ACTA BIOCHIMICA ET BIOPHYSICA SINICA
·
2021
·Vol. 53
·期 12
·1602-1613
·
IF 3.848
Zhao Gang,Shi Xiaobao,Sun Zhanbo,Zhao Pengfei,Lu Zaiming
Progestin and adipoQ receptor 4 (PAQR4) is a novel tumorigenic factor that promotes cell proliferation and metastasis in lung and breast cancer, but its role in hepatocellular carcinoma (HCC) is unknown. The aim of our study was to explore its role and underlying mechanism in the development of HCC. Analysis of GEPIA database indicated that PAQR4 was highly expressed in HCC samples, and the mRNA level of PAQR4 was negatively correlated with the overall survival of HCC patients. Knockdown of PAQR4 in Hep3B cells suppressed cell proliferation by hindering G1/S transition of cell cycle as shown by the flow cytometry analysis. PAQR4 knockdown also expedited the cell apoptosis. Knockdown of PAQR4 repressed the migratory and invasive potential of Hep3B cells. PAQR4 knockdown sensitized Hep3B cells to apatinib-based chemotherapy. PAQR4 knockdown blocked the activation of PI3K/AKT pathway, as reflected by the reduced phosphorylation of AKT and p85. Conversely, overexpression of PAQR4 exerted opposite effects in Huh-7 cells. PI3K inhibitor LY294002 could eliminate the effects of PAQR4 on cell proliferation, apoptosis, chemoresistance, and invasion. In tumor xenograft model, knockdown of PAQR4 suppressed tumor growth in vivo, while PAQR4 overexpression promoted tumor growth. Collectively, our data suggest that PAQR4 has a tumorigenic effect on HCC progression by activating PI3K/AKT pathway.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF DRUG TARGETING
·
2019
·
IF 3.277
Jun Ma,Di Du,Jia Liu,Lei Guo,Yongchuan Li,Aimin Chen,TianWen Ye
Hydrogen sulphide (H2S), a gasotransmitter, plays an important role in the regulation of bone homeostasis. However, the precise effect of H2S on osteoclasts was still elusive. The goal of this study was to determine the potential role of H2S in regulation of osteoclasts and the underlying mechanisms by which H2S affected osteoclastogenesis. The present study applied western blot, quantitative real-time PCR, tartrate-resistant acid phosphatase staining, pit formation assay, immunofluorescence confocal microscopy, transmission electron microscopy and annexin V-fluorescein isothiocyanate/propidium iodide double-staining assay. The results showed that the expressions of cystathionine b-synthase (CBS) and cystathionine c-lyase (CSE) were obviously increased in osteoclast differentiation induced by the receptor activator of nuclear factor kappa-β ligand (RANKL). In addition, H2S promoted RANKL-induced osteoclastogenesis and inhibited apoptosis of mature osteoclasts. Mechanistically, H2S inhibited autophagy in Raw 264.7 cells. Autophagy activator (rapamycin) alleviated the induction of osteoclast differentiation by H2S. Further studies showed that H2S inhibited autophagy by activating the PI3K/AKT/mTOR signalling pathway. Taken together, our results implicated that exogenous H2S could promote osteoclastogenesis by activating the PI3K/AKT/mTOR pathway to downregulate autophagy.
研究领域:
骨骼生物学
·
细胞信号传导
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Heliyon
·
2023
·
IF 4
Xiao-Ping Zhao,Xiao-Li Zheng,Min Huang,Ya-Jia Xie,Xiao-Wen Nie,Ali Adnan Nasim,Xiao-Jun Yao,Xing-Xing Fan
Although some important advances have been achieved in clinical and diagnosis in the past few years, the management of non-small cell lung cancer (NSCLC) is ultimately dissatisfactory due to the low overall cure and survival rates. Epidermal growth factor (EGFR) has been recognized as a carcinogenic driver and is a crucial pharmacological target for NSCLC. DMU-212, an analog of resveratrol, has been reported to have significant inhibitory effects on several types of cancer. However, the effect of DMU-212 on lung cancer remains unclear. Therefore, this study aims to determine the effects and underlying mechanism of DMU-212 on EGFR-mutant NSCLC cells. The data found that the cytotoxicity of DMU-212 on three EGFR-mutant NSCLC cell lines was significantly higher than that of normal lung epithelial cell. Further study showed that DMU-212 can regulate the expression of cell cycle-related proteins including p21 and cyclin B1 to induce G2/M phase arrest in both H1975 and PC9 cells. Moreover, treatment with DMU-212 significantly promoted the activation of AMPK and simultaneously down-regulated the expression of EGFR and the phosphorylation of PI3K, Akt and ERK. In conclusion, our study suggested that DMU-212 inhibited the growth of NSCLCs via targeting of AMPK and EGFR.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
DOI
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Shiyi Yao,Hui Yuan,Luqi Yang,Yin Zhang,Hanyu Wang,Renxuan Li,Tingjun Ye,Wenguo Cui,Lei Wang
Interface friction impedes tissue healing and stimulates interface cells to produce matrix metalloproteinases (MMPs); however, the precise mechanisms underlying matrix degradation, and the formation of fibrous scars remain unclear. This research involved the development of interface lubricating microspheres that inhibit the PI3K/AKT/mTOR signaling pathway in tenocytes. This inhibition significantly decreased MMP-13 expression and increased COL-1 production, thereby facilitating interface repair and regeneration. In vitro experiments demonstrated that interface friction activates the PI3K/AKT/mTOR/MMP-13 signaling pathway, while the use of interface lubricating microspheres reduced friction by 78 %, resulting in a threefold decrease in MMP-13 expression through pathway inhibition. Animal studies showed that the application of interface lubricating microspheres reduced friction at the tendon-bone interface, mitigating MMP-13-mediated matrix degradation and effectively reducing fibrous scar formation (as evidenced by decreased α-SMA expression), thus promoting interface healing following ACLR surgery in rats. Consequently, this study suggests that interface friction can trigger the PI3K/AKT/mTOR signaling pathway in tenocytes, leading to increased MMP-13 expression, matrix degradation, and fibrous scar formation. The use of interface lubricating microspheres can enhance interface healing by inhibiting this pathway, offering strategies for improving interface healing and minimizing fibrous scar formation. Statement of significance Interface healing plays a crucial role following tendon-bone surgeries, yet it is often hindered by challenges such as interface friction and scar formation. In this study, we propose a combined approach in which lubricating microspheres and an anti-matrix degradation drug are used to enhance interface healing. We fabricated novel lubricating microspheres that exhibit outstanding biocompatibility and degradability; these microspheres serve as lubricants for the tendon-bone interface and facilitate the delivery of doxycycline to reduce excessive matrix metalloproteinase (MMP) secretion. The experimental results demonstrated that this method could enhance tendon-bone interface healing in rats, resulting in increased bone formation and higher histological scores than those of the control group. This study represents a preliminary effort to integrate lubrication and anti-matrix degradation in interface healing, potentially offering new insights into the mechanism between interface friction and fibrous scar healing, while promoting interface healing by reducing interfacial friction.
研究领域:
生物医学工程
·
分子生物学
·
再生医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
npj Breast Cancer
·
2024
·Vol. 10
·期 1
·1-15
·
IF 6.5
Rossetti Stefano,Broege Aaron,Sen Adrish,Khan Salmaan,MacNeil Ian,Molden Jhomary,Kopher Ross,Schulz Stephen,Laing Lance
The PI3K, AKT, and mTOR (PAM) pathway is frequently dysregulated in breast cancer (BC) to accommodate high catabolic and anabolic activities driving tumor growth. Current therapeutic options for patients with hormone receptor (HR) + / HER2- advanced BC (ABC) include PAM inhibitors that selectively inhibit only one PAM pathway node, which can lead to drug resistance as cells rapidly adapt to maintain viability. We hypothesized that gedatolisib, which potently inhibits all Class I PI3K isoforms, as well as mTORC1 and mTORC2, may be more effective in BC cells than single-node PAM inhibitors by limiting adaptive resistances. By using multiple functional assays, a panel of BC cell lines was evaluated for their sensitivity to four different PAM inhibitors: gedatolisib (pan-PI3K/mTOR inhibitor), alpelisib (PI3Kα inhibitor), capivasertib (AKT inhibitor), and everolimus (mTORC1 inhibitor). Gedatolisib exhibited more potent and efficacious anti-proliferative and cytotoxic effects regardless of the PAM pathway mutational status of the cell lines compared to the single-node PAM inhibitors. The higher efficacy of gedatolisib was confirmed in three-dimensional culture and in BC PDX models. Mechanistically, gedatolisib decreased cell survival, DNA replication, cell migration and invasion, protein synthesis, glucose consumption, lactate production, and oxygen consumption more effectively than the other PAM inhibitors tested. These results indicate that inhibition of multiple PAM pathway nodes by a pan-PI3K/mTOR inhibitor like gedatolisib may be more effective at inducing anti-tumor activity than single-node PAM inhibitors. A global Phase 3 study is currently evaluating gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2− ABC.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
DOI
高影响因子
International Journal of Clinical and Experimental Pathology
·
2015
·
IF 1.891
Jing Zhao,Li Li,Ling Peng
The previous studies identify mammalian heart is terminal differentiation organs without regenerative capacity. Recently, there is some evidence point that cardiomyocytes are not terminally differentiated cells and cell proliferation may be stimulated in the pathologic heart. The aim of this study is to discover the possible mechanism which involved in cardiomyocytes proliferation process. In this study, the proliferation assay and cell cycle assay showed the proliferation of cardiomyocytes was inhibited when the cells treated with MAPK1 inhibitor. Moreover, the bioinformatics analysis revealed MAPK1 was positively correlated with MALAT1. Meanwhile, the expression of MALAT1 in H9C2 cells with the treatment of MAPK1 siRNA was obvious lower than scramble siRNA treated group. Finally further study suggested H9C2 cells treated with Wortmannin in combination with LY294002 (PI3K/AKT signaling pathway inhibitor), the expression of MALAT1 was dramatically decreased. These results indicated that MAPK1 was able to increase the proliferation of cardiomyocytes via up-regulating the expression of MALAT1 through PI3K/AKT signaling pathway.
研究领域:
心脏病学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH
·
2025
·
IF 1.5
Han Wang,Guan Mengtong,Liao Bo,Han Xiaoyu,Li Kaiting,Chen Qing,Guo Xiya,Niu Yajuan,Zhu Ying,Bai Dingqun
Cellular senescence is an important cause of age-related degenerative diseases, including osteoarthritis (OA). Chondrocyte senescence is crucial in OA onset and progression. As a non-invasive, safe, and widely used physical rehabilitation factor, the effect and mechanism of low intensity pulsed ultrasound (LIPUS) on chondrocyte senescence remain unclear. This study evaluated the inhibitory effect of LIPUS on OA chondrocyte senescence in vitro and in vivo. The effect of LIPUS on chondrocyte senescence was examined by RT-qPCR, enzyme-linked immunosorbent assay (ELISA), and western blotting. Changes in levels of reactive oxygen species (ROS) and γ-h2ax foci in senescent chondrocytes were detected using fluorescent staining. Chondrocyte senescence was evaluated by senescence-associated β-galactosidase (SA-β-gal) staining. The PI3K inhibitor LY294002 and the PI3K agonist 740Y-P were used to investigate whether PI3K/AKT/mTOR signalling was involved in the effect of LIPUS in senescent chondrocytes. Chondrocyte senescence and cartilage degeneration were analyzed in a destabilization of the medial meniscal (DMM) mouse model by immunohistochemistry, hematoxylin and eosin staining, and safranin-O/fast green staining. LIPUS inhibited the expression of the senescence-associated secretory phenotype (SASP) factors CCL4 and CCL2 and the senescence phenotype in doxorubicin-treated chondrocytes by inhibiting the PI3K/AKT/mTOR pathway. LIPUS alleviated chondrocyte senescence and attenuated OA progression in the DMM mice. These results demonstrated a novel role for LIPUS in inhibiting chondrocyte senescence and the SASP by modulating PI3K/AKT/mTOR signalling. Our findings expanded the clinical application of LIPUS and provide a new, non-invasive, and safe treatment approach to prevent and treat age-related degenerative joint disorders.
研究领域:
医学
·
生物学
✓ 已验证
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
·
心血管疾病
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
REPRODUCTION FERTILITY AND DEVELOPMENT
·
2023
·Vol. 35
·期 14
·669-675
·
IF 1.9
Min Liu,Yong-Jie Mi,Juan Dai
Context Aquaporin 7 (AQP7) is selectively expressed in decidualised endometrial stromal cells (ESCs) of mice surrounding the embryonic implantation sites. However, the roles of AQP7 and the underlying mechanism that regulates AQP7 expression in endometrial decidualisation after implantation are still unclear.Aims This study aimed to investigate the role of the PI3K-Akt pathway in regulating the expression of AQP7 in ESCs and decidualisation.Methods Primary ESCs of pregnant mice were isolated to establish in vitro decidualisation models. PI3K inhibitor LY294002 was added to the decidualisation models, then AQP7 expression, changes in decidualised ESC morphology and expression of decidualisation marker molecules were examined.Key results AQP7 knockdown reduced the proliferation and differentiation of ESCs with in vitro induced decidualisation. Furthermore, when the activity of PI3K was inhibited by LY294002, the expression of AQP7 in decidualised ESCs was decreased and both the proliferation and differentiation of ESCs were significantly reduced.Conclusions This indicates that AQP7 is a key molecule involved in endometrial decidualisation and the expression of AQP7 is upregulated through activation of the PI3K-Akt pathways, which promotes the proliferation and differentiation of the ESCs, thus affecting occurrence of decidualisation.Implications This study may provide a new biomarker for the diagnosis of infertility and a new drug target for the prevention and treatment of infertility.
研究领域:
生殖生物学
·
分子生物学
·
医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2017
·Vol. 16
·期 6
·9361-9366
·
IF 1.692
Weixin Zhu,Weihong Qiu,Ailan Lu
Cerebral stroke is a kind of acute cerebrovascular disease with high incidence, morbidity and disability. Treatments against various types of cerebral stroke are limited at preventive measurements due to the lack of effective therapeutic method. The present study aimed to investigate the protective effect of cryptotanshinone (CPT) on cerebral stroke, and investigate the possible mechanism involved in order to develop a novel therapy against stoke. The phosphoinositide 3‑kinase membrane translocation of cerebral stroke rats pretreated with CPT at various concentrations were measured, as well as the phosphorylation of protein kinase B (AKT) and endothelial nitric oxide synthase (eNOS). Additionally, the expression level of B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax) and vascular endothelial growth factor were also assessed using western blotting and reverse transcription‑quantitative polymerase chain reaction. Furthermore, biochemical tests were used to measure the activity of superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) in both the cerebral cortex and peripheral blood. As a result, CPT‑pretreated rats presented declined phosphoinositide 3‑kinase (PI3K) and AKT expression levels, indicating that the PI3K/AKT signaling pathway was inhibited. Increased Bcl‑2 and NO levels in both the cerebral cortex and peripheral blood demonstrated the anti‑apoptosis and blood vessel protection effect of CPT. Furthermore, increased SOD activity and declined MDA levels demonstrated suppressed lipid peroxidation. In conclusion, CPT exhibited a protective effect against cerebral stroke through inhibition of the PI3K/AKT‑eNOS signaling pathway. These results suggested the potential of CPT as a promising agent in the treatment of cerebral stroke.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2023
·
IF 8.8
Pengcheng Cai,Rui Ni,Mengzhu Lv,Huijuan Liu,Jieqiong Zhao,Jianbo He,Lingfei Luo
Summary Biliary epithelial cells (BECs) are a potential source to repair the damaged liver when hepatocyte proliferation is compromised. Promotion of BEC-to-hepatocyte transdifferentiation could be beneficial to the clinical therapeutics of patients with end-stage liver diseases. However, mechanisms underlying the initiation of BEC transdifferentiation remain largely unknown. Here, we show that upon extreme hepatocyte injury, vegfaa and vegfr2/kdrl are notably induced in hepatic stellate cells and BECs, respectively. Pharmacological and genetic inactivation of vascular endothelial growth factor (VEGF) signaling would disrupt BEC dedifferentiation and proliferation, thus restraining hepatocyte regeneration. Mechanically, VEGF signaling regulates the activation of the PI3K-mammalian target of rapamycin complex 1 (mTORC1) axis, which is essential for BEC-to-hepatocyte transdifferentiation. In mice, VEGF signaling exerts conserved roles in oval cell activation and BEC-to-hepatocyte differentiation. Taken together, this study shows VEGF signaling as an initiator of biliary-mediated liver regeneration through activating the PI3K-mTORC1 axis. Modulation of VEGF signaling in BECs could be a therapeutic approach for patients with end-stage liver diseases.
研究领域:
分子生物学
·
肝脏病学
·
再生医学
✓ 已验证
DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Chen Wu,Zhongyun Zhang,Lijie Bai,Shuhui Lei,Min Zou,Zilu Bao,Zhaoxiang Ren,Kaiqun Liu,Hui-Hong Gong,Wenjun Ma,Lvyi Chen
Ethnopharmacological relevance Gout, a painful joint disease with a prevalence ranging from 0.86% to 2.2% in China over the past decade. Traditional medicine has long utilized the medicinal and edible Piper longum L. (PL) fruit spikes for treating gout and other joint conditions like rheumatoid arthritis. However, the exact mechanisms behind its effectiveness remain unclear. Aim of the study This study aimed to investigate the potential of alcoholic extracts from PL fruit spikes as a safe and effective treatment for gout. We used a combined network pharmacology and experimental validation approach to evaluate the mechanisms behind the anti-gout properties of PL. Materials and methods UPLC-Q/TOF-MS analysis determined the major components of PL. Subsequently, network pharmacology analysis predicted potential molecular targets and related signaling pathways for the anti-gout activity of PL. Molecular docking simulations further explored the interactions between PL compounds and proteins and characterized the properties of potential bioactive secondary metabolites. Mouse models of air pouch inflammation and hyperuricemia were further established, and the anti-gout mechanism of PL was confirmed by examining the expression of proteins related to the MAPK and PI3K-AKT pathways in the tissue. Results Our analysis revealed 220 bioactive secondary metabolites within PL extracts. Network pharmacology and molecular docking results indicated that these metabolites primarily combat gout by modulating the PI3K-AKT and MAPK signaling pathways. In vivo experiments have also proven that PL at a dose of 100 mg/kg can optimally reduce acute inflammation of gout and kidney damage caused by high uric acid. The anti-gout mechanism involves the PI3K-AKT/MAPK signaling pathway and its downstream NF-κB pathway. Conclusion This study provides compelling evidence for PL's therapeutic potential in gout management by modulating key inflammatory pathways. The findings offer a strong foundation for future clinical exploration of PL as a gout treatment option.
研究领域:
药理学
·
民族药理学
·
分子生物学
·
炎症研究
·
传统医学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）