Food & Function
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2025
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IF 5.4
Chunyang Wang,Yimei Tang,Yanlin Zhang,Ziying Li,Jun Wang,Jinming Peng,Jie Peng
Maternal obesity impairs placental angiogenesis, increasing the risks of gestational metabolic disorders and fetal developmental compromise. Odd-chain saturated fatty acids (OCS-FAs), particularly pentadecanoic acid (PA, C15:0), demonstrate protective metabolic properties, yet their roles in placental angiogenesis remain unexplored. In this study, pregnant mice were fed a high-fat diet (HFD, 60% kcal) or isocaloric HFD supplemented with 1% (w/w) PA ethyl-ester (HFD + PA). Porcine iliac artery endothelial cells (PIEC) were used to assess angiogenic mechanisms in vitro. Our results showed that PA supplementation induced mild glucose intolerance (elevated 90/120 min glycemia, P < 0.05) without altering the body composition, fasting insulin, HOMA-IR, or plasma lipids (TG, T-CHO, HDL/LDL). PA augmented labyrinth zone (LZ) vascularization (P = 0.052) and upregulated fetal T-CHO transport (P = 0.002). RNA-seq revealed PA-activated PI3K-AKT signaling and enhanced the pro-angiogenic factor expression (HIFα, Lrp1, Flt4, MMP2/14, P < 0.05). Immunohistochemistry confirmed PI3K activation and increased CD31 endothelium in LZ. PA promoted PIEC tube formation (12.5 µM, P < 0.01) in vitro, while heptadecanoic acid (HA, C17:0) had no such effect and inhibited PIEC (12.5–25 µM, P < 0.01). PA's pro-angiogenic effect was abolished by PI3K inhibitor 3-MA (P < 0.01). In conclusion, PA promotes placental angiogenesis by activating the placental PI3K-AKT signaling, despite mild maternal glucose intolerance. These findings highlight PA's potential as a functional nutrient for mitigating gestational metabolic complications.
研究领域:
生殖生物学
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营养科学
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分子信号传导
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发育生理学
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代谢紊乱
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CHEMICAL & PHARMACEUTICAL BULLETIN
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2021
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IF 1.645
Bai-ling Sun,En-bo Cai,Yan Zhao,Yu Wang,Li-min Yang,Jing-Yao Wang
Arctigenin(ARG) , a natural lignans compound isolated from Arctium lappa L. In this study, the anti-tumor effect of ARG on prostate cancer cell PC-3M and the mechanism of apoptosis and autophagy induced by PI3K/Akt/mTOR signaling pathway were discussed, and further confirmed by the joint treatment of ARG and PI3K inhibitor LY294002. Here, the effect of ARG on cell viability was evaluated in PC-3M cells by CCK-8 assay. After the treatment of ARG, colony formation assay was used to detect the anti-proliferation effect. Annexin V-FITC/PI kit and DAPI staining were used to detect the apoptosis level, and cell cycle changes were analyzed by flow cytometry. The expression of autophagy was detected by acridine orange staining. In addition, the expression levels of apoptosis and autophagy-related proteins were analyzed by western blot. The result showed that different concentrations of ARG inhibited the proliferation of PC-3M cells. DAPI staining and flow cytometry showed that ARG induced PC-3M cell apoptosis and arrested cell in G0/G1 phase. Acridine orange staining showed that ARG induced autophagy in PC-3M cells. Western blot experiments showed that ARG inhibited the expression of Bcl-2 , promoted the expression of Bax and cleaved caspase-3. At the same time, the expression of autophagy-related proteins LC3B-II and Beclin-1 increased after ARG treatment, but P62 decreased. In addition, further studies have shown that treatment with LY294002 enhanced the effects of ARG on the expression of proteins associated with apoptosis and autophagy , indicating that ARG may induce apoptosis and autophagy through PI3K/Akt/mTOR pathway.
研究领域:
肿瘤学
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细胞生物学
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药理学
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LIFE SCIENCES
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2018
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IF 3.234
Han Zhang,Fenfen Qin,Anlong Liu,Qinmei Sun,Qisheng Wang,Shuwu Xie,Shengfeng Lu,Dong Zhang,Zhigang Lu
Aims Electro-acupuncture (EA) is frequently recommended as a complementary therapy for premature ovarian failure (POF) in the clinical. However, little information exists about its potential treatment mechanisms. The study was designed to observe the effect of EA to ovarian function and fertility in POF mice model, and investigated its potential mechanisms on PI3K/AKT/mTOR signaling pathway. Materials and methods Forty-five female C57/BL6 mice were divided into the Control, the Model and the EA group. The ovaries morphology of mice was observed by hematoxylin and eosin (HE) staining, and all follicles were counted under microscope. The protein expression of PI3K, phospho-PI3K, AKT, phospho-AKT, mTOR, phospho-mTOR, S6, phospho-S6, 4E-BP1 and phospho-4E-BP1 were detected by western blotting. The data was presented as the ratio of phosphorylation protein to total protein. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E 2 ) and anti-Mullerian hormone (AMH) levels were measured by enzyme-linked immunosorbent assay (ELISA). The fertility was observed by giving treated mice 8 weeks for breeding. Key findings We found that primordial follicle counts were increased in EA group compared to Model group. The phosphorylation of PI3K, AKT, mTOR, 4E-BP1 and S6K in EA group significantly reduced compared to Model group. Serum FSH and LH levels in EA group were decreased compared to Model group, while, serum E 2 and AMH levels in EA group were increased compared with Model group. The litter size in EA group was improved compared to Model group. Significance The effects of EA on the PI3K/AKT/mTOR signaling pathway may represent one of the mechanisms involved in attenuating the mice POF.
研究领域:
生殖生物学
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针灸疗法
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信号转导
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MATERIALS & DESIGN
·
2026
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IF 8.2
Peng Cao,Shuoyi Hui,Kaituo Liu,Lin Tong,Chenxing Zhang,Mingfan Xi,Xingyu Zhu,Daojiang Yu,Guozhong Lyu
Dihydromyricetin-loaded membranes sustain local delivery in diabetic wounds. • The membranes reduce inflammation and promote fibroblast migration. • Repair is linked to phosphoinositide 3-kinase/protein kinase B signaling. • Treatment speeds wound closure, collagen deposition, and angiogenesis. Diabetic wounds remain a major clinical challenge because of persistent inflammation, impaired angiogenesis, and delayed tissue repair. Here, we developed a dihydromyricetin (DHM)-loaded polyvinylpyrrolidone/polyvinyl butyral electrospun nanofiber membrane (PBDEM) as a local therapeutic dressing for diabetic wound treatment. PBDEM improved DHM dispersion and local retention, enabled sustained release, and showed favorable biocompatibility. By integrating network pharmacology, GEO transcriptomic analysis, molecular docking, molecular dynamics simulation, and in vitro and in vivo validation, we identified PI3K/AKT signaling as a key pathway associated with PBDEM action. In vitro , PBDEM reduced high-glucose-induced pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), increased anti-inflammatory factors (TGF-β1 and IL-10), and promoted fibroblast migration. In diabetic mice, PBDEM alleviated early inflammation, accelerated wound closure, and enhanced collagen deposition and angiogenesis. These findings indicate that PBDEM is an active local drug-delivery platform that promotes diabetic wound healing through PI3K/AKT-associated immune regulation. Download: Download high-res image (146KB) Download: Download full-size image
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BIOORGANIC & MEDICINAL CHEMISTRY
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2022
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IF 3.461
Zi-Xiao Wang,Shuai Wang,Xue-Peng Qiao,Wen-Bo Li,Jian-Tao Shi,Yi-Ru Wang,Shi-Wu Chen
PI3Ks and HDACs play essential roles in the occurrence and progression of leukemia. Herein, a series of novel pyrazin-2(1 H )-one derivatives were rationally designed and synthesized as novel dual PI3K and HDAC inhibitors based on scaffold replacement and heterozygous strategies. Most of the target compounds showed potent inhibitory potency to PI3Kα and HDAC6. Especially, compound 9q displayed PI3Kα and HDAC6 inhibitory with IC 50 values of 372 nM and 4.5 nM, and anti-proliferative activity against MV4-11 cells with IC 50 value of 0.093 ± 0.012 μM. Further mechanistic studies revealed that 9q induced apoptosis, arrested the cell cycle in the G2/M phase, promoted the acetylation of α-tubulin, and blocked the PI3K/AKT/mTOR signal way in MV4-11 cells. All the results demonstrated that 9q was a promising lead candidate for further development of novel PI3K/HDAC dual inhibitors for leukemia treatment.
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MOLECULAR AND CELLULAR BIOCHEMISTRY
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2023
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IF 4.3
Lu Yanyu,Min Qianqian,Zhao Xiaoyan,Li Li,Zhao Guojun,Dong Jianzeng
Eupatilin is a pharmacologically active flavonoid with a variety of biological activities, such as anticancer, anti-inflammatory, antioxidant, neuroprotective, anti-allergic and cardioprotective effects. However, whether eupatilin has protective effects on doxorubicin-induced cardiotoxicity remains unknown. Thus, this study aimed to investigate the role of eupatilin in doxorubicin-induced cardiotoxicity. Mice were exposed to a single dose of doxorubicin (15 mg/kg) to generate doxorubicin-induced cardiotoxicity or normal saline as a control. To explore the protective effects, mice were intraperitoneally injected with eupatilin daily for 7 days. Then, we examined the changes in cardiac function, inflammation, apoptosis, and oxidative stress to evaluate the effects of eupatilin on doxorubicin-induced cardiotoxicity. Additionally, RNA-seq analysis was introduced to explore the potential molecular mechanisms. Eupatilin ameliorated doxorubicin-induced cardiotoxicity by attenuating inflammation, oxidative stress, and cardiomyocyte apoptosis and ameliorated doxorubicin-induced cardiac dysfunction. Mechanistically, eupatilin activated the PI3K-AKT signaling pathway, as evidenced by RNA-seq analysis and Western blot analysis. This study provides the first evidence that eupatilin ameliorates doxorubicin-induced cardiotoxicity by attenuating inflammation, oxidative stress, and apoptosis. Pharmacotherapy with eupatilin provides a novel therapeutic regimen for doxorubicin-induced cardiotoxicity.
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NEPHROLOGY
·
2023
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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.
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Journal of Orthopaedic Surgery and Research
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2023
·Vol. 18
·期 1
·1-13
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IF 2.6
Zhang Yang,Liu Wenguang,Liu Zhonghao,Liu Yi
Background Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration and intra-articular inflammation. Daurisoline (DAS) is an isoquinoline alkaloid isolated from Rhizoma Menispermi, whose antitumor and anti-inflammatory pharmacological effects have been demonstrated, but the effects of DAS on OA have rarely been researched. In this study, we aimed to explore the potential role of DAS in OA and its partial mechanism.
Materials and methods The cytotoxicity of H 2 O 2 and DAS toward chondrocytes was detected by the Cell Counting Kit-8 assay. Safranin O staining was used to detect chondrocyte phenotype changes. Cell apoptosis was measured by both flow cytometry and quantitative analysis of the protein levels of the apoptosis-related factors Bax, Bcl-2 and cleaved caspase-3 by western blot. Western blotting and immunofluorescence were used to assess the expression of the autophagy-related proteins LC3, Beclin-1 and p62. In addition, key signal pathway targets and matrix-degrading indicators were measured by western blot. Results Our results indicated that H 2 O 2 induced human chondrocyte apoptosis and activated autophagy in a dose-dependent manner. DAS treatment dose-dependently reversed the expression of apoptosis-related proteins (Bax, Bcl-2 and cleaved caspase3) and the apoptosis rate induced by H 2 O 2 . Western blot and immunofluorescence analyses showed that DAS decreased the H 2 O 2 -induced upregulation of the autophagy marker Beclin-1 and the LC3 II/LC3 I ratio and upregulated the p62 protein level. Mechanistically, DAS inhibited autophagy through the activation of the classical PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis. In addition, DAS alleviated the H 2 O 2 -induced degradation of type II collagen and the high expression of matrix metalloproteinase 3 (MMP3) and MMP13. Conclusion Our research demonstrated that DAS alleviated chondrocyte autophagy caused by H 2 O 2 through activation of the PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis and matrix degradation. In conclusion, these findings suggest that DAS may serve as a promising therapeutic strategy for OA.
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RSC Advances
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2018
·Vol. 8
·期 52
·29637-29644
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IF 2.936
Minyu Zhu,Jinwei Ying,Chaowei Lin,Yu Wang,Kelun Huang,Yang Zhou,Honglin Teng
β-Escin exhibits anticancer effects on a panel of established cancer cells. However, the effects of β-escin on human osteosarcoma (OS) are still unknown. The aim of the present study was to investigate whether β-escin was effective against OS both in vivo and in vitro. Our results showed that β-escin induced dose- and time-dependent effects against MG-63, OS732, U-2OS, HOS and SAOS-2 cell proliferation. β-Escin also exhibited excellent anti-proliferative and pro-apoptotic effects in an established OS xenograft model. β-Escin and cytotoxic drugs, including cisplatin, methotrexate (MTX), doxorubicin (Dox) and ifosfamide (Ifos), synergistically inhibited proliferation of MG-63 and OS732 cells in vitro. Moreover, β-escin induced apoptotic death, activated caspase-3, caspase-8 and caspase-9, and regulated expression of Bax and Bcl-2 in MG-63 cells. In addition, our results showed that β-escin treatment reduced expression of p-PI3K, p-Akt and p-mTOR both in MG-63 cells and in an MG-63 xenograft OS model. Interestingly, SC79, which is an Akt activator, inhibited the anti-proliferative effects of β-escin on MG-63 cells. Taken together, our data support the conclusion that β-escin effectively inhibits OS proliferation both in vivo and in vitro. The inhibitory effect of β-escin, at least in part, is due to the inactivation of the PI3K/Akt signalling pathway.
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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.
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Frontiers in Pharmacology
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2022
·
IF 5.988
Wenbin Luo,Yu Tao,Shengnan Chen,Hao Luo,Xiaoping Li,Shuang Qu,Ken Chen,Chunyu Zeng
Pulmonary ischemia/reperfusion (IR) injury is the leading cause of acute lung injury, which is mainly attributed to reactive oxygen species (ROS) induced cell injuries and apoptosis. Since rosmarinic acid (RA) has been identified as an antioxidant natural ester, this natural compound might protect against pulmonary IR injury. In this study, the mice were given RA daily (50, 75, or 100 mg/kg) by gavage for 7 days before the pulmonary IR injury. We found that hypoxemia, pulmonary edema, and serum inflammation cytokines were aggravated in pulmonary IR injury. RA pretreatment (75 and 100 mg/kg) effectively reversed these parameters, while 50 mg/kg RA pretreatment was less pronounced. Our data also indicated RA pretreatment mitigated the upregulation of pro-oxidant NADPH oxidases (NOX2 and NOX4) and the downregulation of anti-oxidant superoxide dismutases (SOD1 and SOD2) upon IR injury. In vitro studies showed RA preserved the viability of anoxia/reoxygenation (AR)-treated A549 cells (a human lung epithelial cell line), and the results showed the protective effect of RA started at 5 μM concentration, reached its maximum at 15 μM, and gradually decreased at 20-25 μM. Besides, RA pretreatment (15 μM) greatly reduced the lactate dehydrogenase release levels subjected to AR treatment. Moreover, the results of our research revealed that RA eliminated ROS production and reduced alveolar epithelial cell apoptosis through activating the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, which was supported by using wortmannin, because in the presence of wortmannin, the RA-mediated protection was blocked. Meanwhile, wortmannin also reversed the protective effects of RA in mice. Together, our results demonstrate the beneficial role of RA in pulmonary IR injury via PI3K/Akt-mediated anti-oxidation and anti-apoptosis, which could be a promising therapeutic intervention for pulmonary IR injury.
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Food & Nutrition Research
·
2022
·
IF 3.221
Tongxu Guan,Yingce Zheng,Shengzi Jin,Shuang Wang,Mengxin Hu,Xingyao Liu,Siqi Huang,Yun Liu
Background Troxerutin is a flavonoid compound and possesses potential anti-cancer, antioxidant, and anti-inflammatory activities. Besides, cisplatin is one of the most widely used therapeutic agents, but the clinical uses of cisplatin are often associated with multiple side effects, among which nephrotoxicity is more common. Objective and design This study explored the protective effects of troxerutin (150 mg kg −1 day −1 for 14 days) against cisplatin-induced kidney injury and the potential mechanism using Wistar rats as an experimental mammalian model. Results We discovered that troxerutin could significantly alleviate cisplatin-induced renal dysfunction, such as increased levels of blood urea nitrogen and creatinine ( P < 0.01), as well as improved abnormal renal tissue microstructure and ultrastructure. Additionally, troxerutin significantly decreased malondialdehyde (MDA), hydrogen peroxide (H 2 O 2 ), NO, inducible nitric oxide synthase (iNOS) levels ( P < 0.01), p-NF-κB p65/NF-κB p65, TNF-α, Pro-IL-1β, IL-6, B cell lymphoma-2 (Bcl-2)/Bcl-xl associated death promoter (Bad), Cytochrome C (Cyt C), Cleaved-caspase 9, Cleaved-caspase 3, and Cleaved-caspase 8 protein levels ( P < 0.01) in the kidney tissues of cisplatin-treated rats; and increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), total antioxidant capacity (T-AOC) activities ( P < 0.01), IL-10, Bcl-2 protein levels ( P < 0.01). Conclusion These results suggested that the underlying mechanism might be attributed to the regulation of Phosphoinositide 3 kinase/Protein kinase B (PI3K/AKT) pathway via enhancing MAP4 expression to attenuate cellular apoptosis, alleviating oxidative stress and inflammatory response.
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