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Chinese Medical Sciences Journal 2009年第4期24卷 231-235页

作者： Jia-he Wang Yi-jun Zhoux Yi-jun Zhou Li Tian Ping He Department of Geriatrics Shengjing Hospital China Medical University Shenyang 110004 China Department of Endocrinology and Metabolism the Fourth Affiliated Hospital China Medical University Shenyang 110032 China

Objective To explore the mechanisms involved in Staphylococcus aureus （S. aureus） invading human monocytic U937 cells. Methods S. aureus were added to U937 cells at multiplicity of infections （MOI） of 20：1 for 0, 15, 30, 60, and 90 minutes, respectively. Cell apoptosis was analyzed with Hoechst 33258 staining and Annexin V-fluorescein isothiocyanate （FITC）/propidium iodide （PI） flow cytometry analysis. Akt and nuclear factor-κB （NF-κB） activities were detected by Western blotting. Results Infection of U937 cells with S. aureus induced rapid cell death in a time-dependent manner, and the cells displayed characteristic features of apoptosis. S. aureus-induced apoptosis was associated with a prominent downregulation of activated （phosphorylated） Akt and NF-κB. The inhibition of phosphorylated Akt by LY294002 led to the inhibition of NF-κB in a dose-dependent manner. Inhibition of Akt with LY294002 caused further increase in apoptosis of U937 cells. Conclusions S. aureus can stimulate the apoptosis of U937 ceils. S. aureus induces apoptosis of U937 cells by inhibiting Akt-regulated NF-κB.

关键词： Staphylococcus aureus apoptosis U937 cells phosphoinositide 3-kinase nuclear factor-κB

Role of phosphoinositide 3-kinase in the pathogenesis of acute pancreatitis

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World Journal of Gastroenterology 2014年第41期20卷 15190-15199页

作者： Enrico Lupia Luca Pigozzi Alberto Goffi Emilio Hirsch Giuseppe Montrucchio Department of Medical Sciences University of Torino Emergency Medicine Unit "Città della Salute e della Scienza" Hospital Interdepartmental Division of Critical Care Medicine University of Toronto Molecular Biotechnology Center Department of Molecular Biotechnology and Health SciencesUniversity of Torino

A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic damage and is a major determinant of clinical severity. Thus, research has recently focused on molecules that can regulate the inflammatory processes, such as phosphoinositide 3-kinases (PI3Ks), a family of lipid and protein kinases involved in intracellular signal transduction. Studies using genetic ablation or pharmacologic inhibitors of different PI3K isoforms, in particular the class I PI3Kδ and PI3Kγ, have contributed to a greater understanding of the roles of these kinases in the modulation of inflammatory and immune responses. Recent data suggest that PI3Ks are also involved in the pathogenesis of acute pancreatitis. Activation of the PI3K signaling pathway, and in particular of the class IB PI3Kγ isoform, has a significant role in those events which are necessary for the initiation of acute pancreatic injury, namely calcium signaling alteration, trypsinogen activation, and nuclear factor-κB transcription. Moreover, PI3Kγ is instrumental in modulating acinar cell apoptosis, and regulating local neutrophil infiltration and systemic inflammatory responses during the course of experimental acute pancreatitis. The availability of PI3K inhibitors selective for specific isoforms may provide new valuable therapeutic strategies to improve the clinical course of this disease. This article presents a brief summary of PI3K structure and function, and highlights recent advances that implicate PI3Ks in the pathogenesis of acute pancreatitis.

关键词： phosphoinositide 3-kinase Cell signaling Inflammation Pathogenesis Acute pancreatitis

Leptin Regulated Insulin Secretion via Stimulating IRS2-associated phosphoinositide 3-kinase Activity in the isolated Rat Pancreatic Islets

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2003年第1期23卷 13-15,31页

作者：袁莉安汉祥李卓娅邓秀玲 Department of Endocrinology Xiehe Hospital Tongji Medical College Huazhong University of Science and Technology Cancer Research Center in Germany 69120 Heidelberg Department of Immunology School of Basic Medical Sciences Tongji Medical College Huazhong University of Science and Technology

To investigate the molecular mechanism of leptin regulating insulin secretion through determining the regulation of insulin secretion and the insulin receptor substrate (IRS)-2-associated phosphoinositide 3-kinase (PI3K) activity by leptin in the isolated rat pancreatic islets, pancreatic islets were isolated from male SD rats by the collagenase method. The purified islets were incubated with leptin 2 nmol/L for 1 h in the presence of 5.6 mmol/L or 11.1 mmol/L glucose. Insulin release was measured using radioimmunoassay. IRS-2-associated activity of PI3K was determined by immunoprecipitate assay and Western blot. The results showed that in the presence of 5.6 mmol/L glucose, leptin had no significant effect on both insulin secretion and IRS-2-associated PI3K activity, but in the presence of 11.1 mmol/L glucose, insulin release was significantly inhibited after the islets were exposed to leptin for 1 h (P3K inhibitor wortmannin blocked the inhibitory regulation of leptin on insulin release (P3K by 51.5 % (P3K, which might be the molecular mechanism of leptin regulating insulin secretion.

关键词： leptin insulin secretion phosphoinositide 3-kinase signal transduction

Xuebijing improves intestinal microcirculation dysfunction in septic rats by regulating the VEGF-A/PI3K/Akt signaling pathway

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World Journal of Emergency Medicine 2024年第3期15卷 206-213页

作者： A-ling Tang Yan Li Li-chao Sun Xiao-yu Liu Nan Gao Sheng-tao Yan Guo-qiang Zhang Department of Emergency China-Japan Friendship HospitalBeijing 100029China Graduate School Beijing University of Chinese MedicineBeijing 100105China

BACKGROUND:This study aims to explore whether Xuebijing(XBJ) can improve intestinal microcirculation dysfunction in sepsis and its ***:A rat model of sepsis was established by cecal ligation and puncture(CLP).A total of 30 male SD rats were divided into four groups:sham group,CLP group,XBJ + axitinib group,and XBJ *** was intraperitoneally injected 2 h before *** data(blood pressure and heart rate) were *** intestinal microcirculation data of the rats were analyzed via microcirculation ***-linked immunosorbent assay(ELISA) kits were used to detect the serum levels of interleukin-6(IL-6),C-reactive protein(CRP),and tumor necrosis factor-α(TNF-α) in the *** analysis and transmission electron microscopy were used to analyze the injury of small intestinal microvascular endothelial cells and small intestinal mucosa in *** expression of vascular endothelial growth factor A(VEGF-A),phosphoinositide 3-kinase(PI3K),phosphorylated PI3K(p-PI3K),protein kinase B(Akt),and phosphorylated Akt(p-Akt) in the small intestine was analyzed via Western ***:XBJ improved intestinal microcirculation dysfunction in septic rats,alleviated the injury of small intestinal microvascular endothelial cells and small intestinal mucosa,and reduced the systemic inflammatory ***,XBJ upregulated the expression of VEGF-A,p-PI3K/total PI3K,and p-Akt/total Akt in the rat small ***:XBJ may improve intestinal microcirculation dysfunction in septic rats possibly through the VEGF-A/PI3K/Akt signaling pathway.

关键词： Sepsis Xuebijing Vascular endothelial growth factor A Microcirculation Rat phosphoinositide 3-kinase Protein kinase B

Efficacy of luteolin on the human gastric cancer cell line MKN45 and underlying mechanism

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Journal of Traditional Chinese Medicine 2023年第1期43卷 34-41页

作者： DING Yajie LIU Feng LI Zhaoyan Xu Yan CAO Nida ZHANG Guangao WANG Rui ZHAO Aiguang Department of Oncology Medicine Longhua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai 200032China

OBJECTIVE:To investigate the antitumour efficacy of luteolin on gastric cancer(GC)and study the mechanism underpinning the ***:Effects of luteolin on cell growth inhibition,apoptosis,and cell cycle arrest in MKN45 cells were investigated using the cell counting kit-8 *** in the mitochondrial membrane potential after luteolin treatment were assessed using 5,5′,6,6’-tetra-chloro-1,1’,3,3’-tetraethy lbenzimidazolcar bocyanineiodi-de(JC-1)*** investigate whether apoptotic effect by luteolin is related to the phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene(PI3K/Akt)pathway,cells were additionally treated with LY294002,a PI3K/Akt pathway ***,the expressions of apoptosis-related proteins,namely B-cell lymphoma 2(Bcl-2),Bcl-2 associated X protein(Bax),Akt,p-Akt,caspase-3,and cytochrome C,were detected after luteolin ***:The study revealed that in MKN45 cells,luteolin could inhibit the cell proliferation in a time-and dose-dependent manner;block the cell cycle in the Sphase;induce apoptosis;reduce the mitochondrial membrane potential;increase the expression of Bax,caspase-3,and cytochrome C;and decrease the expression of Bcl-2 and *** might be involved in the PI3K/Akt signalling pathway,indicating that this pathway could be a therapeutic target for GC ***:Luteolin could inhibit the proliferation of GC cells and block the cell cycle in the *** mechanism of inducing apoptosis in these cells was related to the PI3K/Akt signalling pathway.

关键词： stomach neoplasms luteolin apoptosis phosphoinositide 3-kinase Akt signal transduction

Suppressive effect of Aurantii Fructus Immaturus and Atractylodis Macrocephalae Rhizoma on glutamic acid-induced autophagy of interstitial cells of Cajal

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Journal of Integrative Medicine 2020年第4期18卷 334-343页

作者： Shuai Yan Yin-zi Yue Ming-ming Sun Ben-sheng Wu Xiao-peng Wang Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica School of PharmacyNanjing University of Chinese MedicineNanjing 210023Jiangsu ProvinceChina Department of Anorectal Surgery Suzhou TCM HospitalNanjing University of Chinese MedicineSuzhou 215009Jiangsu ProvinceChina First Clinical Medical School Nanjing University of Chinese MedicineNanjing 210023Jiangsu ProvinceChina

Objective:To investigate the effects of Aurantii Fructus Immaturus(Zhishi,ZS)and Atractylodis Macrocephalae Rhizoma(Baizhu,BZ)-containing serum on glutamate-induced autophagy in rat colonic interstitial cells of Cajal(ICCs)and to analyze the underlying ***:Rat colonic ICCs cultured in vitro were identified by fluorescence and then stimulated with glutamic acid(5 mmol/L)for 24 h to establish a cell model of *** cells were then treated with different concentrations of ZSBZ-containing serum or rat *** viability of the ICCs was detected with cell counting kit-8 assays,and cell apoptosis rates were examined with flow *** ultrastructure and autophagosomes in the ICCs were observed using transmission electron *** effects of ZSBZ-containing serum on apoptosis-associated mediators were assessed by Western blotting and real-time quantitative polymerase chain *** addition,microtubule-associated protein light chain 3(LC3),p-phosphoinositide 3-kinase(p-PI3 K),p-Akt and p-mammalian target of rapamycin(pm TOR)expression was detected via Western blotting ***:Compared to those in the model group,ICC viability and apoptosis rates were significantly increased by ZSBZ-containing serum(P3,pPI3 K,p-Akt and p-mTOR were significantly lower(P3 K/Akt/mTOR pathway.

关键词： Herbal medicine,Chinese Autophagy phosphoinositide 3-kinase Signal pathway

Emerging role of the KRAS-PDK1 axis in pancreatic cancer

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World Journal of Gastroenterology 2014年第31期20卷 10752-10757页

作者： Riccardo Ferro Marco Falasca Queen Mary University of London Barts and The London School of Medicine and Dentistry Blizard Institute Inositide Signalling GroupUnited Kingdom

Pancreatic cancer is a highly aggressive tumour that is very resistant to treatments and it is rarely diagnosed early because of absence of specific symptoms. Therefore, the prognosis for this disease is very poor and it has the grim supremacy in terms of unfavourable survival rates. There have been great advances in survival rates for many types of cancers over the past few decades but hardly any change for pancreatic cancer. Mutations of the Ras oncogene are the most frequent oncogenic alterations in human cancers. The frequency of KRAS mutations in pancreatic cancer is around 90%. Given the well-established role of KRAS in cancer it is not surprising that it is one of the most attractive targets for cancer therapy. Nevertheless, during the last thirty years all attempts to target directly KRAS protein have failed. Therefore, it is crucial to identify downstream KRAS effectors in order to develop specific drugs able to counteract activation of this pathway. Among the different signalling pathways activated by oncogenic KRAS, the phosphoinositide 3-kinase(PI3K) pathway is emerging as one of the most critical KRAS effector. In turn, PI3 K activates several parallel pathways making the identification of the precise effectors activated by KRAS/PI3 K more difficult. Recent data identify 3-phosphoinositide-dependent protein kinase 1 as a key tumour-initiating event downstream KRAS interaction with PI3 K in pancreatic cancer.

关键词： Pancreatic cancer Signal transduction KRAS phosphoinositide 3-kinase 3-phosphoinositide-dependent protein kinase 1

PTEN at the interface of immune tolerance and tumor suppression

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Frontiers in Biology 2017年第3期12卷 163-174页

作者： Andrew Brandmaier Sheng-Qi Hou Sandra Demaria Silvia C. Formenti Wen H. Shen Department of Radiation Oncology Weill Cornell Medicine Cornell University New York NY 10065 USA

BACKGROUND： PTEN is well known to function as a tumor suppressor that antagonizes oncogenic signaling and maintains genomic stability. The PTEN gene is frequently deleted or mutated in human cancers and the wide cancer spectrum associated with PTEN deficiency has been recapitulated in a variety of mouse models of Pten deletion or mutation. Pten mutations are highly penetrant in causing various types of spontaneous tumors that often exhibit resistance to anticancer therapies including immunotherapy. Recent studies demonstrate that PTEN also regulates immune functionality. OBJECTIVE： To understand the multifaceted functions of PTEN as both a tumor suppressor and an immune regulator. METHODS： This review will summarize the emerging knowledge of PTEN function in cancer immunoediting. In addition, the mechanisms underlying functional integration of various PTEN pathways in regulating cancer evolution and tumor immunity will be highlighted. RESULTS： Recent preclinical and clinical studies revealed the essential role of PTEN in maintaining immune homeostasis, which significantly expands the repertoire of PTEN functions. Mechanistically, aberrant PTEN signaling alters the interplay between the immune system and tumors, leading to immunosuppression and tumor escape. CONCLUSION： Rational design of personalized anti-cancer treatment requires mechanistic understanding of diverse PTEN signaling pathways in modulation of the crosstalk between tumor and immune cells.

关键词： PTEN phosphoinositide 3-kinase regulatory T cells genome epigenome metabolism

PI3K/SHIP2/PTEN pathway in cell polarity and hepatitis C virus pathogenesis

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World Journal of Hepatology 2017年第1期9卷 18-29页

作者： Aline Awad Ama Gassama-Diagne Inserm Unite 1193 Hopital Paul Brousse Univ Paris-Sud UMR-S 1193Univsite Paris-Saclay

Hepatitis C virus(HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. phosphoinositides(PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases. PIs are implicated in a vast array of cellular responses that are central to morphogenesis, such as cytoskeletal changes, cytokinesis and the recruitment of downstream effectors to govern mechanisms involved in polarization and lumen formation. Important reviews of the literature identified phosphatidylinositol(Ptd Ins) 4-kinases, and their lipid products Ptd Ins(4)P, as critical regulators of the HCV life cycle. SH2-containing inositol polyphosphate 5-phosphatase(SHIP2), phosphoinositide 3-kinase(PI3K) and their lipid products Ptd Ins(3,4)P2 and Ptd Ins(3,4,5)P3, respectively, play an important role in the cell membrane and are key to the establishment of apicobasal polarity and lumen formation. In this review, we will focus on these new functions of PI3 K and SHIP2, and their deregulation by HCV, causing a disruption of apicobasal polarity, actin organization and extracellular matrix assembly. Finally we will highlight the involvement of this pathway in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.

关键词： Hepatitis C virus phosphoinositide 3-kinase SH2-containing inositol polyphosphate 5-phosphatase Epithelial cell polarity phosphoinositides

1,5-dicaffeoylquinic acid protects primary neurons from amyloid β1-42-induced apoptosis via PI3K/Akt signaling pathway

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Chinese Medical Journal 2011年第17期124卷 2628-2635页

作者： XIAO Hai-bing CAO Xu WANG Lei RUN Xiao-qin SU Ying TIAN Cheng SUN Sheng-gang LIANG Zhi-hou Department of Neurology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430022 China Department of Neurology Shenzhen People's Hospital Jinan University Shenzhen Guangdong 518020 China Department of Vascular Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430022 China Department of Neurology Shenzhen Sixth People's Hospital (Nanshan Hospital) Shenzhen Guangdong 518052 China

Background Recently, 1,5-dicaffeoylquinic acid （1,5-DQA）, a caffeoylquinic acid derivative isolated from Aster scaber, was found to have neuroprotective effects. However, the protective mechanisms of 1,5-DQA have not yet been clearly identified. The purpose of this study was to explore the protective mechanisms of 1,5-DQA on neuronal culture. Methods We investigated the neuroprotective effects of 1,5-DQA against amyloid IB1-42 （Aβ42）-induced neurotoxicity in primary neuronal culture. To evaluate the neuroprotective effects of 1,5-DQA, primary cultured cortical neurons from neonate rats were pretreated with 1,5-DQA for 2 hours and then treated with 40 pmol/L Aβ42 for 6 hours. Cell counting kit-8, Hoechst staining and Western blotting were used for detecting the protective mechanism. Comparisons between two groups were evaluated by independent t test, and multiple comparisons were analyzed by one-way analysis of variance （ANOVA）. Results 1,5-DQA treated neurons showed increased neuronal cell viability against Aβ42 toxicity in a concentration- dependent manner, both phosphoinositide 3-kinase （PI3K）/Akt and extracellular regulated protein kinase 1/2 （Erkl/2） were activated by 1,5-DQA with stimulating their upstream tyrosine kinase A （Trk A）. However, the neuroprotective effects of 1,5-DQA were blocked by LY294002, a PI3K inhibitor, but not by PD98059, an inhibitor of mitogen-activated protein kinase kinase. Furthermore, 1,5-DQA＇s anti-apoptotic potential was related to the enhanced inactivating phosphorylation of glycogen synthase kinase 313 （GSK3β） and the modulation of expression of apoptosis-related protein Bcl-2/Bax. Conclusion These resutts suggest that 1,5-DQA prevents AI342-induced neurotoxicity through the activation of PI3K/Akt followed by the stimulation of Trk A, then the inhibition of GSK313 as well as the modulation of Bcl-2/Bax.

关键词： Alzheimer's disease," amyloid beta-peptides 1,5-dicaffeoylquinic acid phosphoinositide 3-kinase glycogen synthase kinase 3β extracellular regulated protein kinase