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1.
Polymers (Basel) ; 16(2)2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38276688

RESUMO

Hydrogen uptake/diffusivity in nitrile butadiene rubber (NBR) blended with carbon black (CB) and silica fillers was measured with a volumetric analysis method in the 258-323 K temperature range. The temperature-dependent H2 diffusivity was obtained by assuming constant solubility with temperature variations. The logarithmic diffusivity decreased linearly with increasing reciprocal temperature. The diffusion activation energies were calculated with the Arrhenius equation. The activation energies for NBR blended with high-abrasion furnace CB and silica fillers increased linearly with increasing filler content. For NBR blended with medium thermal CB filler, the activation energy decreased with increasing filler content. The activation energy filler dependency is similar to the glass transition temperature filler dependency, as determined with dynamic mechanical analysis. Additionally, the activation energy was compared with that obtained by the differential pressure method through permeability temperature dependence. The same activation energy between diffusion and permeation in the range of 33-39 kJ/mol was obtained, supporting the temperature-independent H2 solubility and H2 physisorption in polymer composites.

2.
Fish Shellfish Immunol ; 143: 109186, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37884106

RESUMO

The TRAF family member-associated nuclear factor kappa B (NF-κB) activator (TANK) regulates the NF-κB activation through the TRAF-mediated signaling pathway and is involved in the antiviral pathway by inducing the interferon (IFN) production. In the present study, we identified a TANK ortholog from the red-spotted grouper (Epinephelus akaara) and analyzed its immunological functions. The coding sequence of EaTANK consists of 1047 base pairs and encodes a 348 amino acids protein. The predicted molecular weight and theoretical isoelectric point (pI) were 38.92 kDa and 5.39, respectively. According to the phylogenetic analysis, EaTANK was closely clustered with fish TANK orthologs, exhibiting the highest identity (97.1 %) and similarity (97.1 %) to that of Epinephelus lanceolatus. A highly conserved TBK1/IKKi binding domain (TBD) was identified between 110 and 164 residues. Our tissue distribution analysis showed that EaTANK mRNA was ubiquitously expressed in 12 tested tissues, with the highest expression in the spleen and peripheral blood cells (PBCs). According to the immune challenge experiments, EaTANK mRNA expression in PBCs was significantly elevated following stimulation with polyinosinic:polycytidylic acid [poly (I:C)], lipopolysaccharide (LPS), or nervous necrosis virus (NNV). We also observed a significant elevation in the mRNA expression of downstream antiviral pathway-related genes (ISG15, IRF3, and IRF7) in EaTANK-overexpressing fathead minnow (FHM) cells against poly (I:C) stimulation. Moreover, the replication of 6 genes in the VHSV genome was inhibited by the overexpression of EaTANK. Finally, we confirmed that the expression of NFKB1 mRNA and promoter binding activity of NF-κB was significantly increased in poly (I:C)-stimulated EaTANK-overexpressing FHM cells. In conclusion, the results of this study suggest that TANK significantly contributes to the antiviral response and regulation of NF-κB activity in red-spotted grouper.


Assuntos
Bass , Doenças dos Peixes , Animais , NF-kappa B/genética , NF-kappa B/metabolismo , Imunidade Inata/genética , Regulação da Expressão Gênica , Filogenia , Sequência de Aminoácidos , RNA Mensageiro/metabolismo , Antivirais , Proteínas de Peixes/química
3.
Polymers (Basel) ; 15(19)2023 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-37836068

RESUMO

Polyethylene (PE) is widely used as a gas-sealing material in packing films and gas transport pipes. A technique for evaluating the permeability of water-insoluble gases has recently been developed. This technique is a volumetric analysis that is used to calculate the gas permeability by measuring the gas uptake and diffusivity. With this technique, we investigated the permeability of pure gases, such as H2, He, N2, O2 and Ar, enriched under high pressure up to 9 MPa in low-density polyethylene (LDPE), ultrahigh molecular weight polyethylene (UHMWPE) and high-density polyethylene (HDPE). The gas uptake showed a linear pressure-dependent behavior that followed Henry's law, and the diffusivity was independent of the pressure. Furthermore, the logarithmic diffusivity values of the five gases linearly decreased as their molecular kinetic diameters increased. The logarithmic solubility values linearly increased as the critical temperatures of the gases increased. The calculated permeability results were correlated with the volume fraction of the amorphous phase and the fractional free volume. This result newly showed that the amorphous phase was directly correlated to the fractional free volume.

4.
PLoS One ; 18(1): e0280214, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36608059

RESUMO

Carcinogenicity tests predict the tumorigenic potential of various substances in the human body by studying tumor induction in experimental animals. There is a need for studies that explore the use of FVB/N-Trp53em2Hwl/Korl (FVB-Trp53+/-) mice, created by TALEN-mediated gene targeting in Korea, in carcinogenicity tests. This study was performed to determine whether FVB-Trp53+/- mice are a suitable model for short-term carcinogenicity studies. To compare the carcinogenicity at different concentrations, 25, 50, and 75 mg/kg of N-methyl-N-nitrosourea (MNU), a known carcinogen, were administered intraperitoneally to FVB-Trp53+/- and wild-type male mice. After 26 weeks, the survival rate was significantly reduced in FVB-Trp53+/- mice compared to the wild-type mice in the 50 and 75 mg/kg groups. The incidence of thymic malignant lymphoma (TML) in the 50 and 75 mg/kg groups was 54.2 and 59.1% in FVB-Trp53+/- male mice, respectively. TML metastasized to the lungs, spleen, lymph nodes, liver, kidney, and heart in FVB-Trp53+/- male mice. Furthermore, the incidence of primary lung tumors, such as adenomas and adenocarcinomas, was 65.4, 62.5, and 45.4% in the FVB-Trp53+/- mice of the 25, 50, and 75 mg/kg groups, respectively. The main tumor types in FVB-Trp53+/- mice were TML and primary lung tumors, regardless of the dose of MNU administered. These results suggest that systemic tumors may result from malfunctions in the p53 gene and pathway, which is an important factor in the pathogenesis of human cancers. Therefore, FVB-Trp53 heterozygous mice are suitable for short-term carcinogenicity tests using positive carcinogens, and that the best result using MNU, a positive carcinogen, might have a single dose of 50 mg/kg.


Assuntos
Neoplasias Pulmonares , Neoplasias do Timo , Humanos , Camundongos , Masculino , Animais , Metilnitrosoureia/toxicidade , Carcinógenos/toxicidade , Camundongos Endogâmicos , Testes de Carcinogenicidade/métodos
5.
Fish Shellfish Immunol ; 133: 108552, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36669605

RESUMO

Peroxiredoxin 1 is a member of the typical 2-Cys peroxiredoxin family, which serves diverse functions in gene expression, immune and inflammatory responses, and tumor progression. In this study, we aimed to analyze the structural, functional, and immunomodulatory properties of peroxiredoxin 1 from Epinephelus akaara (EaPrx1). The open reading frame of EaPrx1 is 597 base pairs in length, encoding 198 amino acids, with a molecular weight of approximately 22 kDa. The in silico analysis revealed that EaPrx1 shares a conserved thioredoxin fold and signature motifs that are critical for its catalytic activity and oligomerization. Further, EaPrx1 is closely related to Epinephelus lanceolatus Prx1 and clustered in the Fishes group of the vertebrate clade, revealing that EaPrx1 was conserved throughout evolution. In terms of tissue distribution, a high level of EaPrx1 expression was observed in the spleen, brain, and blood tissues. Likewise, in immune challenge experiments, significant transcriptional modulations of EaPrx1 upon lipopolysaccharide, polyinosinic:polycytidylic acid, and nervous necrosis virus injections were noted at different time points, indicating the immunological role of EaPrx1 against pathogenic infections. In the functional analysis, rEaPrx1 exhibited substantial DNA protection, insulin disulfide reduction, and tissue repair activities, which were concentration-dependent. EaPrx1/pcDNA™ 3.1 (+)-transfected fathead minnow cells revealed high cell viability upon arsenic toxicity, indicating the heavy metal detoxification activity of EaPrx1. Taken together, the transcriptional and functional studies imply critical roles of EaPrx1 in innate immunity, redox regulation, apoptosis, and tissue-repair processes in E. akaara.


Assuntos
Bass , Doenças dos Peixes , Animais , Peroxirredoxinas/genética , Peroxirredoxinas/química , Bass/genética , Bass/metabolismo , Imunidade Inata/genética , Antioxidantes/metabolismo , Oxirredução , Filogenia , Regulação da Expressão Gênica , Proteínas de Peixes/química
6.
J Clin Med ; 11(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36431090

RESUMO

Predicting the development of hepatocellular carcinoma (HCC) is a key clinical issue in patients with chronic hepatitis B (CHB). The aim of this study was to develop a precise and simple HCC risk score for up to 10 years. A total of 1895 CHB patients treated with entecavir or tenofovir disoproxil fumarate were retrospectively recruited and randomized into derivation (n = 1239) and validation cohorts (n = 656). Variables proven to be independent risk factors for HCC in the derivation cohort were used to develop the prediction model. The ACCESS-HCC model included five variables (age, cirrhosis, consumption of ethanol, liver stiffness, and serum alanine aminotransferase). Areas under curves were 0.798, 0.762, and 0.883 for HCC risk at 3, 5, and 10 years, respectively, which were higher than those of other prediction models. The scores were categorized according to significantly different HCC incidences: 0-4, low; 5-8, intermediate; and 9-14, high-risk. The annual incidence rates were 0.5%, 3.2%, and 11.3%, respectively. The performance of this model was validated in an independent cohort. The ACCESS-HCC model shows improved long-term prediction and provides three distinct risk categories for HCC in CHB patients receiving antiviral therapy. Further research is needed for external validation using larger cohorts.

7.
Neurochem Res ; 47(12): 3829-3837, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36309631

RESUMO

Selonsertib is a first-in-class apoptosis signal-regulating kinase 1 (ASK1) inhibitor in clinical trials for treating NASH and diabetic kidney disease due to its anti-inflammatory and anti-fibrotic activities. In the present study, we investigated the anti-neuroinflammatory effects and brain pharmacokinetic properties of selonsertib. It inhibited inflammatory cytokines and NO production by suppressing phosphorylated ASK1 in the LPS-stimulated microglial cell line, BV2 cells. Consistent with the in vitro results, selonsertib attenuated plasma and brain TNF-α levels in the LPS-induced murine neuroinflammation model. In vitro and in vivo pharmacokinetic studies of selonsertib were conducted in support of central nervous system (CNS) drug discovery. In both Caco-2 and MDR-MDCK cells, selonsertib exhibited a high efflux ratio, showing that it is a P-gp substrate. Selonsertib was rapidly and effectively absorbed into the systemic circulation after oral treatment, with a Tmax of 0.5 h and oral bioavailability of 74%. In comparison with high systemic exposure with Cmax of 16.2 µg/ml and AUC of 64 µg·h/mL following oral dosing of 10 mg/kg, the brain disposition of selonsertib was limited, with Cmax of 0.08 µg/g and Kp value of 0.004. This study demonstrates that selonsertib can be a therapeutic agent for neuroinflammatory diseases.


Assuntos
Lipopolissacarídeos , MAP Quinase Quinase Quinase 5 , Animais , Camundongos , Encéfalo/metabolismo , Células CACO-2 , Lipopolissacarídeos/farmacologia , MAP Quinase Quinase Quinase 5/metabolismo , MAP Quinase Quinase Quinase 5/farmacologia , Microglia/metabolismo
8.
PLoS One ; 17(7): e0272019, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35881617

RESUMO

Coronavirus disease (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is currently spreading globally. To overcome the COVID-19 pandemic, preclinical evaluations of vaccines and therapeutics using K18-hACE2 and CAG-hACE2 transgenic mice are ongoing. However, a comparative study on SARS-CoV-2 infection between K18-hACE2 and CAG-hACE2 mice has not been published. In this study, we compared the susceptibility and resistance to SARS-CoV-2 infection between two strains of transgenic mice, which were generated in FVB background mice. K18-hACE2 mice exhibited severe weight loss with definitive lethality, but CAG-hACE2 mice survived; and differences were observed in the lung, spleen, cerebrum, cerebellum, and small intestine. A higher viral titer was detected in the lungs, cerebrums, and cerebellums of K18-hACE2 mice than in the lungs of CAG-hACE2 mice. Severe pneumonia was observed in histopathological findings in K18-hACE2, and mild pneumonia was observed in CAG-hACE2. Atrophy of the splenic white pulp and reduction of spleen weight was observed, and hyperplasia of goblet cells with villi atrophy of the small intestine was observed in K18-hACE2 mice compared to CAG-hACE2 mice. These results indicate that K18-hACE2 mice are relatively susceptible to SARS-CoV-2 and that CAG-hACE2 mice are resistant to SARS-CoV-2. Based on these lineage-specific sensitivities, we suggest that K18-hACE2 mouse is suitable for highly susceptible model of SARS-CoV-2, and CAG-hACE2 mouse is suitable for mild susceptible model of SARS-CoV-2 infection.


Assuntos
COVID-19 , Pneumonia , Enzima de Conversão de Angiotensina 2/genética , Animais , Atrofia/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças/patologia , Humanos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Pandemias , Peptidil Dipeptidase A , Pneumonia/patologia , SARS-CoV-2
9.
Fish Shellfish Immunol ; 125: 247-257, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35588907

RESUMO

Apoptosis plays a vital role in maintaining cellular homeostasis in multicellular organisms. Caspase-9 (casp-9) is one of the major initiator caspases that induces apoptosis by activating downstream intrinsic apoptosis pathway genes. Here, we isolated the cDNA sequence (1992 bp) of caspase-9 from Amphiprion clarkii (Accasp-9) that consists of a 1305 bp coding region and encodes a 434 aa protein. In silico analysis showed that Accasp-9 has a theoretical isoelectric point of 5.81 and a molecular weight of 48.45 kDa. Multiple sequence alignment revealed that the CARD domain is located at the N-terminus, whereas the large P-20 and small P-10 domains are located at the C-terminus. Moreover, a highly conserved pentapeptide active site (296QACGG301), as well as histidine and cysteine active sites, are also retained at the C-terminus. In phylogenetic analysis, Accasp-9 formed a clade with casp-9 from different species, distinct from other caspases. Accasp-9 was highly expressed in the gill and intestine compared with other tissues analyzed in healthy A. clarkii. Accasp-9 expression was significantly elevated in the blood after stimulation with Vibrio harveyi and polyinosinic:polycytidylic acid (poly I:C; 12-48 h), but not with lipopolysaccharide. The nucleoprotein expression of the viral hemorrhagic septicemia virus was significantly reduced in Accasp-9 overexpressed fathead minnow (FHM) cells compared with that in the control. In addition, other in vitro assays revealed that cell apoptosis was significantly elevated in poly I:C and UV-B-treated Accasp-9 transfected FHM cells. However, H248P or C298S mutated Accasp-9 significantly reduced apoptosis in UV-B irradiated cells. Collectively, our results show that Accasp-9 might play a defensive role against invading pathogens and UV-B radiation and H248 and C298 active residues are significantly involved in apoptosis in teleosts.


Assuntos
Cyprinidae , Perciformes , Animais , Antivirais , Caspase 3 , Caspase 9 , Filogenia , Poli I-C/farmacologia
10.
Eur J Pharm Sci ; 173: 106177, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35341895

RESUMO

Olaparib is a first-in-class poly (ADP-ribose) polymerase oral inhibitor used to treat various tumors. In this study, we clarified the roles of ABCB1/Abcb1 and ABCG2/Abcg2 transporters in restricting olaparib distribution to the brain. Olaparib was efficiently transported by human ABCG2, human ABCB1, and mouse Abcg2 in vitro. In the in vivo disposition study of olaparib using single or combination knockout mice, the systemic exposure of olaparib did not differ significantly between the strains over an 8-h period. However, the brain-to-plasma unbound concentration ratio of olaparib increased 5.6- and 8.1-fold in Abcb1a/1b and Abcb1a/1b;Abcg2 knockout mice, respectively, compared with wild-type mice. The Abcg2 single knockout mice exhibited a similar brain-to-plasma unbound concentration ratio to wild-type mice. Moreover, the brain distribution of olaparib could be modulated by the ABCB1/ABCG2 dual inhibitor elacridar to reach a similar degree of inhibition to Abcb1a/1b-/-. These findings suggest that olaparib is actively transported by both human and mouse ABCB1/Abcb1 and ABCG2/Abcg2; while Abcb1a/1b is a major determinant of olaparib brain penetration in mice, Abcg2 is likely to be a minor contributor. Concomitant treatment with temozolomide slightly increased the brain distribution of olaparib in mouse, but the clinical impact of the interaction was expected to be limited.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Antineoplásicos , Encéfalo , Ftalazinas , Piperazinas , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/farmacocinética , Encéfalo/metabolismo , Camundongos , Camundongos Knockout , Ftalazinas/farmacocinética , Piperazinas/farmacocinética , Distribuição Tecidual
11.
Polymers (Basel) ; 14(6)2022 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-35335482

RESUMO

With the increasing interest in hydrogen energy, the stability of hydrogen storage facilities and components is emphasized. In this study, we analyzed the effect of high-pressure hydrogen gas treatment in silica-filled EPDM composites with different silica contents. In detail, cure characteristics, crosslink density, mechanical properties, and hydrogen permeation properties were investigated. Results showed that material volume, remaining hydrogen content, and mechanical properties were changed after 96.3 MPa hydrogen gas exposure. With an increase in the silica content, the crosslink density and mechanical properties increased, but hydrogen permeability was decreased. After treatment, high-silica-content composites showed lower volume change than low-silica-content composites. The crack damage due to the decompression caused a decrease in mechanical properties, but high silica content can inhibit the reduction in mechanical properties. In particular, EPDM/silica composites with a silica content of above 60 phr exhibited excellent resistance to hydrogen gas, as no change in their physical and mechanical properties was observed.

12.
Sci Rep ; 12(1): 3328, 2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35228634

RESUMO

We demonstrate a simple experimental technology for characterizing the gas permeation properties of H2, He, N2 and Ar absorbed in polymers. This is based on the volumetric measurement of released gas and an upgraded diffusion analysis program after high-pressure exposure. Three channel measurements of sorption content of gases emitted from polymers after decompression are simultaneously conducted, and then, the gas uptake/diffusivity as a function of exposed pressure are determined in nitrile butadiene rubber (NBR), ethylene propylene diene monomer (EPDM) rubbers, low-density polyethylene (LDPE) and high-density polyethylene (HDPE), which are used for gas sealing materials under high pressure. The pressure-dependent gas transport behaviors of the four gases are presented and compared. Gas sorption follows Henry's law up to 9 MPa, while pressure-dependent diffusion behavior is not observed below 6 MPa. The magnitude of the diffusivity of the four gases decreases in the order DHe > DH2 > DAr > DN2 in all polymers, closely related to the kinetic diameter of the gas molecules. The dependence of gas species on solubility is in contrast to that on diffusivity. The linear correlation between logarithmic solubility and critical temperature of the gas molecule was newly observed.

13.
Polymers (Basel) ; 14(4)2022 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-35215613

RESUMO

Filler effects on H2 diffusion in nitrile butadiene rubbers (NBRs) blended with carbon black and silica fillers of different concentrations are first investigated by employing a volumetric analysis. Total uptake, solubility, and diffusivity of hydrogen for ten filled-NBR, including neat NBR, are determined in an exposed pressure range of 1.3 MPa~92.6 MPa. Filler dependence on hydrogen uptake and diffusion is distinctly observed in the NBRs blended with high abrasion furnace (HAF) carbon black (CB) fillers compared to NBRs blended with medium thermal furnace (MT) CB and silica filler, which is related to the specific surface area of carbon black and interface structure. The HAF CB filled-NBR follows dual sorption behavior combined with Henry's law and the Langmuir model, responsible for two contributions of solubility from polymer and filler. However, a single gas sorption behavior coming from the polymer is observed satisfying Henry's law up to 92.6 MPa for NBR blended with MT CB filled-NBR and silica filled-NBR. Diffusion demonstrates Knudsen and bulk diffusion behavior below and above, respectively, at certain pressures. With increasing pressure, the filler effect on diffusion is reduced, and diffusivity converges to a value. The correlation observed between diffusivity and filler content (or crosslink density) is discussed.

14.
Polymers (Basel) ; 15(1)2022 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-36616510

RESUMO

We investigated the influence of two fillers-CB (carbon black) and silica-on the H2 permeation of EPDM polymers crosslinked with sulfur in the pressure ranges 1.2-90 MPa. H2 uptake in the CB-blended EPDM revealed dual sorption (Henry's law and Langmuir model) when exposed to pressure. This phenomenon indicates that H2 uptake is determined by the polymer chain and filler-surface absorption characteristics. Moreover, single sorption characteristics for neat and silica-blended EPDM specimens obey Henry's law, indicating that H2 uptake is dominated by polymer chain absorption. The pressure-dependent diffusivity for the CB-filled EPDM is explained by Knudsen and bulk diffusion, divided at the critical pressure region. The neat and silica-blended EPDM specimens revealed that bulk diffusion behaviors decrease with decreasing pressure. The H2 diffusivities in CB-filled EPDM composites decrease because the impermeable filler increases the tortuosity in the polymer and causes filler-polymer interactions; the linear decrease in diffusivity in silica-blended EPDM was attributed to an increase in the tortuosity. Good correlations of permeability with density and tensile strength were observed. From the investigated relationships, it is possible to select EPDM candidates with the lowest H2-permeation properties as seal materials to prevent gas leakage under high pressure in H2-refueling stations.

15.
In Vitro Cell Dev Biol Anim ; 57(8): 808-816, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34608569

RESUMO

In vitro spermatogenesis can be performed for marine medaka (Oryzias dancena) via whole testis organ cultures, but spermatogenesis could only be maintained during the early phase of culturing, suggesting that the culture conditions can be further optimized. To improve the culture conditions, we examined the effects of culture temperature, basal media, and medium supplements on spermatogonial proliferation levels during whole testis organ culturing by BrdU incorporation assays. Our results show that a 30°C culture temperature negatively affected spermatogonial proliferation compared to 26°C and 28°C and that the use of Dulbecco's Modified Eagle Medium and Minimum Essential Medium α (α-MEM) was more effective for spermatogonial proliferation than the use of Leibovitz's L-15 Medium (L15). When fetal bovine serum (FBS) was replaced with KnockOut Serum Replacement (KSR), a significantly positive effect was observed for the maintenance of spermatogonial proliferation. However, supplementation of the medium with 17α, 20ß-dihydroxy-4-pregnen-3-one did not show any significant effect. Gene expression analyses of four genes, including Nanos2, SCP3, AMH, and StAR, indicated that the optimized culture conditions consisting of α-MEM and KSR had the most positive influence on the maintenance of spermatogonial proliferation levels in whole testis organ cultures compared to the original culture conditions consisting of L15 and FBS by maintaining the function of Sertoli and Leydig cells. The results from this study will provide useful information for the study of in vitro spermatogenesis in fish.


Assuntos
Técnicas de Cultura de Órgãos/métodos , Oryzias/fisiologia , Espermatogênese/fisiologia , Testículo/fisiologia , Animais , Meios de Cultura , Masculino , Temperatura
16.
J Med Chem ; 64(2): 1037-1053, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33417443

RESUMO

Tryptophan hydroxylase 1 (TPH1) has been recently suggested as a promising therapeutic target for treating obesity and fatty liver disease. A new series of 1,2,4-oxadiazolylphenyl alanine derivatives were identified as TPH1 inhibitors. Among them, compound 23a was the most active in vitro, with an IC50 (half-maximal inhibitory concentration) value of 42 nM, showed good liver microsomal stability, and showed no significant inhibition of CYP and hERG. Compound 23a inhibited TPH1 in the peripheral tissue with limited BBB penetration. In high-fat diet-fed mice, 23a reduced body weight gain, body fat, and hepatic lipid accumulation. Also, 23a improved glucose intolerance and energy expenditure. Taken together, compound 23a shows promise as a therapeutic agent for the treatment of obesity and fatty liver diseases.


Assuntos
Alanina/síntese química , Alanina/farmacologia , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Fígado Gorduroso/tratamento farmacológico , Triptofano Hidroxilase/antagonistas & inibidores , Adiposidade/efeitos dos fármacos , Alanina/análogos & derivados , Animais , Fármacos Antiobesidade/uso terapêutico , Dieta Hiperlipídica , Metabolismo Energético/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Intolerância à Glucose/tratamento farmacológico , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Aumento de Peso/efeitos dos fármacos
17.
Org Biomol Chem ; 17(21): 5249-5252, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31089637

RESUMO

An air-stable N-heterocyclic carbene-copper thiophene-2-carboxylate (CuTC) complex has been prepared for the stereoselective hydroboration of terminal alkynes using pinacolborane (HBpin) or 1,8-naphthalenediaminatoborane (HBdan). The newly synthesized complex can be directly activated by hydroboranes without a cocatalyst such as a base, and exhibits high reactivity for the hydroboration of alkynes under mild conditions. A gram-scale hydroboration of terminal phenylacetylene demonstrated the applicability of the copper complex for the preparation of alkenyl boronates.

18.
In Vitro Cell Dev Biol Anim ; 55(2): 76-81, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30644030

RESUMO

The optimal transfection conditions for efficient transgene delivery into a specific cell type should be empirically determined, particularly in cases involving unusual cell types. We compared the conditions for effective introduction of transgenes into Siberian sturgeon (Acipenser baerii) cell lines by evaluating the cytotoxicity and transfection efficiency of three commercially available transfection reagents: Lipofectamine 2000, X-tremeGENE HP DNA Transfection Reagent, and GeneJuice Transfection Reagent. Plasmid vectors containing the gene encoding enhanced green fluorescent protein were mixed with each of the transfection reagents using reagent-to-plasmid ratios of 1:1, 2:1, and 4:1. Then, the complexes were used to transfect three Siberian sturgeon cell lines derived from the heart, head kidney, and gonad. Cytotoxicity and transfection efficiency were measured via flow cytometry after propidium iodide staining. No significant cytotoxicity was observed at the optimal treatment conditions in all cases, with the exception of Lipofectamine 2000-treated gonad-derived cells. Although the transfection efficiencies in A. baerii cells were generally low, X-tremeGENE HP DNA Transfection Reagent showed the highest transfection efficiency at ratios of 2:1 or 4:1, depending on the cell type. Hence, X-tremeGENE HP DNA Transfection Reagent can be used to effectively transfer foreign genes into three A. baerii cell lines.


Assuntos
Peixes/genética , Transfecção/métodos , Animais , Morte Celular , Linhagem Celular , Rim Cefálico/metabolismo , Indicadores e Reagentes
19.
J Stroke ; 16(2): 91-6, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24949315

RESUMO

BACKGROUND AND PURPOSE: Stroke is common among cancer patients. However, risk factors and biomarkers of stroke in cancer patients are not well established. This study aimed to investigate risk factors and biomarkers as well as etiology of ischemic stroke in cancer patients. METHODS: A retrospective review was conducted in cancer patients with ischemic stroke who were admitted to a general hospital in Busan, Korea, between January 2003 and December 2012. The risk factors and biomarkers for stroke and stroke subtypes in cancer patients were compared with age- and sex-matched noncancer patients with ischemic stroke who were admitted to the same hospital during the same period. RESULTS: One hundred fifty-six cancer patients with ischemic stroke were identified. Cancer patients with ischemic stroke were found to have a significantly lower proportion of hypertension, atrial fibrillation, hyperlipidemia, and ischemic heart disease than noncancer patients with ischemic stroke. However, stroke biomarkers, such as erythrocyte sedimentation rate and high-sensitivity C-reactive protein, fibrinogen, pro-brain natriuretic peptide, and D-dimer levels, were significantly increased in cancer patients with ischemic stroke than in noncancer patients. Large-artery atherosclerosis and stroke of undetermined cause were more common in cancer patients with ischemic stroke than in noncancer patients with ischemic stroke. CONCLUSIONS: Cancer patients with ischemic stroke showed different risk factors, stroke biomarkers, and stroke etiology compared with noncancer patients with ischemic stroke.

20.
J Am Chem Soc ; 135(45): 16912-25, 2013 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-24147834

RESUMO

Previous work has shown that certain steroidal bis-(N-phenyl)ureas, derived from cholic acid, form crystals in the P6(1) space group with unusually wide unidimensional pores. A key feature of the nanoporous steroidal urea (NPSU) structure is that groups at either end of the steroid are directed into the channels and may in principle be altered without disturbing the crystal packing. Herein we report an expanded study of this system, which increases the structural variety of NPSUs and also examines their inclusion properties. Nineteen new NPSU crystal structures are described, to add to the six which were previously reported. The materials show wide variations in channel size, shape, and chemical nature. Minimum pore diameters vary from ~0 up to 13.1 Å, while some of the interior surfaces are markedly corrugated. Several variants possess functional groups positioned in the channels with potential to interact with guest molecules. Inclusion studies were performed using a relatively accessible tris-(N-phenyl)urea. Solvent removal was possible without crystal degradation, and gas adsorption could be demonstrated. Organic molecules ranging from simple aromatics (e.g., aniline and chlorobenzene) to the much larger squalene (M(w) = 411) could be adsorbed from the liquid state, while several dyes were taken up from solutions in ether. Some dyes gave dichroic complexes, implying alignment of the chromophores in the NPSU channels. Notably, these complexes were formed by direct adsorption rather than cocrystallization, emphasizing the unusually robust nature of these organic molecular hosts.

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