Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31.689
Filtrar
1.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445153

RESUMO

In order to achieve a desired therapeutic effect in schizophrenia patients and to maintain their mental wellbeing, pharmacological therapy needs to be continued for a long time, usually from the onset of symptoms and for the rest of the patients' lives. The aim of our present research is to find out the in vivo effect of chronic treatment with atypical neuroleptic iloperidone on the expression and activity of cytochrome P450 (CYP) in rat liver. Male Wistar rats received a once-daily intraperitoneal injection of iloperidone (1 mg/kg) for a period of two weeks. Twenty-four hours after the last dose, livers were excised to study cytochrome P450 expression (mRNA and protein) and activity, pituitaries were isolated to determine growth hormone-releasing hormone (GHRH), and blood was collected for measuring serum concentrations of hormones and interleukin. The results showed a broad spectrum of changes in the expression and activity of liver CYP enzymes, which are important for drug metabolism (CYP1A, CYP2B, CYP2C, and CYP3A) and xenobiotic toxicity (CYP2E1). Iloperidone decreased the expression and activity of CYP1A2, CP2B1/2, CYP2C11, and CYP3A1/2 enzymes but increased that of CYP2E1. The CYP2C6 enzyme remained unchanged. At the same time, the level of GHRH, GH, and corticosterone decreased while that of T3 increased, with no changes in IL-2 and IL-6. The presented results indicate neuroendocrine regulation of the investigated CYP enzymes during chronic iloperidone treatment and suggest a possibility of pharmacokinetic/metabolic interactions produced by the neuroleptic during prolonged combined treatment with drugs that are substrates of iloperidone-affected CYP enzymes.


Assuntos
Antipsicóticos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Isoxazóis/farmacologia , Fígado/efeitos dos fármacos , Piperidinas/farmacologia , Animais , Antipsicóticos/administração & dosagem , Sistema Enzimático do Citocromo P-450/genética , Expressão Gênica/efeitos dos fármacos , Isoxazóis/administração & dosagem , Fígado/metabolismo , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Piperidinas/administração & dosagem , Ratos , Ratos Wistar , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
2.
Nutrients ; 13(7)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34371841

RESUMO

Excessive liver lipid deposition is a vital risk factor for the development of many diseases. Here, we fed Sprague-Dawley rats with a control or α-lipoic acid-supplemented diet (0.2%) for 5 weeks to elucidate the effects of α-lipoic acid on preventive ability, hepatic lipid metabolism-related gene expression, and the involved regulatory mechanisms. In the current study, α-lipoic acid supplementation lowered plasma triglyceride level and hepatic triglyceride content. Reduced hepatic lipid deposition was closely associated with inhibiting fatty acid-binding protein 1 and fatty acid synthase expression, as well as increasing phosphorylated hormone-sensitive lipase expression at the protein level in α-lipoic acid-exposed rats. Hepatic miRNA sequencing revealed increased expression of miR-3548 targeting the 3'untranslated region of Fasn mRNA, and the direct regulatory link between miRNA-3548 and FASN was verified by dual-luciferase reporter assay. Taken together, α-lipoic acid lowered hepatic lipid accumulation, which involved changes in miRNA-mediated lipogenic genes.


Assuntos
Suplementos Nutricionais , Ácido Graxo Sintase Tipo I/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , MicroRNAs/metabolismo , Ácido Tióctico/farmacologia , Animais , Ácido Graxo Sintases/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Expressão Gênica/efeitos dos fármacos , Lipogênese/genética , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Triglicerídeos/metabolismo
3.
Anim Sci J ; 92(1): e13621, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34448516

RESUMO

To determine the effects of Follicle Stimulating Hormone (FSH) treatment and subsequent withdrawal on uterine proliferation and estrogen receptor (ESR), Brahman crossbred heifers (n = 12) were twice daily injected with FSH (4, 3, and 2 mg/injection) on Days 17-19 of the estrous cycle (FSH 3 days) and (4 and 3 mg/injection) on Days 17-18 (FSH 2 days) and withdrawal with saline on Day 19 and (4 mg/injection) on Day 17 (FSH 1 day) and withdrawal with saline on Days 18-19. Uterine tissue was subjectively collected on Day 20 and microscopically classified to four regions: endometrial stroma (ES), surface endometrial gland (EG), deep endometrial gland (DG), and myometrium (Myo). The cell proliferation marker, Ki-67, was quantified as labeling index (LI) in uterine regions, and tissues were immunostained to detect ESR2 followed by image analysis. The LI of ES, EG, and DG was greater (P = 0.0018, P = 0.0005, and P = 0.0103; respectively) in heifers received FSH for 3 days. The expression of ESR2 protein on ES and EG was greatest (P < 0.0001 and P = 0.0036, respectively) in FSH 3 days-treated group. Thus, FSH administration during proestrus stimulates uterine cell proliferation, and ESR2 expressions are affected by FSH during proestrus and differentially distributed in the uterine regions.


Assuntos
Bovinos/genética , Bovinos/metabolismo , Proliferação de Células/efeitos dos fármacos , Ciclo Estral/metabolismo , Ciclo Estral/fisiologia , Hormônio Foliculoestimulante/administração & dosagem , Hormônio Foliculoestimulante/farmacologia , Expressão Gênica/efeitos dos fármacos , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Útero/citologia , Útero/metabolismo , Animais , Ciclo Estral/genética , Feminino
4.
Nutrients ; 13(7)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34371979

RESUMO

Grape pomace (GP) is a winemaking by-product rich in polyphenols and fibre. Supplementation with GP extracts has shown potential benefits against oxidative stress- and inflammation-related pathologies. As a new nutritional target, this paper explores the impact of the ingestion of a grape pomace extract on intestinal barrier functionality. A GP extract was sequentially subjected to gastrointestinal and colonic digestion using the dynamic gastrointestinal simulator (simgi®). This generated two simulated fluids: intestinal-digested extract (IDE) and colonic-digested extract (CDE). The effects of these two fluids on paracellular permeability and the expression of tight junction (TJ) proteins (i.e., zonula occludens-1 (ZO-1) and occludin) were assessed in Caco-2-cell monolayers grown in Transwell® inserts. The IDE fluid significantly (p < 0.001) reduced the paracellular transport of FITC-dextran with respect to the control, whereas no significant differences (p > 0.05) were found for CDE, which could be due, at least partially, to the pro-leaky effect of the colonic digestion medium. Accordant slight increases in the mRNA levels of both ZO-1 and occludin were observed for IDE, but without statistical significance. Additionally, the colonic fermentation of the GP extract promoted the production of short-chain fatty acids (SCFA) and phenolic metabolites and led to changes in the relative abundance of some bacteria that might affect paracellular permeability. Overall, this paper reports first trends about the effects of grape pomace extracts on intestinal permeability that would require further confirmation in future experiments.


Assuntos
Digestão , Frutas/química , Microbioma Gastrointestinal/fisiologia , Intestinos/fisiologia , Extratos Vegetais/metabolismo , Vitis , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Colo/química , Colo/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fermentação , Microbioma Gastrointestinal/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Ocludina/genética , Fenóis/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , RNA Mensageiro/análise , Proteínas de Junções Íntimas/genética , Vinho , Proteína da Zônula de Oclusão-1
5.
Nat Commun ; 12(1): 4960, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400618

RESUMO

Agonists of glucocorticoid receptor (GR) are frequently given to cancer patients with platinum-containing chemotherapy to reduce inflammation, but how GR influences tumor growth in response to platinum-based chemotherapy such as cisplatin through inflammation-independent signaling remains largely unclear. Combined genomics and transcription factor profiling reveal that MAST1, a critical platinum resistance factor that reprograms the MAPK pathway, is upregulated upon cisplatin exposure through activated transcription factor GR. Mechanistically, cisplatin binds to C622 in GR and recruits GR to the nucleus for its activation, which induces MAST1 expression and consequently reactivates MEK signaling. GR nuclear translocation and MAST1 upregulation coordinately occur in patient tumors collected after platinum treatment, and align with patient treatment resistance. Co-treatment with dexamethasone and cisplatin restores cisplatin-resistant tumor growth, whereas addition of the MAST1 inhibitor lestaurtinib abrogates tumor growth while preserving the inhibitory effect of dexamethasone on inflammation in vivo. These findings not only provide insights into the underlying mechanism of GR in cisplatin resistance but also offer an effective alternative therapeutic strategy to improve the clinical outcome of patients receiving platinum-based chemotherapy with GR agonists.


Assuntos
Cisplatino/farmacologia , Proteínas Associadas aos Microtúbulos/metabolismo , Platina/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular , Sobrevivência Celular , Citocinas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/genética , Receptores de Glucocorticoides/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361744

RESUMO

Korean red pine (Pinus densiflora) belongs to the Genus Pinus, and its bark contains a great amount of naturally occurring phenolic compounds. Until now, few studies have been conducted to assess the neuroprotective effects of Pinus densiflora bark extract against brain ischemic injury. The aim of this study was to investigate the neuroprotective effects of pre-treatment with the extract in the hippocampus following 5-min transient forebrain ischemia in gerbils. Furthermore, this study examined the anti-inflammatory effect as a neuroprotective mechanism of the extract. Pinus densiflora bark was extracted by pure water (100 °C), and this extract was quantitatively analyzed and contained abundant polyphenols, flavonoids, and proanthocyanidins. The extract (25, 50, and 100 mg/kg) was orally administered once a day for seven days before the ischemia. In the gerbil hippocampus, death of the pyramidal neurons was found in the subfield cornu ammonis 1 (CA1) five days after the ischemia. This death was significantly attenuated by pre-treatment with 100 mg/kg, not 25 or 50 mg/kg, of the extract. The treatment with 100 mg/kg of the extract markedly inhibited the activation of microglia (microgliosis) and significantly decreased the expression of pro-inflammatory cytokines (interleukin 1ß and tumor necrosis factor α). In addition, the treatment significantly increased anti-inflammatory cytokines (interleukin 4 and interleukin 13). Taken together, this study clearly indicates that pre-treatment with 100 mg/kg of Pinus densiflora bark extract in gerbils can exert neuroprotection against brain ischemic injury by the attenuation of neuroinflammatory responses.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pinus/química , Prosencéfalo/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Flavonoides/química , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Gerbillinae , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação , Interleucina-13/agonistas , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/agonistas , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/química , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
7.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445773

RESUMO

Inadequate vessel maintenance or growth causes ischemia in diseases such as myocardial infarction, stroke, and neurodegenerative disorders. Therefore, developing an effective strategy to salvage ischemic tissues using a novel compound is urgent. Drug repurposing has become a widely used method that can make drug discovery more efficient and less expensive. Additionally, computational virtual screening tools make drug discovery faster and more accurate. This study found a novel drug candidate for pro-angiogenesis by in silico virtual screening. Using Gene Expression Omnibus (GEO) microarray datasets related to angiogenesis studies, differentially expressed genes were identified and characteristic direction signatures extracted from GEO2EnrichR were used as input data on L1000CDS2 to screen pro-angiogenic molecules. After a thorough review of the candidates, a list of compounds structurally similar to TWS-119 was generated using ChemMine Tools and its clustering toolbox. ChemMine Tools and ChemminR structural similarity search tools for small-molecule analysis and clustering were used for second screening. A molecular docking simulation was conducted using AutoDock v.4 to evaluate the physicochemical effect of secondary-screened chemicals. A cell viability or toxicity test was performed to determine the proper dose of the final candidate, ellipticine. As a result, we found ellipticine, which has pro-angiogenic effects, using virtual computational methods. The noncytotoxic concentration of ellipticine was 156.25 nM. The phosphorylation of glycogen synthase kinase-3ß was decreased, whereas the ß-catenin expression was increased in human endothelial cells treated with ellipticine. We concluded that ellipticine at sublethal dosage could be successfully repositioned as a pro-angiogenic substance by in silico virtual screening.


Assuntos
Elipticinas/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Neovascularização Patológica/metabolismo , Ligação Proteica/efeitos dos fármacos , beta Catenina/metabolismo
8.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360903

RESUMO

Despite the fact that many studies have examined the effectiveness of different gaseous postharvest treatments applied at low temperature to maintain table grape quality, the use of ethanol vapor has hardly been investigated. Thus, this work has studied the effectiveness of ethanol vapor-generating sachets in the maintenance of It 681-30 table grape quality, a new cultivar, during storage at low temperature and after the shelf-life period at 20 °C. To this end, various quality assessments have been carried out and the effect of the ethanol treatment on the expression of different genes (phenylpropanoids, transcription factors, PRs, and aquaporins) was determined. The results indicated that the application of ethanol vapor reduced the total decay incidence, weight loss, and the rachis browning index in It 681-30 grapes stored at 0 °C and after the shelf-life period at 20 °C, as compared to non-treated samples. Moreover, the modulation of STS7 and the different PR genes analyzed seems to play a part in the molecular mechanisms activated to cope with fungal attacks during the postharvest of It 681-30 grapes, and particularly during the shelf-life period at 20 °C. Furthermore, the expression of aquaporin transcripts was activated in samples showing higher weight loss. Although further work is needed to elucidate the role of ethanol in table grape quality, the results obtained in this work provide new insight into the transcriptional regulation triggered by ethanol treatment.


Assuntos
Temperatura Baixa , Etanol/farmacologia , Conservação de Alimentos/métodos , Conservantes de Alimentos/farmacologia , Qualidade dos Alimentos , Armazenamento de Alimentos/métodos , Frutas/efeitos dos fármacos , Gases/farmacologia , Vitis/efeitos dos fármacos , Aquaporinas/genética , Frutas/genética , Expressão Gênica/efeitos dos fármacos , Reação de Maillard/efeitos dos fármacos , Proteínas de Plantas/genética , Fatores de Transcrição/genética , Transcrição Genética/efeitos dos fármacos , Vitis/genética , Volatilização
9.
Clin Pharmacol Ther ; 110(3): 702-713, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34255863

RESUMO

The African American (AA) population displays a 1.6 to 3-fold higher incidence of thrombosis and stroke mortality compared with European Americans (EAs). Current antiplatelet therapies target the ADP-mediated signaling pathway, which displays significant pharmacogenetic variation for platelet reactivity. The focus of this study was to define underlying population differences in platelet function in an effort to identify novel molecular targets for future antiplatelet therapy. We performed deep coverage RNA-Seq to compare gene expression levels in platelets derived from a cohort of healthy volunteers defined by ancestry determination. We identified > 13,000 expressed platelet genes of which 480 were significantly differentially expressed genes (DEGs) between AAs and EAs. DEGs encoding proteins known or predicted to modulate platelet aggregation, morphology, or platelet count were upregulated in AA platelets. Numerous G-protein coupled receptors, ion channels, and pro-inflammatory cytokines not previously associated with platelet function were likewise differentially expressed. Many of the signaling proteins represent potential pharmacologic targets of intervention. Notably, we confirmed the differential expression of cytokines IL32 and PROK2 in an independent cohort by quantitative real-time polymerase chain reaction, and provide functional validation of the opposing actions of these two cytokines on collagen-induced AA platelet aggregation. Using Genotype-Tissue Expression whole blood data, we identified 516 expression quantitative trait locuses with Fst values > 0.25, suggesting that population-differentiated alleles may contribute to differences in gene expression. This study identifies gene expression differences at the population level that may affect platelet function and serve as potential biomarkers to identify cardiovascular disease risk. Additionally, our analysis uncovers candidate novel druggable targets for future antiplatelet therapies.


Assuntos
Plaquetas/fisiologia , Grupos de Populações Continentais/genética , RNA Mensageiro/genética , Adolescente , Afro-Americanos/genética , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Citocinas/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Humanos , Masculino , Inibidores da Agregação Plaquetária/uso terapêutico , Testes de Função Plaquetária/métodos
10.
Science ; 373(6557)2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34301855

RESUMO

Stochastic fluctuations in gene expression ("noise") are often considered detrimental, but fluctuations can also be exploited for benefit (e.g., dither). We show here that DNA base excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean expression levels. This amplified expression noise originates from shorter-duration, higher-intensity transcriptional bursts generated by Apex1-mediated DNA supercoiling. The remodeling of DNA topology first impedes and then accelerates transcription to maintain mean levels. This mechanism, which we refer to as "discordant transcription through repair" ("DiThR," which is pronounced "dither"), potentiates cellular reprogramming and differentiation. Our study reveals a potential functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.


Assuntos
Diferenciação Celular , Reprogramação Celular , Reparo do DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , DNA/química , Expressão Gênica , Transcrição Genética , Animais , Células Cultivadas , Simulação por Computador , DNA/genética , DNA/metabolismo , Células-Tronco Embrionárias , Expressão Gênica/efeitos dos fármacos , Idoxuridina/metabolismo , Idoxuridina/farmacologia , Camundongos , Modelos Genéticos , Proteína Homeobox Nanog/genética , Conformação de Ácido Nucleico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Célula Única , Processos Estocásticos , Timidina Quinase/genética , Timidina Quinase/metabolismo , Transcrição Genética/efeitos dos fármacos
11.
Fish Physiol Biochem ; 47(4): 1271-1282, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34228252

RESUMO

In this study, the mechanism that vitamin C (VC) regulates the production of reactive oxygen species (ROS) through Wnt10b signaling was investigated in the gill of zebrafish (Danio rerio). The results showed that 0.5 and 1.0 g/kg VC diets induced the gene expression of Wnt10b, ß-catenin, SOD, CAT, and GSH-PX in gill. In addition, VC decreased the levels of H2O2, O2·- and ·OH, whereas the activities of SOD, CAT, and GSH-PX were increased by VC in the gill of zebrafish. To evaluate the role of Wnt10b in regulating oxidative stress, Wnt10b RNA was further interfered and the gene expression and activities of antioxidant enzymes were detected in gill. The result of Wnt10b RNA interference showed that Wnt10b signaling played a key role in regulating the gene expression of SOD, CAT, and GSH-PX. In all, VC may regulate the production of ROS through Wnt10b signaling in the gill of zebrafish (Danio rerio).


Assuntos
Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Brânquias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Vitaminas/farmacologia , Animais , Proteínas de Peixes/genética , Expressão Gênica/efeitos dos fármacos , Brânquias/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Masculino , Estresse Oxidativo , Oxirredutases/genética , Proteínas Proto-Oncogênicas/genética , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/genética , Peixe-Zebra , beta Catenina/genética
12.
Fish Physiol Biochem ; 47(4): 1313-1327, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34241763

RESUMO

Selenium (Se), an essential component of deiodinases (DIOs), regulates the contents of thyroid hormones and thus improves animal growth. To explore the influences of selenium supplementation on fish growth metabolism, a total of 270 healthy grass carp (Ctenopharyngodon idella) were divided into three groups and feed three graded dietary selenium (0.141, 0.562, and 1.044 mg Se/kg) levels. The results showed that after 60-day feeding, dietary selenium improved the final body weight and specific growth rate (SGR) of grass carp. The hepatic DIO activities in selenium-supplemented groups were higher than those in control group. A significant increase in triiodothyronine (T3), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH) levels was accompanied by a decrease in the contents of thyroxine (T4) and free thyroxine (FT4) in selenium-supplemented groups. The histopathological observation of thyroid suggested that selenium deficiency resulted in hypertrophy of follicular epithelial cells. Moreover, the gene relative expression levels of dio1, dio2, and dio3 showed an increasing trend with the rising concentration of dietary selenium. The transcription levels of HPT axis-related genes (crh, tsh-ß, ttr, tr-s, tpo, nis) and GH/IGF1-related genes (gh, ghr, igf1, igf1r) were significantly upregulated in selenium-supplemented groups. No significant differences in the above indicators were observed between 0.562 and 1.044 mg Se/kg diet group except T3 content and dio1 relative expression ratio. These results indicate that dietary selenium supplementation improves the hepatic DIO activities and thyroid hormone metabolism and regulates the transcription levels of HPT and GH/IGF axis-related genes, which may be responsible for the growth promotion in grass carp.


Assuntos
Carpas , Suplementos Nutricionais , Selênio/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carpas/sangue , Carpas/crescimento & desenvolvimento , Carpas/metabolismo , Expressão Gênica/efeitos dos fármacos , Hormônio do Crescimento/genética , Hipotálamo , Fator de Crescimento Insulin-Like I/genética , Iodeto Peroxidase/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hipófise , Receptor IGF Tipo 1/genética , Receptores da Somatotropina/genética , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/patologia , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue
13.
Chem Biol Interact ; 346: 109580, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34280354

RESUMO

Dichloromethane (DCM), a widely used chlorinated solvent, is classified by IARC (2017) as probably carcinogenic to humans. Exposure to DCM has been associated with increased incidence of cholangiocarcinoma (CCA) in humans. This study aimed to investigate how DCM could contribute to CCA development by investigating the effects of DCM on DNA damage and cell transformation in cholangiocytes (MMNK-1) and on metastatic potential as measured by invasion and cell migration in malignant CCA cell lines (HuCCA-1 and RMCCA-1). MMNK-1 cells treated with the non-cytotoxic concentration of DCM (25 µM, 24 h) significantly increased the levels of mutagenic DNA adducts including 8-hydroxydeoxyguanosine, 8-OHdG, (1.84-fold, p < 0.01) and 8-nitroguanine (1.96-fold, p < 0.01) and enhanced cell transformation by 1.47-fold (p < 0.01). In addition, the expression of various genes involved in carcinogenesis, namely, NFE2L2 (antioxidative response), CXCL8 (inflammation), CDH1 (cell adhesion), MMP9 (tissue remodeling) and MKI67 (cell proliferation) were altered in cholangiocytes treated with DCM. When MMNK-1 cells were transformed by DCM, the expression of all the aforementioned genes was also increased. In malignant cell lines (HuCCA-1 and RMCCA-1), DCM treatment resulted in increased CXCL8 and MMP9 transcription and decreased CDH1 transcription accompanied by increased invasion and migration capabilities of these cells. Taken together, this study demonstrated that DCM exposure could be linked to the development of CCA.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Cloreto de Metileno/toxicidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Adutos de DNA/análise , Adutos de DNA/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Cloreto de Metileno/química , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , RNA Mensageiro/metabolismo
14.
Gene ; 800: 145833, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34274477

RESUMO

As one of the most common benthic invertebrates in freshwater, mayflies are very sensitive to changes in water quality and have high requirements for the water environment to allow their nymphs to successfully live and grow. Neonicotinoids, such as imidacloprid, can enter fresh water and pollute the aquatic environment. The present study had two goals: (1) investigate imidacloprid effects on mayfly larvae Choroterpes (Euthralus) yixingensis, and (2) contribute to the phylogenetic status of Ephemeroptera that has always been controversial. Nymphs were collected from Jinhua, China and exposed to different concentrations imidacloprid (5, 10, 20, and 40 µg/L) in the laboratory. Survival of C. yixingensis nymphs decreased as a function of time and imidacloprid concentration with only ~ 55% survival after 72 h exposure to 40 µg/L imidacloprid. After culture under 40 µg/L imidacloprid for 24 h, the steady state transcript levels of mitochondrial COX3, ND4 and ND4L genes were reduced to just 0.07 ± 0.11, 0.30 ± 0.16, and 0.28 ± 0.13 as compared with respective control values (P < 0.01). Steady state transcript levels of ND4 and ND4L were also significantly reduced in a dose-dependent manner (P < 0.05), suggesting that the steady state transcript pattern of these genes in mayfly nymphs can change in response to different levels of environmental contamination. Hence, the mitochondrial protein-coding genes of mayflies could potentially be developed as biomarkers for water ecotoxicity monitoring in the future. In addition, we used the mitochondrial genome sequence of C. yixingensis for an assessment of the phylogenetic tree of Ephemeroptera. The monophyly of Leptophlebiidae was supported and showed that Leptophlebiidae was a sister group to the clade (Baetidae + Caenidae).


Assuntos
Ephemeroptera/genética , Expressão Gênica/efeitos dos fármacos , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Animais , Ephemeroptera/efeitos dos fármacos , Genoma de Inseto , Genoma Mitocondrial , Proteínas de Insetos/genética , Inseticidas/farmacologia , Ninfa/efeitos dos fármacos , Ninfa/genética , Filogenia
15.
Nat Commun ; 12(1): 4436, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290252

RESUMO

Latent human cytomegalovirus (HCMV) infection is characterized by limited gene expression, making latent HCMV infections refractory to current treatments targeting viral replication. However, reactivation of latent HCMV in immunosuppressed solid organ and stem cell transplant patients often results in morbidity. Here, we report the killing of latently infected cells via a virus-specific nanobody (VUN100bv) that partially inhibits signaling of the viral receptor US28. VUN100bv reactivates immediate early gene expression in latently infected cells without inducing virus production. This allows recognition and killing of latently infected monocytes by autologous cytotoxic T lymphocytes from HCMV-seropositive individuals, which could serve as a therapy to reduce the HCMV latent reservoir of transplant patients.


Assuntos
Citomegalovirus/efeitos dos fármacos , Anticorpos de Domínio Único/farmacologia , Linfócitos T Citotóxicos/imunologia , Latência Viral/efeitos dos fármacos , Células Cultivadas , Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Expressão Gênica/efeitos dos fármacos , Genes Precoces/genética , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/virologia , Receptores de Quimiocinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Anticorpos de Domínio Único/metabolismo , Proteínas Virais/metabolismo , Ativação Viral/efeitos dos fármacos
16.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298867

RESUMO

The hexosamine biosynthetic pathway (HBP) is essential for the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the building block of glycosaminoglycans, thus playing a crucial role in cartilage anabolism. Although O-GlcNAcylation represents a protective regulatory mechanism in cellular processes, it has been associated with degenerative diseases, including osteoarthritis (OA). The present study focuses on HBP-related processes as potential therapeutic targets after cartilage trauma. Human cartilage explants were traumatized and treated with GlcNAc or glucosamine sulfate (GS); PUGNAc, an inhibitor of O-GlcNAcase; or azaserine (AZA), an inhibitor of GFAT-1. After 7 days, cell viability and gene expression analysis of anabolic and catabolic markers, as well as HBP-related enzymes, were performed. Moreover, expression of catabolic enzymes and type II collagen (COL2) biosynthesis were determined. Proteoglycan content was assessed after 14 days. Cartilage trauma led to a dysbalanced expression of different HBP-related enzymes, comparable to the situation in highly degenerated tissue. While GlcNAc and PUGNAc resulted in significant cell protection after trauma, only PUGNAc increased COL2 biosynthesis. Moreover, PUGNAc and both glucosamine derivatives had anti-catabolic effects. In contrast, AZA increased catabolic processes. Overall, "fueling" the HBP by means of glucosamine derivatives or inhibition of deglycosylation turned out as cells and chondroprotectives after cartilage trauma.


Assuntos
Vias Biossintéticas/efeitos dos fármacos , Doenças das Cartilagens/tratamento farmacológico , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Glucosamina/farmacologia , Hexosaminas/metabolismo , Uridina Difosfato N-Acetilglicosamina/farmacologia , Biomarcadores/metabolismo , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Doenças das Cartilagens/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Colágeno Tipo II/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Glicosilação/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Fosforilação/efeitos dos fármacos
17.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298869

RESUMO

Interactions of drugs with the classical epigenetic mechanism of DNA methylation or histone modification are increasingly being elucidated mechanistically and used to develop novel classes of epigenetic therapeutics. A data science approach is used to synthesize current knowledge on the pharmacological implications of epigenetic regulation of gene expression. Computer-aided knowledge discovery for epigenetic implications of current approved or investigational drugs was performed by querying information from multiple publicly available gold-standard sources to (i) identify enzymes involved in classical epigenetic processes, (ii) screen original biomedical scientific publications including bibliometric analyses, (iii) identify drugs that interact with epigenetic enzymes, including their additional non-epigenetic targets, and (iv) analyze computational functional genomics of drugs with epigenetic interactions. PubMed database search yielded 3051 hits on epigenetics and drugs, starting in 1992 and peaking in 2016. Annual citations increased to a plateau in 2000 and show a downward trend since 2008. Approved and investigational drugs in the DrugBank database included 122 compounds that interacted with 68 unique epigenetic enzymes. Additional molecular functions modulated by these drugs included other enzyme interactions, whereas modulation of ion channels or G-protein-coupled receptors were underrepresented. Epigenetic interactions included (i) drug-induced modulation of DNA methylation, (ii) drug-induced modulation of histone conformations, and (iii) epigenetic modulation of drug effects by interference with pharmacokinetics or pharmacodynamics. Interactions of epigenetic molecular functions and drugs are mutual. Recent research activities on the discovery and development of novel epigenetic therapeutics have passed successfully, whereas epigenetic effects of non-epigenetic drugs or epigenetically induced changes in the targets of common drugs have not yet received the necessary systematic attention in the context of pharmacological plasticity.


Assuntos
Epigênese Genética/efeitos dos fármacos , Preparações Farmacêuticas/administração & dosagem , Metilação de DNA/efeitos dos fármacos , Epigenômica/métodos , Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Humanos , Canais Iônicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo
18.
Toxicol Appl Pharmacol ; 426: 115644, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34252412

RESUMO

Per- and polyfluoroalkyl substances (PFAS) are pervasive in the environment resulting in nearly universal detection in people. Human serum PFAS concentrations are strongly associated with increased serum low-density lipoprotein cholesterol (LDL-C), and growing evidence suggests an association with serum triacylglycerides (TG). Here, we tested the hypothesis that perfluorooctanoic acid (PFOA) dysregulates liver and serum triacylglycerides in human peroxisome proliferator activated receptor α (hPPARα)-expressing mice fed an American diet. Mice were exposed to PFOA (3.5 mg/L) in drinking water for 6 weeks resulting in a serum concentration of 48 ± 9 µg/ml. In male and female hPPARα mice, PFOA increased total liver TG and TG substituted with saturated and monounsaturated fatty acids. Lack of expression of PPARα alone also increased total liver TG, and PFOA treatment had little effect on liver TG in PPARα null mice. In hPPARα mice, PFOA neither significantly increased nor decreased serum TG; however, there was a modest increase in TG associated with very low-density cholesterol particles in both sexes. Intriguingly, in female PPARα null mice, PFOA significantly increased serum TG, with a similar trend in males. PFOA also modified fatty acid and TG homeostasis-related gene expression in liver, in a hPPARα-dependent manner, but not in adipose. The results of our study and others reveal the importance of context (serum concentration and genotype) in determining the effect of PFOA on lipid homeostasis.


Assuntos
Caprilatos/toxicidade , Dieta Ocidental , Dislipidemias/induzido quimicamente , Fluorcarbonetos/toxicidade , Fígado/efeitos dos fármacos , PPAR alfa/genética , Animais , Peso Corporal/efeitos dos fármacos , Dislipidemias/genética , Dislipidemias/metabolismo , Dislipidemias/patologia , Feminino , Expressão Gênica/efeitos dos fármacos , Genótipo , Lipidômica , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Transgênicos , Tamanho do Órgão/efeitos dos fármacos , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Estados Unidos
19.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281170

RESUMO

miRNAs regulate gene expression post-transcriptionally in various processes, e.g., immunity, development, and diseases. Since their experimental analysis is complex, in silico target prediction is important for directing investigations. TnP is a candidate peptide for anti-inflammatory therapy, first discovered in the venom of Thalassophryne nattereri, which led to miRNAs overexpression in LPS-inflamed zebrafish post-treatment. This work aimed to predict miR-21, miR-122, miR-731, and miR-26 targets using overlapped results of DIANA microT-CDS and TargetScanFish software. This study described 513 miRNAs targets using highly specific thresholds. Using Gene Ontology over-representation analysis, we identified their main roles in regulating gene expression, neurogenesis, DNA-binding, transcription regulation, immune system process, and inflammatory response. miRNAs act in post-transcriptional regulation, but we revealed that their targets are strongly related to expression regulation at the transcriptional level, e.g., transcription factors proteins. A few predicted genes participated concomitantly in many biological processes and molecular functions, such as foxo3a, rbpjb, rxrbb, tyrobp, hes6, zic5, smad1, e2f7, and npas4a. Others were particularly involved in innate immunity regulation: il17a/f2, pik3r3b, and nlrc6. Together, these findings not only provide new insights into the miRNAs mode of action but also raise hope for TnP therapy and may direct future experimental investigations.


Assuntos
Anti-Inflamatórios/farmacologia , Venenos de Peixe/farmacologia , Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Peptídeos/farmacologia , Animais , Biologia Computacional/métodos , Simulação por Computador , Proteínas de Ligação a DNA/metabolismo , Ontologia Genética , Imunidade Inata/genética , Lipopolissacarídeos/farmacologia , MicroRNAs/biossíntese , MicroRNAs/metabolismo , Fatores de Transcrição/metabolismo , Transcriptoma , Peixe-Zebra
20.
Molecules ; 26(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204601

RESUMO

Interferonopathies are rare genetic conditions defined by systemic inflammatory episodes caused by innate immune system activation in the absence of pathogens. Currently, no targeted drugs are authorized for clinical use in these diseases. In this work, we studied the contribution of sulforaphane (SFN), a cruciferous-derived bioactive molecule, in the modulation of interferon-driven inflammation in an immortalized human hepatocytes (IHH) line and in two healthy volunteers, focusing on STING, a key-component player in interferon pathway, interferon signature modulation, and GSTM1 expression and genotype, which contributes to SFN metabolism and excretion. In vitro, SFN exposure reduced STING expression as well as interferon signature in the presence of the pro-inflammatory stimulus cGAMP (cGAMP 3 h vs. SFN+cGAMP 3 h p value < 0.0001; cGAMP 6 h vs. SFN+cGAMP 6 h p < 0.001, one way ANOVA), restoring STING expression to the level of unstimulated cells. In preliminary experiments on healthy volunteers, no appreciable variations in interferon signature were identified after SFN assumption, while only in one of them, presenting the GSTM1 wild type genotype related to reduced SFN excretion, could a downregulation of STING be recorded. This study confirmed that SFN inhibits STING-mediated inflammation and interferon-stimulated genes expression in vitro. However, only a trend towards the downregulation of STING could be reproduced in vivo. Results obtained have to be confirmed in a larger group of healthy individuals and in patients with type I interferonopathies to define if the assumption of SFN could be useful as supportive therapy.


Assuntos
Inflamação/metabolismo , Isotiocianatos/farmacologia , Sulfóxidos/farmacologia , Adulto , Linhagem Celular Tumoral , Feminino , Expressão Gênica/efeitos dos fármacos , Genótipo , Glutationa Transferase/metabolismo , Voluntários Saudáveis , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação/tratamento farmacológico , Interferons/efeitos adversos , Interferons/genética , Interferons/farmacologia , Isotiocianatos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Sulfóxidos/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...