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Inhibiting focal adhesion kinase:A potential target for enhancing therapeutic efficacy in colorectal cancer therapy

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World Journal of Gastrointestinal Oncology 2018年第10期10卷 290-292页

作者： Keun--Yeong Jeong division of research and Development Metimedi Pharmaceuticals

Focal adhesion kinase(FAK) is a major integrin- dep-endent tyrosine phosphorylated protein, recently, FAK association with colorectal cancer(CRC) has gained at-tention. The various cancer-promoting mechanisms that associated with FAK can be implicated in the progression of CRC. The interactions between structural features of FAK and various kinases could be closely related to growth, survival, and metastasis in CRC cells. These interactions include human epithelial growth factor re-ceptor, c-Met, platelet-derived growth factor receptor, vascular endothelial growth factor receptor, and Src. Such interactions can trigger the survival signaling of CRC cells and are also involved signaling downstream of phosphatidylinositol 3-kinase, AKT, and the extracellular regulated kinase. Based on this scientific background, many pharmaceutical companies are taking efforts to develop FAK inhibitors to treat solid cancer including CRC. Although the anti-cancer efficacies have been noted in many studies, the commercial drugs have not been deve-loped yet. Therefore, the FAK research on CRC is expec-ted to gain momentum and be highly appreciated as a potential field for developing the new drugs. Therefore, the studies on FAK that effect on the progression of human CRC s would be possible to suggest various app-roaches to CRC treatment, and FAK could be a potential target as an anticancer candidate for CRC therapies.

关键词： Colorectal cancer Focal adhesion kinase Focal adhesion kinase inhibitor Anticancer effect

Involvement of Sphingosine 1-Phosphate (S1P) Receptor Type 1 and Type 4 in Migratory Response of Mouse T Cells toward S1P

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Cellular & Molecular Immunology 2006年第6期3卷 429-437页

作者： Hirofumi Matsuyuki Yasuhiro Maeda Kazuhiro Yano Kunio Sugahara Kenji Chiba Takayuki Kohno Yasuyuki Igarashi research Laboratory III (Immunology) Pharmaceuticals Research Division Mitsubishi Pharma Corporation Yokohama Japan Discovery Technology Laboratory pharmaceuticals research division Mitsubishi Pharma Corporation Yokohama Japan Department of Biomembrane and Biofunctional Chemistry Graduate School of Pharmaceutical Sciences Hokkaido University Sapporo Japan

Sphingosine 1-phosphate （S1P）, a pleiotropic lysophospholipid, regulates signal transduction pathway via Gprotein-coupled receptors termed S1P1-5 in several types of the cells including lymphocytes. Higher levels of S1P4 mRNA as well as S1P1 mRNA are expressed in lymphoid tissues such as the spleen, thymus, lymph nodes, and Payer＇s patches. In contrast to S1P1 that plays an essential role in lymphocyte egress, little is known about the role of S1P4 in immune system. In this study, we found that S1P at 10 to 100 nM significantly induced the cell migration and the significant levels of S1P1 and S1P4 mRNA were expressed in mouse CD4 T cells, D10.G4.1 mouse Th2 cells, and ***-2 mouse thymoma cells. In D10.G4.1 and ***-2 cells, S1P-induced migration was almost completely inhibited by pretreatment with pertussis toxin, Clostoridium difficile toxin B, and （S）-enantiomer of FTY720-phosphate, a potent agonist at S1P1 and S1P4. The members of the Rho family small GTPase, Cdc42 and Rac were activated by S1P stimulation in these cells. The transfection with dominant negative or constitutively active forms of Cdc42 and Rac revealed that the activation of both Cdc42 and Rac is essential for S1P-induced migration of these cells. The immunoprecipitation assays using CHO cells co-expressing both S1P4 and S1P1 receptors indicated that S1P4 and S1P1 are associated on the cell surface. These results suggest that the association of S1P4 and S1PI plays an important role in migratory response of mouse T cells toward S1P.

关键词： S1Pi S1P4 S1P FTY720 T cell migration

Strategies for constructing seven-membered rings:Applications in natural product synthesis

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Chinese Chemical Letters 2024年第6期35卷 53-70页

作者： Peng Chen Lijuan Liang Yufei Zhu Zhimin Xing Zhenhua Jia Teck-Peng Loh College of Advanced Interdisciplinary Science and Technology Henan University of TechnologyZhengzhou 450001China division of Chemistry and Biological Chemistry School of Chemistry Chemical Engineeringand BiotechnologyNanyang Technological UniversitySingapore 637371Singapore Institute of Advanced Synthesis School of Chemistry and Molecular Engineering Nanjing Tech UniversityNanjing 211816China State Key Laboratory of Applied Organic Chemistry Department of ChemistryLanzhou UniversityLanzhou 730000China

The seven-membered ring motifs are found in bioactive pharmaceuticals and a wide range of natural products,including alkaloids and terpenoids,which hold significant importance in synthetic chemistry and has garnered considerable attention from both academia and *** the challenges faced in the past decade,the total synthesis of natural products incorporating the non-aromatic cycloheptane skeletons remains a compelling ***,numerous elegant strategies for constructing the sevenmembered ring system have been successfully *** review focuses on the recent advancements in this field from 2017 to April 2023,highlighting key transformations utilized to construct the non-aromatic cycloheptane core structures and serves as a valuable guide for synthetic chemists engaged in the total synthesis of natural products containing seven-membered ring motifs.

关键词： Seven-membered rings Total synthesis Natural products Synthetic strategy Cycloheptane

Protective effects of ursodeoxycholic acid on chenodeoxycholic acid-induced liver injury in hamsters

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World Journal of Gastroenterology 2007年第37期13卷 5003-5008页

作者： Tomomichi Iwaki Kaoru Ishizaki Shuji Kinoshita Hideki Tanaka Atsushi Fukunari Makoto Tsurufuji Teruaki Imada research Laboratory Ⅲ (Immunology) Pharmaceuticals Research Division Mitsubishi Pharma Corporation Yokohama Japan Pharmacokinetics Laboratory Pharmaceuticals Research Division Mitsubishi Pharma Corporation Chiba Japan Discovery Technology Laboratory Pharmaceuticals Research Division Mitsubishi Pharma Corporation Yokohama Japan

AIM: To investigate the effects of ursodeoxycholic acid (UDCA) on chenodeoxycholic acid (CDCA)-induced liver injury in hamsters, and to elucidate a correlation between liver injury and bile acid profiles in the liver. METHODS: Liver injury was induced in hamsters by administration of 0.5% (w/w) CDCA in their feed for 7 d. UDCA (50 mg/kg and 150 mg/kg) was administered for the last 3 d of the experiment. RESULTS: At the end of the experiment, serum alanine aminotransferase (ALT) increased more than 10 times and the presence of liver injury was confirmed histologically. Marked increase in bile acids was observed in the liver. The amount of total bile acids increased approximately three-fold and was accompanied by the increase in hydrophobic bile acids, CDCA and lithocholic acid (LCA). UDCA (50 mg/kg and 150 mg/kg) improved liver histology, with a significant decrease (679.3 ± 77.5 U/L vs 333.6 ± 50.4 U/L and 254.3 ± 35.5 U/ L, respectively, P < 0.01) in serum ALT level. UDCA decreased the concentrations of the hydrophobic bile acids, and as a result, a decrease in the total bile acid level in the liver was achieved. CONCLUSION: The results show that UDCA improves oral CDCA-induced liver damage in hamsters. The protective effects of UDCA appear to result from a decrease in the concentration of hydrophobic bile acids, CDCA and LCA, which accumulate and show the cytotoxicity in the liver.

关键词：肝脏疾病临床特征治疗药物肝损伤

Administration frequency as well as dosage of PTH are associated with development of cortical porosity in ovariectomized rats

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Bone research 2017年第2期5卷 109-122页

作者： Aya Takakura Ji-Won Lee Kyoko Hirano Yukihiro Isogai Toshinori Ishizuya Ryoko Takao-Kawabata Tadahiro Iimura pharmaceuticals research Center Asahi Kasei Pharma Corporation Shizuoka Japan Graduate School of Medicine Division of Analytical BioMedicine Ehime University Ehime Japan division of Bio-Imaging Proteo-Science Center (PROS) Ehime University Ehime Japan division of Analytical Bio-Medicine Advanced Research Support Center (ADRES) Ehime University Ehime Japan and Artificial Joint Integrated Center Ehime University Hospital Ehime Japan

To investigate whether the administration frequency of parathyroid hormone(PTH) is associated with the development of cortical porosity, this study established 15 dosage regimens of teriparatide [human PTH(1–34), TPTD] with four distinct concentrations and four distinct administration frequencies of TPTD to 16-week-old ovariectomized rats. Our analyses demonstrated that the bone mineral density, mechanical properties, and bone turnover were associated with the total amount of TPTD administered. Our observations further revealed that the cortical porosity was markedly developed as a result of an increased administration frequency with a lower concentration of total TPTD administration in our setting, although the highest concentration also induced cortical porosity. Deconvolution fluorescence tiling imaging on calcein-labeled undecalcified bone sections also demonstrated the development of cortical porosity to be closely associated with the bone site where periosteal bone formation took place. This site-specific cortical porosity involved intracortical bone resorption and an increased number and proximity of osteocytic lacunae,occasionally causing fused lacunae. Taken together, these findings suggested the involvement of local distinctions in the rate of bone growth that may be related to the site-specific mechanical properties in the development of cortical porosity induced by frequent and/or high doses of TPTD.

关键词： frequency Administration PTH

IL-6 prevents Th2 cell polarization by promoting SOCS3-dependent suppression of IL-2 signaling

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Cellular & Molecular Immunology 2023年第6期20卷 651-665页

作者： Holly Bachus Erin McLaughlin Crystal Lewis Amber M.Papillion Etty N.Benveniste Dave Durell Hill Alexander F.Rosenberg AndréBallesteros-Tato Beatriz León Department of Medicine Division of Clinical Immunology and RheumatologyUniversity of Alabama at BirminghamBirminghamALUSA Department of Microbiology University of Alabama at BirminghamBirminghamALUSA Department of Cell Developmental and Integrative BiologyUniversity of Alabama at BirminghamBirminghamALUSA informatics Institute University of Alabama at BirminghamBirminghamALUSA Alexion pharmaceuticals Inc.New HavenCTUSA

Defective interleukin-6 (IL-6) signaling has been associated with Th2 bias and elevated IgE levels. However, the underlying mechanism by which IL-6 prevents the development of Th2-driven diseases remains unknown. Using a model of house dust mite (HDM)-induced Th2 cell differentiation and allergic airway inflammation, we showed that IL-6 signaling in allergen-specific T cells was required to prevent Th2 cell differentiation and the subsequent IgE response and allergic inflammation. Th2 cell lineage commitment required strong sustained IL-2 signaling. We found that IL-6 turned off IL-2 signaling during early T-cell activation and thus inhibited Th2 priming. Mechanistically, IL-6-driven inhibition of IL-2 signaling in responding T cells was mediated by upregulation of Suppressor Of Cytokine Signaling 3 (SOCS3). This mechanism could be mimicked by pharmacological Janus Kinase-1 (JAK1) inhibition. Collectively, our results identify an unrecognized mechanism that prevents the development of unwanted Th2 cell responses and associated diseases and outline potential preventive interventions.

关键词： Th2 cell polarization IL-6 IL-2 SOCS3 JAK1 inhibitor

Predictive factors associated with carcinoid syndrome in patients with gastrointestinal neuroendocrine tumors

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World Journal of Gastroenterology 2017年第40期23卷 7283-7291页

作者： Beilei Cai Michael S Broder Eunice Chang Tingjian Yan David C Metz Novartis pharmaceuticals Corporation One Health Plaza Partnership for Health Analytic research LLC 280 S. Beverly Dr. division of Gastroenterology University of Pennsylvania Health System 3400 Civic Center Boulevard Perelman Center for Advanced Medicine

AIM To discover unknown factors associated with carcinoid syndrome(CS) with the goal of earlier diagnosis of *** In this retrospective case-control study using United States administrative claims, patients(≥ 18 years) newly-diagnosed with gastrointestinal neuroendocrine tumors(GI NETs) without CS(controls) were exactly matched to patients with CS(cases) based on NET diagnosis date at a 3-to-1 ratio. Study index date was first CS diagnosis(controls: same distance from NET diagnosis as cases). The most observed conditions, excluding CS-associated symptoms/diagnoses, during the year before index date were assessed. Forwardstepwise logistic regression models were used to derive predictors, and were validation within another claims database. RESULTS In the development database, 1004 patients with GI NETs were identified; 251(25%) had CS and 753(75%) were controls. In the validation database, 724 patients with GI NETs were identified; 181(25%) had CS and 543(75%) were controls. A total of 33 common diagnoses(excluding conditions already known to be associated with CS) in the development database were entered in forward step-wise logistic regression models. In the final, validated logistic regression model, three factors prior to CS diagnosis were found consistently associated with higher risks for CS, including liver disorder [odds ratio(95%CI): 3.38(2.07-5.51)], enlargement of lymph nodes [2.13(1.10-4.11)], and abdominal mass [3.79(1.87-7.69)].CONCLUSION GI NET patients with CS were 2-4 times as likely to have preexisting diagnoses(i.e., liver disorder, enlarged lymph nodes, abdominal mass) than non-CS patients.

关键词： Carcinoid syndrome Gastrointestinal neuroendocrine tumors Predictive factors Data mining

Ketamine enhances structural plasticity in human dopaminergic neurons:possible relevance for treatment-resistant depression

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Neural Regeneration research 2018年第4期13卷 645-646页

作者： Ginetta Collo Emilio Merlo Pich Department of Molecular and Translational Medicine Section of PharmacologyUniversity of Brescia Department of Biomedicine University of Basel Neuroscience Therapeutic Area Unit Takeda Pharmaceuticals International division of Brain Science Imperial College

Depression refers to a series of mental health issues characterized by loss of interest and enjoyment in everyday life,low mood and selected emotional,cognitive,physical and behavioral *** is a common disorder,affecting 5–15%of the general *** diagnosed as major depressive disorder（MDD）,patients are currentlytreated with pharmacological agents such as serotonin or noradren- aline uptake inhibitors （SSRI or SNRI） or tricyclics.

关键词： MEK ERK Ketamine enhances structural plasticity in human dopaminergic neurons:possible relevance for treatment-resistant depression TRD MDD

Inhibitory effect of Cyrtomium falcatum on melanogenesis in α-MSH-stimulated B16F10 murine melanoma cells

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亚太热带生物医学杂志:英文版 2023年第9期13卷 403-410页

作者： Xian-Rong Zhou Jung Hwan Oh Fatih Karadeniz Hyunjung Lee Hyo Eun Kim Migeon Jo Youngwan Seo Chang-Suk Kong Department of Bioscience Silla UniversityBusan 46958Korea Collaborative Innovation Center for Child Nutrition and Health Development Chongqing University of EducationChongqing 400067China Marine Biotechnology Center for pharmaceuticals and Foods Silla UniversityBusan 46958Korea Nutritional Education Graduate School of EducationSilla UniversityBusan 46958Korea Department of Food and Nutrition Silla UniversityBusan 46958Korea division of Convergence on Marine Science Korea Maritime and Ocean UniversityBusan 49112Korea

Objective:To explore the anti-melanogenic potential of Cyrtomium ***:The effects of Cyrtomium falcatum crude extract and its solvent fractions on tyrosinase activity,melanin content,and the expressions of melanogenesis-related genes and proteins were analyzed inα-melanocyte-stimulating hormone(α-MSH)-stimulated B16F10 ***:α-MSH treatment significantly increased tyrosinase activity,and extracellular and intracellular melanin content,as well as the expression levels of tyrosinase,microphthalmia-associated transcription factor(MITF),tyrosinase-related protein(TRP)-1,and TRP-2 in B16F10 *** with Cyrtomium falcatum crude extract and its solvent fractions reduced tyrosinase activity and extracellular and intracellular melanin content and downregulated the expression levels of tyrosinase,MITF,TRP-1,and TRP-2 in a dose-dependent ***:Cyrtomium falcatum has potential anti-melanogenesis effects and can be used as a potential source material in cosmeceutical industry for the research and development of novel lead molecules with whitening properties.

关键词： Cyrtomium falcatum Melanogenesis α-MSH B16F10 melanoma cells