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中国药理学与毒理学杂志 2018年第9期32卷 717-718页

作者： LI Shuo WANG Zhi-yuan LI Fei LI Jin Beijing Institute of Pharmacology and Toxicology Beijing 100850 China

OBJECTIVE phosphoinositide 3-kinase(PI3K) activation was reported to participate in the development of effect of some drugs,such as morphine and cocaine *** previous found nischarin is associated with the activation of *** is our great interest to investigate the involvement of nischarin in PI3K dependent modulation of morphine versus cocaine *** In order to study the role of nischarin in drug dependence and tolerance,nischarin knockout mice were used for our *** of psychological dependence was studied by conditioned place preference(CPP),and the effect of physical dependence was tested by naloxone-precipitated withdrawal *** brain tissues were harvested 24 h after the behavioral experiment for the further *** PI3K specific inhibitor LY294002 significantly blocked the acquisition of morphine-induced CPP in wild-type mice,but had no effect on its *** comparison,LY294002 failed to block the acquisition of cocaine-induced CPP but inhibited the ***,we found naloxoneprecipitated withdrawal signs in the morphine dependent mice was inhibited by *** knockout in mice could abolish the effect of LY294002 on blocking the effects of morphine,but had no effect on *** PI3K activation is involved in the different phases of morphine and cocaine dependence,and nischarin plays an important role in the process.

关键词： morphine cocaine phosphoinositide 3-kinase

phosphoinositide and phospholipid phosphorylation and hydrolysis pathways<br/>—Organophosphate and organochlorine pesticides effects<br>

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Advances in Biological Chemistry 2013年第3期3卷 22-35页

作者： Teresa Fonovich Gladis Magnarelli Escuela de Ciencia y Tecnología. Universidad Nacional de San Martín San Martín Buenos Aires Argentina Instituto Multidisciplinario de Investigación y Desarrollo de la Patagonia Norte (IDEPA) Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Universidad Nacional del Comahue Neuquén Argentina

Phospholipid and phosphoinositide phosphorylation pathways have been shown to be of crucial importance on producing lipid mediators. The earlier findings reported on lipid molecules playing roles in different metabolic pathways used to assign them the exclusive role of second messenger generators. Several researchers have recently described how direct interaction of phospholipids and phosphoinositides with molecules or organelles, without the need for producing second messenger molecules, is responsible for their mechanism of action. Organophosphate and organochlorine pesticide toxicity mechanisms have been extensively studied in relation to their well known effects on cholinesterase activities and on the alterations of electric activity in the nervous system of different organisms respectively. There is little but consistent evidence that some compounds, including in both groups of pesticides, are also able to interact with phospholipid and phosphoinositide phosphorylation pathways in several organisms and tissues. The present review consists of an actualization of basic research on phospholipid and phosphoinositide phosphorylation and hydrolysis pathways, as well as a description of some reported evidences for the effects of the above mentioned pesticides on them.

关键词： Phosphatidylinositol-4 5-biphosphate phosphoinositide Phospholipid Phosphatidylcholine Organophosphate Pesticides Organochlorine Pesticides

Cathelicidin LL-37 restoring glucocorticoid function in smoking and lipopolysaccharide-induced airway inflammation in rats

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Chinese Medical Journal 2019年第5期132卷 569-576页

作者： Jian-Zhen Weng Yan Wang Tie-Ying Sun Department of Respiratory and Critical Care Medicine Beijing Hospital National Center of Gerontology Beijing 100730 China

Background Glucocorticoids have been widely used to treat patients with chronic obstructive pulmonary disease (COPD). Nevertheless, corticosteroid insensitivity is a major barrier to the effective treatment of COPD and its mechanism remains unclear. This study aimed to evaluate the effect of cathelicidin LL-37 on corticosteroid insensitivity in COPD rat model, and to explore the involved mechanisms. Methods COPD model was established by exposing male Wistar rats to cigarette smoke combined with intratracheal instillation of lipopolysaccharide (LPS). Inhaled budesonide and LL-37 were consequently applied to COPD models separately or collectively to confirm the effects on inflammatory cytokines (tumor necrosis factor [TNF]-α and transforming growth factor [TGF]-β)by enzymelinked immunosorbent assay (ELISA) and lung tissue histopathological morphology. Expression of histone deacetylase-2 (HDAC2) and phosphorylation of Akt (p-AKT) in lung were also measured. Results Briefly, COPD model rats showed an increased basal release of inflammatory cytokines (lung TNF-α:45.7±6.1 vs. 20.1 ± 3.8pg/mL, Pphosphoinositide 3-kinase (PI3K)/Akt (0.5±0.1 fold of control vs. 0.2±0.1 fold of control, P = 0.04) and a decrease in HDAC2 expression and activity (expression: 13.1 ±0.4 μmol/μg vs. 17.4± 1.1 μmol/μg, P<0.01;activity: 1.1 ±0.1 unit vs. 1.4±0.1 unit, P< 0.01), compared with control group. In addition, LL-37 enhanced the anti-inflammatory effect of budesonide in an additive manner. Treatment with combination of inhaled corticosteroids (ICS) and LL-37 led to a significant increase of HDAC2 expression and activity (expression: 15.7±0.4 μmol/μg vs. 14.1 ±0.9 μmol/μg, P<0.01;activity: 1.3±0.1 unit

关键词： Chronic obstructive pulmonary disease Glucocorticoid insensitivity Histone deacetylase-2 phosphoinositide 3-kinase/Akt pathway

Role and mechanism of matrine alone and combined with acitretin for HaCaT cells and psoriasis-like murine models

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Chinese Medical Journal 2019年第17期132卷 2079-2088页

作者： Wei-Wei Jiang Yi-Meng Wang Xiao-Yu Wang Qian Zhang Si-Man Zhu Chun-Lei Zhang Department of Dermatology Peking University Third Hospital Beijing 100191 China

Background: Acitretin and matrine have been used in the treatment of psoriasis in China. This study was designed to investigate the role and related mechanisms of matrine alone and in combination with acitretin in the treatment of psoriasis in vitro and in vivo. Methods: HaCaT cells were treated with matrine at different concentrations of 0 (blank control), 0.2, 0.4, 0.8, and 1.6 mg/mL for 24, 48, 72 h, respectively. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium cell viability assay was used to assess the growth and proliferation of HaCaT cells. Cell cycle and apoptosis were detected by flow cytometry. Expression of protein was detected by Western blotting. Autophagy was observed by transmission electron microscopy. Then HaCaT cells were assigned to normal saline (NS) control group, matrine (0.4 mg/mL) group, acitretin (10 μmol/L) group, and matrine plus acitretin group, and the above methods were repeated. In animal experiments, the cumulative score (erythema, scaling, thickening) as a measure of the severity of inflammation was used to measure the skin performance of mice after treated with matrine 50 mg/kg, acitretin 4.5 mg/kg or combination of the two drugs on the psoriasis-like mouse models, respectively. Pathological findings of the lesions were observed, and the protein expressions in the lesions were detected by immunohistochemistry. Results: Cell proliferation inhibition was seen in HaCaT cells with treatment of matrine in a dose- and time-dependent manner (P < 0.01, respectively). Cell cycle G0/G1 phase arrest was observed in a dose-dependent way (P < 0.01). The expression of p21 (P < 0.05), LC3II/I (P < 0.01), and Beclin 1 (P < 0.01) increased and the expression of cyclin D1 (P < 0.05) decreased with increasing doses of matrine. Compared with the blank control, more autophagosomes were seen in HaCaT cells treated with matrine at 0.4 mg/mL by transmission electron microscopy (2.667 ± 1.202 vs. 21.33 ± 1.453, t = 9

关键词： Psoriasis Autophagy phosphoinositide 3-kinase Protein kinase B Mammalian target of rapamycin

A likely role for the PH-domain containing protein, PEPP2/ PLEKHA5, at the membrane-microtubule cytoskeleton interface

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BIOCELL 2013年第3期37卷 55-61页

作者： Yi ZOU Timothy C COX School of Molecular Biosciences University of AdelaideAdelaideSouth Australia and Department of Anatomy&Developmental BiologyMonash UniversityClaytonVictoriaAustralia

PH(pleckstrin homology)domains are well known to bind membrane phosphoinositides with different specificities and direct PH domain-containing proteins to discrete subcellular compartments with assistances of alternative binding *** domain-containing proteins have been found to be involved in a wide range of cellular events,including signalling,cytoskeleton rearrangement and vesicular *** we showed that a novel PH domain-containing protein,PEPP2(also known as PLEKHA5),displays moderate phosphoinositide binding *** length PEPP2 was observed to variably associate with both the plasma membrane and *** membrane-associated PEPP2 nucleated at cell-cell contacts and the leading edge of migrating *** of PEPP2 increased membrane microviscosity,indicating a potential role for PEPP2 in regulating function of microtubule-dependent membrane functions.

关键词： microtubule membrane phosphoinositide microviscosity PH domain

Cilia and their role in neural tube development and defects

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Reproductive and Developmental Medicine 2022年第2期6卷 67-78页

作者： Lu Yan Yu-Fang Zheng Obstetrics and Gynecology Hospital of Fudan University Shanghai 200011China Deptartment of Cellular and Developmental Biology School of Life SciencesFudan UniversityShanghai 200438China

Cilia are microtubule-based filamentous organelles that play a vital role in embryogenesis. Multiple signal transduction pathways are orchestrated by cilia, such as Hedgehog and planar cell polarity signals. Various studies, spanning over last 2 decades, have emphasized the role of cilia-mediated signaling cascades in regulating neural tube patterning and development. Moreover, the deficiency of certain ciliary genes have been reported to cause neural tube defects (NTDs), which are a set of disorders that occur due to perturbation of normal neural tube closure. However, the mechanisms underlying cilia dysfunction resulting NTDs remain unclear. Recent studies have highlighted the association of phosphoinositide signaling with cilia, thereby conferring novel insights into the function of cilia during neural tube development. Here, we have reviewed recent studies on cilia, focusing on the molecular mechanism underlying the involvement of cilia in neural tube development and the role of ciliary disruption in the development of NTDs.

关键词： Cilia Sonic hedgehog phosphoinositide Intra-flagellar transport Neural tube defect

A likely role for a novel PH-domain containing protein,PEPP2,in connecting membrane and cytoskeleton

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BIOCELL 2012年第3期36卷 127-132页

作者： YI ZOU WENPING ZHONG Department of Biology School of Life Science and TechnologyJinan UniversityGuangzhouChina

PH domains(pleckstrin homology)are well known to bind membrane phosphoinositides with different specificities and direct PH domain-containing proteins to discrete subcellular apartments with assistances of alternative binding *** domain-containing proteins are found to be involved in a wide range of cellular events,including signalling,cytoskeleton rearrangement and vesicular *** we showed that a novel PH domain-containing protein,PEPP2,displayed moderate phosphoinositide binding *** length PEPP2 associated with both plasma membrane and *** membrane-associated PEPP2 nucleated at cell-cell contacts and the leading edge of migrating *** of PEPP2 increased membrane microviscosity,indicating a potential role of PEPP2 in regulating function of membrane and microtubules.

关键词： microtubule membrane phosphoinositide microviscosity wortmannin

Chemokine ligand 20 enhances progression of hepatocellular carcinoma via epithelial-mesenchymal transition

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World Journal of Gastroenterology 2015年第2期21卷 475-483页

作者： Ke-Zhu Hou Zhi-Qiang Fu Hua Gong Department of First General Surgery Shidong Hospital

AIM: To identify the mechanisms of chemokine ligand 20(CCL20)-induced hepatocellular carcinoma(HCC) metastasis and evaluate it as a prognostic marker. METHODS: Expression of CCL20 was evaluated by immunohistochemistry in HCC tissues from 62 patients who underwent curative resection. The relationship between CCL20 expression and clinicopathologic features was analyzed. Univariate and multivariate analyses were performed to evaluate its predictive value for recurrence and survival of HCC patients. The expression levels ofepithelial-mesenchymal transition(EMT)-and signaling pathway-related proteins were evaluated by Western blotting and immunocytochemistry. The effects of CCL20 on HCC cell proliferation and migration were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenoltetrazolium bromide(MTT) and Transwell assays. RESULTS: CCL20 immunoreactivity was detected in all 62 patient specimens. CCL20 expression was associated with preoperative alpha-fetoprotein level(P = 0.043), tumor size(P = 0.000), tumor number(P = 0.008), vascular invasion(P = 0.014), and tumor differentiation(P = 0.007). Patients with high CCL20 expression had poorer recurrence-free and overall survivals compared to those with low CCL20 expression(both P < 0.001). CCL20 induced EMT-like changes in HCC cells and increased their proliferation and migration ability(P < 0.05). Western blotting and immunofluorescence staining showed that CCL20 induced an EMT-like phenotype in HCC cells, and increased expression of phosphorylated AKT, β-catenin and vimentin, and decreased E-cadherin expression(P < 0.05). The correlation analysis revealed that high CCL20 expression in HCC tissue specimens was negatively correlated with E-cadherin expression(13.33%, 4/30), and positively correlated with vimentin(90.0%, 27/30), β-catenin(96.67%, 29/30) and p-AKT(76.67%, 23/30) ***: CCL20 expression is associated with HCC recurrence and patient survival and promotes HCC cell proliferation and migration by in

关键词： Chemokine ligand 20 phosphoinositide kinase-3/AKT

CDS2 Deficiency Converts Outcome of VEGFa Signaling from Angiogenesis to Vascular Regression

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CDS2 Deficiency Converts Outcome of VEGFa Signaling from Ang...

TIPE2 in Dendritic Cells Promotes T Cell Activation and Inhibits the Induction of pTreg

中国生物化学与分子生物学会2019年全国学术会议暨学会成立四十周年

作者： Wencao Zhao Le Cao Hanru Ying Xiaolong Zhu Luyang Yu Xuri Li Dianqing Wu Weijun Pan Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and Health Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Department of Plastic and Reconstructive Surgery Shanghai Ninth People’s Hospital Shanghai Jiaotong University School of Medicine College of Life Sciences Zhejiang University State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat-sen University Department of Pharmacology Vascular Biology and Therapeutic Program School of Medicine Yale University

Response of endothelial cells to signaling stimulation is critical for vascular morphogenesis, homeostasis and function. Vascular endothelial growth factor-a(VEGFa) has been recognized as a pro-angiogenic factor in vertebrate developmental, physiological and pathological conditions for decades. Here we showthat genetic ablation of CDP-diacylglycerol synthetase-2(CDS2), a metabolic enzyme that controls phosphoinositide recycling, can alter the output of VEGFa signaling from angiogenesis to unexpected vessel regression. Live imaging analysis uncovered the presence of angiogenic endothelium reverse migration in cds2 mutant zebrafish upon VEGFa stimulation, and endothelium regression also occurred in postnatal retina and implanted tumor models in endothelium-specific CDS2 knockout mice. Mechanistically, VEGFa stimulation reduced phosphatidylinositol(4,5)-bisphosphate availability in the absence of CDS2-controlledphosphoinositide metabolism, subsequently causing phosphatidylinositol(3,4,5)-triphosphate(PIP3) deficiency and FOXO1 activation to trigger regression of CDS2-null endothelium. Thus, our evidence indicates that the effect of VEGFa on vasculature is context dependent rather than always pro-angiogenic as previously believed.

关键词： vessel regression phosphoinositide VEGFa CDS2 FOXO1 zebrafish

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TIPE2 in Dendritic Cells Promotes T Cell Activation and Inhi...