Frontiers in Pharmacology
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2020
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IF 4.225
Li Shaoguang,Wang Xuewen,Wang Gang,Shi Peiying,Lin Shilan,Xu Dafen,Chen Bing,Liu Ailin,Huang Liying,Lin Xinhua,Yao Hong
Colorectal cancer is one type of cancer with high incidence rate and high mortality worldwide. Thus, developing new chemotherapeutic drugs is important. The Selaginella doederleinii Hieron ethyl acetate (SDEA) extract showed good anti-colon cancer effect in vitro and in vivo, but its mechanism is unclear. This study aimed to further reveal the anti-colon cancer effect of SDEA and its possible mechanism. The effects on cell viability, apoptosis, autophagy, and cell cycle in colorectal cells (HT29 and HCT116) were studied using MTT assay, fluorescence microscopy, transmission electron microscopy, and flow cytometry. The mechanisms were further studied using cell transfection, Western blot, and real-time quantitative polymerase chain reaction assay. The effect of xenotransplantation in vivo was observed using immunohistochemistry. Results showed that SDEA inhibited cell proliferation and induced cell morphological changes, cell cycle arrest, autophagy, and apoptosis. It also induced loss of mitochondrial membrane potential, increased the autophagic flux, raised the ratio of Bax/Bcl-2, activated caspases, and inhibited PI3K-Akt-mTOR signaling pathways. Furthermore, SDEA inhibited the growth of xenograft tumors in a dose-dependent manner. Immunohistochemistry analysis confirmed the alteration of autophagy- and apoptosis-related proteins and immunohistochemical microvascular density in xenografts, which were consistent with the results in vitro. Therefore, SDEA is important for developing candidate drugs against colorectal cancers.
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Oncology Letters
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2020
·Vol. 20
·期 6
·1-1
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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.
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JOURNAL OF ETHNOPHARMACOLOGY
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2017
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IF 2.981
Zhongcheng Ke,Gang Wang,Lei Yang,Huihui Qiu,Hao Wu,Mei Du,Juan Chen,Jie Song,Xiaobin Jia,Liang Feng
Ethnopharmacological relevance Radix paeoniae rubra , also known as chishao (CS), is a frequently used traditional Chinese medicine that can promote blood circulation to remove blood stasis . It has been widely used for the prevention and treatment of cardiovascular diseases in China. Although terpene glycoside (TG), the major component in CS, has been shown to possess cardioprotective properties, the mechanism underlying CS-TG's preventive effect against myocardial ischemia injury is unknown. This study was conducted to explore the protective and curative effects of CS-TG against isoproterenol (ISO)-induced myocardial ischemic injury in rats and investigate the underlying myocardial protective mechanisms. Materials and methods A rat model of ISO-induced myocardial ischemia was established to evaluate the protective effect of CS-TG in ameliorating heart injury. Myocardial ischemia was induced by administering ISO (40 mg/kg/d) subcutaneously for 2 days. Serum was collected and analyzed for the levels of different cardiac biomarkers, and heart tissues were isolated and prepared for ATP analysis, glycogen content determination, histopathology assay, and ultrastructure observation. The regulatory effects of CS-TG on myocardial apoptosis in rats were studied by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and the levels of cleaved caspase-3, Bax, and Bcl-2 were detected by western blotting . Furthermore, in vitro experiments were conducted to examine whether the CS-TG's cardioprotective effects were linked to the inhibition of apoptosis via activation of the phosphoinositide-3-kinase/serine-threonine kinase AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Results CS-TG (300 mg/kg/d) significantly decreased serum levels of creatine kinase and lactate dehydrogenase in ISO-induced myocardial ischemic rats. Analysis of ATP and glycogen contents, myocardial ultrastructure, and pathological examination showed that CS-TG (300 mg/kg/d) significantly improved energy metabolism and alleviated myocardial injury in vivo. In addition, the expression of p-AKT and p-mTOR in rats subjected to CS-TG significantly elevated, while the levels of caspase-3 and Bax/Bcl-2 dramatically reduced. Moreover, treatment with LY294002 , a PI3K inhibitor, abrogated CS-TG (200 μg/mL) induced down-regulation of cleaved caspase-3, Bax/Bcl-2 in the serum. Conclusions CS-TG protects the heart from ISO-induced myocardial ischemia, potentially by improving cardiac energy metabolism and inhibiting cardiomyocyte apoptosis via activation of the PI3K/AKT/mTOR signaling pathway. Thus, CS -TG might be a potential therapeutic candidate for the prevention and treatment of myocardial ischemia.
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Heliyon
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2024
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IF 3.4
Hongyan Li,Yanzhi Zeng,Guangjun Wang,Kai Zhang,Wangbao Gong,Zhifei Li,Jingjing Tian,Yun Xia,Wenping Xie,Jun Xie,Shouqi Xie,Ermeng Yu
Diets with high carbohydrate (HC) was reported to have influence on appetite and intermediary metabolism in fish. To illustrate whether betaine could improve appetite and glucose-lipid metabolism in aquatic animals, mandarin fish ( Siniperca chuatsi ) were fed with the HC diets with or without betaine for 8 weeks. The results suggested that betaine enhanced feed intake by regulating the hypothalamic appetite genes. The HC diet-induced downregulation of AMPK and appetite genes was also positively correlated with the decreased autophagy genes, suggesting a possible mechanism that AMPK/mTOR signaling might regulate appetite through autophagy. The HC diet remarkably elevated transcriptional levels of genes related to lipogenesis, while betaine alleviated the HC-induced hepatic lipid deposition. Additionally, betaine supplementation tended to store the energy storage as hepatic glycogen. Our findings proposed the possible mechanism for appetite regulation through autophagy via AMPK/mTOR, and demonstrated the feasibility of betaine as an aquafeed additive to regulate appetite and intermediary metabolism in fish.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Jianfa Wu,Lingli Jiang,Sihong Wang,Lei Peng,Rong Zhang,Zhou Liu
The involvement of Interferon-stimulated exonuclease gene 20 (ISG20) has been reported in renal clear cell carcinoma, hepatocellular carcinoma, and cervical cancer. However, its role in ovarian cancer chemotherapy remains unclear. In this study, we conducted a comparative analysis of TGF-β1 and ISG20 in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells and tissues using qRT-PCR and a tissue immunofluorescence analysis. We also investigated the impact of ISG20-targeted drugs (IFN-γ) and TGF-β1 inhibitors on cisplatin response both in vivo and in vitro. Additionally, we assessed the effects of TGF-β1 or ISG20 on the polarization of tumor-associated macrophages through flow cytometry and ELISA analysis. Our findings revealed that ISG20 expression was lower in cisplatin-resistant tissues compared to cisplatin-sensitive tissues; however, overexpression of ISG20 sensitized ovarian cancer to cisplatin treatment. Furthermore, activation of ISG20 expression with IFN-γ or TGF-β1 inhibitors enhanced the sensitivity of ovarian cancer cells to cisplatin therapy. Notably, our results demonstrated that TGF-β1 promoted M2-type macrophage polarization as well as PI3K/mTOR pathway activation by suppressing ISG20 expression both in vivo and in vitro. In conclusion, our study highlights the critical role played by ISG20 within the network underlying cisplatin resistance in ovarian cancer. Targeting ISG20 using IFN-γ or TGF-β1 inhibitors may represent a promising therapeutic strategy for treating ovarian cancer.
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Cancer Cell International
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2021
·Vol. 21
·期 1
·1-15
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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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Antioxidants
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2022
·Vol. 11
·期 5
·908
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IF 7.675
Yuan Zhang,Tun Sun,Meng Li,Yanling Lin,Yue Liu,Shusheng Tang,Chongshan Dai
Ivermectin (IVM) could cause potential neurotoxicity; however, the precise molecular mechanisms remain unclear. This study explores the cytotoxicity of IVM in human neuroblastoma (SH-SY5Y) cells and the underlying molecular mechanisms. The results show that IVM treatment (2.5–15 μM) for 24 h could induce dose-dependent cell death in SH-SY5Y cells. Compared to the control, IVM treatment significantly promoted the production of ROS, mitochondrial dysfunction, and cell apoptosis. IVM treatment also promoted mitophagy and autophagy, which were charactered by the decreased expression of phosphorylation (p)-Akt and p-mTOR proteins, increased expression of LC3II, Beclin1, ATG5, PINK, and Pakin1 proteins and autophagosome formation. N-acetylcysteine treatment significantly inhibited the IVM-induced production of ROS and cell death in SH-SY5Y cells. Autophagy inhibitor (e.g., 3-methyladenine) treatment significantly inhibited IVM-induced autophagy, oxidative stress, and cell apoptosis. Taken together, our results reveal that IVM could induce autophagy and apoptotic cell death in SH-SY5Y cells, which involved the production of ROS, activation of mitochondrial pathway, and inhibition of Akt/mTOR pathway. Autophagy inhibition improved IVM-induced oxidative stress and apoptotic cell death in SH-SY5Y cells. This current study provides new insights into understanding the molecular mechanism of IVM-induced neurotoxicity and facilitates the discovery of potential neuroprotective agents.Keywords:ivermectin;neurotoxicity;oxidative stress;apoptosis;autophagy;Akt/mTOR pathway
研究领域:
神经科学
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细胞生物学
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药理学
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TISSUE & CELL
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2026
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IF 3.1
Yang Li,Xinchang Feng,Lingpeng Zheng
Type 2 diabetes mellitus (T2DM) has become a leading cause of chronic liver disease worldwide. Farrerol has been demonstrated to ameliorate multiple metabolic disorders. However, the role of farrerol in hepatic insulin resistance (IR) in T2DM, as well as the underlying mechanism, remain unclear. The present study aims to elucidate these issues. A rat model of T2DM was used to evaluate the effect of farrerol on IR in vivo. BRL 3 A cells were stimulated with palmitic acid to obtain an in vitro model of IR to further determine the role and mechanism of farrerol in hepatic IR. The involvement of the AMPK pathway was investigated using a selective and ATP-competitive AMPK inhibitor Compound C and specific siRNA targeting AMPKα1. The present study demonstrated that farrerol administration reduced HOMA-IR index, ameliorated dyslipidemia, and regulated glucose tolerance in diabetic rats. Additionally, farrerol administration alleviated hepatic damage, inflammation and oxidative stress accompanied by restored the AMPKα1/mTOR/SREBP-1 pathway in the liver of diabetic rats. Furthermore, in an in vitro model, farrerol enhanced glucose uptake, inhibited lipid accumulation, restored the membrane translocation of GLUT-2, suppressed inflammation and oxidative stress, and regulated the AMPKα1/mTOR/SREBP-1 pathway in palmitic acid-induced BRL 3 A cells. However, incubation with AMPK inhibitor or AMPKα1 knockdown reversed the protective effects of farrerol in vitro . Our findings demonstrate that farrerol ameliorates hepatic IR and associated metabolic dysfunctions by regulating the AMPKα1/mTOR/SREBP-1 pathway. Farrerol may be a promising therapeutic target for the treatment of IR in T2DM.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
WenBin Liu,ZhengWei Tan,YueChao Zhao,YanNa Zhao,XiaoLing Yu,BoLin Wang,FengLin Shen,Ai Mi,JinJian Lan,RuiLan Gao
Panaxadiol saponin (PND) is a latent targeted drug for the treatment of aplastic anemia (AA). In this study, we examined the effects of PND on ferroptosis in iron-overload AA and Meg-01 cells. We utilized RNA-seq to analyze differentially expressed genes in iron-induced Meg-01 cells treated with PND. The effects of PND or combined with deferasirox (DFS) on iron deposition, labile iron pool (LIP), several ferroptosis events, apoptosis, mitochondrial structure, as well as ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR pathway-related markers in iron-induced Meg-01 cells were examined by Prussian-blue staining, flow cytometer, ELISA, Hoechst 33342 staining, transmission electron microscope, and Western blot assays, respectively. Additionally, an AA mice model with iron overload was established. Then, the blood routine was assessed, and the number of bone marrow-derived mononuclear cells (BMMNCs) in mice was counted. Also, serum iron, ferroptosis events, apoptosis, histology, T lymphocyte percentage, ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR signaling-related targets in primary megakaryocytes of AA mice with iron overload were assessed by commercial kits, TUNEL staining, hematoxylin and eosin (H&E) staining, Prussian blue staining, flow cytometer, and qRT-PCR analysis, respectively. PND suppressed iron-triggered iron overload, and apoptosis, and ameliorated mitochondrial morphology in Meg-01 cells. Importantly, PND ameliorated ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR signaling-related marker expressions in iron-induced Meg-01 cells or primary megakaryocytes of AA mice with iron overload. Moreover, PND ameliorated body weight, peripheral blood cell counts, the number of BMMNCs, and histological injury in the iron-overload AA mice. Also, PND improved the percentage of T lymphocytes in the iron-overload AA mice. PND attenuates ferroptosis against iron-overload AA mice and Meg-01 cells via activating Nrf2/HO-1 and PI3K/AKT/mTOR pathway and is a promising novel therapeutic candidate for AA.
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JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Pan Su,Mengdi Wu,Xiaoting Yin,Mengyuan Li,Yucheng Li,Ming Bai,Baoying Wang,Erping Xu
Ethnopharmacological relevance Modified Xiaoyao San (MXYS), a clinical empirical modified formula based on famous traditional Chinese herbal prescription Xiaoyao San, according to the “yu syndrome” theory of traditional Chinese medicine . MXYS has been shown to be an excellent effective therapy for depression patients in clinic, but the antidepressant mechanisms remain unclear. Aim of the study A growing body of evidence indicates the microglia autophagy and M1 polarized microglia (proinflammatory phenotype)-mediated neuroinflammation act critical roles in the pathogenesis of depression. This study aimed to investigate whether MXYS exerts antidepressant efficacy through inhibition of M1 polarized microglia-mediated neuroinflammation and modulation of autophagy involved in PI3K/Akt/mTOR pathway. Materials and methods In present research, the lipopolysaccharide (LPS)-induced depressive mice and LPS-stimulated N9 microglia cell line were utilized. Behavioral tests (sucrose preference, tail suspension and open field tests) were carried out to evaluate the antidepressant effect of MXYS. The neuronal damage was measured by Nissl's staining in LPS-treated mice. The proinflammatory cytokine levels, the autophagic markers, microglia M1 polarization as well as the PI3K/Akt/mTOR pathway related proteins of MXYS treatment were analyzed by ELISA kits, Western blot and immunofluorescence staining in vivo and vitro . Finally, the influence of autophagy antagonist (3-MA) on the protective effect of MXYS-containing serum in the LPS-stimulated N9 microglia was investigated. Results Treatment of LPS-induced depressive mice with MXYS significantly reversed depression-like behaviors, accompanied by reduction of proinflammatory cytokine levels (TNF-α, IL-1β) and amelioration of neuronal damage in prefrontal cortex. MXYS suppressed microglia M1 polarization and promoted autophagy in prefrontal cortex and LPS-stimulated N9 cells. Importantly, the remarkable inhibitory effect of the MXYS-medicated serum on microglia M1 polarization was blocked by autophagy antagonist 3-MA in LPS-stimulated N9 cells. Meanwhile, the MXYS treatment exhibited an excellent inhibition effect of PI3K/Akt/mTOR pathway in vivo and vitro . Conclusion Our research suggests that the antidepressant effect of MXYS in LPS-induced depressive mice may be related to alleviate neuroinflammation through suppression of microglia M1 polarization via enhancing autophagy involved in inactivation of the PI3K/Akt/mTOR pathway.
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ENVIRONMENTAL POLLUTION
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2022
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IF 9.988
Wenjing Pu,Xuesheng Chu,Huiling Guo,Gang Huang,Ting Cui,Bingyan Huang,Xueyan Dai,Caiying Zhang
Cadmium (Cd) and excess molybdenum (Mo) have multiple organ toxicity, and testis is one of their important target organs, but the reproductive toxicity of Mo and Cd combined treatment is still unclear. To explore the effects of Mo and Cd co-exposure on DNA damage and autophagy from the insight of ATM/AMPK/mTOR axis in duck testes, we randomly assigned 40 healthy 8-day-old ducks to control, Mo (100 mg/kg Mo), Cd (4 mg/kg Cd), and Mo + Cd groups for 16 weeks. Results found that Mo and/or Cd exposure caused trace elements imbalance, oxidative stress with a decrease in the activities of GSH-Px, CAT , T-SOD and GSH content, an increase in the concentrations of H 2 O 2 and MDA and pathological damage. Additionally, Mo and/or Cd markedly raised DNA damage-related factors expression levels and 8-OHdG content, caused G1/S arrest followed by decreasing CDK2 and Cyclin E protein levels and increasing CDK1 and Cyclin B protein levels, and activated ATM/AMPK/mTOR axis by enhancing p-ATM/ATM, p-AMPK/AMPK and reducing p-mTOR/mTOR protein levels, eventually triggered autophagy by elevating LC3A, LC3B, Atg5, Beclin-1 mRNA levels and LC3II/LC3I, Beclin-1 protein levels and reducing P62, Dynein, mTOR mRNA levels and P62 protein level. Moreover, these changes were most apparent in the combined group. Altogether, the results reveal that autophagy caused by Mo and/or Cd may be associated with activating the DNA damage-mediated ATM/AMPK/mTOR axis in duck testes, and Mo and Cd co-exposure exacerbates these changes.
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JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-16
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IF 9.429
Liu Jie,Hu Xiaochun,Feng Lei,Lin Yun,Liang Shujing,Zhu Zhounan,Shi Shuo,Dong Chunyan
Background Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4‐(2‐aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. Results ABS and PEG-NH 2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. Conclusion Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility. Graphical Abstract
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危险品化学品经营许可证（带存储）