JOURNAL OF CELLULAR PHYSIOLOGY
·
2023
·Vol. 238
·期 6
·1256-1274
·
IF 5.6
Zhe Li,Tong Xu,Xue Fan,Kai Chen,Chunyan Wan,Xiang Li,Hang Yin,Shu Li
Both bisphenol A (BPA) and selenium (Se) deficiency can affect the expression of microRNAs (miRNAs), which can specifically regulate its target mRNA and induce apoptosis, and play a significant role in cardiovascular injury diseases. To explore the mechanism of apoptosis induced by BPA and Se deficiency in chicken arterial endothelial tissue and the role of miRNAs in this process, the model of BPA exposure/Se deficiency in chicken and PAEC cells have been employed. The targeting relationship between miR-215-3p and iodothyronine deiodinase 1 (Dio1) in PAEC was verified by double luciferase gene report. The level of miR-215-3p was detected by qRT-PCR. The oxidative stress level of arterial endothelial cells was detected by oxidative stress kit and DCFH-DA probe method. The PI3K/AKT pathway, mitochondrial dynamics, and apoptosis-related genes were detected by qRT-PCR and western blot. The mitochondrial ATP level and nitric oxide synthases (NOSs) level were detected with the kit. TUNEL, acridine orange/ethidium bromide, and flow cytometry were used to detect the level of apoptosis. The results showed that BPA exposure and Se deficiency led to overexpression of miR-215-3p, aggravated oxidative stress, inhibited activation of PI3K/AKT pathway, promoted mitochondrial division, increased expression of apoptosis related genes, and finally led to apoptosis of chicken arterial endothelial cells. We also established knockdown/overexpression models of miR-215-3p and Dio1 in vitro, and found that overexpression of miR-215-3p and knockout of Dio1 can induce apoptosis. Interestingly, miR-215-3p-Inhibitor and N-acetyl- l -cysteine (NAC) partially prevented apoptosis caused by BPA exposure and Se deficiency, and LY294002 aggravated apoptosis. These results suggest that BPA exposure aggravates the apoptosis of Se deficient arterial endothelial cells in chickens by regulating the ROS/PI3K/AKT pathway activated by miR-215-3p/Dio1. The miR-215-3p/Dio1 axis provides a new way to understand the toxic mechanism of BPA exposure and Se deficiency, and reveals a new regulatory model of apoptosis damage in vascular diseases.
研究领域:
毒理学
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分子生物学
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心血管疾病
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microRNA调控
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2024
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IF 2.7
Hongmei Chang,Siqi Zhao,Yuzhu Lei,Yunhua Hu,Yizhong Yan,Guanling Song
Titanium dioxide nanoparticles (nano-TiO 2 ) can cause a reduction in sperm counts, and lactate production in Sertoli cells plays a key role in spermatogenesis. The aim of this study was to evaluate the effect of nano-TiO 2 on lactate production in mouse Sertoli cell line (TM4 cells) and to investigate whether the effect is mediated through the PI3K/AKT/HIF-1α pathway. After TM4 cells were treated with different concentrations of nano-TiO 2 for 48 h, cell viability, contents of glucose and lactate, and the expression levels of GLUT3 and key enzymes (HK1, HK2, PFKM, ENO1, LDH) during lactate production were detected. PI3K/AKT/HIF-1α pathway proteins were measured. In addition, PI3K agonist (IGF-1) was added to explore whether nano-TiO 2 regulates HIF-1α through PI3K/AKT pathway, thereby affecting the production of lactate in TM4 cells. The results showed that nano-TiO 2 significantly inhibited TM4 cell viability, increased glucose content, decreased lactate content, and downregulated the expression levels of GLUT3 and key enzymes during lactate production. Meanwhile, nano-TiO 2 decreased the expression of PI3K/AKT pathway phosphorylated proteins and HIF-1α, and IGF attenuated this effect of nano-TiO 2 . Collectively, nano-TiO 2 downregulated the expression level of proteins and enzymes related to lactate production in TM4 cells by inhibiting PI3K/AKT/HIF-1α pathway, resulting in the decrease of lactate production in TM4 cells.
研究领域:
生殖生物学
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细胞生物学
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纳米技术
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR MEDICINE
·
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.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
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.
研究领域:
材料科学
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生物材料
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组织工程
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干细胞生物学
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牙科研究
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Zuo Wanyun,Liu Na,Zeng Yunhong,Xiao Zhenghui,Wu Keke,Yang Fan,Li Biao,Song Qingqing,Xiao Yunbin,Liu Qiming
Luteolin is a flavonoid compound with a variety of pharmacological effects. In this study, we explored the effects of luteolin on monocrotaline (MCT) induced rat pulmonary arterial hypertension (PAH) and underlying mechanisms. A rat PAH model was generated through MCT injection. In this model, luteolin improved pulmonary vascular remodeling and right ventricular hypertrophy, meanwhile, luteolin could inhibit the proliferation and migration of pulmonary artery smooth muscle cells induced by platelet-derived growth factor-BB (PDGF-BB) in a dose-dependent manner. Moreover, our results showed that luteolin could downregulate the expression of LATS1 and YAP, decrease YAP nuclear localization, reduce the expression of PI3K, and thereby restrain the phosphorylation of AKT induced by PDGF-BB. In conclusion, luteolin ameliorated experimental PAH, which was at least partly mediated through suppressing HIPPO-YAP/PI3K/AKT signaling pathway. Therefore, luteolin might become a promising candidate for treatment of PAH.
研究领域:
药理学
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心血管疾病
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
NEPHROLOGY
·
2023
·
IF 2.5
Ziyuan Liu,Huilong Xiang,Qin Deng,Wanting Fu,Yang Li,Zejun Yu,Yinsheng Qiu,Zhinan Mei,Lingyun Xu
Aim Inflammation and apoptosis are main pathological processes that lead to the development of hyperuricemic nephropathy (HN). This study aims to explore whether baicalin (BA) and baicalein (BAI) can relieve the damage through PI3K/AKT/NF-κB signal pathway and provide more reliable and precise evidence for the treatment of HN. Methods HN mice were induced by yeast extract with potassium oxonate (PO), and HK-2 cells were induced by monosodium urate (MSU). Molecular docking, western blot, q-PCR, and other methods were used to explore the changes of various indicators in HN mice and HK-2 cells. Results Molecular docking results showed that BA and BAI had good binding ability with PI3K, AKT, p65 and IκBα. BA and BAI significantly ameliorated the levels of renal function, decreased the p-PI3K, p-AKT and p-p65 expression, down-regulated the BAX/BCL2 and CASP3, and blunted the mRNA levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-18 in both renal tissue of HN mice and HK-2 cells induced by MSU. BA and BAI also decreased the oxidative stress level of MSU-induced HK-2 cells. Conclusion BA and BAI were confirmed to attenuate HN through alleviating renal inflammatory and apoptosis in cells and tissues by inhibiting PI3K/AKT/NF-κB pathway. BA and BAI were expected to be developed as new anti-HN drugs.
研究领域:
药理学
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肾病学
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分子生物学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2018
·Vol. 40
·期 2
·867-876
·
IF 2.976
Zhibo Dai,Ligang Wang,Xiaoxiong Wang,Boxian Zhao,Wenyang Zhao,Shashank Singh Bhardwaj,Junyi Ye,Zhiqin Yin,Jun Zhang,Shiguang Zhao
Oxymatrine (OM), a natural quinolizidine alkaloid extracted from the traditional Chinese herb Sophora flavescens, has been revealed to produce antitumor activities in various cancer cell lines, including glioblastoma lines, in vitro. However, the mechanisms by which OM exerts its antitumor effect against glioma are poorly understood. The aim of this study was to investigate the role of OM in the proliferation, apoptosis and invasion of glioma cells and to reveal the underlying mechanisms. The effects of OM on U251MG cells in vitro were determined using a Cell Counting Kit‑8 (CCK‑8) assay, flow cytometric analysis, Annexin V‑FITC/PI staining, DAPI staining, a terminal deoxynucleotidyl transferase‑mediated dUTP nick end‑labeling (TUNEL) assay, a Transwell assay and western blotting. Our data indicated that OM inhibited proliferation, arrested the cell cycle at the G0/G1 phase, decreased the expression levels of G1 cell cycle regulatory proteins (cyclin D1, CDK4 and CDK6), inhibited invasion and induced apoptosis in glioma cells. Additional investigations revealed that the expression levels of p‑STAT3 and key proteins in the EGFR/PI3K/Akt/mTOR signaling pathway, such as p‑EGFR, p‑Akt and p‑mTOR, were markedly decreased after OM treatment, while the total STAT3, EGFR, Akt and mTOR levels were not affected. These findings indicated that the EGFR/PI3K/Akt/mTOR signaling pathway and STAT3 suppression may be a potential mechanism of the OM‑mediated antitumor effect in glioblastoma cells and that EGFR may be a target of OM. Hence, OM may be a promising drug and may offer a novel therapeutic strategy for malignant gliomas in the future.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Lianhua Tang,Juan Deng,Pi Shi,Siyuan Zou,Hongyan Ran,Fei Yin,Jianhui Liu
Rosmarinic acid (RA), a polyphenolic compound, exhibits diverse pharmacological activities, including anti-inflammatory, antioxidant, and antitumor effects. Despite its therapeutic potentials, the mechanisms underlying its efficacy in ulcerative colitis (UC), a chronic inflammatory bowel disease characterized by intestinal epithelial barrier dysfunction, remain incompletely elucidated. This study investigates RA's protective effects in UC using complementary in vivo and in vitro models. In a dextran sulfate sodium (DSS)-induced murine colitis model, RA administration significantly attenuated disease severity, mitigating weight loss, preventing colon shortening, and reducing histopathological inflammatory infiltration. RA restored intestinal barrier integrity via upregulation of key tight junction proteins such as ZO-1, occludin, claudin-1 in colonic tissues. Mechanistic analyses in lipopolysaccharide (LPS)-stimulated NCM460 human colonic epithelial cells revealed that RA inhibited phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation, as evidenced by reducing AKT phosphorylation (p-AKT), while enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Pharmacological PI3K inhibition with LY294002 abolished RA-induced upregulation of Nrf2 and TJPs, confirming the PI3K/AKT/Nrf2 axis as the central signaling cascade mediating RA's protective effects. Collectively, these findings elucidate a novel mechanism by which RA preserves intestinal barrier integrity through PI3K/AKT/Nrf2 axis modulation and propose a targeted therapeutic strategy for UC management.
研究领域:
药理学
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分子生物学
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胃肠病学
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免疫学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL UROLOGY AND NEPHROLOGY
·
2023
·
IF 2
Wang Hongjie,Zhang Yunxia,Liu Huan,Li Shuang
Purpose To investigate the role and underlying mechanism of GDF11 on diabetic nephropathy (DN)-related mitochondrial dysfunction and apoptosis. Methods A DN model of rats was established in this study. Human Kidney-2 (HK-2) cells were cultured under high-glucose (HG) condition with or without recombinant GDF11 (rGDF11). Mitochondrial morphology of HK-2 cells was analyzed by transmission electron microscope and MitoTracker Red CMXRos staining. Mitochondrial membrane potential (MMP) and ROS production were monitored using JC-1 assay kit and MitoSOX staining, respectively. Cell apoptosis was detected by TUNEL or flow cytometry assays. Results Herein, we observed that GDF11 was down-regulated in renal cortex and serum of DN rats, which was accompanied by renal mitochondrial morphological abnormalities. In line with the findings in vivo, HK-2 cells exposed to HG presented with mitochondrial morphological alterations and further apoptosis accompanied by GDF11 reduction. In addition, HG promoted a decrease in MMP while an increase in mitochondrial ROS production. Conversely, rGDF11 treatment significantly alleviated these HG-induced mitochondrial defects in HK-2 cells. Meanwhile, HK-2 cell apoptosis induced by HG was simultaneously suppressed by rGDF11. Mechanistically, the decreased levels of p-AKT induced by HG were attenuated after rGDF11 administration. Inhibition of the PI3K/AKT pathway resisted the effects of rGDF11 on the MMP and apoptosis of HK-2 cells. In addition, we identified that GDF11 is a target of miR-32-5p. Up-regulation of miR-32-5p could inhibit the expression of GDF11. Conclusion rGDF11 treatment rescued HG-induced HK-2 cell mitochondrial dysfunction and apoptosis, which may be dependent on the activation of the PI3K/AKT pathway.
研究领域:
肾病学
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细胞生物学
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分子生物学
·
糖尿病
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Xiu Yanghui,Su Yu,Gao Lihua,Yuan Hui,Xu Sennan,Liu Ying,Qiu Yan,Liu Zhen,Li Yuhang
Introduction: Chronic non-healing wound is a considerable clinical challenge and research into the discovery of novel pro-healing agents is underway as existing therapeutic approaches cannot sufficiently meet current needs.Method: We studied the effects of corylin in cell line fibroblasts and macrophages by Western blots, PCR, Flow cytometry assay, Immunofluorescence.Results: We showed that corylin, a main flavonoid extracted from Psoralea corylifolia L, reduced inflammatory responses, promoted collagen deposition, and accelerated the healing of full-thickness skin wounds in mice. Exploration of the underlying mechanisms showed that corylin activated the PI3K/AKT signaling, leading to fibroblasts’ migration, proliferation, and scratch healing. Corylin also activated sirtuin 1 (SIRT1) signaling, enhanced the deacetylation and cytoplasmic translocation of NF-κB p65, and therefore reduced lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Furthermore, inhibition of PI3K/AKT and sirtuin 1 pathway with LY294002 and EX527 prevent the therapeutic potency of corylin against chronic wounds.Conclusion: In summary, our results suggested that corylin may be a candidate for the development of novel pro-healing agents.
研究领域:
药理学
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伤口愈合
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免疫学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF TRACE ELEMENTS IN MEDICINE AND BIOLOGY
·
2019
·
IF 2.895
Yiming Li,Guanhui Chen,Yi He,Xiliu Zhang,Binghui Zeng,Chao Wang,Chen Yi,Dongsheng Yu
Background Patients with metabolic bone diseases often have high risk of titanium implant failure due to compromised bone regeneration ability. Clinical evidence indicates that the poor osteogenic ability is partly because of excessive oxidative stress. To date, specific treatments for these patients are urgently needed. Ebselen, a non-toxic organoselenium compound, is reported to be a potent antioxidant agent. In this study, we hypothesized that ebselen exerted protective effects on osteogenic differentiation of bone-marrow-derived mesenchymal stem cells (BMSCs) under oxidative stress. Methods BMSCs were isolated from SD rats, and their morphology and multiple differentiation abilities were characterized. Proliferation rates of BMSCs treated with different concentrations of ebselen were analyzed. Then BMSCs were pretreated by hydrogen peroxide (H 2 O 2 ), after which ebselen at different concentrations (0, 1, 5, 10 μM) was added, alkaline phosphatase (ALP) activity, mineralization and osteogenic-related protein levels were evaluated and an optimum concentration of ebselen was selected. Subsequently, intracellular reactive oxygen species (ROS) generation and the role of the PI3K/AKT pathway were also investigated. Results Ebselen within a proper range could promote the proliferation of BMSCs. H 2 O 2 -induced oxidative stress suppressed osteogenic differentiation of BMSCs, which was verified by the decrease in ALP activity, calcium deposition, Runx2 and β-catenin expression. However, ebselen could alleviate osteogenic dysfunction of BMSCs. We also observed that ebselen reduced ROS accumulation in H 2 O 2 -pretreated BMSCs. Moreover, the pro-osteogenic effects afforded by ebselen were almost abolished by the Akt inhibitor. Conclusion We concluded that ebselen could attenuate osteogenic dysfunction of BMSCs induced by H 2 O 2 through an antioxidant effect and the activation of the PI3K/Akt pathway, suggesting that ebselen has a potential therapeutic effect for patients with metabolic bone diseases.
研究领域:
干细胞生物学
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骨科
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2020
·
IF 2.971
Zhaohui Wang,Zhi Chen,Bingsheng Li,Bo Zhang,Yongchao Du,Yuhang Liu,Yao He,Xiang Chen
Context Renal interstitial fibrosis (RIF) is characterized by the accumulation of inflammatory cytokines and epithelial-mesenchymal transition (EMT). Curcumin exerts antifibrogenic, anti-inflammatory and antiproliferative effects.Objective To explore the mechanisms underlying the effects of curcumin on RIF.Materials and methods Eight-week-old male C57BL/6 mice were intragastrically administered curcumin (50 mg/kg/day) for 14 days after undergoing unilateral ureteral obstruction (UUO) operations. Renal function (blood urea nitrogen [BUN] and serum creatinine [Scr]) and inflammatory cytokine levels were tested using colorimetric assays and ELISA, respectively. EMT markers were evaluated through immunohistochemistry, western blotting and qPCR. Transforming growth factor beta 1 (TGF-β1; 10 ng/mL) and lipopolysaccharides (LPS; 100 ng/mL) were used to stimulate EMT and an inflammatory response in human renal proximal tubular epithelial (HK-2) cells, respectively, for further investigation.Results In vivo, curcumin significantly improved the levels of BUN and Scr by 28.7% and 21.3%, respectively. Moreover, curcumin reduced the levels of IL-6, IL-1β and TNF-α by 22.5%, 30.3% and 26.7%, respectively, and suppressed vimentin expression in UUO mice. In vitro, curcumin reduced the expression of vimentin and α-smooth muscle actin in TGF-β1-induced HK-2 cells. In LPS-induced HK-2 cells, curcumin decreased the release of IL-6, IL-1β and TNF-α by 43.4%, 38.1% and 28.3%, respectively. In addition, curcumin reduced the expression of TLR4, p-PI3K, p-AKT, p-NF- κB and p-IκBα in both LPS- and TGF-β1-induced HK-2 cells.Discussion and conclusions Curcumin repressed EMT and the inflammatory response by inhibiting the TLR4/NF-κB and PI3K/AKT pathways, demonstrating its potential utility in RIF treatment.
研究领域:
肾病学
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药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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