-mTOR pathways were activated after drug treatment in addition to endogenous and exogenous apoptotic pathways. The addition of the ROS inhibitor N-acetylcysteine (NAC) upregulated the expression level of Bcl-2 protein, decreased p38 phosphorylation, increased ERK phosphorylation and restored the levels of PI3K and p-mTOR after ChA treatment. These suggest that ChA induces apoptosis by regulating oxidative stress, MAPK, and PI3K-AKT-mTOR signaling pathways in T-24 cells.
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Theranostics
·
2025
·Vol. 15
·期 10
·4734
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IF 13.3
Zi-Yue Xi,Chuan-Yong Fan,Ying-Ying Jiang,Xin-Ran Xi,Gan-Yu Nie,Shuang Zhu,Jun-Jie Zhang,Lu Xu
Background: Traditional programmed cell death, including ferroptosis, cuproptosis, and apoptosis, has demonstrated excellent anti-tumor effects and declared their complete mechanisms, however, the zinc ion-mediated tumor inhibiting mechanisms remain insufficiently explored. In this study, a self-generated oxygen nanocatalytic system (ZnO@COF@EM, ZCE) was developed to stimulate cascade amplified effect (CAE) of reactive oxygen species (ROS) generation leading to Znproptosis. The underlying Znproptosis mechanism to disrupt mitochondrial (Mito) metabolism was also investigated. Methods: Specifically, the principle of Znproptosis caused by accumulated zinc and ROS, which served as key factors, was declared through western blot analysis and genetic testing. The mechanism of generated ROS (·OH and 1 O 2 ) under NIR irradiation by ZCE was detected by UV scanning curves, confocal laser scanning microscopy (CLSM) images, and density functional analysis. The injury condition of Fe-S protein of mitochondria metabolism, which triggered Znproptosis with FDX2/LIAS pathway by zinc and ROS, was examined by PCR test and MTT assay. Notably, a Mito-targeting strategy for ZCE was proposed by using molecular docking technology, wherein Zn 2+ was recognized by zinc finger proteins (ZFPs) with the Mito. Results: ZCE, along with CAE, produced abundant ROS (2.42-time more than control group). At the quantum chemical level, the CAE mechanism was associated with a narrower highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap and increased electronic energy motion within ZCE, which prolonged the excited triplet state (ETS). At the gene level, Znproptosis was achieved by regulating FDX2 and ZIP7 proteins to damage Fe-S protein. The cell cycle was interrupted by Chk2/Cdc25C/Cdc2 and Chk2/p21/Cyclin B1 pathways, leading to the arrest of G1/S and G2/M phases of the cell cycle and inhibition of the Akt/mTOR signaling pathway. Moreover, Znproptosis induced by overloading zinc ions and ROS resulted in a significant antitumor effect (up to 83.81%). Conclusion: Hence, the research reveals a detailed Znproptosis mechanism in nanocatalytic system. Through regulating FDX2/LIAS pathway, Znproptosis could improve the death rate of mitochondria by decreasing the production of Fe-S protein, contributing to advancements in the field of antitumor therapy.
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