npj Breast Cancer
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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
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分子生物学
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药理学
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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
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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
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
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生物学
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产品关联
DOI
PubMed
高影响因子
REPRODUCTION FERTILITY AND DEVELOPMENT
·
2023
·Vol. 35
·期 14
·669-675
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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
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分子生物学
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医学
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
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2017
·Vol. 16
·期 6
·9361-9366
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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
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药理学
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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 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
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民族药理学
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分子生物学
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炎症研究
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传统医学
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DOI
PubMed
高影响因子
Brazilian Journal of Pharmaceutical Sciences
·
2022
·
IF 1.214
Zhang Rong,Huang Limin,Pan Di,Zhang Wen
Drug resistance is a crucial obstacle to achieve satisfactory chemotherapeutic effects. Numerous studies have shown that the PI3K/Akt signaling pathway plays a significant role in various processes of cellular events and tumor progression, while few studies have focused on the PI3K/Akt signaling pathway in drug resistance of endothelial cells. The present study aims to explore the relationship of PI3K/Akt signaling and cellular resistance to anticancer drugs in human microvessel endothelial cells (HMEC-1). We established stable sunitinib-resiatant human microvessel endothelial cells (HMEC-su) after long-term exposure to sunitinib (a small-molecule tyrosine kinase receptor inhibitor) for 12 months. HMEC-su showed significant alternations of cell morphology and exhibited a 2.32-fold higher IC50 of sunitinib than parental HMEC-1 cells. Expression of P-glycoprotein (P-gp) and breast cancer-resistance protein (ABCG2) which mediates drug efflux, increased significantly in HMEC-su lines compared with HMEC-1 cells by western blots assay. Our study further demonstrates that LY294002 (blocking the PI3K/Akt pathway) enhances the sensibility of HMEC-su to suntinib and inhibits the gene transcription and protein expression of P-gp, ABCG2 in HMEC-su cells. In conclusion, these results indicate that LY294002 could reverse P-gp and ABCG2 mediated-drug resistance to sunitinib in HMEC-su cells by inhibiting PI3K/Akt signaling.
研究领域:
肿瘤学
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药理学
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细胞生物学
✓ 已验证
DOI
高影响因子
Marine Drugs
·
2025
·Vol. 23
·期 1
·22
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IF 5.4
Xia Zheng,Xiaofei Liu,Zhuo Wang,Rui Li,Qiaoli Zhao,Bingbing Song,Kit-Leong Cheong,Jianping Chen,Saiyi Zhong
Chondroitin sulfate (CS), a class of glycosaminoglycans covalently attached to proteins to form proteoglycans, is widely distributed in the extracellular matrix and cell surface of animal tissues. In our previous study, CS was used as a template for the synthesis of seleno-chondroitin sulfate (SeCS) through the redox reaction of ascorbic acid (Vc) and sodium selenite (Na2SeO3) and we found that SeCS could inhibit tumor cell proliferation and invasion. However, its effect on angiogenesis and its underlying mechanism are unknown. In this study, we analyzed the effect of SeCS on tube formation in vitro, based on the inhibition of tube formation and migration of human umbilical vein endothelial cells (HUVECs), and evaluated the in vivo angiogenic effect of SeCS using the chick embryo chorioallantoic membrane (CAM) assay. The results showed that SeCS significantly inhibited the angiogenesis of chicken embryo urothelium. Further mechanism analysis showed that SeCS had a strong inhibitory effect on VEGFR2 expression and its downstream PI3K/Akt signaling pathway, which contributed to its anti-angiogenic effects. In summary, SeCS showed good anti-angiogenic effects in an HUVEC cell model and a CAM model, suggesting that it may be a potential angiogenesis inhibitor.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2018
·Vol. 17
·期 1
·393-397
·
IF 1.41
Rendong Wei,Haidong Liu,Ru Chen,Yunjian Sheng,Tao Liu
Astragaloside Ⅳ (AS‑Ⅳ) in improving liver cirrhosis injury in rats and its effect on the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling pathway were observed. Rat model of liver cirrhosis was induced by injection of carbon tetrachloride (CCl4). A total of 36 Sprague‑Dawley (SD) rats were randomly divided into three groups: the normal control group (n=10), the model control group (n=13), and the AS‑Ⅳ group (n=13). The normal control group was injected with olive oil and given carboxymethyl cellulose (CMC)‑Na (10 ml/kg/day), the model control group was given CMC‑Na (10 ml/kg/day), and the AS‑Ⅳ group underwent intragastric administration of AS‑Ⅳ (20 ml/kg/day). The content of alanine transaminase (ALT) and aspartate transaminase (AST) of rats was detected. The levels of tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑6 and IL‑1β in serum were detected via enzyme‑linked immunosorbent assay (ELISA). Hematoxylin and eosin (H&E) staining was applied to observe morphological changes in liver tissues. The expression of collagens in liver tissues was detected via Masson's trichrome staining. Additionally, the expression of proteins in liver tissues was detected via western blotting. Compared with those in the blank group, the levels of AST, ALT, TNF‑α, IL‑6 and IL‑1β were higher, the expression level of collagens in liver tissues was increased, and the expression ratios of phosphorylated (p)‑PI3K/PI3K, p‑Akt/Akt and p‑mTOR/mTOR proteins were increased in the model group. Compared with the model group, AS‑Ⅳ could significantly decrease the content of AST, ALT, TNF‑α, IL‑6 and IL‑β in serum of rats, obviously inhibit the expression of collagens in liver tissues and decrease the expression ratios of p‑PI3K/PI3K, p‑Akt/Akt and p‑mTOR/mTOR proteins in liver tissues. AS‑Ⅳ can inhibit the inflammatory response so as to reduce the expression of collagens, and its mechanism may play a key role by inhibiting the PI3K/Akt/mTOR signaling pathway.
研究领域:
药理学
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肝病学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
FITOTERAPIA
·
2025
·
IF 2.6
Taoli Sun,Wei Yuan,Xinru Li,BoHou Xia,Jianhua Huang,Meihong Piao,Wen Chen,Qinhui Tuo
Atherosclerosis (AS), a leading cause of cardiovascular diseases, remains a major challenge due to the lack of effective preventive and therapeutic strategies. This study investigated the anti-atherosclerotic effects and underlying mechanisms of Prunella vulgaris polyphenols (PVPs). PVPs were found to significantly reduce lipid deposition in the aorta and enhance plaque stability by increasing fibrous cap thickness and collagen content, while simultaneously reducing MMP-9 and CD68 protein expressions. Moreover, PVPs alleviated hepatic lipid accumulation by upregulating ABCA1 and downregulating SREBP1 protein expressions. The PI3K-Akt pathway was identified as a key mechanism underlying the therapeutic effects of PVPs, with STAT3 predicted as a critical target involved in lipid metabolism. These predictions were further validated experimentally, demonstrating that PVPs effectively inhibited STAT3 activation while enhancing the PI3K-Akt pathway. Taken together, these findings reveal that PVPs exert anti-atherosclerotic effects by modulating lipid metabolism through the inhibition of STAT3 and activation of the PI3K-Akt pathway.
研究领域:
药理学
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生物化学
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分子生物学
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心血管医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Yue Wang,Ying Li,Liang Wang,Buze Chen,Miaolin Zhu,Chunyi Ma,Chunyan Mu,Aibin Tao,Shibao Li,Lan Luo,Ping Ma,Shuai Ji,Ting Lan
Ovarian cancer is one of the most common gynecological malignancies in women worldwide with a poor survival rate. Cinnamaldehyde (CA), a bioactive substance isolated from cinnamon bark, is a natural drug and has shown that it can inhibit the progression of other tumors. However, the role of CA in ovarian cancer and its mechanism is poorly understood. In this study, wound healing assays, plate cloning, CCK-8, and transwell assays were used to determine cell proliferation and invasion. Western blot and flow cytometry were used to detect apoptosis levels. Western blot and immunofluorescence were used to detect changes in cellular EMT levels. The Western blot was used to detect levels of the PI3K/AKT signaling pathway. In vivo , we established a subcutaneous transplantation tumor model in nude mice to verify the role of CA in the progression and metastasis of ovarian cancer. Our data showed that in vitro CA was able to inhibit the cell viability of ovarian cancer. The results of scratch assay and transwell assay also showed that CA inhibited the proliferation and invasion ability of A2780 and SKOV3 cells. In addition, CA promoted apoptosis by increasing the expression of cleaved-PARP and cleaved-caspase 3 in ovarian cancer cells. Mechanistically, we found that CA inhibited the EGF-induced PI3K/AKT signaling pathway and reduced the phosphorylation levels of mTOR, PI3K, and AKT. The EGF-induced EMT process was also abolished by CA. The EMT process induced by AKT-specific activator SC79 was also suppressed by CA. Furthermore, in in vivo , CA significantly repressed the progression of ovarian cancer as well as liver metastasis. In all, our results suggest that CA inhibits ovarian cancer progression and metastasis in vivo and in vitro and inhibits EGF-induced EMT processes through the PI3K/AKT signaling pathway.
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOLOGICAL PROCEDURES ONLINE
·
2024
·Vol. 26
·期 1
·1-15
·
IF 3.7
Wang Huizhi,Min Jingyu,Ding Yuntao,Yu Zhengyue,Zhou Yujing,Wang Shunyu,Gong Aihua,Xu Min
Background Gastric cancer (GC) is a common malignancy and a leading cause of cancer-related death with high morbidity and mortality. Methyl-CpG binding domain protein 3 (MBD3), a key epigenetic regulator, is abnormally expressed in several cancers, participating in progression and metastasis. However, the role of MBD3 in GC remains unknown. Methods MBD3 expression was assessed via public databases and validated by western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). The prognosis of MBD3 was analysed via bioinformatics based on the TCGA dataset. The migration, invasion and proliferation of GC cells were examined by transwell, wound healing, cell counting kit (CCK)-8, colony-formation and xenograft mouse models. Epithelial-mesenchymal transition (EMT) and phosphatidylinositide 3-kinases/ protein Kinase B (PI3K/AKT) pathway markers were evaluated by Western blotting. RNA sequencing was used to identify the target of MBD3. Results MBD3 expression was higher in GC tissues and cells than in normal tissues and cells. Additionally, high MBD3 levels were associated with poor prognosis in GC patients. Subsequently, we proved that MBD3 enhanced the migration, invasion and proliferation abilities of GC cells. Moreover, western blot results showed that MBD3 promoted EMT and activated the PI3K/AKT pathway. RNA sequencing analysis showed that MBD3 may increase actin γ1 (ACTG1) expression to promote migration and proliferation in GC cells. Conclusion MBD3 promoted migration, invasion, proliferation and EMT by upregulating ACTG1 via PI3K/AKT signaling activation in GC cells and may be a potential diagnostic and prognostic target.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症生物学
✓ 已验证
DOI
PubMed
高影响因子
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