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2-aminoethyl Dihydrogen Phosphate as a Modulator of Proliferative and Apoptotic Effects in Breast Cancer Cell Lines

Journal of Pharmacy and Pharmacology 2021年第3期9卷 83-97页

作者： Manuela Garcia Laveli da Silva Laertty Garcia de Sousa Cabral Monique Gonçalves Alves Thais deoliveira conceição Henrique Hesse Rosa Andrea Nogueira Laiso daniel da conceição rabelo Durvanei Augusto Maria Development and Innovation Laboratory Butantan InstituteSao PauloSP 05503-900Brazil Faculty of Medicine University of São PauloSao PauloSP 01246-000Brazil

Background: Breast cancer is a type of cancer that affects more women throughout the world, in developing anddeveloped countries. 2-AEH2P is a phospholipid analog of cellular membrane, which makes it different from existing molecules fortheir absorption, stability and display anti-inflammatory, anti-proliferative and pro-apoptotic properties. Methods: MCF-7 humanbreast adenocarcinoma cells were treated with 2-AEH2P. The viability and adhesion cells were evaluated by MTT assay. Cell cyclephases, apoptosis, markers and mitochondrial potential were assessed by flow cytometry. Morphological ultrastructural analyzeswere performed by laser confocal microscopy. Results: MCF-7 Tumor cells acquired round shapes, lost cytoplasmic expansions,formed clusters in suspension and decreased significantly viability. There were changes in the morphology, membrane fragmentationand loss of cytoplasmic projection. The obtained concentrations for IC50% were 37.2;25.8;1.8 mM for periods of 24, 48 and 72 h,respectively. Changes in the distribution of cell population phases of the cell cycle showed an increase in fragmented DNA and anincrease in the G2/M phase. The expression β-gal showed proliferative reduction induced by 2-AEH2P. Laser confocal microscopyshowed changes in the mitochondrial membrane and alteration in distribution. Proliferative index of MCF-7 tumor cells treated with2-AEH2P decreased significantly when compared to fibroblast normal cells. The compound 2-AEH2P is a phospholipid withantiproliferative potential and apoptosis modulator.

关键词： Human Breast Adenocarcinoma MCF-7 2-AEH2P Antitumor Apoptosis Cell cycle Senescence

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Clinical oncology Translational Study Phase-1 with Antitumor Phosphorylethanolamine(2-AEH_(2)P)in Dogs with Neoplasms

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Journal of Pharmacy and Pharmacology 2021年第5期9卷 179-196页

作者： olivia Gonçalves de Almeida Leitão da Cunha Lucas Campos de SáRodrigues daniel da conceição rabelo Rosa Andrea Nogueira Laiso Sergio Mestieri Chammas Laertty Garcia de Sousa Cabral Durvanei Augusto Maria Development and Innovation Laboratory Butantan InstituteAvenue Vital Brasil1500Sao Paulo 05503-900Brazil Faculty of Veterinary Medicine and Animal Science Sao Paulo UniversitySao Paulo 01246-000Brazil Veretinary Hospital Estima Avenue Granadeiro GuimaraesTaubaté155Sao PauloBrazil Faculty of Medicine of the University of São Paulo São Paulo 01246-000Brazil

The animal has the potential to serve as a clinical model for human disease,due to striking similarities and homologies in *** clinical development of a new drug may influence its final destination,and a careful and thoughtful approach to Phase-1 clinical trials is ***(2-AEH2P)is a new cytostatic phospholipid agent that,unlike most chemotherapeutic drugs used today,does not target DNA or cytoskeleton,but act on the cell *** carried out by our group have shown several effects of 2-AEH2P controlling the progression of the cell cycle,in the alterations of the mitochondrial electrical potential capable of inducing apoptosis and autophagy in several types of human and animal tumor *** aim of this study is to establish the recommended safety dose of a 2-AEH2P monophosphoester,in dogs with tumor following the Phase 1 study model proposed by *** Phase-1 study following the Fibonacci model,2-AEH2P was safe at all staggered doses up to 150 mg/Kg for 8 *** administration in staggered doses according to the Fibonacci model,showed that the drug is safe,no advent of mortality during the study period or acute toxicity were *** is not a drug with hemolytic properties or that induces *** does not lead to changes in liver and renal functions and was able to modulate leukocyte production.2-AEH2P is new compound with antitumor potential,being useful for future veterinary and human tumors,as a combination of chemotherapeutic agents.

关键词： Cancer metabolism phospholipids monophosphoester Fibonacci Model clinical study.

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Association between the CYBA and NoX4 genes of NADPH oxidase and its relationship with metabolic syndrome in non-alcoholic fatty liver disease in Brazilian population

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Hepatobiliary & Pancreatic Diseases International 2018年第4期17卷 330-335页

作者： Fabiola rabelo Jose Tadeu Stefano Ana Mercedes Cavaleiro Rodrigo Vieira Costa Lima daniel Ferraz de Campos Mazo Flair Jose Carrilho Maria Lúcia Correa-Giannellac Claudia P.oliveiraa Departamento de Gastroenterologia Faculdade de Medicina FMUSPUniversidade de Sao PauloSao PauloSPBrazil Hospital das Clinicas HCFMUSP Departamento de GastroenterologiaLIM07Faculdade de MedicinaUniversidade de Sao PauloSao PauloSPBrazil Laboratório de Carboidratos e Radioimunensaio LIM18Hospital das Clinicas HCFMUSP(LIM07)Faculdade de MedicinaUniversidade de Sao PauloSao PauloBrazil Programa de Pos-Graduacao em Medicina Universidade Nove de Julho(UNINOVE)Sao PauloBrazil

Background: oxidative stress has been implicated in the progression of severe forms of non-alcoholic fatty liver disease(NAFLD). NADPH oxidase produces reactive oxygen species. In the present study, we investigated for the first time two single nucleotide polymorphisms(SNPs) in the regulatory region of genes encoding NADPH oxidase 4(NoX4) and p22 phox(CYBA) in ***: A total of 207 biopsy-proven NAFLD patients [simple steatosis(n = 27); nonalcoholic steatohepatitis(NASH)(n = 180)] were evaluated. Genomic DNA was extracted from peripheral blood cells, and polymorphisms in CYBA(unregistered) and NoX4(rs3017887) were determined by direct sequencing of ***: Associations of CYBA-675 T/A with high-density lipoprotein(HDL)(TT vs TA vs AA; P observed only in NASH patients. For polymorphisms in the NoX4 gene, NoX4(rs3017887) CA + AA genotypes was significant associated with alanine aminotransferase(ALT)(CA + AA vs CC; P = 0.02). However, there was no association of SNPs in the CYBA and NoX4 genes encoding the NADPH oxidase system proteins and the presence of NASH. Regarding the clinical results, it was observed that the most advanced degrees of fibrosis occurred in patients diagnosed with type 2 diabetes mellitus(66.9% vs 37.5%, P ose who were more obese(32.2 vs 29.0 kg/m2,P on, serum glucose and insulin levels increased significantly in the presence of ***: There were associations between the presence of the allele A in the NoX4 SNP and a higher concentration of ALT in the NAFLD population; between the presence of the AA genotype in the polymorphism of the CYBA-675 T/A CYBA gene and a higher level of TGL and lower HDL in NASH patients. The presence of metabolic syndrome was associated with advanced degrees of fibrosis in NAFLD patients.

关键词： Non-alcoholic fatty liver disease Nonalcoholic steatohepatitis Genetic polymorphism Metabolic syndrome

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Hypolactasia is associated with insulin resistance in nonalcoholic steatohepatitis

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World Journal of Hepatology 2016年第24期8卷 1019-1027页

作者： daniel Ferraz de Campos Mazo Rejane Mattar Jose Tadeu Stefano Joyce Matie Kinoshita da Silva-Etto Marcio Augusto Diniz Sebastiao Mauro Bezerra Duarte Fabíola rabelo Rodrigo Vieira Costa Lima Priscila Brizolla de Campos Flair Jose Carrilho Claudia P oliveira Division of Gastroenterology and Hepatology Department of Gastroenterology(LIM 07)University of Sao Paulo School of Medicine

AIM To assess lactase gene(LCT)-13910C>T polymorphisms in Brazilian non-alcoholic fatty liver disease(NAFLD) and nonalcoholic steatohepatitis(NASH) patients in comparison with healthy *** This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology outpatient Unit of the Hospital das Clínicas, S?o Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence(LCT-13910C>T) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients(steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher's exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were *** No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients(66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls(59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism(LCT-13910C>T) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase nonpersistence(low lactase activity or hypolactasia) phenotype was associated with higher insulin levels(23.47 ± 15.94 μU/m L vs 15.8 ± 8.33 μU/m L, P = 0.027) and a higher frequency of insulin resistance(91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes(P = 0.651), dyslipidaemia(P = 0.328), h

关键词： Lactose intolerance Genetic polymorphism Insulin resistance Non-alcoholic fatty liver disease Nonalcoholic steatohepatitis

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Genetic ancestry analysis in non-alcoholic fatty liver disease patients from Brazil and Portugal

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World Journal of Hepatology 2015年第10期7卷 1433-1438页

作者： Lourianne Nascimento Cavalcante Jose Tadeu Stefano Mariana V Machado daniel F Mazo Fabiola rabelo Kiyoko Abe Sandes Flair Jose Carrilho Helena Cortez-Pinto Andre Castro Lyra Claudia P de oliveira Gastro-Hepatology Department Hospital Sao Rafael Division of Gastroenterology and Hepatology Department of GastroenterologyUniversity of Sao Paulo School of Medicine Department of Gastroenterology Laboratory of NutritionUniversity Hospital of Santa Maria University Life Sciences Department University of Bahia State Faculty of Medicine Federal University of Bahia

AIM:To study the association between genetic ancestry,non-alcoholic fatty liver disease(NAFLD) metabolic characteristics in two cohorts of patients,from Brazil and Portugal. METHoDS:We included 131 subjects from Brazil [(n = 45 with simple steatosis(S. Steatosis) and n = 86 with nonalcoholic steatohepatitis(NASH)] and 90 patients from Portugal(n = 66,S. Steatosis; n = 24,NASH). All patients had biopsy-proven NAFLD. In histologic evaluation NAFLD activity score was used to assess histology and more than 5 points defined NASH in this study. Patients were divided into two groups according to histology diagnosis:simple steatosis or non-alcoholic statohepatitis. Genetic ancestry was assessed using real-time polymerase chain reaction. Seven ancestry informative markers(AT3-I/D,LPL,Sb19.3,APo,FYNull,PV92,and CKMM) with the greatest ethnicgeographical differential frequencies(≥ 48%) were used to define genetic ancestry. data were analyzed using R PRoJECTS software. Ancestry allele frequencies between groups were analyzed by GENEPoP onlineand the estimation of genetic ancestry contribution was evaluated by ADMIX-95 software. The 5% alpha-error was considered as significant(P ore frequent among the elderly patients with diabetes(NASH 56 ± 1.1 years old vs S. Steatosis 51 ± 1.5 years old,P = 3.7 x 10-9),dyslipidemia(NASH 63% vs S. Steatosis 37%,P = 0.009),higher fasting glucose levels(NASH 124 ± 5.2 vs S. Steatosis 106 ± 5.3,P = 0.001) and Homeostatic Model of Assessment index > 2.5 [NASH 5.3(70.8%) vs S. Steatosis 4.6(29.2%) P = 0.04]. In the Portuguese study population,dyslipidemia was present in all patients with NASH(P = 0.03) and hypertension was present in a larger percentage of subjects in the S. Steatosis group(P = 0.003,respectively). The genetic ancestry contribution among Brazilian and Portuguese individuals with NASH was similar to those with S. Steatosis from each cohort(Brazilian cohort:P = 0.75; Po

关键词： Ancestry Nonalcoholic fatty liver disease Simple steatosis Nonalcoholic steatohepatitis Admixed population

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