Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 13.003
Filtrar
1.
J Oleo Sci ; 68(10): 995-1002, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582668

RESUMO

Coleus forskohlii extract (CFE), a popular weight-loss herbal product, induces hepatic cytochrome P450 (CYP) and fatty liver in mice; however, its main bioactive ingredient, forskolin, does not show such effects. To ensure the safety of CFE as a dietary supplement, identification of the compounds implicated in the induction of hepatic CYP and fatty liver is required. In this study, we separated a crude CFE extract into 5 fractions (Fr.) by column chromatography and administered the fractions to mice for one week to assess their ability to induce CYP and fatty liver. CYP induction was detected for all fractions, indicating that many compounds may be involved in CYP induction, while fatty liver was only detected for Fr. 2. Further isolation and purification of Fr. 2 by column chromatography identified 14-deoxycoleon U as a major compound and crocetin dialdehyde as a pigment compound. An in vivo mouse study revealed that crocetin dialdehyde had no effect on the liver and, as 14-deoxycoleon U was the major compound in Fr. 2, it is likely that the active compound inducing fatty liver in CFE is 14-deoxycoleon U. These findings will facilitate the preparation of standardized safe CFE ingredients for dietary supplements.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Fígado Gorduroso/induzido quimicamente , Fígado/efeitos dos fármacos , Fígado/enzimologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plectranthus/química , Animais , Indução Enzimática/efeitos dos fármacos , Fígado Gorduroso/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Extratos Vegetais/isolamento & purificação
3.
Med Hypotheses ; 131: 109314, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443750

RESUMO

Metabolic targeting of liver 5-aminolevulinate synthase (5-ALAS) by inhibition of heme utilisation by tryptophan (Trp) 2,3-dioxygenase (TDO) or the use of tryptophan is proposed as a therapy of acute hepatic porphyrias. 5-ALAS, the rate-limiting enzyme of heme biosynthesis, is under negative feedback control by a small regulatory heme pool in the hepatic cytosol. Acute porphyric attacks, precipitated by fasting, certain hormones and some drugs, involve induction of 5-ALAS secondarily to depletion of the above pool, and the resultant elevation of 5-ALA levels initiates the abdominal and neurological symptoms of attacks. By utilising the regulatory heme, cytosolic TDO undermines the feedback control, thus allowing 5-ALAS induction to occur, e.g. upon glucocorticoid induction of TDO during fasting (starvation) and exogenous glucocorticoid administration. Currently, glucose therapy is the preferred strategy for reversing moderate attacks induced by fasting (calorie restriction), with more severe attacks being treated by intravenous heme preparations. Reversal of fasting-induced attacks by glucose is explained by the previously demonstrated reversal of increased heme utilisation by TDO. Inhibitors of this utilisation are therefore potential therapeutic targets in acute attacks and also for maintenance of a symptomless state. Existing TDO inhibitors other than glucose include allopurinol, nicotinamide and recently developed potent inhibitors such as LM10 used in cancer therapy. Based on studies in rats, the hypothesis predicts that the safety or otherwise of drugs in the hepatic porphyrias is determined by their ability to inhibit TDO utilisation of heme under basal conditions or after glucocorticoid induction or heme activation of TDO, in parallel with reciprocal changes in 5-ALAS induction. Tryptophan is also proposed as a potential therapy of acute attacks either alone or as an adjunct to the recently proposed 5-ALAS1 gene silencing. Trp increases heme biosynthesis by enhancing 5-ALA dehydratase activity and, based on a Trp-5-ALA model presented herein, Trp offers several advantages over heme therapy, namely rapid conversion of 5-ALA into heme, a greatly enhanced heme availability, a near complete inhibition of 5-ALAS induction, assumed rapid clearance of 5-ALA and hence accelerated resolution of symptoms of attacks, and finally provision of the neuroprotective metabolite kynurenic acid to neutralise the neurological symptoms. The hypothesis also addresses heme regulation in species lacking the TDO free apoenzyme and its glucocorticoid induction mechanism and proposes detailed assessment of heme biosynthesis in these species. Detailed proposals for testing the hypothesis are presented.


Assuntos
5-Aminolevulinato Sintetase/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Heme/metabolismo , Terapia de Alvo Molecular , Porfirias Hepáticas/tratamento farmacológico , Triptofano Oxigenase/antagonistas & inibidores , Triptofano/uso terapêutico , 5-Aminolevulinato Sintetase/genética , Alopurinol/farmacologia , Alopurinol/uso terapêutico , Animais , Indução Enzimática/efeitos dos fármacos , Jejum/metabolismo , Retroalimentação Fisiológica , Inativação Gênica , Glucose/metabolismo , Glucose/uso terapêutico , Cobaias , Heme/uso terapêutico , Humanos , Cinurenina/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Modelos Biológicos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Porfirias Hepáticas/induzido quimicamente , Porfirias Hepáticas/genética , Porfirias Hepáticas/metabolismo , Roedores , Especificidade da Espécie , Triptofano/efeitos adversos , Triptofano/farmacologia
4.
Molecules ; 24(13)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284478

RESUMO

Dihydroartemisinin (DHA) is a derivative of the herb Artemisia annua L. that has prominent immunomodulatory activity; however, its underlying mechanism remains elusive. Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition characterized as an autoimmune disorder that includes dysfunctions in the T helper (Th)/T regulatory cell (Treg) balance, which normally plays pivotal roles in immune homeostasis. The aim of this study was to explore the potential of DHA to ameliorate IBD by restoring the Th/Treg cell balance. To this end, we established mouse models of colitis induced by oxazolone (OXA) and 2,4,6-trinitro-benzene sulfonic acid (TNBS). We then treated mice with DHA at 4, 8, or 16 mg/kg/day. DHA treatment ameliorated colitis signs and reduced lymphocyte infiltration and tissue fibrosis. Moreover, DHA decreased the numbers of Th1 and Th17 cells and Th9 and Th22 cells in TNBS- or OXA-induced colitis, respectively, and increased Tregs in both models. DHA (0.8 mg/mL) also inhibited activated CD4+ T lymphocytes, which was accompanied by apoptosis induction. Moreover, it promoted heme oxygenase-1 (HO-1) production in vitro and in vivo, concomitant with CD4+ T cell apoptosis and restoration of the Th/Treg balance, and these effects were blocked by treatment with the HO-1 inhibitor Sn-protoporphyrin IX. Overall, these results suggest that DHA is a novel and valuable candidate for IBD therapy or Th/Treg immunoregulation.


Assuntos
Apoptose , Artemisininas/uso terapêutico , Heme Oxigenase-1/biossíntese , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apoptose/efeitos dos fármacos , Artemisininas/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/imunologia , Modelos Animais de Doenças , Indução Enzimática/efeitos dos fármacos , Doenças Inflamatórias Intestinais/enzimologia , Ativação Linfocitária/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Camundongos , Oxazolona , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Ácido Trinitrobenzenossulfônico
5.
Cytogenet Genome Res ; 158(1): 17-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31261155

RESUMO

Osteoarthritis (OA) is a degenerative disease characterized by progressive articular cartilage destruction and joint marginal osteophyte formation with different degrees of synovitis. Docosahexaenoic acid (DHA) is an unsaturated fatty acid with anti-inflammatory, antioxidant, and antiapoptotic functions. In this study, the human chondrosarcoma cell line SW1353 was cultured in vitro, and an OA cell model was constructed with inflammatory factor IL-1ß stimulation. After cells were treated with DHA, cell apoptosis was measured. Western blot assay was used to detect protein expression of apoptosis-related factors (Bax, Bcl-2, and cleaved caspase-3) and mitogen-activated protein kinase (MAPK) signaling pathway family members, including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38 MAPK. Our results show that IL-1ß promotes the apoptosis of SW1353 cells, increases the expression of Bax and cleaved caspase-3, and activates the MAPK signaling pathway. In contrast, DHA inhibits the expression of IL-1ß, inhibits IL-1ß-induced cell apoptosis, and has a certain inhibitory effect on the activation of the MAPK signaling pathway. When the MAPK signaling pathway is inhibited by its inhibitors, the effects of DHA on SW1353 cells are weakened. Thus, DHA enhances the apoptosis of SW1353 cells through the MAPK signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Interleucina-1beta/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Butadienos/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Interleucina-1beta/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Nitrilos/farmacologia , Inibidores de Proteínas Quinases/farmacologia
7.
Prep Biochem Biotechnol ; 49(5): 521-528, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31017522

RESUMO

Staphylococcus aureus, among other staphylococcal species, developed multidrug resistance and causes serious health risks that require complex treatments. Therefore, the development of novel and effective strategies to combat these bacteria has been gaining importance. Since Staphylococcus simulans lysostaphin is a peptidoglycan hydrolase effective against staphylococcal species, the enzyme has a significant potential for biotechnological applications. Despite promising results of lysostaphin as a bacteriocin capable of killing staphylococcal pathogens, it is still not widely used in healthcare settings due to its high production cost. In this study, medium engineering techniques were applied to improve the expression yield of recombinant lysostaphin in E. coli. A new effective inducible araBAD promoter system and different mediums were used to enhance lysostaphin production. Our results showed that the composition of autoinduction media enhanced the amount of lysostaphin production 5-fold with the highest level of active lysostaphin at 30 °C. The production cost of 1000 U of lysostaphin was determined as 4-fold lower than the previously proposed technologies. Therefore, the currently developed bench scale study has a great potential as a large-scale fermentation procedure to produce lysostaphin efficiently.


Assuntos
Proteínas de Bactérias/biossíntese , Meios de Cultura/metabolismo , Lisostafina/biossíntese , Engenharia Metabólica/métodos , Proteínas Recombinantes/biossíntese , Arabinose/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Meios de Cultura/química , Indução Enzimática/efeitos dos fármacos , Estabilidade Enzimática , Escherichia coli/genética , Fermentação , Lisostafina/isolamento & purificação , Engenharia Metabólica/economia , Regiões Promotoras Genéticas/efeitos dos fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Staphylococcus/química , Staphylococcus/metabolismo , Temperatura Ambiente , Fatores de Tempo
8.
Biochem Biophys Res Commun ; 512(1): 7-13, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30853184

RESUMO

Fibrosis is a serious health problem often leading to accompanying organ failure. During the manifestation of the disease, an accumulation of different extracellular matrix (ECM) molecules, such as proteoglycans, takes place. There is no appropriate therapeutic option available to heal fibrosis to date. Current research focuses primarily on targets such as the cytokine transforming growth factor-ß1 (TGF-ß1), which is assumed to be one of the key mediators of fibrosis. Both xylosyltransferase isoforms, XT-I and XT-II, catalyze the rate-limiting step of the proteoglycan biosynthesis. Consequently, inhibiting XT activity could be a promising approach to treat fibrosis. It was shown in earlier studies that nucleotides and nucleosides have anti-fibrotic properties and decrease XT activity in cell-free systems. In contrast, we evaluated the mechanisms beyond an UDP-mediated induction of intracellular XT-activity in normal human dermal fibroblasts (NHDF). The observed pseudo-fibrotic XT increasement could be attributed to a compensation of decreased UDP-glucuronate decarboxylase 1 (UXS1) mRNA expression as well as a diminished intracellular UDP-xylose concentration. In summary, our results describe a so far unknown XT-inductive pathway and show that UDP could be a promising molecule for the development of an anti-fibrotic therapy. Nevertheless, XT activity has to be inhibited in parallel intracellularly.


Assuntos
Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Pentosiltransferases/biossíntese , Difosfato de Uridina/farmacologia , Carboxiliases/antagonistas & inibidores , Carboxiliases/genética , Carboxiliases/metabolismo , Células Cultivadas , Desenvolvimento de Medicamentos , Indução Enzimática/efeitos dos fármacos , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Fibroblastos/patologia , Fibrose/tratamento farmacológico , Fibrose/enzimologia , Fibrose/patologia , Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Xilose/metabolismo
9.
J Biochem Mol Toxicol ; 33(7): e22327, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30920066

RESUMO

The present study investigated the impact of coexposure to fluoride and diethylnitrosamine (DEN) on hepatorenal function in adult rats. The animals were exposed to fluoride (15 mg/L in drinking water) and DEN (10 mg/kg) singly or coexposed to both compounds for 14 days. Results demonstrated that the fluoride or DEN mediated increase in hepatorenal toxicity was intensified in the coexposure group. Additionally, the decrease in antioxidant enzyme activities as well as the elevation in reactive oxygen and nitrogen species, and lipid peroxidation was markedly aggravated in rats coexposed to DEN and fluoride. Furthermore, the increase in levels of nitric oxide, tumor necrosis factor-α and interleukin-1ß, myeloperoxidase and caspase-3 activities as well as histological lesions was more pronounced in the liver and kidney of rats coexposed to DEN and fluoride. Conclusively, coexposure to fluoride and DEN exacerbated hepatorenal damage via enhancement of oxido-inflammatory responses and caspase-3 activation in rats.


Assuntos
Caspase 3/metabolismo , Dietilnitrosamina/toxicidade , Fluoretos/toxicidade , Rim/metabolismo , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Indução Enzimática/efeitos dos fármacos , Rim/patologia , Fígado/patologia , Masculino , Ratos , Ratos Wistar
11.
Cell Mol Biol (Noisy-le-grand) ; 65(1): 94-99, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30782300

RESUMO

The present study was carried out to evolve an effective treatment strategy for chronic obstructive pulmonary disease (COPD). Astaxanthin (AS) is abundantly present in red pigments of crustaceans, and has also been proven to have considerable biological activities. The anti-inflammatory effect of AS was evaluated in lipopolysaccharide (LPS)-exposed RAW264.7 macrophages. It was found that AS markedly inhibited elevation of NO and pro-inflammatory mediators. Moreover, it downregulated iNOS in LPS-stimulated RAW264.7 cells, suppressed the release of pro-inflammatory cytokines, and decreased ROS levels in mice exposed to cigarette smoke (CS) and LPS. These results imply that AS has therapeutic and prophylactic potential in the airway inflammatory response associated with COPD.


Assuntos
Heme Oxigenase-1/biossíntese , Pneumonia/tratamento farmacológico , Pneumonia/etiologia , Fumar/efeitos adversos , Animais , Líquido da Lavagem Broncoalveolar , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Indução Enzimática/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Pulmão/enzimologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Pneumonia/genética , Pneumonia/patologia , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Xantofilas/química , Xantofilas/farmacologia , Xantofilas/uso terapêutico
12.
Eur J Med Chem ; 164: 391-398, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30611980

RESUMO

Although pediatric leukemia is generally treatable, certain leukemic subtypes face poor prognosis in the clinic suggesting new selective therapeutic agents are needed. Thus, to identify selective apoptosis inducers, a small-molecule library screening approach was conducted using an isogenic leukemic murine p185+ B-ALL cell line pair (BCR-ABL-WT and the BAX/BAK deficient BCR-ABL-DKO). Gratifyingly, the investigation revealed several compounds featuring substituted aromatic five-membered-ring heterocycles with significant activity against murine and human leukemic cellular models. The identified compounds represent potentially novel antileukemic molecular scaffolds exemplified by compounds 1, 2 and 7, which demonstrated EC50 values in the nanomolar and low micromolar range against various leukemia subtypes (SUP-B15, KOPN-8, NALM-06, UoC-B1 cellular models) and pro-apoptotic properties in solid tumor cell models (MDA-MB-231, SUM149) with ample therapeutic index in normal cells. Herein, we highlight compounds 1, 2 and 7 which promote cell death mediated by caspase 3/7 induction. Our study establishes a strategic platform for the development of potent and selective anti-leukemic agents.


Assuntos
Antineoplásicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Leucemia/tratamento farmacológico , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspases/genética , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Indução Enzimática/efeitos dos fármacos , Compostos Heterocíclicos/química , Humanos , Camundongos , Bibliotecas de Moléculas Pequenas/uso terapêutico , Índice Terapêutico
13.
Int J Biochem Cell Biol ; 108: 98-110, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30682488

RESUMO

Cholangiocarcinoma (CCA) is one of the most common fatal carcinomas and is well known to be lack of effective treatment. Thus, novel therapeutic strategies are greatly needed. Evodiamine, a quinozole alkaloid isolated from evodia rutaecarpa Bentham, has been demonstrated to exhibit anti-tumor effects on many cancer cells. However, little is known in terms of the effects on cholangiocarcinoma. In this study, we studied whether this traditional Chinese Medicine could serve as new potential therapeutic drugs to treat CCA. We discovered that evodiamine inhibited CCA cell proliferation and induced apoptosis. Moreover, evodiamine inhibited CCA cell migration and invasion. Mechanistically, our studies demonstrated that evodiamine inhibited the activation of IL-6 -induced STAT3 signaling activation, and the inhibitory effect was likely due to the upregulation of phosphatase shatterproof 2 (SHP-2), a negative feedback regulator of IL-6/STAT3. Blockage of SHP-2 through small interference RNA (siRNA) abolished the evodiamine -induced IL-6/STAT3 signaling inhibition. Moreover, in vivo experiment showed evodiamine inhibited the tumor growth of nude mice bearing TFK-1 xenografts. In summary, our results implied evodiamine as a promising anti-cancer agent in the treatment of CCA, and the mechanism is likely due to the inhibition of IL-6/STAT3 signaling with upregulating the expression levels of SHP-2.


Assuntos
Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/biossíntese , Quinazolinas/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Camundongos , Invasividade Neoplásica , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Arterioscler Thromb Vasc Biol ; 39(3): 387-401, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30651003

RESUMO

Objective- Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3; FURIN) as a member of several coronary artery disease-associated pathways. Thus, our objective is to determine the role of FURIN in atherosclerosis. Approach and Results- In vitro, FURIN inhibitor treatment resulted in reduced monocyte migration and reduced macrophage and vascular endothelial cell inflammatory and cytokine gene expression. In vivo, administration of an irreversible inhibitor of FURIN, α-1-PDX (α1-antitrypsin Portland), to hyperlipidemic Ldlr-/- mice resulted in lower atherosclerotic lesion area and a specific reduction in severe lesions. Significantly lower lesional macrophage and collagen area, as well as systemic inflammatory markers, were observed. MMP2 (matrix metallopeptidase 2), an effector of endothelial function and atherosclerotic lesion progression, and a FURIN substrate was significantly reduced in the aorta of inhibitor-treated mice. To determine FURIN's role in vascular endothelial function, we administered α-1-PDX to Apoe-/- mice harboring a wire injury in the common carotid artery. We observed significantly decreased carotid intimal thickness and lower plaque cellularity, smooth muscle cell, macrophage, and inflammatory marker content, suggesting protection against vascular remodeling. Overexpression of FURIN in this model resulted in a significant 67% increase in intimal plaque thickness, confirming that FURIN levels directly correlate with atherosclerosis. Conclusions- We show that systemic inhibition of FURIN in mice decreases vascular remodeling and atherosclerosis. FURIN-mediated modulation of MMP2 activity may contribute to the atheroprotection observed in these mice.


Assuntos
Aterosclerose/prevenção & controle , Furina/antagonistas & inibidores , Placa Aterosclerótica/tratamento farmacológico , alfa 1-Antitripsina/uso terapêutico , Animais , Aorta/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Artéria Carótida Primitiva , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Indução Enzimática/efeitos dos fármacos , Furina/genética , Furina/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Metaloproteinase 2 da Matriz/análise , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/fisiologia , Placa Aterosclerótica/patologia , Receptores de LDL/deficiência , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologia , Remodelação Vascular , alfa 1-Antitripsina/farmacologia
15.
Neurochem Res ; 44(1): 147-153, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29357018

RESUMO

Regulation of glutamate metabolism via glutamate dehydrogenase (GDH) might be the promising therapeutic approach for treating neurodegenerative disorders. In the central nervous system, glutamate functions both as a major excitatory neurotransmitter and as a key intermediate metabolite for neurons. GDH converts glutamate to α-ketoglutarate, which serves as a TCA cycle intermediate. Dysregulated GDH activity in the central nervous system is highly correlated with neurological disorders. Indeed, studies conducted with mutant mice and allosteric drugs have shown that deficient or overexpressed GDH activity in the brain can regulate whole body energy metabolism and affect early onset of Parkinson's disease, Alzheimer's disease, temporal lobe epilepsy, and spinocerebellar atrophy. Moreover, in strokes with excitotoxicity as the main pathophysiology, mice that overexpressed GDH exhibited smaller ischemic lesion than mice with normal GDH expression. In additions, GDH activators improve lesions in vivo by increasing α-ketoglutarate levels. In neurons exposed to an insult in vitro, enhanced GDH activity increases ATP levels. Thus, in an energy crisis, neuronal mitochondrial activity is improved and excitotoxic risk is reduced. Consequently, modulating GDH activity in energy-depleted conditions could be a sound strategy for maintaining the mitochondrial factory in neurons, and thus, protect against metabolic failure.


Assuntos
Sistemas de Liberação de Medicamentos/tendências , Glutamato Desidrogenase/metabolismo , Ácido Glutâmico/metabolismo , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Trifosfato de Adenosina/metabolismo , Animais , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Indução Enzimática/efeitos dos fármacos , Indução Enzimática/fisiologia , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Neuroproteção/efeitos dos fármacos , Neuroproteção/fisiologia
16.
Oncogene ; 38(4): 596-608, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30171263

RESUMO

Pancreas cancer cells have a tendency to invade along nerves. Such cancerous nerve invasion (CNI) is associated with poor outcome; however, the exact mechanism that drives cancer cells to disseminate along nerves is unknown. Immunohistochemical analysis of human pancreatic ductal adenocarcinoma (PDAC) specimens showed overexpression of the L1 cell adhesion molecule (L1CAM) in cancer cells and in adjacent Schwann cells (SC) in invaded nerves. By modeling the neural microenvironment, we found that L1CAM secreted from SCs acts as a strong chemoattractant to cancer cells, through activation of MAP kinase signaling. L1CAM also upregulated expression of metalloproteinase-2 (MMP-2) and MMP-9 by PDAC cells, through STAT3 activation. Using a transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we show that treatment with anti-L1CAM Ab significantly reduces CNI in vivo. We provide evidence of a paracrine response between SCs and cancer cells in the neural niche, which promotes cancer invasion via L1CAM secretion.


Assuntos
Carcinoma Ductal Pancreático/patologia , Metaloproteases/biossíntese , Invasividade Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Molécula L1 de Adesão de Célula Nervosa/fisiologia , Neoplasias Pancreáticas/patologia , Animais , Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/genética , Meios de Cultivo Condicionados , Indução Enzimática/efeitos dos fármacos , Humanos , Metaloproteases/genética , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/imunologia , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Células de Schwann/fisiologia , Regulação para Cima
17.
Int J Biol Macromol ; 126: 549-554, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30594624

RESUMO

NADPH oxidase-derived superoxide (O2-) generation is usually considered as an important factor to the pathogenesis of cardiovascular diseases. Nitric oxide (NO), previously viewed as a key regulator of cardiovascular function, is identified to induce expression of heme oxygenase-1 (HO-1), an antioxidant enzyme in blood vessels. In this study, we tested whether NO might modulate NADPH oxidase activity in vascular endothelium via HO-1. In vascular endothelial cells, NO donor (diethylenetriamine/nitric oxide adduct) significantly attenuated NADPH oxidase-derived O2- generation via a HO-1-dependent mechanism. Mechanistically, the protective effects of NO were (1) linked to increased expression of HO-1, (2) similar to the effects of NADPH oxidase inhibitor, (3) could be abolished by the specific siRNA against HO-1 expression or HO-1 activity inhibitor and (4) similar to the effects of HO-1 end product bilirubin. Moreover, bilirubin seemed to interrupt the assembly and activation of NADPH oxidase. In addition, NO inhibited H2O2-induced endothelial dysfunction through activation of HO-1. In agreement with these in vitro data, aortic NADPH oxidase activity was increased in NO-deficient mice while the endothelial function was simultaneously impaired. Our results suggested that suppression of NADPH oxidase-dependent oxidative stress may represent a novel mechanism underlying the cardiovascular protection of NO/HO-1 pathway.


Assuntos
Endotélio Vascular/metabolismo , Heme Oxigenase-1/metabolismo , NADPH Oxidases/metabolismo , Óxido Nítrico/farmacologia , Substâncias Protetoras/farmacologia , Superóxidos/metabolismo , Animais , Bilirrubina/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Indução Enzimática/efeitos dos fármacos , Heme Oxigenase-1/biossíntese , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Sístole/efeitos dos fármacos
18.
Chemosphere ; 218: 273-281, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30472611

RESUMO

Ultraviolet (UV) filters are widely used in personal care products and due to their lipophilicity these chemicals tend to bioaccumulate in the aquatic biota. 4-Methylbenzylidene camphor (4-MBC) is one of the most used UV-filters, and it is commonly detected in freshwater fish tissues. This substance is suspected to be an endocrine disruptor due to its interaction with Hypothalamus-Pituitary-Gonadal (HPG) and HP-Thyroid (HPT)-axis. The main objective of this study was to evaluate the effects of 4-MBC on apical endpoints, biochemical markers and on genes involved in endocrine pathways in Danio rerio. Zebrafish embryos were exposed to 4-MBC (0.083-0.77 mg/l) from 0 to 96 h post-fertilization (hpf). Hatching, heart rate and malformations were the apical endpoints assessed. Alterations on neurotransmission and oxidative stress were evaluated through acetylcholinesterase (AChE), catalase (CAT) and glutathione S-transferase (GST) enzymatic activities. Endocrine effects were analysed by the expression of genes involved in HPG and HPT-axis of embryos exposed 96 h to the EC10 of 4-MBC (0.19 mg/l). Exposure to 4-MBC induced morphological abnormalities during embryonic development, including notochord curvature, delayed absorption of yolk sac and pericardial oedema. Concentration of 0.77 mg/l 4-MBC decreased embryo heart rate at 48h. At neurotransmission level, an induction of AChE at concentrations above 0.15 mg/l was observed. Malformations and decreased heart rate along with alterations observed at neurotransmission level might have compromised zebrafish larvae equilibrium. Glutathione S-transferase induction above 0.15 mg/l 4-MBC suggests activation of detoxification processes. Furthermore, observed brain aromatase gene down-regulation by 4-MBC suggests impairment of normal functioning of HPG axis in zebrafish.


Assuntos
Cânfora/análogos & derivados , Embrião não Mamífero/efeitos dos fármacos , Peixe-Zebra/embriologia , Acetilcolinesterase/genética , Animais , Cânfora/toxicidade , Disruptores Endócrinos/farmacologia , Sistema Endócrino/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Filtração/instrumentação , Glutationa Transferase/genética , Estresse Oxidativo/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Peixe-Zebra/metabolismo
19.
J Biosci Bioeng ; 127(4): 486-491, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30366719

RESUMO

An inducer is crucial for cellulase production. In this study, duckweed was used as an inducer of cellulase production by Trichoderma reesei RUT C30. In a reaction induced by 50 g/L duckweed in shake flasks, the filter-paper activity (FPA) reached 6.5 FPU/mL, a value comparable to that induced by avicel. The enzyme-hydrolysis rate induced by steam-exploded corn stalk was 54.2%, representing a 28% improvement over that induced by avicel. The duckweed starch was hydrolyzed to glucose, which was subsequently used for biomass accumulation during the fermentation process. Furthermore, to optimize the control of the fermentation process, a combined substrate of avicel and duckweed was used to induce cellulase production by T. reesei RUT C30. The cellulase production and hydrolysis rates of the combined substrate, compared with avicel alone, were 39.6% and 36.7% higher, respectively. The results of this study suggest that duckweed is a good inducer of cellulase production in T. reesei, and it might aid in decreasing the cost of lignocellulosic materials hydrolysis.


Assuntos
Alismatales/fisiologia , Celulase/biossíntese , Trichoderma , Alismatales/química , Técnicas de Cultura Celular por Lotes , Biomassa , Celulose/farmacologia , Indução Enzimática/efeitos dos fármacos , Fermentação , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Hidrólise/efeitos dos fármacos , Extratos Vegetais/farmacologia , Vapor , Trichoderma/efeitos dos fármacos , Trichoderma/enzimologia , Trichoderma/genética , Trichoderma/metabolismo , Zea mays/química
20.
Sci Rep ; 8(1): 18051, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30575795

RESUMO

In methylotrophic yeasts, the expression of methanol-inducible genes is repressed by ethanol even in the presence of methanol, a phenomenon called ethanol repression. The mechanism of ethanol repression in Komagataella phaffii (Pichia pastoris) was studied, and acetyl-CoA synthesis from ethanol by sequential reactions of alcohol dehydrogenase, aldehyde dehydrogenase and acetyl-CoA synthetase (ACS) was involved in ethanol repression. Molecular analysis of the ACS-encoding gene product KpAcs1 revealed that its N-terminal motif, which is conserved in methylotrophic yeasts, was required for ethanol repression. ACS activity was downregulated during methanol-induced gene expression, which partially depended on autophagy. In addition, acetyl-CoA synthesis and phosphorylation of a transcription factor KpMxr1 were found to contribute to ethanol repression in a synergistic manner.


Assuntos
Acetilcoenzima A/biossíntese , Etanol/farmacologia , Metanol/farmacologia , Pichia/efeitos dos fármacos , Pichia/genética , Acetilcoenzima A/metabolismo , Indução Enzimática/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Organismos Geneticamente Modificados , Pichia/enzimologia , Pichia/metabolismo , Saccharomycetales/efeitos dos fármacos , Saccharomycetales/enzimologia , Saccharomycetales/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA