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1.
Anim Sci J ; 94(1): e13887, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37986212

RESUMO

This study aimed to assess the behavior and stress status of pregnant sows following supplementation with Italian ryegrass silage (IRS) and the impact of feeding the IRS on feeding costs. Six sows with an initial body weight (BW) of 238.6 ± 5.9 kg were allotted to a 6 × 3 Latin square design with a 5-day acclimatization period followed by a 5-day data collection period. A commercial diet was replaced by IRS on a dry matter (DM) basis up to 0%, 9%, and 13% in the control treatment and the two test treatments, respectively. Apart from collecting data on daily feed intake and BW, urine was collected, and video footage was recorded for the last day of each treatment for analysis of urinary cortisol and behavior. There were no leftovers with all diets and nutrient uptake was unaffected (p > 0.05), while BW gain decreased (p < 0.05) to be a limited range from 1% to 3%, with increased inclusion of IRS. Both the behavior of sows and cortisol concentration were unaffected (p > 0.05). Furthermore, it was estimated that feeding 13% DM of IRS would reduce feed costs by 17%. IRS would be acceptable in replacing up to 13% of the commercial diet and cutting feeding costs.


Assuntos
Lolium , Silagem , Gravidez , Animais , Suínos , Feminino , Silagem/análise , Lactação , Hidrocortisona , Ração Animal/análise , Ingestão de Alimentos , Dieta/veterinária , Suplementos Nutricionais/análise , Itália
2.
PLoS One ; 18(9): e0291670, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37725623

RESUMO

The COVID-19 antibody test was developed to investigate the humoral immune response to SARS-CoV-2 infection. In this study, we examined whether S antibody titers measured using the anti-SARS-CoV-2 IgG II Quant assay (S-IgG), a high-throughput test method, reflects the neutralizing capacity acquired after SARS-CoV-2 infection or vaccination. To assess the antibody dynamics and neutralizing potency, we utilized a total of 457 serum samples from 253 individuals: 325 samples from 128 COVID-19 patients including 136 samples from 29 severe/critical cases (Group S), 155 samples from 71 mild/moderate cases (Group M), and 132 samples from 132 health care workers (HCWs) who have received 2 doses of the BNT162b2 vaccinations. The authentic virus neutralization assay, the surrogate virus neutralizing antibody test (sVNT), and the Anti-N SARS-CoV-2 IgG assay (N-IgG) have been performed along with the S-IgG. The S-IgG correlated well with the neutralizing activity detected by the authentic virus neutralization assay (0.8904. of Spearman's rho value, p < 0.0001) and sVNT (0.9206. of Spearman's rho value, p < 0.0001). However, 4 samples (2.3%) of S-IgG and 8 samples (4.5%) of sVNT were inconsistent with negative results for neutralizing activity of the authentic virus neutralization assay. The kinetics of the SARS-CoV-2 neutralizing antibodies and anti-S IgG in severe cases were faster than the mild cases. All the HCWs elicited anti-S IgG titer after the second vaccination. However, the HCWs with history of COVID-19 or positive N-IgG elicited higher anti-S IgG titers than those who did not have it previously. Furthermore, it is difficult to predict the risk of breakthrough infection from anti-S IgG or sVNT antibody titers in HCWs after the second vaccination. Our data shows that the use of anti-S IgG titers as direct quantitative markers of neutralizing capacity is limited. Thus, antibody tests should be carefully interpreted when used as serological markers for diagnosis, treatment, and prophylaxis of COVID-19.


Assuntos
Vacina BNT162 , COVID-19 , Humanos , COVID-19/diagnóstico , COVID-19/prevenção & controle , SARS-CoV-2 , Anticorpos Bloqueadores , Anticorpos Antivirais , Imunoglobulina G
3.
JCO Clin Cancer Inform ; 6: e2200070, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36162012

RESUMO

PURPOSE: Several studies reported the possibility of predicting genetic abnormalities in non-small-cell lung cancer by deep learning (DL). However, there are no data of predicting ALK gene rearrangement (ALKr) using DL. We evaluated the ALKr predictability using the DL platform. MATERIALS AND METHODS: We selected 66 ALKr-positive cases and 142 ALKr-negative cases, which were diagnosed by ALKr immunohistochemical staining in our institution from January 2009 to March 2019. We generated virtual slide of 300 slides (150 ALKr-positive slides and 150 ALKr-negative slides) using NanoZoomer. HALO-AI was used to analyze the whole-slide imaging data, and the DenseNet network was used to build the learning model. Of the 300 slides, we randomly assigned 172 slides to the training cohort and 128 slides to the test cohort to ensure no duplication of cases. In four resolutions (16.0/4.0/1.0/0.25 µm/pix), ALKr prediction models were built in the training cohort and ALKr prediction performance was evaluated in the test cohort. We evaluated the diagnostic probability of ALKr by receiver operating characteristic analysis in each ALKr probability threshold (50%, 60%, 70%, 80%, 90%, and 95%). We expected the area under the curve to be 0.64-0.85 in the model of a previous study. Furthermore, in the test cohort data, an expert pathologist also evaluated the presence of ALKr by hematoxylin and eosin staining on whole-slide imaging. RESULTS: The maximum area under the curve was 0.73 (50% threshold: 95% CI, 0.65 to 0.82) in the resolution of 1.0 µm/pix. In this resolution, with an ALKr probability of 50% threshold, the sensitivity and specificity were 73% and 73%, respectively. The expert pathologist's sensitivity and specificity in the same test cohort were 13% and 94%. CONCLUSION: The ALKr prediction by DL was feasible. Further study should be addressed to improve accuracy of ALKr prediction.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inteligência Artificial , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Amarelo de Eosina-(YS) , Rearranjo Gênico , Hematoxilina , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Receptores Proteína Tirosina Quinases/genética
4.
Methods Mol Biol ; 2524: 173-182, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35821471

RESUMO

The rapid microbe detection (RMD) method can detect a trace amount of adenosine triphosphate (ATP) equivalent to that generated by single cell of lactic acid bacteria (LAB). For the improved detection of LAB contamination in beer without cultivation, it is necessary to eliminate the influence of beer-derived ATP and to improve the signal-to-noise ratio. In this protocol, the beer sample is filtered using a membrane filter, thereby avoiding the formation of beer foam to the fullest extent. By washing the beer components remaining on the filter with an ethanol solution and a weakly alkaline solution and then culturing the filter in an agar medium, the beer-derived ATP remaining on the filter can be removed and the ATP of LAB cells is increased. As a result, the signal-to-noise ratio of the RMD method can be dramatically improved.


Assuntos
Cerveja , Lactobacillales , Trifosfato de Adenosina , Meios de Cultura , Testes Imunológicos
5.
Clin Lab ; 68(6)2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35704722

RESUMO

BACKGROUND: Rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using saliva samples has emerged as a preferred technique since sample collection is easy and noninvasive. In addition, several commercial high-throughput PCR kits that do not require RNA extraction/purification have been developed and are now available for testing saliva samples. However, an optimal protocol for SARS-CoV-2 RT-PCR testing of saliva samples using the RNA extraction/purification-free kits has not yet been established. The aim of this study was to establish optimal preanalytical conditions, including saliva sample collection, storage, and dilution for RNA extraction/purification-free RT-PCR (direct RT-PCR). METHODS: Patients suspected with COVID-19 from March 02 to August 31, 2020, were enrolled in this study. A total of 248 samples, including 43 nasopharyngeal swabs and 205 saliva samples, were collected from 66 patients (37 outpatients and 29 inpatients) and tested using the 2019 Novel Coronavirus Detection Kit (nCoV-DK, Shimadzu Corporation, Kyoto, Japan). RESULTS: The detection results obtained using nasopharyngeal swabs and saliva samples matched 100%. The sampling time, i.e., either awakening time or post-breakfast, had no significant effect on the viral load of the saliva samples. Although saliva samples are routinely diluted to reduce viscosity, we observed that dilution negatively affected PCR sensitivity. Saliva samples could be stored at room temperature (25°C) for 24 hours or at 4°C for up to 48 hours. CONCLUSIONS: This study demonstrated the appropriate conditions of saliva sample collection, processing, and storage, and indicated that the nCoV-DK is applicable to saliva samples, making the diagnosis method simple and safe.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , Teste para COVID-19 , Técnicas de Laboratório Clínico/métodos , Estudos de Viabilidade , Humanos , Refeições , Nasofaringe , RNA , RNA Viral/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Saliva/química , Manejo de Espécimes/métodos , Temperatura
6.
J Glob Antimicrob Resist ; 26: 279-284, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34284125

RESUMO

OBJECTIVES: The emergence of carbapenem-resistant Pseudomonas aeruginosa has become a serious worldwide medical problem. The aim of this study was to determine the genetic and epidemiological properties of carbapenem-resistant P. aeruginosa strains isolated from hospitals in Nepal. METHODS: A total of 43 carbapenem-resistant P. aeruginosa isolates obtained from patients in two hospitals in Nepal between 2018 and 2020 were analysed. Their whole genomes were sequenced by next-generation sequencing. A phylogenetic tree was constructed from single nucleotide polymorphism (SNP) concatemers. Multilocus sequence typing (MLST) was performed and antimicrobial resistance genes were identified. RESULTS: Of the 43 isolates, 17 harboured genes encoding carbapenemases, including IMP-1, IMP-26, KPC-2, NDM-1, VIM-2 and VIM-5, and 12 harboured genes encoding 16S rRNA methylases, including RmtB4 and RmtF2. The carbapenem-resistant P. aeruginosa isolated in Nepal belonged to various sequence types (STs), including ST235 (5 isolates), ST244 (7 isolates), ST274 (1 isolate), ST357 (10 isolates), ST654 (3 isolates), ST664 (1 isolate), ST773 (1 isolate), ST823 (3 isolates), ST1047 (8 isolates), ST1203 (2 isolates) and ST3453 (2 isolates). CONCLUSION: To the best of our knowledge, this is the first molecular epidemiological analysis of carbapenem-resistant P. aeruginosa clinical isolates from Nepal. The findings strongly suggest that P. aeruginosa isolates producing carbapenemases and 16S rRNA methylases have spread throughout medical settings in Nepal.


Assuntos
Carbapenêmicos , Pseudomonas aeruginosa , Carbapenêmicos/farmacologia , Humanos , Tipagem de Sequências Multilocus , Nepal/epidemiologia , Filogenia , Pseudomonas aeruginosa/genética , RNA Ribossômico 16S
7.
Anim Sci J ; 92(1): e13531, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33638258

RESUMO

The purpose of this study was to investigate the effects of feeding Bacillus subtilis on rumen fermentation, blood metabolites, nutrient digestibility, and energy and nitrogen balances in non-lactating crossbred (Holstein-Friesian × Bos indicus) cows. Four cows were assigned to the control and B. subtilis diets in a crossover design, and respiratory and metabolic experiments were conducted. For the B. subtilis diet, B. subtilis DSM15544 spores were added at the rate of 1.0 × 1010  CFU/head/day to the control diet. At 4 hr after feeding, cows fed the B. subtilis diet had increased levels of i-butyric acid in the rumen fluid and tended to have lower concentrations of plasma non-esterified fatty acids when compared with cows fed the control diet. This suggests that feeding B. subtilis could improve energy efficiency. However, there was no effect on energy retention in this study. Although there were no effects on nutrient digestibility, nitrogen balance, or methane production, heat production was significantly higher in cows fed the B. subtilis diet than in those fed the control diet.


Assuntos
Bacillus subtilis , Bovinos/metabolismo , Dieta/veterinária , Suplementos Nutricionais , Digestão/fisiologia , Fermentação/fisiologia , Nutrientes/metabolismo , Probióticos/administração & dosagem , Rúmen/metabolismo , Animais , Ácido Butírico/metabolismo , Bovinos/sangue , Estudos Cross-Over , Metabolismo Energético/fisiologia , Ácidos Graxos/sangue , Feminino , Hibridização Genética , Nitrogênio/metabolismo , Termogênese/fisiologia
8.
Biocontrol Sci ; 24(1): 29-37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880311

RESUMO

 In this study, we developed a system, known as MicroStarTM Rapid Microbe Detection System (RMDS) , to detect Lactobacillus brevis, which usually requires 2-4 days for examination by the conventional plate count procedure, for beer quality control using a bioluminescence method within 24 hr and also aimed to develop a technology to detect bacterial growth without the need for cultivation. We used a highly sensitive luminous reagent that increased the activity of the luciferin- luciferase reaction to 2.5×10-18 mol ATP/0.2 µl and could detect even a single lactic acid bacterial cell. The limitation of the method was that ATP derived from the beer hindered bacterial measurement and the supply of energy source to secure ATP of lactic acid bacterial cell. The sample beer was filtered through a membrane filter, avoiding the formation of beer foam to the best extent, the filter was cleaned with 10% ethanol and 0.1% sodium hydrogen carbonate solution, and incubated on a GMY agar plate (1% glucose, 0.2% malic acid, 0.67% yeast nitrogen base, 1% agar; pH 5.2) at room temperature for 2 hr. Post incubation of the filter, bacterial cell count was measured with RMDS. This method could overcome the hindrance of ATP measurement and could stably detect lactic acid bacteria without the need for cultivation.


Assuntos
Cerveja/microbiologia , Cerveja/normas , Microbiologia de Alimentos/normas , Qualidade dos Alimentos , Lactobacillales/isolamento & purificação , Medições Luminescentes/métodos , Contagem de Colônia Microbiana , Levilactobacillus brevis/isolamento & purificação , Controle de Qualidade , Fatores de Tempo
9.
Nat Commun ; 9(1): 4530, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30382098

RESUMO

Induced-fit or conformational selection is of profound significance in biological regulation. Biological receptors alter their conformation to respond to the shape and electrostatic surfaces of guest molecules. Here we report a water-soluble artificial molecular host that can sensitively respond to the size, shape, and charged state of guest molecules. The molecular host, i.e. nanocube, is an assembled structure consisting of six gear-shaped amphiphiles (GSAs). This nanocube can expand or contract its size upon the encapsulation of neutral and anionic guest molecules with a volume ranging from 74 to 535 Å3 by induced-fit. The responding property of this nanocube, reminiscent of a feature of biological molecules, arises from the fact that the GSAs in the nanocubes are connected to each other only through the hydrophobic effect and very weak intermolecular interactions such as van der Waals and cation-π interactions.

10.
PLoS One ; 13(4): e0195923, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29698492

RESUMO

The XN series automated hematology analyzer has been equipped with a body fluid (BF) mode to count and differentiate leukocytes in BF samples including cerebrospinal fluid (CSF). However, its diagnostic accuracy is not reliable for CSF samples with low cell concentration at the border between normal and pathologic level. To overcome this limitation, a new flow cytometry-based technology, termed "high sensitive analysis (hsA) mode," has been developed. In addition, the XN series analyzer has been equipped with the automated digital cell imaging analyzer DI-60 to classify cell morphology including normal leukocytes differential and abnormal malignant cells detection. Using various BF samples, we evaluated the performance of the XN-hsA mode and DI-60 compared to manual microscopic examination. The reproducibility of the XN-hsA mode showed good results in samples with low cell densities (coefficient of variation; % CV: 7.8% for 6 cells/µL). The linearity of the XN-hsA mode was established up to 938 cells/µL. The cell number obtained using the XN-hsA mode correlated highly with the corresponding microscopic examination. Good correlation was also observed between the DI-60 analyses and manual microscopic classification for all leukocyte types, except monocytes. In conclusion, the combined use of cell counting with the XN-hsA mode and automated morphological analyses using the DI-60 mode is potentially useful for the automated analysis of BF cells.


Assuntos
Líquidos Corporais/citologia , Citometria de Fluxo/métodos , Automação , Líquido Cefalorraquidiano/citologia , Citometria de Fluxo/instrumentação , Humanos , Contagem de Leucócitos , Leucócitos/citologia , Derrame Pleural/patologia , Reprodutibilidade dos Testes
11.
PLoS One ; 13(2): e0190886, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29425230

RESUMO

Morphological microscopic examinations of nucleated cells in body fluid (BF) samples are performed to screen malignancy. However, the morphological differentiation is time-consuming and labor-intensive. This study aimed to develop a new flowcytometry-based gating analysis mode "XN-BF gating algorithm" to detect malignant cells using an automated hematology analyzer, Sysmex XN-1000. XN-BF mode was equipped with WDF white blood cell (WBC) differential channel. We added two algorithms to the WDF channel: Rule 1 detects larger and clumped cell signals compared to the leukocytes, targeting the clustered malignant cells; Rule 2 detects middle sized mononuclear cells containing less granules than neutrophils with similar fluorescence signal to monocytes, targeting hematological malignant cells and solid tumor cells. BF samples that meet, at least, one rule were detected as malignant. To evaluate this novel gating algorithm, 92 various BF samples were collected. Manual microscopic differentiation with the May-Grunwald Giemsa stain and WBC count with hemocytometer were also performed. The performance of these three methods were evaluated by comparing with the cytological diagnosis. The XN-BF gating algorithm achieved sensitivity of 63.0% and specificity of 87.8% with 68.0% for positive predictive value and 85.1% for negative predictive value in detecting malignant-cell positive samples. Manual microscopic WBC differentiation and WBC count demonstrated 70.4% and 66.7% of sensitivities, and 96.9% and 92.3% of specificities, respectively. The XN-BF gating algorithm can be a feasible tool in hematology laboratories for prompt screening of malignant cells in various BF samples.


Assuntos
Líquidos Corporais/citologia , Citometria de Fluxo/métodos , Neoplasias/patologia , Algoritmos , Líquido Ascítico/patologia , Automação Laboratorial/instrumentação , Líquido Cefalorraquidiano/citologia , Corantes , Amarelo de Eosina-(YS) , Citometria de Fluxo/instrumentação , Citometria de Fluxo/estatística & dados numéricos , Hematologia/instrumentação , Humanos , Contagem de Leucócitos/instrumentação , Azul de Metileno , Microscopia , Neoplasias/diagnóstico , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/patologia
12.
Bioorg Med Chem Lett ; 27(15): 3495-3498, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28602640

RESUMO

We designed and synthesized novel δ opioid receptor (DOR) agonists 3a-i with an azatricyclodecane skeleton, which was a novel structural class of DOR agonists. Among them, 3b exhibited high values of binding affinity and potent agonistic activity for the DOR that were approximately equivalent to those of 2 which bore an oxazatricyclodecane skeleton. In vitro assays using the blood-brain barrier (BBB) permeability test kit supported the idea that 3b achieved an excellent BBB permeability by converting an oxygen atom of 2 to a carbon atom (methylene group) in the core skeleton. As a result, 3b showed potent antinociceptive effects.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos Opioides/farmacocinética , Barreira Hematoencefálica/metabolismo , Ciclodecanos/farmacologia , Ciclodecanos/farmacocinética , Receptores Opioides delta/agonistas , Administração Cutânea , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Ciclodecanos/síntese química , Ciclodecanos/química , Desenho de Fármacos , Humanos , Camundongos , Receptores Opioides delta/metabolismo
13.
Exp Anim ; 66(4): 321-327, 2017 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-28626157

RESUMO

Daily torpor is a physiological adaptation in mammals and birds characterized by a controlled reduction of metabolic rate and body temperature during the resting phase of circadian rhythms. In laboratory mice, daily torpor is induced by dietary caloric restriction. However, it is not known which nutrients are related to daily torpor expression. To determine whether dietary protein is a key factor in inducing daily torpor in mice, we fed mice a protein-restricted (PR) diet that included only one-quarter of the amount of protein but the same caloric level as a control (C) diet. We assigned six non-pregnant female ICR mice to each group and recorded their body weights and core body temperatures for 4 weeks. Body weights in the C group increased, but those in the PR group remained steady or decreased. Mice in both groups did not show daily torpor, but most mice in a food-restricted group (n=6) supplied with 80% of the calories given to the C group exhibited decreased body weights and frequently displayed daily torpor. This suggests that protein restriction is not a trigger of daily torpor; torpid animals can conserve their internal energy, but torpor may not play a significant role in conserving internal protein. Thus, opportunistic daily torpor in mice may function in energy conservation rather than protein saving.


Assuntos
Animais de Laboratório/fisiologia , Regulação da Temperatura Corporal/fisiologia , Dieta com Restrição de Proteínas , Proteínas Alimentares/administração & dosagem , Camundongos Endogâmicos ICR/metabolismo , Camundongos Endogâmicos ICR/fisiologia , Torpor/fisiologia , Animais , Peso Corporal , Metabolismo Energético/fisiologia , Feminino
14.
Bioorg Med Chem Lett ; 27(12): 2742-2745, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28522254

RESUMO

We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2-4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2-4 showed pronouncedly improved agonistic activities for the DOR. Compound 2a with the 17-cyclopropylmethyl substituent was a potent agonist with the highest selectivity for the DOR and was expected to be a lead compound for novel and selective DOR agonists.


Assuntos
Compostos Heterocíclicos de Anel em Ponte/farmacologia , Receptores Opioides delta/agonistas , Relação Dose-Resposta a Droga , Compostos Heterocíclicos de Anel em Ponte/síntese química , Compostos Heterocíclicos de Anel em Ponte/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
15.
Hinyokika Kiyo ; 60(6): 287-90, 2014 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-25001645

RESUMO

A 62-year-old male came to our clinic complaining of residual sensation of urine and urinary frequency. He was diagnosed with neurogenic bladder, and has been performing clean intermittent self catheterization once or twice a day. According to his urination record of voided volume (VV) and post-void residual urine volume (PVR) on every urination, we investigated the relationship between pre-void bladder capacity (BC) and PVR. BC was expressed as the sum of VV and PVR. The PVR of BC 300-400, 400-500, 500-600 and ≧600 ml was 141.1, 167.7, 186.8 and 193.3 ml, respectively. PVR significantly increased as BC increased (p<0.01). Although there are few reports about the relationship between BC and PVR, the present results show that bladder over distension may reduce the contractility of the urinary bladder.


Assuntos
Bexiga Urinaria Neurogênica/fisiopatologia , Bexiga Urinária/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Micção
16.
Br J Pharmacol ; 170(6): 1242-52, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24024968

RESUMO

BACKGROUND AND PURPOSE: Two distinct α1 -adrenoceptor phenotypes (α1A and α1L ) have recently been demonstrated to originate from a single α1A -adrenoceptor gene. Here, we examined the agonist profiles of recombinant α1A and α1L phenotypes and of lower urinary tract (LUT) α1 -adrenoceptors. EXPERIMENTAL APPROACH: A series of drugs (A61603, Ro 115-1240, NS-49 , MK017 and ESR1150) originally developed for stress urinary incontinence (SUI) therapy were used to stimulate recombinant α1A - and α1L -adrenoceptor phenotypes, and their potencies and intrinsic activity estimated from Ca(2+) responses. Agonist-induced contractions were also examined in LUT tissues of rats and humans and in human mesenteric artery and rat tail artery. KEY RESULTS: All the drugs were potent agonists of the α1A -adrenoceptor compared with the α1L -adrenoceptor phenotype. Among them, Ro 115-1240 was shown to be an α1A -specific partial agonist that produced partial contractions through α1A -adrenoceptors in rat prostate and tail artery, but not in the other LUT tissues and human mesenteric artery. In contrast, P-come 102 showed full agonist activity at α1A - and α1L -adrenoceptors, but was less selective than noradrenaline for α1A -adrenoceptors. Like noradrenaline, P-come 102 was highly potent at inducing contractions in all of the LUT tissues tested. However, the potency and intrinsic activity of P-come 102 were significantly lower than those of noradrenaline in human mesenteric artery. CONCLUSIONS AND IMPLICATIONS: The α1A - and α1L -adrenoceptor phenotypes and LUT α1 -adrenoceptors were demonstrated to have distinct agonist profiles. As adrenergic contractions in LUT are predominantly mediated through α1L -adrenoceptors, the development of α1L -selective agonists may provide clinically useful drugs for SUI therapy.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Receptores Adrenérgicos alfa 1/fisiologia , Bexiga Urinária/efeitos dos fármacos , Idoso , Animais , Artérias/efeitos dos fármacos , Artérias/fisiologia , Células CHO , Cálcio/fisiologia , Cricetulus , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Wistar , Proteínas Recombinantes , Uretra/efeitos dos fármacos , Uretra/fisiologia , Bexiga Urinária/fisiologia
17.
Expert Opin Ther Pat ; 23(9): 1181-208, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23705966

RESUMO

INTRODUCTION: The δ opioid receptor mediates various pharmacological effects such as antinociceptive and antidepressant effects, whereas it does not appear to induce µ opioid-like side effects such as dependence, respiratory depression and constipation. Therefore, the δ opioid receptor is a promising drug target. AREAS COVERED: This review covers literature and patents concerning non-peptidic δ opioid receptor agonists, antagonists, modulators and ligands from 2000 to 2012. Pharmacological effects induced by δ receptor agonists or antagonists are also discussed. EXPERT OPINION: Potential therapeutic effects by δ receptor agonists are antinociceptive, antidepressant, anxiolytic, cardioprotective and neuroprotective effects. Among them, anxiolytic effects are of particular interest because the anxiolytic effects by a δ receptor agonist have been observed in humans. Although non-peptidic δ receptor agonists were reported to show convulsive effects via the δ opioid receptor, some δ receptor agonists are known to produce no convulsive behaviors. Therefore, it may be possible to eliminate convulsion induced by a δ receptor agonist. Many δ receptor antagonists were also reported but there is little new information about pharmacological effects by a δ receptor antagonist. Although detailed results were not revealed, two δ receptor antagonists with µ receptor agonistic or antagonistic properties are in the late stages of the clinical trial.


Assuntos
Desenho de Fármacos , Receptores Opioides delta/agonistas , Receptores Opioides delta/antagonistas & inibidores , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Animais , Ensaios Clínicos como Assunto , Humanos , Terapia de Alvo Molecular , Patentes como Assunto , Receptores Opioides delta/metabolismo
18.
Int J Biochem Cell Biol ; 45(2): 438-47, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23032698

RESUMO

It has been well demonstrated that excessive blood glucose level could be detrimental to the myocardial function through the variety of mechanisms, of which endoplasmic reticulum stress (ERS) could play an unprecedented role through the activation of unfolded protein response (UPR). Recently, reports are coming out with the evidences that UPR signaling proteins are regulated differentially depend on the experimental conditions and cell types. In addition, ERS has been proposed to be closely associated with the regulation of lipogenesis. Therefore, in this study we tried to find out the expressions of myocardial UPR signaling proteins as well as proteins involved in lipid and glucose metabolism in non-obese type 2 diabetic mellitus (DM) condition using Spontaneous Diabetic Torii (SDT) rat. We have found the significant up-regulation of oxidative, nitrosative and ERS marker proteins in the myocardium of the SDT rats, in comparison to its normal (Sprague-Dawley - SD) rats. In addition, the sub-arm of UPR signaling proteins, such as p-PERK, p-eIF2α, ATF6, CHOP/GADD153, TRAF2, apoptotic signaling proteins, such as BAD, cytochrome C, cleaved caspase-7 and -12, were significantly up-regulated in the SDT rats, in comparison to the SD rats. Interestingly, there were no significant changes in the phosphorylation of IRE-1α, and XBP-1 protein expression. In addition, the proteins involved in lipid and glucose metabolisms, such as PPARα, PPARγ, CPT1, PGC-1α except GLUT4, and the proteins involved in insulin signaling, such as p-Akt and p-PI3K were shown significant attenuation in its expressions in the SDT rats, when compared with the SD rats. Taken together, it is suggested that the activation of PERK and ATF6 pathway are the major determinant rather than the IRE-1α-XBP1 pathway for the ERS-mediated metabolic dysfunction, which might eventually leads to diabetic cardiomyopathy in non-obese type 2 DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Estresse do Retículo Endoplasmático , Hiperglicemia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Resposta a Proteínas não Dobradas , Fator 6 Ativador da Transcrição/metabolismo , Animais , Apoptose , Diabetes Mellitus Tipo 2/complicações , Cardiomiopatias Diabéticas/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos
19.
J Am Chem Soc ; 133(42): 16920-9, 2011 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-21888429

RESUMO

We synthesized two high-pressure polymorphs PbNiO(3) with different structures, a perovskite-type and a LiNbO(3)-type structure, and investigated their formation behavior, detailed structure, structural transformation, thermal stability, valence state of cations, and magnetic and electronic properties. A perovskite-type PbNiO(3) synthesized at 800 °C under a pressure of 3 GPa crystallizes as an orthorhombic GdFeO(3)-type structure with a space group Pnma. The reaction under high pressure was monitored by an in situ energy dispersive X-ray diffraction experiment, which revealed that a perovskit-type phase was formed even at 400 °C under 3 GPa. The obtained perovskite-type phase irreversibly transforms to a LiNbO(3)-type phase with an acentric space group R3c by heat treatment at ambient pressure. The Rietveld structural refinement using synchrotron X-ray diffraction data and the XPS measurement for both the perovskite- and the LiNbO(3)-type phases reveal that both phases possess the valence state of Pb(4+)Ni(2+)O(3). Perovskite-type PbNiO(3) is the first example of the Pb(4+)M(2+)O(3) series, and the first example of the perovskite containing a tetravalent A-site cation without lone pair electrons. The magnetic susceptibility measurement shows that the perovskite- and LiNbO(3)-type PbNiO(3) undergo antiferromagnetic transition at 225 and 205 K, respectively. Both the perovskite- and LiNbO(3)-type phases exhibit semiconducting behavior.

20.
Inorg Chem ; 50(13): 6392-8, 2011 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-21644498

RESUMO

LiNbO(3)-type MnMO(3) (M = Ti, Sn) were synthesized under high pressure and temperature; their structures and magnetic, dielectric, and thermal properties were investigated; and their relationships were discussed. Optical second harmonic generation and synchrotron powder X-ray diffraction measurements revealed that both of the compounds possess a polar LiNbO(3)-type structure at room temperature. Weak ferromagnetism due to canted antiferromagnetic interaction was observed at 25 and 50 K for MnTiO(3) and MnSnO(3), respectively. Anomalies in the dielectric permittivity were observed at the weak ferromagnetic transition temperature for both the compounds, indicating the correlation between magnetic and dielectric properties. These results indicate that LiNbO(3)-type compounds with magnetic cations are new candidates for multiferroic materials.

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