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[PMID]: 28789911 [Au] Autor: Yamagishi H; Inoue T; Nakajima Y; Maeda J; Tominaga H; Usuda H; Hondo T; Moritomo A; Nakamori F; Ito M; Nakamura K; Morio H; Higashi Y; Inami M; Shirakami S [Ad] Endereço: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: hiroaki.yamagishi@astellas.com. [Ti] Título: Discovery of tricyclic dipyrrolopyridine derivatives as novel JAK inhibitors. [So] Source: Bioorg Med Chem;25(20):5311-5326, 2017 Oct 15. [Is] ISSN: 1464-3391 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Janus kinases (JAKs) play a crucial role in cytokine mediated signal transduction. JAK inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the tricyclic imidazo-pyrrolopyridinone 2 is a potent JAK inhibitor; however, it had poor oral absorption due to low membrane permeability. Here, we report the structural modification of compound 2 into the tricyclic dipyrrolopyridine 18a focusing on reduction of polar surface area (PSA), which exhibits potent in vitro activity, improved membrane permeability and good oral bioavailability. Compound 18a showed efficacy in rat heterotopic cardiac transplants model. [Mh] Termos MeSH primário: Adjuvantes Imunológicos/farmacologia Descoberta de Drogas Janus Quinases/antagonistas & inibidores Inibidores de Proteínas Quinases/farmacologia Piridinas/farmacologia Pirróis/farmacologia [Mh] Termos MeSH secundário: Adjuvantes Imunológicos/administração & dosagem Adjuvantes Imunológicos/química Administração Oral Animais Disponibilidade Biológica Permeabilidade da Membrana Celular/efeitos dos fármacos Modelos Animais de Doenças Relação Dose-Resposta a Droga Feminino Sobrevivência de Enxerto/efeitos dos fármacos Transplante de Coração Seres Humanos Janus Quinases/metabolismo Masculino Estrutura Molecular Inibidores de Proteínas Quinases/administração & dosagem Inibidores de Proteínas Quinases/química Piridinas/administração & dosagem Piridinas/química Pirróis/administração & dosagem Pirróis/química Ratos Ratos Endogâmicos ACI Ratos Endogâmicos Lew Ratos Sprague-Dawley Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Adjuvants, Immunologic); 0 (Protein Kinase Inhibitors); 0 (Pyridines); 0 (Pyrroles); EC 2.7.10.2 (Janus Kinases) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171107 [Lr] Data última revisão: 171107 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170810 [St] Status: MEDLINE

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[PMID]: 28616971 [Au] Autor: Wang P; Mills LH; Song JH; Yu J; Zhu BT [Ad] Endereço: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City, Kansas 66160, United States. [Ti] Título: Lack of Cell Proliferative and Tumorigenic Effects of 4-Hydroxyestradiol in the Anterior Pituitary of Rats: Role of Ultrarapid O-Methylation Catalyzed by Pituitary Membrane-Bound Catechol-O-Methyltransferase. [So] Source: Chem Res Toxicol;30(7):1448-1462, 2017 Jul 17. [Is] ISSN: 1520-5010 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: In animal models, estrogens are complete carcinogens in certain target sites. 4-Hydroxyestradiol (4-OH-E ), an endogenous metabolite of 17ß-estradiol (E ), is known to have prominent estrogenic activity plus potential genotoxicity and mutagenicity. We report here our finding that 4-OH-E does not induce pituitary tumors in ACI female rats, whereas E produces 100% pituitary tumor incidence. To probe the mechanism, we conducted a short-term animal experiment to compare the proliferative effect of 4-OH-E in several organs. We found that, whereas 4-OH-E had little ability to stimulate pituitary cell proliferation in ovariectomized female rats, it strongly stimulates cell proliferation in certain brain regions of these animals. Further, when we used in vitro cultured rat pituitary tumor cells as models, we found that 4-OH-E has similar efficacy as E in stimulating cell proliferation, but its potency is approximately 3 orders of magnitude lower than that of E . Moreover, we found that the pituitary tumor cells have the ability to selectively metabolize 4-OH-E (but not E ) with ultrahigh efficiency. Additional analysis revealed that the rat pituitary expresses a membrane-bound catechol-O-methyltransferase that has an ultralow K value (in nM range) for catechol estrogens. On the basis of these observations, it is concluded that rapid metabolic disposition of 4-OH-E through enzymatic O-methylation in rat anterior pituitary cells largely contributes to its apparent lack of cell proliferative and tumorigenic effects in this target site. [Mh] Termos MeSH primário: Catecol O-Metiltransferase/metabolismo Estrogênios de Catecol/farmacologia Adeno-Hipófise/efeitos dos fármacos Adeno-Hipófise/metabolismo [Mh] Termos MeSH secundário: Animais Biocatálise Carcinogênese/efeitos dos fármacos Proliferação Celular/efeitos dos fármacos Estrogênios de Catecol/química Feminino Seres Humanos Metilação Adeno-Hipófise/citologia Adeno-Hipófise/enzimologia Ratos Ratos Endogâmicos ACI Células Tumorais Cultivadas [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Estrogens, Catechol); C3ZO03450E (4-hydroxyestradiol); EC 2.1.1.6 (Catechol O-Methyltransferase) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171002 [Lr] Data última revisão: 171002 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170616 [St] Status: MEDLINE [do] DOI: 10.1021/acs.chemrestox.7b00096

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[PMID]: 28185998 [Au] Autor: Vogl TJ; Qian J; Tran A; Oppermann E; Naguib NN; Korkusuz H; Nour Eldin NE; Bechstein WO [Ad] Endereço: Institute for Diagnostic and Interventional Radiology, Frankfurt University Hospital, Frankfurt/Main, Germany. t.vogl@em.uni-frankfurt.de. [Ti] Título: Study on the effect of chemoembolization combined with microwave ablation for the treatment of hepatocellular carcinoma in rats. [So] Source: Diagn Interv Radiol;23(2):150-155, 2017 Mar-Apr. [Is] ISSN: 1305-3612 [Cp] País de publicação: Turkey [La] Idioma: eng [Ab] Resumo: PURPOSE: We aimed to evaluate the combining effects of transarterial chemoembolization (TACE) and open local thermal microwave ablation in a hepatocellular carcinoma animal model. METHODS: Tumor cubes were implanted into the liver of 30 male inbred ACI rats. Groups of 10 animals were treated at 13 days (TACE or microwave ablation) and 16 days (microwave ablation) postimplantation with combined therapy of TACE (0.1 mg mitomycin C; 0.1 mg iodized oil; 5.0 mg degradable starch microspheres) and microwave ablation (2450 Mhz; 45 s; 35 W) (study group A), TACE alone (control group B), or microwave ablation alone (control group C). At day 12 and day 25 tumor size was measured via magnetic resonance imaging and the relative growth ratio was calculated. Hepatic specimens were immunohistochemically examined for the expression of vascular endothelial growth factor (VEGF). RESULTS: Mean growth rates were 1.34±0.19 in group A, 3.19±0.13 in group B, and 4.18±0.19 in group C. Compared with control groups B and C, tumor growth rate in group A was significantly inhibited (P < 0.01). The VEGF-antibody reaction in peritumoral tissue (staining intensity at portal triad, percent antibody reaction and staining intensity at central vein) was significantly lower in group A compared with group B (P < 0.01). No significant difference between group A and group C could be observed. CONCLUSION: This investigation shows improved results of TACE followed by microwave ablation as treatment of hepatocellular carcinoma in a rat model, compared with single therapy regimen regarding the inhibition of growth rate and reduction of VEGF-level in peritumoral tissue. [Mh] Termos MeSH primário: Carcinoma Hepatocelular/terapia Ablação por Cateter/métodos Quimioembolização Terapêutica/métodos Neoplasias Hepáticas/terapia [Mh] Termos MeSH secundário: Animais Carcinoma Hepatocelular/patologia Linhagem Celular Tumoral Terapia Combinada Seres Humanos Neoplasias Hepáticas/patologia Imagem por Ressonância Magnética Masculino Micro-Ondas Ratos Ratos Endogâmicos ACI Resultado do Tratamento Ensaios Antitumorais Modelo de Xenoenxerto [Pt] Tipo de publicação: JOURNAL ARTICLE [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170911 [Lr] Data última revisão: 170911 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170211 [St] Status: MEDLINE [do] DOI: 10.5152/dir.2016.16617

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[PMID]: 27275096 [Au] Autor: Qian J; Oppermann E; Tran A; Imlau U; Qian K; Vogl TJ [Ad] Endereço: Jun Qian, Kun Qian, Department of Radiology, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China. [Ti] Título: Transarterial administration of integrin inhibitor loaded nanoparticles combined with transarterial chemoembolization for treating hepatocellular carcinoma in a rat model. [So] Source: World J Gastroenterol;22(21):5042-9, 2016 Jun 07. [Is] ISSN: 2219-2840 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: AIM: To compare the effect of transarterial chemoembolization (TACE) plus GRGDSP (Gly-Arg-Gly-Asp-Ser-Pro, integrin-inhibitor) loaded nanoparticles with TACE alone or TACE + GRGDSP in a rat model of liver tumor. METHODS: Morris hepatoma 3924A tumors were implanted in the livers of 30 ACI rats. The ACI rats were divided randomly into three groups (10 animals each). Tumor volume before treatment (V1) was examined by magnetic resonance imaging (MRI), and then, after laparotomy and placement of a PE-10 catheter into the hepatic artery, the following interventional protocols were performed: TACE (mitomycin C + lipiodol + degradable starch microspheres) + GRGDSP loaded nanoparticles for group A; TACE + GRGDSP for group B (control group 1); TACE alone for group C (control group 2). Tumor volume (V2) was assessed by MRI and the mean ratio of the post-treatment to pretreatment tumor volumes (V2/V1) was calculated. Immunohistochemical analysis was performed to assess the quantification of matrix metalloprotein 9 (MMP-9) and vascular endothelial growth factor (VEGF) positive tumor cells in each treatment group. RESULTS: The mean tumor growth ratios (V2/V1) were 1.3649 ± 0.1194 in group A, 2.0770 ± 0.1595 in group B, and 3.2148 ± 0.1075 in group C. Compared with groups B and C, group A showed a significant reduction in tumor volume. Lower expression of MMP-9 and VEGF in hepatocellular carcinoma was observed in group A than in groups B and C. The angiogenesis of tumor was evaluated using anti-VEGF antibodies, and the metastasis of tumor was assessed using anti-MMP-9 antibody. MMP-9 and VEGF were expressed in all specimens. The immunoexpression of these proteins was confirmed by the presence of red cytoplasmic staining in tumor cells. Lower expression of MMP-9 and VEGF in hepatocellular carcinoma was observed in group A than in groups B and C. CONCLUSION: Transarterial administration of integrin inhibitor loaded nanoparticles combined with TACE evidently retards tumor growth and intrahepatic metastases compared with TACE alone or TACE plus integrin inhibitor in an animal model of hepatocellular carcinoma. [Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem Carcinoma Hepatocelular/terapia Quimioembolização Terapêutica/métodos Integrinas/antagonistas & inibidores Neoplasias Hepáticas Experimentais/terapia Nanomedicina/métodos Nanopartículas Oligopeptídeos/administração & dosagem [Mh] Termos MeSH secundário: Animais Carcinoma Hepatocelular/metabolismo Carcinoma Hepatocelular/patologia Proliferação Celular/efeitos dos fármacos Óleo Etiodado/administração & dosagem Artéria Hepática Imuno-Histoquímica Injeções Intra-Arteriais Integrinas/metabolismo Neoplasias Hepáticas Experimentais/metabolismo Neoplasias Hepáticas Experimentais/patologia Imagem por Ressonância Magnética Masculino Metaloproteinase 9 da Matriz/metabolismo Ratos Endogâmicos ACI Carga Tumoral/efeitos dos fármacos Fator A de Crescimento do Endotélio Vascular [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Integrins); 0 (Oligopeptides); 0 (Vascular Endothelial Growth Factor A); 0 (vascular endothelial growth factor A, rat); 8008-53-5 (Ethiodized Oil); 91037-75-1 (glycyl-arginyl-glycyl-aspartyl-seryl-proline); EC 3.4.24.35 (Matrix Metalloproteinase 9); EC 3.4.24.35 (Mmp9 protein, rat) [Em] Mês de entrada: 1704 [Cu] Atualização por classe: 170410 [Lr] Data última revisão: 170410 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160609 [St] Status: MEDLINE [do] DOI: 10.3748/wjg.v22.i21.5042

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[PMID]: 27215551 [Au] Autor: Vogl TJ; Oppermann E; Qian J; Imlau U; Tran A; Hamidavi Y; Korkusuz H; Bechstein WO; Nour-Eldin NE; Gruber-Rouh T; Hammerstingl R; Naguib NN [Ad] Endereço: Institute for Diagnostic and Interventional Radiology, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany. T.Vogl@em.uni-frankfurt.de. [Ti] Título: Transarterial chemoembolization of hepatocellular carcinoma in a rat model: the effect of additional injection of survivin siRNA to the treatment protocol. [So] Source: BMC Cancer;16:325, 2016 05 23. [Is] ISSN: 1471-2407 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Transarterial chemoembolization is one of the most widely accepted interventional treatment options for treatment of hepatocellular carcinoma. Still there is a lack of a standard protocol regarding the injected chemotherapeutics. Survivin is an inhibitor of Apoptosis protein that functions to inhibit apoptosis, promote proliferation, and enhance invasion. Survivin is selectively up-regulated in many human tumors. Small interfering RNA (siRNA) can trigger an RNA interference response in mammalian cells and induce strong inhibition of specific gene expression including Survivin. The aim of the study is to assess the effectiveness of the additional injection of Survivin siRNA to the routine protocol of Transarterial Chemoembolization (TACE) for the treatment of hepatocellular carcinoma in a rat model. METHODS: The study was performed on 20 male ACI rats. On day 0 a solid Morris Hepatoma 3924A was subcapsullary implanted in the liver. On day 12 MRI measurement of the initial tumor volume (V1) was performed. TACE was performed on day 13. The rats were divided into 2 groups; Group (A, n = 10) in which 0.1 mg mitomycin, 0.1 ml lipiodol and 5.0 mg degradable starch microspheres were injected in addition 2.5 nmol survivin siRNA were injected. The same agents were injected in Group (B,=10) without Survivin siRNA. MRI was repeated on day 25 to assess the tumor volume (V2). The tumor growth ratio (V2/V1) was calculated. Western blot and immunohistochemical analysis were performed. RESULTS: For group A the mean tumor growth ratio (V2/V1) was 1.1313 +/- 0.1381, and was 3.1911 +/- 0.1393 in group B. A statistically significant difference between both groups was observed regarding the inhibition of tumor growth (P < 0.0001) where Group A showed more inhibition compared to Group B. Similarly immunohistochemical analysis showed significantly lower (p < 0.002) VEGF staining in group A compared to group B. Western Blot analysis showed a similar difference in VEGF expression (P < 0.0001). CONCLUSION: The additional injection of Survivin siRNA to the routine TACE protocol increased the inhibition of the hepatocellular carcinoma growth in a rat animal model compared to regular TACE protocol. [Mh] Termos MeSH primário: Carcinoma Hepatocelular/terapia Quimioembolização Terapêutica/métodos Óleo Etiodado/administração & dosagem Proteínas Inibidoras de Apoptose/antagonistas & inibidores Neoplasias Hepáticas/terapia Mitomicina/administração & dosagem RNA Interferente Pequeno/administração & dosagem [Mh] Termos MeSH secundário: Animais Terapia Combinada/métodos Óleo Etiodado/uso terapêutico Seres Humanos Injeções Intra-Arteriais Masculino Mitomicina/uso terapêutico Transplante de Neoplasias RNA Interferente Pequeno/farmacologia Ratos Ratos Endogâmicos ACI Resultado do Tratamento [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (BIRC5 protein, human); 0 (Inhibitor of Apoptosis Proteins); 0 (RNA, Small Interfering); 50SG953SK6 (Mitomycin); 8008-53-5 (Ethiodized Oil) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171120 [Lr] Data última revisão: 171120 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160525 [St] Status: MEDLINE [do] DOI: 10.1186/s12885-016-2357-3

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[PMID]: 26891909 [Au] Autor: Kariya T; Ueta H; Xu XD; Koga D; Ezaki T; Yu E; Kusumi S; Kitazawa Y; Sawanobori Y; Ushiki T; Issekutz T; Matsuno K [Ad] Endereço: Department of Anatomy (Macro), Dokkyo Medical University, School of Medicine, Tochigi, Japan. [Ti] Título: Direct evidence for activated CD8+ T cell transmigration across portal vein endothelial cells in liver graft rejection. [So] Source: J Gastroenterol;51(10):985-98, 2016 Oct. [Is] ISSN: 1435-5922 [Cp] País de publicação: Japan [La] Idioma: eng [Ab] Resumo: BACKGROUND: Lymphocyte recruitment into the portal tract is crucial not only for homeostatic immune surveillance but also for many liver diseases. However, the exact route of entry for lymphocytes into portal tract is still obscure. We investigated this question using a rat hepatic allograft rejection model. METHODS: A migration route was analyzed by immunohistological methods including a recently developed scanning electron microscopy method. Transmigration-associated molecules such as selectins, integrins, and chemokines and their receptors expressed by hepatic vessels and recruited T-cells were analyzed by immunohistochemistry and flow cytometry. RESULTS: The immunoelectron microscopic analysis clearly showed CD8ß(+) cells passing through the portal vein (PV) endothelia. Furthermore, the migrating pathway seemed to pass through the endothelial cell body. Local vascular cell adhesion molecule-1 (VCAM-1) expression was induced in PV endothelial cells from day 2 after liver transplantation. Although intercellular adhesion molecule-1 (ICAM-1) expression was also upregulated, it was restricted to sinusoidal endothelia. Recipient T-cells in the graft perfusate were CD25(+)CD44(+)ICAM-1(+)CXCR3(+)CCR5(-) and upregulated α4ß1 or αLß2 integrins. Immunohistochemistry showed the expression of CXCL10 in donor MHCII(high) cells in the portal tract as well as endothelial walls of PV. CONCLUSIONS: We show for the first time direct evidence of T-cell transmigration across PV endothelial cells during hepatic allograft rejection. Interactions between VCAM-1 on endothelia and α4ß1 integrin on recipient effector T-cells putatively play critical roles in adhesion and transmigration through endothelia. A chemokine axis of CXCL10 and CXCR3 also may be involved. [Mh] Termos MeSH primário: Linfócitos T CD8-Positivos/fisiologia Rejeição de Enxerto/imunologia Transplante de Fígado/efeitos adversos Migração Transendotelial e Transepitelial [Mh] Termos MeSH secundário: Aloenxertos/imunologia Animais Linfócitos T CD8-Positivos/química Quimiocina CXCL10/análise Endotélio/química Endotélio/metabolismo Receptores de Hialuronatos/análise Imuno-Histoquímica Integrina alfa4beta1/metabolismo Molécula 1 de Adesão Intercelular/análise Molécula 1 de Adesão Intercelular/metabolismo Subunidade alfa de Receptor de Interleucina-2/análise Antígeno-1 Associado à Função Linfocitária/metabolismo Masculino Microscopia Eletrônica de Varredura Veia Porta Ratos Endogâmicos ACI Ratos Endogâmicos Lew Receptores CCR5/análise Receptores CXCR3/análise Regulação para Cima Molécula 1 de Adesão de Célula Vascular/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Chemokine CXCL10); 0 (Cxcl10 protein, rat); 0 (Cxcr3 protein, rat); 0 (Hyaluronan Receptors); 0 (Integrin alpha4beta1); 0 (Interleukin-2 Receptor alpha Subunit); 0 (Lymphocyte Function-Associated Antigen-1); 0 (Receptors, CCR5); 0 (Receptors, CXCR3); 0 (Vascular Cell Adhesion Molecule-1); 126547-89-5 (Intercellular Adhesion Molecule-1) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160220 [St] Status: MEDLINE [do] DOI: 10.1007/s00535-016-1169-1

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[PMID]: 26861028 [Au] Autor: Möller FJ; Pemp D; Soukup ST; Wende K; Zhang X; Zierau O; Muders MH; Bosland MC; Kulling SE; Lehmann L; Vollmer G [Ad] Endereço: Department of Molecular Cell Physiology and Endocrinology, Institute for Zoology, Technische Universität Dresden, 01062, Dresden, Germany. frank.moeller@tu-dresden.de. [Ti] Título: Soy isoflavone exposure through all life stages accelerates 17ß-estradiol-induced mammary tumor onset and growth, yet reduces tumor burden, in ACI rats. [So] Source: Arch Toxicol;90(8):1907-16, 2016 Aug. [Is] ISSN: 1432-0738 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: There is an ongoing debate whether the intake of soy-derived isoflavones (sISO) mediates beneficial or adverse effects with regard to breast cancer risk. Therefore, we investigated whether nutritional exposure to a sISO-enriched diet from conception until adulthood impacts on 17ß-estradiol (E2)-induced carcinogenesis in the rat mammary gland (MG). August-Copenhagen-Irish (ACI) rats were exposed to dietary sISO from conception until postnatal day 285. Silastic tubes containing E2 were used to induce MG tumorigenesis. Body weight, food intake, and tumor growth were recorded weekly. At necropsy, the number, position, size, and weight of each tumor were determined. Plasma samples underwent sISO analysis, and the morphology of MG was analyzed. Tumor incidence and multiplicity were reduced by 20 and 56 %, respectively, in the sISO-exposed rats compared to the control rats. Time-to-tumor onset was shortened from 25 to 20 weeks, and larger tumors developed in the sISO-exposed rats. The histological phenotype of the MG tumors was independent of the sISO diet received, and it included both comedo and cribriform phenotypes. Morphological analyses of the whole-mounted MGs also showed no diet-dependent differences. Lifelong exposure to sISO reduced the overall incidence of MG carcinomas in ACI rats, although the time-to-tumor was significantly shortened. [Mh] Termos MeSH primário: Estradiol/toxicidade Isoflavonas/toxicidade Neoplasias Mamárias Experimentais/induzido quimicamente Feijão de Soja/química Carga Tumoral/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Dieta Feminino Isoflavonas/isolamento & purificação Isoflavonas/farmacologia Neoplasias Mamárias Experimentais/metabolismo Neoplasias Mamárias Experimentais/patologia Ratos Endogâmicos ACI Fatores de Tempo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Isoflavones); 4TI98Z838E (Estradiol) [Em] Mês de entrada: 1703 [Cu] Atualização por classe: 170817 [Lr] Data última revisão: 170817 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160211 [St] Status: MEDLINE [do] DOI: 10.1007/s00204-016-1674-2

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[PMID]: 26708158 [Au] Autor: Hivelin M; Klimczak A; Cwykiel J; Sonmez E; Nasir S; Gatherwright J; Siemionow M [Ad] Endereço: Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA. [Ti] Título: Immunomodulatory Effects of Different Cellular Therapies of Bone Marrow Origin on Chimerism Induction and Maintenance Across MHC Barriers in a Face Allotransplantation Model. [So] Source: Arch Immunol Ther Exp (Warsz);64(4):299-310, 2016 Aug. [Is] ISSN: 1661-4917 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: Many more patients would benefit from vascularized composite allotransplantation if less toxic and safer immunosuppressive protocols will become available. Tolerance induction protocols with donor cells co-transplantation are one of the promising pathways to reduce maintenance immunosupressive regimens. We investigated the role of donor bone marrow cells (BMC), mesenchymal stromal cells (MSC) and in vivo created chimeric cells (CC) used as supportive therapies in a fully MHC-mismatched rat face transplantation model. Twenty-four fully MHC-mismatched hemiface transplantations were performed between ACI (RT1(a)) donors and Lewis (RT1(l)) recipients under combined seven-day immunosuppressive regimen of anti-αß-T-cell receptor (TCR) monoclonal antibody and cyclosporin A. We studied four experimental groups-group 1: no cellular therapy; group 2: supportive therapy with BMC; group 3: supportive therapy with MSC; group 4: supportive therapy with CC generated in a primary chimera. We evaluated clinical and histological rejection grades, transplanted cells migration, donor-specific chimerism in the peripheral blood and bone marrow compartments, and CD4(+)/CD25(+) T-cell levels. Face allograft rejection was observed at 26.8 ± 0.6 days post-transplant (PT) in the absence of cellular therapy, at 34.5 ± 1.1 days for group 2, 29.3 ± 0.8 days for group 3, and 30.3 ± 1.38 PT for group 4. The longest survival was observed in allografts supported by co-transplantation of BMC. All support in cellular therapies delayed face allograft rejection by chimerism induction and/or immunomodulatory properties of co-transplanted cells. Survival time was comparable between groups, however, further studies, with different cell dosages, delivery routes and delivery times are required. [Mh] Termos MeSH primário: Células da Medula Óssea/citologia Células da Medula Óssea/imunologia Quimerismo Transplante de Face/métodos Complexo Principal de Histocompatibilidade Células Mesenquimais Estromais/citologia Células Mesenquimais Estromais/imunologia [Mh] Termos MeSH secundário: Animais Biópsia Medula Óssea/metabolismo Movimento Celular Sobrevivência Celular Face Citometria de Fluxo Rejeição de Enxerto Sobrevivência de Enxerto Imunossupressão Imunossupressores/uso terapêutico Fenótipo Ratos Ratos Endogâmicos ACI Ratos Endogâmicos Lew Receptores de Antígenos de Linfócitos T/imunologia Transplante Homólogo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Immunosuppressive Agents); 0 (Receptors, Antigen, T-Cell) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 170206 [Lr] Data última revisão: 170206 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 151229 [St] Status: MEDLINE [do] DOI: 10.1007/s00005-015-0380-8

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[PMID]: 26122135 [Au] Autor: Fukahori H; Chida N; Maeda M; Tasaki M; Kawashima T; Noto T; Tsujimoto S; Nakamura K; Oshima S; Hirose J; Higashi Y; Morokata T [Ad] Endereço: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. Electronic address: hidehiko.fukahori@astellas.com. [Ti] Título: Effect of novel PKCθ selective inhibitor AS2521780 on acute rejection in rat and non-human primate models of transplantation. [So] Source: Int Immunopharmacol;27(2):232-7, 2015 Aug. [Is] ISSN: 1878-1705 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Selective inhibition of protein kinase Cθ (PKCθ) may be useful in inducing T cell-specific immunosuppression with a reduced rate of side effects. To our knowledge, however, no reports have been published regarding the selective inhibition of PKCθ by small-molecule compounds in animal models of allograft rejection. Here, we investigated the effect of the newly synthesized PKCθ selective inhibitor AS2521780 in mono- and combination therapies on acute rejection in ACI-to-Lewis rat cardiac and non-human primate (NHP) renal transplantation models. In the rat cardiac transplantation model, AS2521780 significantly prolonged graft survival to 14days at 10mg/kg twice daily (b.i.d.) and to 20days at 30mg/kg b.i.d. In contrast, acute rejection occurred in all recipients in the non-treated group by Days 5 or 6 post-transplantation. Significant improvements (P<0.001) in graft survival were observed following treatment with a combination of AS2521780 at 3mg/kg b.i.d. and a suboptimal dose of tacrolimus (0.02mg/kg) or mycophenolate mofetil (15mg/kg). In the NHP renal transplantation model, AS2521780 at 3mg/kg b.i.d. and tacrolimus at 1mg/kg (suboptimal dose) significantly improved graft survival compared to tacrolimus alone (P<0.05). The present study of AS2521780 in rat cardiac and NHP renal transplantation models demonstrates the potential of PKCθ as a novel drug target for organ transplantation. As AS2521780 was well tolerated and the dose of tacrolimus or mycophenolate mofetil can be reduced when used in combination with this drug, immunosuppressive regimens containing selective inhibitors of PKCθ might have good safety profiles. [Mh] Termos MeSH primário: Adamantano/análogos & derivados Rejeição de Enxerto/tratamento farmacológico Proteína Quinase C/antagonistas & inibidores Inibidores de Proteínas Quinases/uso terapêutico Pirimidinas/uso terapêutico [Mh] Termos MeSH secundário: Adamantano/uso terapêutico Animais Transplante de Coração Imunossupressores/uso terapêutico Isoenzimas/antagonistas & inibidores Transplante de Rim Macaca fascicularis Masculino Ácido Micofenólico/análogos & derivados Ácido Micofenólico/uso terapêutico Ratos Endogâmicos ACI Ratos Endogâmicos Lew Tacrolimo/uso terapêutico [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (AS2521780); 0 (Immunosuppressive Agents); 0 (Isoenzymes); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); EC 2.7.11.13 (Protein Kinase C); HU9DX48N0T (Mycophenolic Acid); PJY633525U (Adamantane); WM0HAQ4WNM (Tacrolimus) [Em] Mês de entrada: 1605 [Cu] Atualização por classe: 161125 [Lr] Data última revisão: 161125 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150701 [St] Status: MEDLINE

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[PMID]: 26017290 [Au] Autor: Eto T [Ad] Endereço: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki, 210-0821 Japan. [Ti] Título: Strain preservation of rats: vitrification of two-cell stage embryos for multiple inbred strains. [So] Source: Cryo Letters;36(2):114-9, 2015 Mar-Apr. [Is] ISSN: 0143-2044 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: OBJECTIVE: We examined whether the vitrification method using P10 and PEPeS is suitable for the cryopreservation of two-cell stage embryos collected from multiple rat strains with the objective of strain preservation of inbred rat strains. RESULTS: The average numbers of two-cell stage embryos collected per female for F344/Jcl, ACI/N, BUF/N, and WKY/N strains were 7.0 to 12.0, and survival rates of the embryos after vitrification were 94.2 to 96.3 % The in vitro development rates of vitrified embryos transferred were 47.1 to 60.8 %. CONCLUSION: At least two offspring produced from the embryos collected from one female are required for strain preservation of inbred strain. Taken together, the results of the experiment indicated expected numbers of surviving fetuses for embryos collected from one female were 3.2 to 6.7, and all were usable for strain preservation. The results suggest that this vitrification method is suitable for strain preservation of multiple inbred rat strains. [Mh] Termos MeSH primário: Criopreservação/métodos Ratos Endogâmicos/embriologia Vitrificação [Mh] Termos MeSH secundário: Animais Criopreservação/veterinária Transferência Embrionária Desenvolvimento Embrionário Feminino Masculino Ratos Endogâmicos ACI/embriologia Ratos Endogâmicos BUF/embriologia Ratos Endogâmicos F344/embriologia Ratos Endogâmicos WKY/embriologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Em] Mês de entrada: 1508 [Cu] Atualização por classe: 150528 [Lr] Data última revisão: 150528 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150529 [St] Status: MEDLINE

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