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1.
Int J Med Sci ; 17(16): 2511-2530, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029094

RESUMO

ShuFeng JieDu capsule (SFJDC), a traditional Chinese medicine, has been recommended for the treatment of COVID-19 infections. However, the pharmacological mechanism of SFJDC still remains vague to date. The active ingredients and their target genes of SFJDC were collected from TCMSP. COVID-19 is a type of Novel Coronavirus Pneumonia (NCP). NCP-related target genes were collected from GeneCards database. The ingredients-targets network of SFJDC and PPI networks were constructed. The candidate genes were screened by Venn diagram package for enrichment analysis. The gene-pathway network was structured to obtain key target genes. In total, 124 active ingredients, 120 target genes of SFJDC and 251 NCP-related target genes were collected. The functional annotations cluster 1 of 23 candidate genes (CGs) were related to lung and Virus infection. RELA, MAPK1, MAPK14, CASP3, CASP8 and IL6 were the key target genes. The results suggested that SFJDC cloud be treated COVID-19 by multi-compounds and multi-pathways, and this study showed that the mechanism of traditional Chinese medicine (TCM) in the treatment of disease from the overall perspective.


Assuntos
Antivirais/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Pneumonia Viral/tratamento farmacológico , Mapas de Interação de Proteínas/efeitos dos fármacos , Antivirais/química , Cápsulas/farmacologia , Caspase 3/genética , Caspase 8/genética , Infecções por Coronavirus/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Pandemias , Pneumonia Viral/genética , Mapas de Interação de Proteínas/genética , Fator de Transcrição RelA/genética
2.
Yakugaku Zasshi ; 140(10): 1199-1206, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999198

RESUMO

Potential risks to the fetus or infant should be considered prior to medication during pregnancy and lactation. It is essential to evaluate the exposure levels of drugs and their related factors in addition to toxicological effects. Epilepsy is one of the most common neurological complications in pregnancy; some women continue to use antiepileptic drugs (AEDs) to control seizures. Benzodiazepines (BZDs) are widely prescribed for several women who experience symptoms such as anxiety and insomnia during the postpartum period. In this review, we describe the 1) transport mechanisms of AEDs across the placenta and the effects of these drugs on placental transporters, and 2) the transfer of BZDs into breast milk. Our findings indicated that carrier systems were involved in the uptake of gabapentin (GBP) and lamotrigine (LTG) in placental trophoblast cell lines. SLC7A5 was the main contributor to GBP transport in placental cells. LTG was transported by a carrier that was sensitive to chloroquine, imipramine, quinidine, and verapamil. Short-term exposure to 16 AEDs had no effect on folic acid uptake in placental cells. However, long-term exposure to valproic acid (VPA) affected the expression of folate carriers (FOLR1, SLC46A1). Furthermore, VPA administration changed the expression levels of various transporters in rat placenta, suggesting that sensitivity to VPA differed across gestational stages. Lastly, we developed a method for quantifying eight BZDs in human breast milk and plasma using LC/MS/MS, and successfully applied it to quantify alprazolam in breast milk and plasma donated by a lactating woman.


Assuntos
Anticonvulsivantes/metabolismo , Benzodiazepinas/metabolismo , Transporte Biológico/genética , Aleitamento Materno , Gabapentina/metabolismo , Lactação/metabolismo , Lamotrigina/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/fisiologia , Troca Materno-Fetal , Leite Humano/metabolismo , Placenta/metabolismo , Ácido Valproico/metabolismo , Anticonvulsivantes/efeitos adversos , Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Linhagem Celular , Epilepsia/tratamento farmacológico , Feminino , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Gabapentina/efeitos adversos , Expressão Gênica/efeitos dos fármacos , Humanos , Lamotrigina/efeitos adversos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Transportador de Folato Acoplado a Próton/genética , Transportador de Folato Acoplado a Próton/metabolismo , Ácido Valproico/efeitos adversos
3.
Yakugaku Zasshi ; 140(10): 1207-1212, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999199

RESUMO

T-type calcium channels are low-threshold voltage-gated calcium channel and characterized by unique electrophysiological properties such as fast inactivation and slow deactivation kinetics. All subtypes of T-type calcium channel (Cav3.1, 3.2 and 3.3) are widely expressed in the central nerve system, and they have an important role in homeostasis of sleep, pain response, and development of epilepsy. Recently, several reports suggest that T-type calcium channels may mediate neuronal plasticity in the mouse brain. We succeeded to develop T-type calcium channel enhancer ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a]pyridine]-2-ene-3-carboxylate (SAK3) which enhances Cav3.1 and 3.3 currents in each-channel expressed neuro2A cells. SAK3 can promote acetylcholine (ACh) release in the mouse hippocampus via enhancing T-type calcium channel. In this review, we have introduced the role of T-type calcium channel, especially Cav3.1 channel in the mouse hippocampus based on our previous data using SAK3 and Cav3.1 knockout mice.


Assuntos
Canais de Cálcio Tipo T/efeitos dos fármacos , Canais de Cálcio Tipo T/fisiologia , Imidazóis/farmacologia , Neurônios/fisiologia , Compostos de Espiro/farmacologia , Acetilcolina/metabolismo , Animais , Encéfalo/fisiologia , Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/metabolismo , Células Cultivadas , Sistema Nervoso Central/metabolismo , Fenômenos Eletrofisiológicos , Epilepsia/etiologia , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Homeostase , Camundongos , Plasticidade Neuronal , Dor/etiologia , Ratos , Sono/fisiologia
4.
J Toxicol Sci ; 45(9): 549-558, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879254

RESUMO

Trimethyltin chloride (TMT) is a stabilizer by-product in the process of manufacturing plastic, which is a kind of very strong toxic substance, and has acute, cumulative and chronic toxicity. TMT may cause bradycardia in patients with occupational poisoning, the mechanism of which has not been reported. This study explored the mechanism of TMT resulting in bradycardia of C57BL/6 mice. TMT was administered to mice to measure heart rate, serum succinate dehydrogenase (SDH) level, and myocardial Na+/K+-ATPase activity and expression. The effects of TMT on myocardial apoptosis were observed by changing the expressions of caspase-3, Bax and Bcl-2 in myocardium. It was found that the heart rate and SDH activity in serum of mice gradually decreased with the increase of TMT dose compared with the control group. The activity and the expression of Na+/K+-ATPase in the heart tissue of mice exposed to TMT was measured and gradually decreased with the increase of dose and time. We measured the expression of Bcl-2, Bax, caspase-3 and cleaved caspase-3 in the heart tissues of TMT exposed mice and found that the expressions of Bax, caspase-3 and cleaved caspase-3 increased and the expressions of Bcl-2 decreased in the heart tissues of the TMT-exposed mice at different doses. With the extension of TMT exposure time, the expression of Bax and caspase-3 increased and the expression of Bcl-2 decreased in the heart tissues of TMT exposed mice. Our findings suggest the mechanisms of TMT resulting in bradycardia may be associated with the inhibited activity and decreased content of Na+/K+-ATPase, thus further leading to the changes of Bcl-2, Bax, caspase-3 and cleaved caspase-3 in the mice's ventricular tissues.


Assuntos
Apoptose/efeitos dos fármacos , Bradicardia/etiologia , Miocárdio/metabolismo , Miocárdio/patologia , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Compostos de Trimetilestanho/toxicidade , Animais , Apoptose/genética , Bradicardia/genética , Caspase 3/genética , Caspase 3/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
5.
Nat Commun ; 11(1): 4809, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968055

RESUMO

Kinase inhibitors (KIs) represent an important class of anti-cancer drugs. Although cardiotoxicity is a serious adverse event associated with several KIs, the reasons remain poorly understood, and its prediction remains challenging. We obtain transcriptional profiles of human heart-derived primary cardiomyocyte like cell lines treated with a panel of 26 FDA-approved KIs and classify their effects on subcellular pathways and processes. Individual cardiotoxicity patient reports for these KIs, obtained from the FDA Adverse Event Reporting System, are used to compute relative risk scores. These are then combined with the cell line-derived transcriptomic datasets through elastic net regression analysis to identify a gene signature that can predict risk of cardiotoxicity. We also identify relationships between cardiotoxicity risk and structural/binding profiles of individual KIs. We conclude that acute transcriptomic changes in cell-based assays combined with drug substructures are predictive of KI-induced cardiotoxicity risk, and that they can be informative for future drug discovery.


Assuntos
Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Perfilação da Expressão Gênica/métodos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Transcriptoma , Antineoplásicos/farmacologia , Cardiotoxicidade/tratamento farmacológico , Linhagem Celular , Relação Dose-Resposta a Droga , Aprovação de Drogas , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Análise de Regressão , Medição de Risco , Fatores de Risco , Alinhamento de Sequência , Estados Unidos , United States Food and Drug Administration
6.
Bull Environ Contam Toxicol ; 105(4): 559-564, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32974765

RESUMO

In this work, we propose to evaluate the effect of agriculture intensification under greenhouses on the biochemical and transcriptomic responses of the earthworms Eisenia andrei. This work was conducted on two sites in Téboulba and Sahline (Monastir governorate) and a control site in an experimental plot that is undergoing organic farming. For this purpose, the earthworms Eisenia andrei were exposed to the soils during 7 and 14 days. The physicochemical properties of the soils were analyzed. The biochemical biomarkers of metallothioneins (MTs) and malondialdehyde (MDA) accumulations were also assessed. Moreover, the gene expression level of the MTs was analyzed. The results of our study revealed a significant trace element accumulation accompanied by a high level of MDA and MT proteins. Moreover, a significant expression of the MT gene was observed in earthworms exposed to the soils from Sahline and Téboulba. Hence, this work reveals that intensive agriculture can affect the biological responses of earthworms and consequently, the soil's biofertility.


Assuntos
Agricultura , Biomarcadores Ambientais/fisiologia , Metais Pesados/metabolismo , Oligoquetos/efeitos dos fármacos , Poluentes do Solo/metabolismo , Solo/química , Agricultura/métodos , Animais , Expressão Gênica/efeitos dos fármacos , Malondialdeído/metabolismo , Metalotioneína/metabolismo , Oligoquetos/genética , Oligoquetos/metabolismo , Tunísia
7.
Ecotoxicol Environ Saf ; 203: 111041, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888612

RESUMO

Although the production and use of PCB153 have been banned globally, PCB153 pollution remains because of its persistence and long half-life in the environment. There is ongoing evidence that exposure to PCB153 may influence gut microbiota health and increase the risk of host health. It is needed to illuminate whether there are associations between gut microbiota dysregulation and PCB153-induced host diseases. Importantly, it is urgently needed to find specific strains as biomarkers to monitor PCB153 pollution and associated disorders. The work aims to investigate the change of gut microbiota composition, structure and diversity and various host physiological indexes, to ravel the chain causality of PCB153, gut microbiota health and host health, and to find potential gut microbiota markers for PCB153 pollution. Here, adult female mice were administrated with PCB153. Obtained results indicated that PCB153 led to gut microbiota health deterioration. PCB153 exposure also induced obesity, hepatic lipid accumulation, abdominal adipose tissue depots and dyslipidemia in mice. Furthermore, specific gut microbiota significantly correlated with the host health indexes. This work provides support for the relationship between gut microbiota aberrance derived from PCB153 and risk of host health, and offers some indications of possible indicative functions of gut microbiota on PCB153 pollution.


Assuntos
Dislipidemias/induzido quimicamente , Monitoramento Ambiental/métodos , Poluentes Ambientais/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/induzido quimicamente , Bifenilos Policlorados/toxicidade , Animais , Biomarcadores/análise , Colo/microbiologia , Dislipidemias/metabolismo , Dislipidemias/microbiologia , Feminino , Conteúdo Gastrointestinal/microbiologia , Microbioma Gastrointestinal/genética , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/microbiologia , RNA Ribossômico 16S
8.
Ecotoxicol Environ Saf ; 203: 111019, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888606

RESUMO

Sulfur dioxide (SO2) is one of the most common and harmful air pollutants. High concentrations of SO2 can induce a series of defensive responses in Arabidopsis plants. However, the role of photosynthesis in the plant response to SO2 stress is not clear. Here, we report the photosynthetic responses of Arabidopsis plants to SO2 stress. Exposure to 30 mg/m3 SO2 decreased stomatal conductance (Gs) and transpiration rate (Tr) but increased photosynthetic pigments and net photosynthetic rate (Pn). The contents of carbohydrates and sucrose were not altered. The transcript levels of most genes related to photosystem II (PSII), cytochrome b6/f (Cytb6f), photosystem I (PSI) and carbon fixation were upregulated, revealing one important regulatory circuit for the maintenance of chloroplast homeostasis under SO2 stress. Exposure to SO2 triggered reactive oxygen species (ROS) generation, accompanied by increases in superoxide dismutase (SOD) activity and the contents of cysteine (Cys), glutathione (GSH) and non-protein thiol (NPT), which maintained cellular redox homeostasis. Together, our results indicated that chloroplast photosynthesis was involved in the plant response to SO2 stress. The photosynthetic responses were related to photosynthetic pigments, photosynthesis gene expression and redox regulation.


Assuntos
Poluentes Atmosféricos/toxicidade , Arabidopsis/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Pigmentos Biológicos/metabolismo , Dióxido de Enxofre/toxicidade , Arabidopsis/genética , Arabidopsis/metabolismo , Cloroplastos/metabolismo , Regulação para Baixo , Fotossíntese/genética , Complexo de Proteína do Fotossistema I/metabolismo , Complexo de Proteína do Fotossistema II/metabolismo , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Regulação para Cima
9.
Am J Chin Med ; 48(6): 1475-1489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907364

RESUMO

Inadequate responses to traditional chemotherapeutic agents in cholangiocarcinoma (CCA) emphasize a requirement for new effective compounds for the treatment of this malignancy. This study aimed to investigate the antiproliferative property of cucurbitacin B on KKU-100 CCA cells. The determination of underlying molecular mechanisms was also carried out. The results revealed that cucurbitacin B suppressed growth and replicative ability to form colonies of CCA cells, suggesting the antiproliferative effect of this compound against the cells. Flow cytometry analysis demonstrated that the interfering effect of cucurbitacin B on the CCA cell cycle at the G2/M phase was accountable for its antiproliferation property. Accompanied with cell cycle disruption, cucurbitacin B altered the expression of proteins involved in the G2/M phase transition including downregulation of cyclin A, cyclin D1, and cdc25A, and upregulation of p21. Additional molecular studies demonstrated that cucurbitacin B suppressed the activation of focal adhesion kinase (FAK) which consequently resulted in inhibition of its kinase-dependent and kinase-independent downstream targets contributing to the regulation of cell proliferation including PI3K/PDK1/AKT and p53 proteins. In this study, the transient knockdown of FAK using siRNA was employed to ascertain the role of FAK in CCA cell proliferation. Finally, the effect of cucurbitacin B on upstream receptor tyrosine kinases regulating FAK activation was elucidated. The results showed that the inhibitory effect of cucurbitacin B on FAK activation in CCA cells is mediated via interference of EGFR and HER2 expression. Collectively, cucurbitacin B might be a promising drug for CCA treatment by targeting FAK protein.


Assuntos
Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Quinase Piruvato Desidrogenase (Transferência de Acetil)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Triterpenos/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Neoplasias dos Ductos Biliares/dietoterapia , Linhagem Celular Tumoral , Colangiocarcinoma/tratamento farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Triterpenos/uso terapêutico
10.
Am J Chin Med ; 48(6): 1369-1383, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32933311

RESUMO

Age-related myocardial dysfunction is a very large healthcare burden. Here, we aimed to investigate whether ginsenoside Rb1 (Rb1) improves age-related myocardial dysfunction and to identify the relevant molecular mechanism. Young mice and aged mice were injected with Rb1 or vehicle for 3 months. Then, their cardiac function was inspected by transthoracic echocardiography. Serum and myocardium tissue were collected from all mice for histological or molecular expression analyses, including aging-related proteins, markers relevant to fibrosis and inflammation, and markers indicating the activation of the nuclear factor-kappa B (NF-[Formula: see text]B) pathway. Compared with the control condition, Rb1 treatment significantly increased the ejection fraction percentage and significantly decreased the internal diameter and volume of the left ventricle at the end-systolic and end-diastolic phases in aged mice. Rb1 treatment reduced collagen deposition and collagen I, collagen III, and transforming growth factor-[Formula: see text]1 protein expression levels in aged hearts. Rb1 also decreased the aging-induced myocardial inflammatory response, as measured by serum or myocardial interleukin-6 and tumor necrosis factor-[Formula: see text] levels. Furthermore, Rb1 treatment in aged mice increased cytoplasmic NF-[Formula: see text]B but decreased nuclear NF-[Formula: see text]B, which indicated the suppression of the NF-[Formula: see text]B signaling pathway by regulating the translocation of NF-[Formula: see text]B. Rb1 could alleviate aging-related myocardial dysfunction by suppressing fibrosis and inflammation, which is potentially associated with regulation of the NF-[Formula: see text]B signaling pathway.


Assuntos
Envelhecimento , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , NF-kappa B/genética , NF-kappa B/metabolismo , Fitoterapia , Animais , Anti-Inflamatórios , Colágeno/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais , Volume Sistólico/efeitos dos fármacos
11.
Biomed Environ Sci ; 33(8): 583-592, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32933610

RESUMO

Objective: To screen the differentially expressed proteins (DEPs) in human bronchial epithelial cells (HBE) treated with atmospheric fine particulate matter (PM 2.5). Methods: HBE cells were treated with PM 2.5 samples from Shenzhen and Taiyuan for 24 h. To detect overall protein expression, the Q Exactive mass spectrometer was used. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and Perseus software were used to screen DEPs. Results: Overall, 67 DEPs were screened in the Shenzhen sample-treated group, of which 46 were upregulated and 21 were downregulated. In total, 252 DEPs were screened in the Taiyuan sample-treated group, of which 134 were upregulated and 118 were downregulated. KEGG analysis demonstrated that DEPs were mainly enriched in ubiquitin-mediated proteolysis and HIF-1 signal pathways in Shenzhen PM 2.5 samples-treated group. The GO analysis demonstrated that Shenzhen sample-induced DEPs were mainly involved in the biological process for absorption of various metal ions and cell components. The Taiyuan PM 2.5-induced DEPs were mainly involved in biological processes of protein aggregation regulation and molecular function of oxidase activity. Additionally, three important DEPs, including ANXA2, DIABLO, and AIMP1, were screened. Conclusion: Our findings provide a valuable basis for further evaluation of PM 2.5-associated carcinogenesis.


Assuntos
Poluentes Atmosféricos/análise , Brônquios/metabolismo , Células Epiteliais/metabolismo , Expressão Gênica/efeitos dos fármacos , Material Particulado/análise , Brônquios/efeitos dos fármacos , Biologia Computacional , Células Epiteliais/efeitos dos fármacos , Humanos , Espectrometria de Massas , Tamanho da Partícula , Proteômica
13.
Aquat Toxicol ; 227: 105586, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32882451

RESUMO

Estrogenic effects triggered by androgens have been previously shown in a few studies. Aromatization and direct binding to estrogen receptors (ERs) are the most proposed mechanisms. For example, previously, a modulation of vitellogenin A (VtgA) by testosterone (T), an aromatizable androgen, was reported in brown trout primary hepatocytes. The effect was reversed by an ER antagonist. In this study, using the same model the disruption caused by T and by the non-aromatizable androgen - dihydrotestosterone (DHT), was assessed in selected estrogenic targets. Hepatocytes were exposed (96 h) to six concentrations of each androgen. The estrogenic targets were VtgA, ERα, ERß1 and two zona pellucida genes, ZP2.5 and ZP3a.2. The aromatase CYP19a1 gene and the androgen receptor (AR) were also included. Modulation of estrogenic targets was studied by quantitative real-time PCR and immunohistochemistry, using an HScore system. VtgA and ERα were up-regulated by DHT (1, 10, 100 µM) and T (10, 100 µM). In contrast, ERß1 was down-regulated by DHT (10, 100 µM), and T (100 µM). ZP2.5 mRNA levels were increased by DHT and T (1, 10, 100 µM), while ZP3a.2 was up-regulated by DHT (100 µM) and T (10, 100 µM). Positive correlations were found between VtgA and ERα mRNA levels and ZPs and ERα, after exposure to both androgens. The mRNA levels of CYP19a1 were not changed, while AR expression tended to increase after micromolar DHT exposures. HScores for Vtg and ZPs corroborated the molecular findings. Both androgens triggered estrogen signaling through direct binding to ERs, most probably ERα.


Assuntos
Androgênios/toxicidade , Di-Hidrotestosterona/toxicidade , Estrogênios/metabolismo , Hepatócitos/efeitos dos fármacos , Testosterona/toxicidade , Truta/metabolismo , Poluentes Químicos da Água/toxicidade , Androgênios/metabolismo , Animais , Células Cultivadas , Di-Hidrotestosterona/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Estrogênios/genética , Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Cultura Primária de Células , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Testosterona/metabolismo , Vitelogeninas/genética , Vitelogeninas/metabolismo , Poluentes Químicos da Água/metabolismo
14.
Ecotoxicol Environ Saf ; 205: 111338, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956867

RESUMO

Lead (Pb) is well-recognized for its great hazards to human and wildlife health. It has negative influences on multiple organs and systems of birds. Especially, lead exposure caused adverse impacts on bird reproduction. In this study, one week old female Japanese quails were randomly allocated into four groups and each group was respectively fed with 0, 50 ppm, 500 ppm and 1000 ppm Pb in drinking water for 36 days to determine the effects of chronic lead exposure on ovarian development and function. The results showed that Pb did accumulate in the ovary and ovarian development was delayed by high dose lead exposure (500 ppm and 1000 ppm). Moreover, high Pb dosage induced ovarian histopathological damages characterized by granulosa cells disorganization, follicle atresia and interstitial cell degeneration. Meanwhile, the concentration of estradiol (E2) was significantly decreased and mRNA levels of genes involved with ovarian steroidogenesis were significantly down-regulated by high concentration Pb. In addition, Pb exposure caused increasing cell apoptosis and significant changes of the expression of genes involved with cell death in the ovary. High dose Pb exposure also inhibited thyroid hormone release and disrupted ovarian thyroid deiodination apart from causing thyroid histopathological injury such as follicular deformation and atrophy. The study indicated that Pb might cause ovarian malfunction by inducing ovary and thyroid microstructural damages, thyroid hormone and estrogen release inhibition and ovarian steroidogenesis disruption.


Assuntos
Coturnix/metabolismo , Poluentes Ambientais/toxicidade , Estradiol/metabolismo , Expressão Gênica/efeitos dos fármacos , Chumbo/toxicidade , Ovário/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Adolescente , Animais , Apoptose/efeitos dos fármacos , Coturnix/genética , Coturnix/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Poluentes Ambientais/metabolismo , Estradiol/genética , Feminino , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/patologia , Humanos , Chumbo/metabolismo , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Ovário/patologia , Distribuição Aleatória , Reprodução/efeitos dos fármacos , Reprodução/genética , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Hormônios Tireóideos/genética
15.
Nat Commun ; 11(1): 4903, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994412

RESUMO

The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with high reproducibility. The generation of a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene and its use in targeted ObLiGaRe results in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somatic in vivo editing can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse allows robust and tunable genome editing granting flexibility, speed and uniformity at less cost, leading to high throughput and practical preclinical in vivo therapeutic testing.


Assuntos
Sistemas CRISPR-Cas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Descoberta de Drogas/métodos , Edição de Genes/métodos , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteína 9 Associada à CRISPR/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Doxiciclina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Vetores Genéticos/genética , Células HEK293 , Ensaios de Triagem em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Transgênicos , RNA Guia/genética , Recombinação Genética/efeitos dos fármacos , Reprodutibilidade dos Testes , Ativação Transcricional/efeitos dos fármacos , Transfecção/métodos , Transgenes/genética
16.
Ecotoxicol Environ Saf ; 203: 110974, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888622

RESUMO

Ammonia (NH3), an environmental pollutant, poses a serious threat to human and avian health. Although previous studies have showed that NH3 caused kidney injury, the molecular mechanisms of nephrotoxicity induced by NH3 remain unclear. To explore the mechanisms of NH3 nephrotoxicity, a total of 36 broiler chicks at one day of age were exposed to NH3. After 42 days of exposure, blood samples were collected to determine creatinine and uric acid; and kidney samples were weighted and then collected to detect ultrastructural changes, oxidative stress parameters, ATPases, necroptosis- and mitochondrial dynamics-related genes. The results showed that chickens exposed to NH3 showed lower relative kidney weight and an increase concentration in serum creatinine and uric acid. NH3 exposure caused nephrocyte necrosis and increased the expression of necroptosis-related genes (TNF-α, RIPK1, RIPK3, MLKL, and JNK). Besides, the activities of antioxidant systems (SOD, CAT, GSH-Px, and T-AOC) were reduced, whereas the concentrations of H2O2 and MDA were elevated. Lower activities of ATPases were obtained in NH3 treatment groups. Furthermore, the mitochondrial fission-related genes drp1 and mff were activated, and mitochondrial fusion-related genes opa1, mfn1 and mfn2 were suppressed after NH3 exposure. Based on the above results, we conclude that NH3 caused-oxidative stress and mitochondrial dysfunction mediated nephrocyte necroptosis in chickens. This study may provide new insight into NH3 nephrotoxicity.


Assuntos
Amônia/toxicidade , Poluentes Ambientais/toxicidade , Rim/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Galinhas , Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/metabolismo , Rim/ultraestrutura , Testes de Função Renal , Dinâmica Mitocondrial/genética , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
17.
Gene ; 760: 145003, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32739587

RESUMO

Imiquimod (IMQ) is approved as a first-line treatment for genital warts caused by human papillomavirus (HPV) infection. However, the recurrence rate is very high. HPV E7 protein plays a critical role in HPV immune escape. However, the role of HPV11 E7 protein in genital warts recurrence during IMQ treatment is not clear. Here, we found that the expression profile of NHEK cells was obviously changed after IMQ treatment, and a large number of genes encoding cytokines and genes involved in cytokine-mediated signaling pathways and cellular metabolic signaling pathways were up- or downregulated. HPV11E7 overexpression inhibited the IMQ-induced production of of multiple chemokines and colony-stimulating factors in NHEK cells. Furthermore, we found that HPV11E7 could impair the activation of mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, our results suggested that HPV11 E7 diminishes the production of chemokines, colony-stimulating factors and other cytokines via inhibition of the MAPK signaling pathway, which suppresses the therapeutic effect of IMQ and promotes the recurrence of diseases, such as condyloma acuminatum.


Assuntos
Imiquimode/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Quimiocinas/biossíntese , Quimiocinas/genética , Quimiocinas/metabolismo , Fatores Estimuladores de Colônias/biossíntese , Fatores Estimuladores de Colônias/metabolismo , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Papillomavirus Humano 11/metabolismo , Humanos , Imiquimode/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Oncogênicas Virais/imunologia , Infecções por Papillomavirus/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
18.
PLoS One ; 15(8): e0237040, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764823

RESUMO

As type-I-allergies show an increasing prevalence in the general populace, orthodontic patients may also be affected by histamine release during treatment. Human periodontal ligament fibroblasts (PDLF) are regulators of orthodontic tooth movement. However, the impact of histamine on PDLF in this regard is unknown. Therefore PDLF were incubated without or with an orthodontic compressive force of 2g/cm2 with and without additional histamine. To assess the role of histamine-1-receptor (H1R) H1R-antagonist cetirizine was used. Expression of histamine receptors and important mediators of orthodontic tooth movement were investigated. PDLF expressed histamine receptors H1R, H2R and H4R, but not H3R. Histamine increased the expression of H1R, H2R and H4R as well as of interleukin-6, cyclooxygenase-2, and prostaglandin-E2 secretion even without pressure application and induced receptor activator of NF-kB ligand (RANKL) protein expression with unchanged osteoprotegerin secretion. These effects were not observed in presence of H1R antagonist cetirizine. By expressing histamine receptors, PDLF seem to be able to respond to fluctuating histamine levels in the periodontal tissue. Increased histamine concentration was associated with enhanced expression of proinflammatory mediators and RANKL, suggesting an inductive effect of histamine on PDLF-mediated osteoclastogenesis and orthodontic tooth movement. Since cetirizine inhibited these effects, they seem to be mainly mediated via histamine receptor H1R.


Assuntos
Histamina/farmacologia , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/fisiologia , Técnicas de Movimentação Dentária , Células Cultivadas , Cetirizina/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Expressão Gênica/efeitos dos fármacos , Histamina/fisiologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Mediadores da Inflamação/metabolismo , Modelos Biológicos , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligamento Periodontal/citologia , Ligante RANK/genética , Ligante RANK/metabolismo , Receptores Histamínicos H1/fisiologia , Estresse Mecânico
19.
Ecotoxicol Environ Saf ; 204: 111065, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32784014

RESUMO

In the present study, chemical analysis of contaminants (three classes of organic pollutants and seven metals) and elutriate toxicity test were adopted to evaluate the potential environmental hazards of dredged sediment samples from five sites (SS1-5) along Huangpu River Channel (Shanghai Harbor, China). The metal Pb, Cu, Cr, Zn and the organic pollutants including total hexachlorocyclohexane (HCHs) and total dichlorodiphenyltrichloroethane (DDTs) in the five samples exceeded the threshold for effects level (TEL) to varying degrees. The probable effect concentration quotients (QPECm) of contaminants from the five dredged samples were all above 0.25, which means potential toxicity risks. Elutriate toxicity tests using medaka fish (Oryzias melastigma) and manila clam (Ruditapes philippinarum) showed that SS2 caused mortality to both species and SS1 caused mortality to fish. To explore the molecular biomarkers that may reflect the toxic effects, differential expressed genes were identified by RNA-Seq-based transcriptome profiling from the survived clams exposed to the two polluted elutriates (SS1, SS2). In clams exposed to SS1 and SS2 elutriate, 368 and 860 differential expressed genes (DEGs) were up-regulated, 199 and 1304 genes were down-regulated, respectively. Fourteen DEGs were selected from the enriched pathways that reflect cytotoxicity and responses to xenobiotics for the following quantitative real time PCR analysis. The transcriptomic profiling and the selected gene's expression patterns from clams exposed to SS1 and SS2 showed significant differences with the non-contaminated and control groups. Using the expression data of the selected gene battery in Factor Analysis allowed the discrimination between contaminated and non-contaminated sites and may reflect an influence gradient of sites. The development of the assay of these molecular biomarkers may provide a rapid and high-throughput tool for the quality assessment of the dredging sediments.


Assuntos
Bivalves/efeitos dos fármacos , Monitoramento Ambiental/métodos , Expressão Gênica/efeitos dos fármacos , Sedimentos Geológicos/química , Rios/química , Poluentes Químicos da Água/toxicidade , Animais , Bivalves/genética , China , DDT/toxicidade , Hexaclorocicloexano/toxicidade , Metais Pesados/toxicidade , Testes de Toxicidade
20.
Life Sci ; 259: 118293, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32822714

RESUMO

AIMS: Liver fibrosis is an inflammatory and fibrogenic process that occurs following chronic liver damage. TGFß1 is the key inducer of fibrosis. MiR-21 and miR-122 are two miRNAs that their expression changes during fibrosis. In the present study, we investigate the effects of curcumin, quercetin, and atorvastatin on the expression levels of miR-21 and miR-122 and evaluated their correlation with TGFß1 expression in bile duct ligation (BDL)-induced fibrotic rats. MATERIALS AND METHODS: Thirty two adult male Wistar rats were divided into 8 groups (n = 8 for each): Sham, Sham + curcumin (100 mg/kg/day), Sham + quercetin (30 mg/kg/day), Sham + atorvastatin (15 mg/kg/day), BDL, BDL + curcumin, BDL + quercetin, BDL + atorvastatin and treated for four weeks via oral gavage. The expression of miR-21, miR-122, and TGFß1 was evaluated via RT-qPCR. KEY FINDINGS: The expression levels of TGFß1 and miR-21 were significantly increased in the BDL group compared to the Sham group (P < 0.05), but the expression of miR-122 was significantly decreased in the BDL group compared to the Sham group (P < 0.05). Curcumin, quercetin, and atorvastatin treatment lead to down-regulation of miR-21 and TGFß1 and up-regulation of miR-122 in the BDL groups. There was no significant difference between these drugs in altering gene expression and all had the same effects. Moreover, a direct significant correlation was observed between mir-21 and TGFß1 and an inverse significant correlation between mir-122 and TGFß1 expression. SIGNIFICANCE: In summary, targeting these molecular pathways may partially prevent the progression of liver fibrosis.


Assuntos
Atorvastatina/farmacologia , Curcumina/farmacologia , Cirrose Hepática/metabolismo , MicroRNAs/metabolismo , Quercetina/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
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