ENDOCRINE JOURNAL
·
2019
·
IF 1.94
Lili Zhuang,Hongmei Qu,Jianxiang Cong,Huangguan Dai,Xiaoyan Liu
MicroRNAs (miRNAs), which is a type of non-coding and single-stranded small molecule RNA, bind either completely or incompletely to 3’-UTR of the target gene mRNA to inhibit mRNA translation or degradation. In our study, we aimed to explore the roles and mechanisms of miR-181c in the apoptosis of RL95-2 human endometrial carcinoma cells. Cell activity and apoptosis were detected by cell counting Kit-8 (CCK-8) assay and flow cytometry (FCM), respectively. Related mRNAs and proteins expression was determined by quantitative real-time reverse transcription PCR (qRT-PCR) and western blot assays, respectively. The binding capacity of PTEN-3’-UTR and miR-181c was assessed by luciferase reporter assay. The obtained results suggested that E2 evidently increased the cell activity of RL95-2 cells. In addition, miR-181c inhibitor suppressed the cell viability and enhanced the apoptosis capacity of E2-induced RL95-2 cells and distinctly reduced the miR-181c expression. We also found that miR-181c could bind to PTEN-3’-UTR and miR-181c inhibitor up-regulated the expression level of PTEN in E2-induced RL95-2 cells. Besides, overexpression of PTEN markedly promoted the apoptosis of E2-induced RL95-2 cells through regulating the Bax and Bcl-2 expression, and modulated the expression of AKT pathway, p53 and Cyclin D. In conclusion, our findings revealed that miR-181c affected the estrogen-dependent endometrial carcinoma cell growth by targeting PTEN. The potential effects of miR-181c on the apoptosis of E2-induced RL95-2 cells suggest that miR-181c could be an effective target for endometrial carcinoma therapies.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2020
·
IF 4.225
Xie Xin,Wang Hong-Xia,Li Nan,Deng Ya-Wen,Bi Hai-Lian,Zhang Yun-Long,Xia Yun-Long,Li Hui-Hua
Cardiac hypertrophy without appropriate treatment eventually progresses to heart failure. Our recent data demonstrated that the immunoproteasome subunit β5i promotes cardiac hypertrophy. However, whether β5i is a promising therapeutic target for treating hypertrophic remodeling remains unknown. Here, we investigated the effects of PR-957, a β5i-specific inhibitor, on angiotensin II (Ang II)–induced hypertrophic remodeling in the murine heart. The infusion of Ang II increased immunoproteasome chymotrypsin-like activity and β5i catalytic subunit expression in the heart, whereas PR-957 treatment fully blocked the enhanced immunoproteasome activity caused by Ang II. Moreover, the administration of PR-957 significantly suppressed Ang II–induced cardiac hypertrophy, fibrosis, and inflammation. Mechanistically, PR-957 treatment inhibited phosphatase and tensin homolog on chromosome ten (PTEN) degradation, thereby inhibiting multiple signals including AKT/mTOR, ERK1/2, transforming growth factor-β, and IKB/NF-kB. Furthermore, PTEN blocking by its specific inhibitor VO-OHpic markedly attenuated the inhibitory effect of PR-957 on Ang II–induced cardiac hypertrophy in mice. We conclude that PR-957 blocks PTEN degradation and activates its downstream mediators, thereby attenuating Ang II–induced cardiac hypertrophy. These findings highlight that PR-957 may be a potential therapeutic agent for Ang II-induced hypertrophic remodeling.
研究领域:
心脏病学
·
药理学
·
分子生物学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2020
·
IF 5.115
Lingling Ou,Haiyingjie Lin,Yuwei Song,Guoqiang Tan,Xiujuan Gui,Jinyuan Li,Xiaoting Chen,Zhendong Deng,Shaoqiang Lin
Background Gene therapy is considered a novel way to treat osteosarcoma, and microRNAs are potential therapeutic targets for osteosarcoma. miR-214 has been found to promote osteosarcoma aggression and metastasis. Graphene oxide (GO) is widely used for gene delivery for the distinct physiochemical properties and minimal cytotoxicity. Methods Polyethyleneimine (PEI)-functionalized GO complex was well-prepared and loaded with miR-214 inhibitor at different concentrations. The load efficacy was tested by gel retardation assay and the cy3-labeled fluorescence of cellular uptake. The experiments of wound healing, immunofluorescence staining, Western blot, qRT-PCR and immunohistochemical staining were performed to measure the inhibitory effect of the miR-214 inhibitor systematically released from the complexes against MG63, U2OS cells and xenograft tumors. Results The systematic mechanistic elucidation of the efficient delivery of the miR-214 inhibitor by GO-PEI indicated that the inhibition of cellular miR-214 caused a decrease in osteosarcoma cell invasion and migration and an increase in apoptosis by targeting phosphatase and tensin homolog (PTEN). The synergistic combination of the GO-PEI-miR-214 inhibitor and CDDP chemotherapy showed significant cell death. In a xenograft mouse model, the GO-PEI-miR-214 inhibitor significantly inhibited tumor volume growth. Conclusion This study indicates the potential of functionalized GO-PEI as a vehicle for miRNA inhibitor delivery to treat osteosarcoma with low toxicity and miR-214 can be a good target for osteosarcoma therapy.
研究领域:
肿瘤学
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分子生物学
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纳米技术
·
药学
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DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
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2022
·
IF 5.486
Jing Fu,Xiaobo Zhang,Huiwen Zheng,Guobin Yang,Zhi Chen,Guohua Yuan
WW domain–containing E3 Ubiquitin-protein ligase 2 (WWP2) has been found to positively regulate odontoblastic differentiation by monoubiquitinating the transcription factor Kruppel-like factor 5 (KLF5) in a cell culture system. However, the in vivo role of WWP2 in mouse teeth remains unknown. To explore this, here we generated Wwp2 knockout (Wwp2 KO) mice. We found that molars in Wwp2 KO mice exhibited thinner dentin, widened predentin, and reduced numbers of dentinal tubules. In addition, expression of the odontoblast differentiation markers Dspp and Dmp1 was decreased in the odontoblast layers of Wwp2 KO mice. These findings demonstrate that WWP2 may facilitate odontoblast differentiation and dentinogenesis. Furthermore, we show for the first time that phosphatase and tensin homolog (PTEN), a tumor suppressor, is expressed in dental papilla cells and odontoblasts of mouse molars and acts as a negative regulator of odontoblastic differentiation. Further investigation indicated that PTEN is targeted by WWP2 for degradation during odontoblastic differentiation. We demonstrate PTEN physically interacts with and inhibits the transcriptional activity of KLF5 on Dspp and Dmp1. Finally, we found WWP2 was able to suppress the interaction between PTEN and KLF5, which diminished the inhibition effect of PTEN on KLF5. Taken together, this study confirms the essential role of WWP2 and the WWP2–PTEN–KLF5 signaling axis in odontoblast differentiation and dentinogenesis in vivo .
研究领域:
分子生物学
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发育生物学
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牙科科学
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DOI
PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2021
·Vol. 44
·期 6
·780-788
·
IF 2.233
Fu Li,Suping Wang,Manxiang Niu
Gastric cancer is one of the most common malignancies with a high mortality rate world. This study intends to make clear the role and mechanism of the Scutellarin (Scu), a flavonoid isolated from Erigeron breviscapus (Vant.) Hand.-Mazz, in regulating the evolvement of gastric cancer. We selected different doses of Scu to treat gastric cancer cells (MGC-803 and AGS). Then, cell counting kit-8 (CCK8) assay was conducted to verify the proliferation of tumor cells, while flow cytometry was adopted to test the apoptosis rate. Meanwhile, Western blot was conducted to examine epithelial–mesenchymal transition (EMT) markers and the expression of phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K) and apoptosis-related proteins (Bax, Bcl2 and Caspase3). Moreover, xenograft tumor experiment in nude mice was established to verify the effect of Scu on tumor growth. Furthermore, the knockdown model of PTEN was constructed, and the influence of PTEN on the anti-tumor effect of Scu was investigated. As a result, Scu inhibited cell proliferation, EMT and promoted the apoptosis in gastric cancer dose-dependently. Additionally, Scu attenuated tumor cell growth in vivo. Besides, Scu enhanced the expression of PTEN while reduced the phosphorylated level of PI3K. Moreover, the mechanistic study proved that Scu inactivated PI3K by up-regulating PTEN, thus dampening tumor progression. In conclusion, Scu dampened the growth and EMT of gastric cancer by regulating the PTEN/PI3K pathway.
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2019
·
IF 3.448
Zhaopeng Yan,Bin Zang,Xiaoying Gong,Jiangyue Ren,Rui Wang
Aims Acute pancreatitis (AP) is usually complicated with multiple organ insufficiency, including renal injury. Hyperlipidemia is regarded as a risk factor to induce AP. High-fat diet-induced hyperlipidemic pancreatitis (HP) increased nowadays and showed more severe symptoms and complications than other AP. However, detailed mechanisms or mediators involved in HP complicated with acute renal injury were less studied. Here, we aimed to study how miR-214 expresses in the HP and whether miR-214 has functions to regulate pathological kidney damages induced by HP. Main methods Sprague-Dawley rats were adopted to establish HP model complicated with acute renal injury through long-term high-fat diet and sodium taurocholic injection. Models were injected with LV-rno-miR-214-3p or LV-anti-rno-miR-214-3p to exogenously regulate miR-214-3p to study its impacts on HP via a series of molecular and histological experiments. Key findings MiR-214-3p was found to be up-regulated in the kidney, pancreas and serum of HP rats and also could intensify the pathological alterations, kidney and pancreas damages and fibrosis induced by HP. Inflammatory response in HP was enhanced when miR-214-3p was overexpressed. Besides, miR-214-3p up-regulation was showed to inhibit PTEN expression but increased P-Akt levels in the HP kidney, which might be a possible mechanism to induce severe symptoms of pancreatitis. Knockdown of miR-214-3p showed opposite effects. Significance MiR-214-3p is indicated to exacerbate the tissue damages and inflammatory response caused by HP complicated with acute renal injury, which may provide a novel therapeutic perspective targeting miR-214-3p to treat HP with acute renal injury.
研究领域:
分子生物学
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病理学
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药理学
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DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2018
·
IF 4.936
Liming Yu,Zhi Li,Xue Dong,Xiaodong Xue,Yu Liu,Shu Xu,Jian Zhang,Jinsong Han,Yang Yang,Huishan Wang
Diabetes exacerbates oxidative/nitrative stress during myocardial ischemia-reperfusion (MI/R) injury. Recent studies highlighted the cardioprotective actions of polydatin. However, its effect on diabetic MI/R injury and the underlying mechanisms remain unknown. This work was undertaken to evaluate the effect of polydatin on diabetic MI/R injury with a focus on Notch1/Hes1 signaling and myocardial oxidative/nitrative stress. Streptozotocin- (STZ-) induced diabetic rats were administered with polydatin (20 mg/kg/d) in the absence or presence of DAPT (a γ-secretase inhibitor) or LY294002 (a PI3K/Akt inhibitor) and then subjected to MI/R injury. Polydatin administration preserved cardiac function and reduced myocardial infarct size. Moreover, polydatin ameliorated myocardial oxidative/nitrative stress damage as evidenced by decreased myocardial superoxide generation, malondialdehyde, gp91phox expression, iNOS expression, NO metabolite level, and nitrotyrosine content and increased eNOS phosphorylation. However, these effects were blocked by DAPT administration. DAPT also inhibited the stimulatory effect of polydatin on the Notch1/Hes1-Pten/Akt signaling pathway in a diabetic myocardium. Additionally, LY294002 not only abolished polydatin’s antiapoptotic effect but also reversed its inhibitory effect on myocardial oxidative/nitrative stress. Polydatin effectively reduced MI/R injury and improved left ventricular functional recovery under diabetic condition by ameliorating oxidative/nitrative stress damage. Importantly, Notch1/Hes1-mediated activation of Pten/Akt signaling played a crucial role in this process.
研究领域:
心脏病学
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药理学
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分子生物学
·
糖尿病研究
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DOI
PubMed
高影响因子
ANNALS OF CLINICAL AND LABORATORY SCIENCE
·
2022
·Vol. 52
·期 1
·48-59
·
IF 1.18
Guomin Lv,Yan Chen,Zhengyue Cheng,Lixiang Lin,Huasong Shen
Objective Osteoporosis is likely becoming a new disease challenge with increasing aging population. Circ_0006873 dysregulation mayserve as an event linked to osteoporosis. Thus, this study sought to evaluate the function and mechanism of circ_0006873 onosteoporosis. Methods Clinical serum samples collected from 30 osteoporosis patients were utilized to obtain circ_0006873 and miR-142-5p expressiondata. The link between circ_0006873, miR-142-5p, and phosphatase and tensin homolog (PTEN) was demonstrated via online tools(starBase, circinteractome), RNA Immunoprecipitation (RIP) and dual-Luciferase reporter assays. After knockdown or overexpression,cell counting kit-8 (CCK-8) assay measured cell viability. Alizarin red S (ARS) staining as well Alkaline phosphatase (ALP)staining detected osteoblastic differentiation levels. Quantitative real-time PCR (qRT-PCR) and western blot analyzed expressionof RNAs and proteins after transfection or during osteoblastic differentiation. Results circ_0006873 was upregulated in osteoporosis patients and decreased during osteoblastic differentiation. Following experimentsrevealed that cell viability, proliferation-related factors, osteogenic marker genes (ALP, Runx2, Bglap) and osteoblasticdifferentiation degree were promoted after circ_0006873 knockdown but inhibited after overexpression. Circ_0006873 spongedmiR-142-5p, which was downregulated in osteoporosis patients and became higher during osteoblastic differentiation. Rescueassay indicated miR-142-5p mimic could reverse the effects of circ_0006873 overexpression on cell viability and osteogenicmarkers, and also could activate Akt pathway. Furthermore, circ_0006873 can negatively target miR-142-5p via regulating PTENto inhibit osteoblastic differentiation. Conclusion Circ_0006873 sponges miR-142-5p thereby enhances PTEN expression to suppress osteoblastic differentiation via regulationof Akt signaling pathway, thus, may provide a treatment approach for osteoporosis.
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产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2025
·
IF 5.5
Huijun Yu,Xiao Xu,Xian Wang,Xiaonan Qiu,Qinxin Wang,Mengke Lu,Fengyi Du,Qi Guo,Miaomiao Zhang
Photothermal therapy (PTT) faces critical limitations due to tumor hypoxia, intrinsic resistance, and metastasis. To address these challenges, we developed a trimodal nanoplatform (R-R/PB@PPy NEs) by synergizing Prussian blue (PB)/polypyrrole (PPy) nanozymes, tumor suppressor reactivation, and immune modulation. Through Fe3+ -mediated one-step oxidative polymerization, PB and PPy were integrated into a hybrid nanozyme and further functionalized with rosiglitazone (PPAR-γ agonist) and rutin (tumor-targeting ligand). The R-R/PB@PPy NEs achieved a photothermal conversion efficiency of 31.6% and catalase/superoxide dismutase-like enzymatic activity, persistently alleviating hypoxia via oxygen generation. Simultaneously, AKT/mTOR-mediated PTEN upregulation suppressed tumor proliferation and metastasis. Rutin-mediated tumor targeting enhanced drug accumulation at tumor sites, which synergistically amplified immunogenic cell death induction, promoting dendritic cell maturation and cytotoxic T-cell infiltration. In vivo, this platform completely inhibited 4T1 tumor growth, eradicated lung metastasis, and prevented recurrence (0% at 56 days) with an 80% long-term survival rate and no systemic toxicity. By unifying catalytic nanozyme design, PTEN-driven sensitization, and immune activation, this study establishes an interdisciplinary strategy to overcome resistance in PTT, offering a translatable approach for precision cancer therapy through tumor microenvironment modulation.
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Jing Zhang,Juan Gao,Xianlong Li,Dengna Lin,Zhihui Li,Jialei Wang,Junfeng Chen,Zhiliang Gao,Bingliang Lin
Balancing hepatocyte death and proliferation is key to non-transplantation treatments for acute liver failure (ALF), which has a high short-term mortality rate. Small extracellular vesicles (sEVs) may act as mediators in the repair of damaged liver tissue by mesenchymal stem cells (MSCs). We aimed to investigate the efficacy of human bone marrow MSC-derived sEVs (BMSC-sEVs) in treating mice with ALF and the molecular mechanisms involved in regulating hepatocyte proliferation and apoptosis. Small EVs and sEV-free BMSC concentrated medium were injected into mice with LPS/D-GalN-induced ALF to assess survival, changes in serology, liver pathology, and apoptosis and proliferation in different phases. The results were further verified in vitro in L-02 cells with hydrogen peroxide injury. BMSC-sEV-treated mice with ALF had higher 24 h survival rates and more significant reductions in liver injury than mice treated with sEV-free concentrated medium. BMSC-sEVs reduced hepatocyte apoptosis and promoted cell proliferation by upregulating miR-20a-5p, which targeted the PTEN/AKT signaling pathway. Additionally, BMSC-sEVs upregulated the mir-20a precursor in hepatocytes. The application of BMSC-sEVs showed a positive impact by preventing the development of ALF, and may serve as a promising strategy for promoting ALF liver regeneration. miR-20a-5p plays an important role in liver protection from ALF by BMSC-sEVs.
研究领域:
干细胞生物学
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分子生物学
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肝病学
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再生医学
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DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR HISTOLOGY
·
2026
·Vol. 57
·期 1
·30
·
IF 2.2
Xiang Shouyu,Liu Wei,Tang Cheng,Xie Chuhai,Hu Hailan,Zhou Jianhui,Cao Yanming,Ling Long
Bone marrow mesenchymal stem cells (BMSCs) play a significant role in bone defect repair. Currently, the limited survival and function of transplanted BMSCs pose major obstacles to tissue repair mediated by these cells. Therefore, the exploration of BMSCs transplantation activity has become an urgent clinical problem. In this experiment, we constructed lentiviral vectors with overexpression and silencing of miR-19b-3p and utilized a rat fracture model. The effects of BMSCs proliferation were examined using CCK-8, the Annexin V-FITC apoptosis kit and TUNEL assay, the effects of BMSCs osteogenic differentiation were detected using ALP and Alizarin red staining. Furthermore, Western blotting and qRT-PCR were employed to examine the expression of key proteins in the PTEN/Akt/mTOR signaling pathway and autophagy-related proteins. Moreover, the impact of miR-19b-3p on bone microstructure was assessed using Micro CT, HE, Safranin O/Fast Green, as well as Masson staining, and Immunohistochemistry analysis examined PTEN, p62 and Runx2 expression levels on fracture site. By constructing lentiviral vectors with overexpression and silencing of miR-19b-3p, we found that silencing miR-19b-3p significantly promoted the proliferation as well as the osteogenic differentiation of BMSCs under hypoxia. Western blotting and qRT-PCR results showed that silencing miR-19b-3p significantly increased PTEN, LC3, and Beclin1 expression while decreasing p-Akt, p-mTOR, and p62 expression. Furthermore, by constructing the fracture rats and administering hypoxia-treated BMSCs transfected with miR-19b-3p via tail vein injection, we found that silencing miR-19b-3p obviously increased the formation of trabecular and promoted the healing of the fractures. Immunohistochemistry analysis showed that silencing miR-19b-3p upregulated PTEN and Runx2 expression levels and suppressed p62 expression with statistical significance. In summary, these findings suggest that miR-19b-3p may regulate BMSCs’ autophagy and osteogenic differentiation under hypoxia via the PTEN/Akt/mTOR signaling pathway, thereby promoting fracture healing and providing a potential target for the treatment of fractures.
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2020
·
IF 6.793
Caiying Zhang,Tianjin Lin,Gaohui Nie,Ruiming Hu,Shaoxing Pi,Zejing Wei,Chang Wang,Chenghong Xing,Guoliang Hu
Cadmium (Cd) and excess molybdenum (Mo) are harmful to animals, but the combined nephrotoxic mechanism of Cd and Mo in duck remains poorly elucidated. To assess joint effects of Cd and Mo on pyroptosis via ROS/PTEN/PI3K/AKT axis in duck renal tubular epithelial cells, cells were cultured with 3CdSO 4 ·8H 2 O (4.0 μM), (NH 4 ) 6 Mo 7 O 24 ·4H 2 O (500.0 μM), MCC950 (10.0 μM), BHA (100.0 μM) and combination of Cd and Mo or Cd, Mo and MCC950 or Cd, Mo and BHA for 12 h, and the joint cytotoxicity was explored. The results manifested that toxicity of non-equitoxic binary mixtures of Mo and Cd exhibited synergic interaction. Mo or/and Cd elevated ROS level, PTEN mRNA and protein levels, and decreased PI3K, AKT and p-AKT expression levels. Simultaneously, Mo or/and Cd upregulated ASC, NLRP3, NEK7, Caspase-1, GSDMA, GSDME, IL-18 and IL-1β mRNA levels and Caspase-1 p20, NLRP3, ASC, GSDMD protein levels, increased the percentage of pyroptotic cells, LDH , NO , IL-18 and IL-1β releases as well as relative conductivity. Moreover, NLRP3 inhibitor MCC950 and ROS scavenger BHA could ameliorate the above changed factors induced by Mo and Cd co-exposure. Collectively, our results reveal that combination of Mo and Cd synergistically cause oxidative stress and trigger pyroptosis via ROS/PTEN/PI3K/AKT axis in duck tubular epithelial cells.
研究领域:
毒理学
·
细胞生物学
·
分子生物学
·
动物科学
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DOI
PubMed
高影响因子
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