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Pesquisa : D02.455.426.100.050 [Categoria DeCS]
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[PMID]:29203736
[Au] Autor:Lutsenko RV; Vlasova EV; Kolot EG; Gladka VM; Sidorenko AG
[Ad] Endereço:Higher State Educational Establishment Of Ukraine, "Ukrainian Medical Stomatological Academy", Poltava, Ukraine.
[Ti] Título:The exchange of monoamines during the experimental neurosis on the background of using of amide "2-hydroxy-n-naphthalen-1-yl-2-(2-oxo-,2-dihydroindol-3-ylidene)".
[So] Source:Wiad Lek;70(5):895-900, 2017.
[Is] ISSN:0043-5147
[Cp] País de publicação:Poland
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Incessant increase in the frequency and distribution of anxiety disorders stipulates searching, research and study of the mechanism of action of new substances for their correction, including the group of 2-oxoindolin-3-glyoxylic acid derivatives. THE AIM: To research the effect of N-(1-naphthyl) amide-2-oxoindolin-3-glyoxylic acid on monoaminergic system of subjected to experimental neurosis of rats. MATERIALS AND METHODS: The experiments were performed on male Wistar rats, who have weight 180-220g and were researching the effect of 2-hydro-N-naphthalen-1-yl-2-(2-oxy-1,2-dihydroindol-3-ylidene)-acetamide (compound 18) at a dose (12 mg/kg), by intragastric drug injection of subjected to experimental neurosis rats, during 30 days (1 time in three days), for monoamines content (epinephrine, norepinephrine, dopamine and serotonin) in the blood, their decay products (homovanillic acid, vanillylmandelic acid and 5-oxyindolacetic acid) in the urine and the ratio of end products of the reaction to their predecessors. RESEARCH: It was established that during the preventive-therapeutic application of N-(1-naphthyl)amide-2-oxoindolin-3-glyoxylic acid, it effectively adjusts the level of monoamines, reducing the content of adrenaline and increasing the content of noradrenaline, dopamine and 5-HT in the blood. The compound also reduces the content of products exchange of mediators (HVA,VMA and 5-OIAA) in the urine. The 2-oxoindolin derivatives reduces the ratio between HVA/dopamine, VMA/(noradrenaline + adrenaline) and 5-OIAA/5-HT, it testifies about the normalizing of enzymes activity, which are involved in the process of exchange and maintaining the constancy of monoamines. The results show that in the mechanisms of anxiolytic action of compound 18, a significant role plays the normalization of content and exchange of neurotransmitters in the organism, which caused an experimental neurosis. CONCLUSION: Compound 2-hydro-N-naphthalen-1-yl-2-(2-oxo-1,2-dihydroindol-3-ylidene)-acetamide by the experimental 30-day neurosis, was reducing the expression of neurotransmitter imbalance in the blood, apparently due to correction of enzymatic synthesis links and biotransformation of monoamines.
[Mh] Termos MeSH primário: Adamantano/análogos & derivados
Ansiolíticos/farmacologia
Transtornos de Ansiedade/tratamento farmacológico
Benzimidazóis/farmacologia
Transtorno Depressivo/tratamento farmacológico
Morfolinas/farmacologia
[Mh] Termos MeSH secundário: Adamantano/farmacologia
Animais
Monoaminas Biogênicas/farmacologia
Seres Humanos
Masculino
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-((2-morpholino)ethylthio)-5-ethoxybenzimidazole); 0 (Anti-Anxiety Agents); 0 (Benzimidazoles); 0 (Biogenic Monoamines); 0 (Morpholines); 0 (N-(2-adamantyl)-N-p-bromophenylamine); PJY633525U (Adamantane)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE


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[PMID]:28465627
[Au] Autor:Falzone M; Crespo E; Jones K; Khan G; Korn VL; Patel A; Patel M; Patel K; Perkins C; Siddiqui S; Stenger D; Yu E; Gelber M; Scheffler R; Nayda V; Ravin A; Komal R; Rudolf JD; Shen B; Gullo V; Demain AL
[Ad] Endereço:Research Institute of Scientists Emeriti (RISE), Charles A. Dana Research Institute, Drew University, Madison, NJ, USA.
[Ti] Título:Nutritional control of antibiotic production by Streptomyces platensis MA7327: importance of l-aspartic acid.
[So] Source:J Antibiot (Tokyo);70(7):828-831, 2017 Jul.
[Is] ISSN:0021-8820
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Streptomyces platensis MA7327 is a bacterium producing interesting antibiotics, which act by the novel mechanism of inhibiting fatty acid biosynthesis. The antibiotics produced by this actinomycete are platensimycin and platencin plus some minor related antibiotics. Platensimycin and platencin have activity against antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus; they also lack toxicity in animal models. Platensimycin also has activity against diabetes in a mouse model. We have been interested in studying the effects of primary metabolites on production of these antibiotics in our chemically defined production medium. In the present work, we tested 32 primary metabolites for their effect. They included 20 amino acids, 7 vitamins and 5 nucleic acid derivatives. Of these, only l-aspartic acid showed stimulation of antibiotic production. We conclude that the stimulatory effect of aspartic acid is due to its role as a precursor involved in the biosynthesis of aspartate-4-semialdehyde, which is the starting point for the biosynthesis of the 3-amino-2,4-dihydroxy benzoic acid portion of the platensimycin molecule.
[Mh] Termos MeSH primário: Antibacterianos/isolamento & purificação
Ácido Aspártico/administração & dosagem
Streptomyces/metabolismo
[Mh] Termos MeSH secundário: Adamantano/isolamento & purificação
Aminoácidos/administração & dosagem
Aminoácidos/metabolismo
Aminobenzoatos/isolamento & purificação
Aminofenóis/isolamento & purificação
Anilidas/isolamento & purificação
Antibacterianos/biossíntese
Ácido Aspártico/química
Ácidos Nucleicos/administração & dosagem
Ácidos Nucleicos/metabolismo
Compostos Policíclicos/isolamento & purificação
Vitaminas/administração & dosagem
Vitaminas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids); 0 (Aminobenzoates); 0 (Aminophenols); 0 (Anilides); 0 (Anti-Bacterial Agents); 0 (Nucleic Acids); 0 (Polycyclic Compounds); 0 (Vitamins); 0 (platencin); 30KYC7MIAI (Aspartic Acid); PJY633525U (Adamantane); Q3DQ78KOFY (platensimycin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1038/ja.2017.49


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[PMID]:29036231
[Au] Autor:Zhang Q; Xiao X; Li M; Yu M; Ping F; Zheng J; Wang T; Wang X
[Ad] Endereço:Key Laboratory of Endocrinology, Translational Medicine Center, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
[Ti] Título:Vildagliptin increases butyrate-producing bacteria in the gut of diabetic rats.
[So] Source:PLoS One;12(10):e0184735, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Emerging evidence supports a key role for the gut microbiota in metabolic diseases, including type 2 diabetes (T2D) and obesity. The dipeptidyl peptidase-4 inhibitor vildagliptin is highly efficacious in treating T2D. However, whether vildagliptin can alter the gut microbiome is still unclear. This study aimed to identify whether vildagliptin modifies the gut microbiota structure during T2D treatment. Diabetic Sprague-Dawley (SD) rats were induced by a high-fat diet and streptozotocin injection (HFD/STZ). Diabetic rats were orally administered a low dose of vildagliptin (LV, 0.01 g/kg/d vildagliptin), high dose of vildagliptin (HV, 0.02 g/kg/d vildagliptin), or normal saline for 12 weeks. Fasting blood glucose, blood glucose after glucose loading, and serum insulin levels were significantly reduced in the LV and HV groups compared with those in the T2D group. The serum GLP-1 level increased more in the vildagliptin-treated group than in the T2D group. Pyrosequencing of the V3-V4 regions of 16S rRNA genes revealed that vildagliptin significantly altered the gut microbiota. The operational taxonomic units (OTUs) and community richness (Chao1) index were significantly reduced in the vildagliptin and diabetic groups compared with those in the control group. At the phylum level, a higher relative abundance of Bacteroidetes, lower abundance of Firmicutes, and reduced ratio of Fimicutes/Bacteroidetes were observed in the vildagliptin-treated group. Moreover, vildagliptin treatment increased butyrate-producing bacteria, including Baceroides and Erysipelotrichaeae, in the diabetic rats. Moreover, Lachnospira abundance was significantly negatively correlated with fasting blood glucose levels. In conclusion, vildagliptin treatment could benefit the communities of the gut microbiota.
[Mh] Termos MeSH primário: Adamantano/análogos & derivados
Diabetes Mellitus Experimental/tratamento farmacológico
Diabetes Mellitus Tipo 2/tratamento farmacológico
Inibidores da Dipeptidil Peptidase IV/farmacologia
Microbioma Gastrointestinal/efeitos dos fármacos
Nitrilos/farmacologia
Pirrolidinas/farmacologia
[Mh] Termos MeSH secundário: Adamantano/farmacologia
Administração Oral
Animais
Glicemia/efeitos dos fármacos
Butiratos/metabolismo
Diabetes Mellitus Experimental/sangue
Diabetes Mellitus Experimental/microbiologia
Diabetes Mellitus Tipo 2/sangue
Diabetes Mellitus Tipo 2/microbiologia
Microbioma Gastrointestinal/genética
Microbioma Gastrointestinal/fisiologia
Peptídeo 1 Semelhante ao Glucagon/sangue
Resistência à Insulina
Interleucina-6/sangue
Masculino
RNA Ribossômico 16S/genética
Distribuição Aleatória
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Butyrates); 0 (Dipeptidyl-Peptidase IV Inhibitors); 0 (Interleukin-6); 0 (Nitriles); 0 (Pyrrolidines); 0 (RNA, Ribosomal, 16S); 89750-14-1 (Glucagon-Like Peptide 1); I6B4B2U96P (vildagliptin); PJY633525U (Adamantane)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184735


  4 / 2811 MEDLINE  
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[PMID]:28977602
[Au] Autor:Brown SM; Smith CE; Meuth AI; Khan M; Aroor AR; Cleeton HM; Meininger GA; Sowers JR; DeMarco VG; Chandrasekar B; Nistala R; Bender SB
[Ad] Endereço:Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri 65201.
[Ti] Título:Dipeptidyl Peptidase-4 Inhibition With Saxagliptin Ameliorates Angiotensin II-Induced Cardiac Diastolic Dysfunction in Male Mice.
[So] Source:Endocrinology;158(10):3592-3604, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Activation of the renin-angiotensin-aldosterone system is common in hypertension and obesity and contributes to cardiac diastolic dysfunction, a condition for which no treatment currently exists. In light of recent reports that antihyperglycemia incretin enhancing dipeptidyl peptidase (DPP)-4 inhibitors exert cardioprotective effects, we examined the hypothesis that DPP-4 inhibition with saxagliptin (Saxa) attenuates angiotensin II (Ang II)-induced cardiac diastolic dysfunction. Male C57BL/6J mice were infused with either Ang II (500 ng/kg/min) or vehicle for 3 weeks receiving either Saxa (10 mg/kg/d) or placebo during the final 2 weeks. Echocardiography revealed Ang II-induced diastolic dysfunction, evidenced by impaired septal wall motion and prolonged isovolumic relaxation, coincident with aortic stiffening. Ang II induced cardiac hypertrophy, coronary periarterial fibrosis, TRAF3-interacting protein 2 (TRAF3IP2)-dependent proinflammatory signaling [p-p65, p-c-Jun, interleukin (IL)-17, IL-18] associated with increased cardiac macrophage, but not T cell, gene expression. Flow cytometry revealed Ang II-induced increases of cardiac CD45+F4/80+CD11b+ and CD45+F4/80+CD11c+ macrophages and CD45+CD4+ lymphocytes. Treatment with Saxa reduced plasma DPP-4 activity and abrogated Ang II-induced cardiac diastolic dysfunction independent of aortic stiffening or blood pressure. Furthermore, Saxa attenuated Ang II-induced periarterial fibrosis and cardiac inflammation, but not hypertrophy or cardiac macrophage infiltration. Analysis of Saxa-induced changes in cardiac leukocytes revealed Saxa-dependent reduction of the Ang II-mediated increase of cardiac CD11c messenger RNA and increased cardiac CD8 gene expression and memory CD45+CD8+CD44+ lymphocytes. In summary, these results demonstrate that DPP-4 inhibition with Saxa prevents Ang II-induced cardiac diastolic dysfunction, fibrosis, and inflammation associated with unique shifts in CD11c-expressing leukocytes and CD8+ lymphocytes.
[Mh] Termos MeSH primário: Adamantano/análogos & derivados
Aorta/efeitos dos fármacos
Diástole/efeitos dos fármacos
Dipeptídeos/farmacologia
Inibidores da Dipeptidil Peptidase IV/farmacologia
Coração/efeitos dos fármacos
Rigidez Vascular/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adamantano/farmacologia
Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Angiotensina II/toxicidade
Animais
Pressão Sanguínea/efeitos dos fármacos
Linfócitos T CD4-Positivos/efeitos dos fármacos
Antígenos CD8/efeitos dos fármacos
Antígenos CD8/metabolismo
Cardiomegalia/induzido quimicamente
Dipeptidil Peptidase 4/efeitos dos fármacos
Dipeptidil Peptidase 4/metabolismo
Ecocardiografia
Fibrose/induzido quimicamente
Expressão Gênica/efeitos dos fármacos
Coração/fisiopatologia
Inflamação
Interleucina-17/metabolismo
Interleucina-18/metabolismo
Linfócitos/efeitos dos fármacos
Macrófagos/efeitos dos fármacos
Macrófagos/metabolismo
Masculino
Camundongos
Proteínas Proto-Oncogênicas c-jun/efeitos dos fármacos
Proteínas Proto-Oncogênicas c-jun/metabolismo
Transdução de Sinais
Vasoconstritores/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (CD8 Antigens); 0 (Dipeptides); 0 (Dipeptidyl-Peptidase IV Inhibitors); 0 (Interleukin-17); 0 (Interleukin-18); 0 (Proto-Oncogene Proteins c-jun); 0 (Traf3ip2 protein, mouse); 0 (Vasoconstrictor Agents); 11128-99-7 (Angiotensin II); 9GB927LAJW (saxagliptin); EC 3.4.14.5 (Dipeptidyl Peptidase 4); PJY633525U (Adamantane)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00416


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[PMID]:28886889
[Au] Autor:Suslov E; Zarubaev VV; Slita AV; Ponomarev K; Korchagina D; Ayine-Tora DM; Reynisson J; Volcho K; Salakhutdinov N
[Ad] Endereço:Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia.
[Ti] Título:Anti-influenza activity of diazaadamantanes combined with monoterpene moieties.
[So] Source:Bioorg Med Chem Lett;27(19):4531-4535, 2017 10 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The antiviral activity of several diaza-adamantanes containing monoterpenoid moieties against a rimantadine-resistant strain of the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. Hetero-adamantanes containing monoterpene moieties at the aminal position of the heterocycle were found to exhibit lower activity compared to compounds with a diaza-adamantane fragment and a monoterpene moiety linked via an amino group at the 6-position of the hetero-adamantane ring. The highest selectivity index (a ratio of the 50% cytotoxic concentration to the 50% inhibitory concentration) out of 30 was observed for compound 8d, which contains a citronellal monoterpenoid moiety. Diaza-adamantane 8d was superior to its adamantane-containing analog 5 both in its anti-influenza activity and selectivity. Furthermore, 8d has more balanced physicochemical properties than 5, making the former a more promising drug candidate. Modelling these compounds against an influenza virus M2 ion channel predicted plausible binding modes to both the wild-type and the mutant (S31N).
[Mh] Termos MeSH primário: Adamantano/farmacologia
Antivirais/farmacologia
Compostos Aza/farmacologia
Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos
Monoterpenos/farmacologia
[Mh] Termos MeSH secundário: Adamantano/química
Antivirais/síntese química
Antivirais/química
Compostos Aza/química
Relação Dose-Resposta a Droga
Testes de Sensibilidade Microbiana
Estrutura Molecular
Monoterpenos/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Aza Compounds); 0 (Monoterpenes); PJY633525U (Adamantane)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170910
[St] Status:MEDLINE


  6 / 2811 MEDLINE  
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[PMID]:28832656
[Au] Autor:Kenawy S; Hegazy R; Hassan A; El-Shenawy S; Gomaa N; Zaki H; Attia A
[Ad] Endereço:Pharmacology Department, Medical division, National Research Centre, Giza, Egypt.
[Ti] Título:Involvement of insulin resistance in D-galactose-induced age-related dementia in rats: Protective role of metformin and saxagliptin.
[So] Source:PLoS One;12(8):e0183565, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Age-related dementia is one of the most devastating disorders affecting the elderly. Recently, emerging data suggest that impaired insulin signaling is the major contributor in the development of Alzheimer's dementia (AD), which is the most common type of senile dementia. In the present study, we investigated the potential therapeutic effects of metformin (Met) and saxagliptin (Saxa), as insulin sensitizing agents, in a rat model of brain aging and AD using D-galactose (D-gal, 150 mg/kg/day, s.c. for 90 successive days). Six groups of adult male Wistar rats were used: normal, D-gal, Met (500 mg/kg/day, p.o), and Saxa (1 mg/kg/day, p.o) control groups, as well as D-gal/Met and D-gal/Sax treated groups. Impaired learning and memory function was observed in rats treated with D-gal using Morris water maze test. Biochemical and histopathological findings also revealed some characteristic changes of AD in the brain that include the increased content of acetylcholine, glutamate, and phosphorelated tau, as well as deposition of amyloid plaques and neurofibrillary tangles. Induction of insulin resistance in experimentally aged rats was evidenced by increased blood glycated hemoglobin, brain contents of insulin and receptors for advanced glycated end-products, as well as decreased brain insulin receptor level. Elevation of oxidative stress markers and TNF-α brain content was also demonstrated. Met and Saxa, with a preference to Met, restored the normal memory and learning functions in rats, improved D-gal-induced state of insulin resistance, oxidative stress and inflammation, and ameliorated the AD biochemical and histopathological alterations in brain tissues. Our findings suggest that D-gal model of aging results in a diminishing of learning and memory function by producing a state of impaired insulin signaling that causes a cascade of deleterious events like oxidative stress, inflammation, and tau hyper-phosphorylation. Reversing of these harmful effects by the use of insulin-sensitizing drugs like Met and Saxa suggests their involvement in alleviation insulin resistance as the underlying pathology of AD and hence their potential use as anti-dementia drugs.
[Mh] Termos MeSH primário: Adamantano/análogos & derivados
Envelhecimento/patologia
Demência/induzido quimicamente
Dipeptídeos/toxicidade
Galactose/toxicidade
Hipoglicemiantes/uso terapêutico
Resistência à Insulina
Metformina/uso terapêutico
[Mh] Termos MeSH secundário: Adamantano/toxicidade
Animais
Biomarcadores/metabolismo
Peso Corporal/efeitos dos fármacos
Encéfalo/efeitos dos fármacos
Encéfalo/metabolismo
Encéfalo/patologia
Demência/patologia
Demência/prevenção & controle
Hemoglobina A Glicada/metabolismo
Locomoção/efeitos dos fármacos
Masculino
Proteínas do Tecido Nervoso/metabolismo
Estresse Oxidativo
Ratos
Ratos Wistar
Tempo de Reação/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Dipeptides); 0 (Glycated Hemoglobin A); 0 (Hypoglycemic Agents); 0 (Nerve Tissue Proteins); 9100L32L2N (Metformin); 9GB927LAJW (saxagliptin); PJY633525U (Adamantane); X2RN3Q8DNE (Galactose)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170824
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183565


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[PMID]:28807765
[Au] Autor:Sa-Nguanmoo P; Tanajak P; Kerdphoo S; Jaiwongkam T; Pratchayasakul W; Chattipakorn N; Chattipakorn SC
[Ad] Endereço:Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
[Ti] Título:SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats.
[So] Source:Toxicol Appl Pharmacol;333:43-50, 2017 Oct 15.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dipeptidyl peptidase-4 inhibitor (vildagliptin) has been shown to exert beneficial effects on insulin sensitivity and neuroprotection in obese-insulin resistance. Recent studies demonstrated the neuroprotection of the sodium-glucose co-transporter 2 inhibitor (dapagliflozin) in diabetes. However, the comparative effects of both drugs and a combination of two drugs on metabolic dysfunction and brain dysfunction impaired by the obese-insulin resistance have never been investigated. Forty male Wistar rats were divided into two groups, and received either a normal-diet (ND, n=8) or a high-fat diet (HFD, n=32) for 16weeks. At week 13, the HFD-fed rats were divided into four subgroups (n=8/subgroup) to receive either a vehicle, vildagliptin (3mg/kg/day) dapagliflozin (1mg/kg/day) or combined drugs for four weeks. ND rats were given a vehicle for four weeks. Metabolic parameters and brain function were investigated. The results demonstrated that HFD rats developed obese-insulin resistance and cognitive decline. Dapagliflozin had greater efficacy on improved peripheral insulin sensitivity and reduced weight gain than vildagliptin. Single therapy resulted in equally improved brain mitochondrial function, insulin signaling, apoptosis and prevented cognitive decline. However, only dapagliflozin improved hippocampal synaptic plasticity. A combination of the drugs had greater efficacy in improving brain insulin sensitivity and reducing brain oxidative stress than the single drug therapy. These findings suggested that dapagliflozin and vildagliptin equally prevented cognitive decline in the obese-insulin resistance, possibly through some similar mechanisms. Dapagliflozin had greater efficacy than vildagliptin for preserving synaptic plasticity, thus combined drugs could be the best therapeutic approach for neuroprotection in the obese-insulin resistance.
[Mh] Termos MeSH primário: Adamantano/análogos & derivados
Anti-Inflamatórios
Compostos Benzidrílicos
Inibidores da Dipeptidil Peptidase IV
Glucosídeos
Fármacos Neuroprotetores
Nitrilos
Pirrolidinas
Transportador 2 de Glucose-Sódio/antagonistas & inibidores
[Mh] Termos MeSH secundário: Adamantano/farmacologia
Adamantano/uso terapêutico
Animais
Anti-Inflamatórios/farmacologia
Anti-Inflamatórios/uso terapêutico
Apoptose/efeitos dos fármacos
Compostos Benzidrílicos/farmacologia
Compostos Benzidrílicos/uso terapêutico
Encéfalo/efeitos dos fármacos
Encéfalo/metabolismo
Encéfalo/fisiologia
Transtornos Cognitivos/tratamento farmacológico
Transtornos Cognitivos/metabolismo
Transtornos Cognitivos/fisiopatologia
Dieta Hiperlipídica
Inibidores da Dipeptidil Peptidase IV/farmacologia
Inibidores da Dipeptidil Peptidase IV/uso terapêutico
Glucosídeos/farmacologia
Glucosídeos/uso terapêutico
Insulina/fisiologia
Resistência à Insulina
Potenciação de Longa Duração/efeitos dos fármacos
Masculino
Malondialdeído/sangue
Malondialdeído/metabolismo
Aprendizagem em Labirinto/efeitos dos fármacos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Memória/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Mitocôndrias/fisiologia
Fármacos Neuroprotetores/farmacologia
Fármacos Neuroprotetores/uso terapêutico
Nitrilos/farmacologia
Nitrilos/uso terapêutico
Obesidade/tratamento farmacológico
Obesidade/metabolismo
Obesidade/fisiopatologia
Estresse Oxidativo/efeitos dos fármacos
Pirrolidinas/farmacologia
Pirrolidinas/uso terapêutico
Ratos Wistar
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol); 0 (Anti-Inflammatory Agents); 0 (Benzhydryl Compounds); 0 (Dipeptidyl-Peptidase IV Inhibitors); 0 (Glucosides); 0 (Insulin); 0 (Neuroprotective Agents); 0 (Nitriles); 0 (Pyrrolidines); 0 (Reactive Oxygen Species); 0 (Sglt2 protein, rat); 0 (Sodium-Glucose Transporter 2); 4Y8F71G49Q (Malondialdehyde); I6B4B2U96P (vildagliptin); PJY633525U (Adamantane)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170816
[St] Status:MEDLINE


  8 / 2811 MEDLINE  
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[PMID]:28726401
[Au] Autor:Shi Y; Duan YH; Ji YY; Wang ZL; Wu YR; Gunosewoyo H; Xie XY; Chen JZ; Yang F; Li J; Tang J; Xie X; Yu LF
[Ad] Endereço:Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , 3663 North Zhongshan Road, Shanghai 200062, China.
[Ti] Título:Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with in Vivo Efficacy in a Mouse Model of Multiple Sclerosis.
[So] Source:J Med Chem;60(16):7067-7083, 2017 Aug 24.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Selective CB agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB antagonists (27 or 28, IC = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB over CB receptor. Particularly, compound 57 displayed a potent agonist activity on the CB receptor (EC = 114-142 nM) without observable agonist or antagonist activity on the CB receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.
[Mh] Termos MeSH primário: Adamantano/análogos & derivados
Agonistas de Receptores de Canabinoides/uso terapêutico
Indóis/uso terapêutico
Esclerose Múltipla/tratamento farmacológico
Receptor CB2 de Canabinoide/agonistas
[Mh] Termos MeSH secundário: Adamantano/síntese química
Adamantano/farmacocinética
Adamantano/uso terapêutico
Animais
Células CHO
Agonistas de Receptores de Canabinoides/síntese química
Agonistas de Receptores de Canabinoides/farmacocinética
Antagonistas de Receptores de Canabinoides/síntese química
Antagonistas de Receptores de Canabinoides/farmacologia
Cricetulus
Feminino
Indóis/síntese química
Indóis/farmacocinética
Ligantes
Camundongos Endogâmicos C57BL
Simulação de Acoplamento Molecular
Receptor CB1 de Canabinoide/agonistas
Receptor CB1 de Canabinoide/antagonistas & inibidores
Receptor CB2 de Canabinoide/antagonistas & inibidores
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cannabinoid Receptor Agonists); 0 (Cannabinoid Receptor Antagonists); 0 (Cnr2 protein, mouse); 0 (Indoles); 0 (Ligands); 0 (N-(adamantan-1-yl)-1-(4-hydroxybutyl)-1H-indole-2-carboxamide); 0 (Receptor, Cannabinoid, CB1); 0 (Receptor, Cannabinoid, CB2); PJY633525U (Adamantane)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00724


  9 / 2811 MEDLINE  
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[PMID]:28714741
[Au] Autor:Kim G; Oh S; Jin SM; Hur KY; Kim JH; Lee MK
[Ad] Endereço:a Division of Endocrinology and Metabolism, Department of Medicine , Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , Republic of Korea.
[Ti] Título:The efficacy and safety of adding either vildagliptin or glimepiride to ongoing metformin therapy in patients with type 2 diabetes mellitus.
[So] Source:Expert Opin Pharmacother;18(12):1179-1186, 2017 Aug.
[Is] ISSN:1744-7666
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To compare the effects of either vildagliptin or glimepiride on glycemic variability, oxidative stress, and endothelial parameters in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin alone. METHODS: In this randomized, open-label, parallel study, 34 patients with T2DM being treated with metformin having an HbA1c of 7.0-10.0% were allocated into either the vildagliptin or glimepiride group. A mixed-meal tolerance test and 72-hour continuous glucose monitoring were conducted, and urinary 8-iso-prostaglandinF (PGF ) and endothelial-dependent flow-mediated dilatation (FMD) were evaluated at baseline and after 12 weeks of treatment. RESULTS: Similar significant improvements in HbA1c level were shown in both vildagliptin (-0.8%) and glimepiride (-0.9%) groups after treatment (Ps<0.001). The mean amplitude of glycemic excursions (MAGE) and the mean of daily differences (MODD) were significantly decreased by vildagliptin (P = 0.044 and P = 0.031, respectively) but not by glimepiride. Glimepiride was significantly associated with a higher incidence of hypoglycemia than vildagliptin (P = 0.005). There were no significant differences in urinary 8-iso-PGF or FMD between the two groups. CONCLUSIONS: Vildagliptin effectively improved glucose level with a significantly greater reduction in glycemic variability and hypoglycemia than glimepiride in patients with T2DM ongoing metformin therapy. The two drugs showed no significant differences in urinary 8-iso-PGF and FMD. TRIAL REGISTRATION: NCT01404676.
[Mh] Termos MeSH primário: Adamantano/análogos & derivados
Diabetes Mellitus Tipo 2/tratamento farmacológico
Hipoglicemiantes/uso terapêutico
Metformina/uso terapêutico
Nitrilos/uso terapêutico
Pirrolidinas/uso terapêutico
Compostos de Sulfonilureia/uso terapêutico
[Mh] Termos MeSH secundário: Adamantano/administração & dosagem
Adamantano/efeitos adversos
Adamantano/uso terapêutico
Glicemia/efeitos dos fármacos
Dinoprosta/análogos & derivados
Dinoprosta/urina
Quimioterapia Combinada
Feminino
Hemoglobina A Glicada/análise
Seres Humanos
Hipoglicemia/induzido quimicamente
Hipoglicemiantes/administração & dosagem
Hipoglicemiantes/efeitos adversos
Masculino
Metformina/administração & dosagem
Metformina/efeitos adversos
Meia-Idade
Nitrilos/administração & dosagem
Nitrilos/efeitos adversos
Pirrolidinas/administração & dosagem
Pirrolidinas/efeitos adversos
Compostos de Sulfonilureia/administração & dosagem
Compostos de Sulfonilureia/efeitos adversos
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Glycated Hemoglobin A); 0 (Hypoglycemic Agents); 0 (Nitriles); 0 (Pyrrolidines); 0 (Sulfonylurea Compounds); 0 (hemoglobin A1c protein, human); 27415-26-5 (8-epi-prostaglandin F2alpha); 6KY687524K (glimepiride); 9100L32L2N (Metformin); B7IN85G1HY (Dinoprost); I6B4B2U96P (vildagliptin); PJY633525U (Adamantane)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1080/14656566.2017.1353080


  10 / 2811 MEDLINE  
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[PMID]:28694203
[Au] Autor:Dong XW; Jia YL; Ge LT; Jiang B; Jiang JX; Shen J; Jin YC; Guan Y; Sun Y; Xie QM
[Ad] Endereço:Key Laboratory of Respiratory Drugs Research, Zhejiang University School of Medicine, Hangzhou 310058, China.
[Ti] Título:Soluble epoxide hydrolase inhibitor AUDA decreases bleomycin-induced pulmonary toxicity in mice by inhibiting the p38/Smad3 pathways.
[So] Source:Toxicology;389:31-41, 2017 Aug 15.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Bleomycin (BLM) has potent tumor cell-killing properties that have given it an important place in cancer chemotherapy, but pulmonary toxicity is its major adverse effect. Soluble epoxide hydrolase (sEH) inhibitors have been reported to have protective effects in fibrosis models, but the effects of AUDA, an sEH inhibitor of BLM-induced pulmonary toxicity and fibrosis, remain to be researched. In this study, we assessed the effects of AUDA on the BLM-induced pulmonary fibrosis in a mouse model, and transforming growth factor (TGF)-ß -induced epithelial proliferation and epithelial-mesenchymal transition (EMT) in vitro by monitoring changes in pulmonary function, inflammatory response, fibrotic remodeling, and signaling pathways. AUDA was administered by intragastric administration (i.g) daily for three weeks, starting at seven days after intratracheal instillation of BLM. All examinations were performed 24h after the last i.g. In vivo, AUDA significantly improved BLM-induced decline in lung function and body weight, and inhibited inflammatory cell accumulation and the mRNA and protein expression of interleukin (IL)-1ß, TGF-ß , and matrix metalloproteinase 9 (MMP-9) in lung tissue. Moreover, AUDA attenuated BLM-induced deposition of collagen fibers, destruction of alveolar structures, and pulmonary parenchyma. Additionally, AUDA regulated the expression of α-smooth muscle actin (α-SMA) and E-cadherin by inhibiting the Smad3/p38 signaling pathway. In vitro, AUDA significantly inhibited TGF-ß -induced epithelial cells and fibroblast proliferation, reduced sEH expression and α-SMA expression, and increased epoxyeicosatrienoic acid (EET) levels and E-cadherin expression in epithelial cells. These effects were blocked by AUDA by downregulating the Smad3 and p38 signaling pathways. Taken together, these data indicate that treatment with sEH inhibitors may improve BLM-induced pulmonary toxicity.
[Mh] Termos MeSH primário: Adamantano/análogos & derivados
Bleomicina
Inibidores Enzimáticos/farmacologia
Epóxido Hidrolases/antagonistas & inibidores
Ácidos Láuricos/farmacologia
Pulmão/efeitos dos fármacos
Fibrose Pulmonar/prevenção & controle
Proteína Smad3/metabolismo
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Mh] Termos MeSH secundário: Adamantano/farmacologia
Animais
Biomarcadores/metabolismo
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Colágeno/metabolismo
Citocinas/metabolismo
Citoproteção
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Epóxido Hidrolases/metabolismo
Feminino
Seres Humanos
Mediadores da Inflamação/metabolismo
Pulmão/enzimologia
Pulmão/patologia
Pulmão/fisiopatologia
Camundongos Endogâmicos ICR
Pneumonia/induzido quimicamente
Pneumonia/enzimologia
Pneumonia/prevenção & controle
Fibrose Pulmonar/induzido quimicamente
Fibrose Pulmonar/enzimologia
Fibrose Pulmonar/patologia
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (12-(3-adamantan-1-ylureido)dodecanoic acid); 0 (Biomarkers); 0 (Cytokines); 0 (Enzyme Inhibitors); 0 (Inflammation Mediators); 0 (Lauric Acids); 0 (Smad3 Protein); 0 (Smad3 protein, mouse); 11056-06-7 (Bleomycin); 9007-34-5 (Collagen); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); EC 3.3.2.- (Epoxide Hydrolases); PJY633525U (Adamantane)
[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:170712
[St] Status:MEDLINE



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