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1.
Appl Microbiol Biotechnol ; 104(5): 1849-1857, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31925484

RESUMO

This article summarizes the current knowledge about the presence of naproxen in the environment, its toxicity to nontarget organisms and the microbial degradation of this drug. Currently, naproxen has been detected in all types of water, including drinking water and groundwater. The concentrations that have been observed ranged from ng/L to µg/L. These concentrations, although low, may have a negative effect of long-term exposure on nontarget organisms, especially when naproxen is mixed with other drugs. The biological decomposition of naproxen is performed by fungi, algae and bacteria, but the only well-described pathway for its complete degradation is the degradation of naproxen by Bacillus thuringiensis B1(2015b). The key intermediates that appear during the degradation of naproxen by this strain are O-desmethylnaproxen and salicylate. This latter is then cleaved by 1,2-salicylate dioxygenase or is hydroxylated to gentisate or catechol. These intermediates can be cleaved by the appropriate dioxygenases, and the resulting products are incorporated into the central metabolism. KEY POINTS: •High consumption of naproxen is reflected in its presence in the environment. •Prolonged exposure of nontargeted organisms to naproxen can cause adverse effects. •Naproxen biodegradation occurs mainly through desmethylnaproxen as a key intermediate.


Assuntos
Exposição Ambiental/efeitos adversos , Naproxeno/metabolismo , Naproxeno/toxicidade , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade , Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/toxicidade , Organismos Aquáticos/efeitos dos fármacos , Organismos Aquáticos/metabolismo , Bacillus thuringiensis/metabolismo , Proteínas de Bactérias/metabolismo , Biodegradação Ambiental , Redes e Vias Metabólicas/efeitos dos fármacos , Naproxeno/análogos & derivados , Naproxeno/análise , Poluentes Químicos da Água/análise
2.
Biochim Biophys Acta Rev Cancer ; 1873(1): 188341, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31931113

RESUMO

Understanding the molecular mechanisms driving resistance to anti-cancer drugs is both a crucial step to define markers of response to therapy and a clinical need in many cancer settings. YAP and TAZ transcriptional cofactors behave as oncogenes in different cancer types. Deregulation of YAP/TAZ expression or alterations in components of the multiple signaling pathways converging on these factors are important mechanisms of resistance to chemotherapy, target therapy and hormone therapy. Moreover, response to immunotherapy may also be affected by YAP/TAZ activities in both tumor and microenvironment cells. For these reasons, various compounds inhibiting YAP/TAZ function by different direct and indirect mechanisms have been proposed as a mean to counter-act drug resistance in cancer. A particularly promising approach may be to simultaneously target both YAP/TAZ expression and their transcriptional activity through BET inhibitors.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Neoplasias/genética , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transativadores/genética , Fatores de Transcrição/genética , Microambiente Tumoral/genética
3.
Biochim Biophys Acta Rev Cancer ; 1873(1): 188332, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31751601

RESUMO

An important feature shared by many cancer cells is drastically altered metabolism that is critical for rapid growth and proliferation. The distinctly reprogrammed metabolism in cancer cells makes it possible to manipulate the levels of metabolites for cancer treatment. Citrate is a key metabolite that bridges many important metabolic pathways. Recent studies indicate that manipulating the level of citrate can impact the behaviors of both cancer and immune cells, resulting in induction of cancer cell apoptosis, boosting immune responses, and enhanced cancer immunotherapy. In this review, we discuss the recent developments in this emerging area of targeting citrate in cancer treatment. Specifically, we summarize the molecular basis of altered citrate metabolism in both tumors and immune cells, explore the seemingly conflicted growth promoting and growth inhibiting roles of citrate in various tumors, discuss the use of citrate in the clinic as a novel biomarker for cancer progression and outcomes, and highlight the new development of combining citrate with other therapeutic strategies in cancer therapy. An improved understanding of complex roles of citrate in the suppressive tumor microenvironment should open new avenues for cancer therapy.


Assuntos
Apoptose/efeitos dos fármacos , Ácido Cítrico/antagonistas & inibidores , Metabolismo Energético/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Apoptose/imunologia , Proliferação de Células/genética , Citrato (si)-Sintase/antagonistas & inibidores , Citrato (si)-Sintase/genética , Citrato (si)-Sintase/metabolismo , Ácido Cítrico/metabolismo , Humanos , Neoplasias/imunologia , Neoplasias/metabolismo , Interferência de RNA , Microambiente Tumoral/genética
4.
Int J Cancer ; 146(7): 1780-1790, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31291465

RESUMO

The prevalence of colorectal cancer (CRC) has markedly increased worldwide in the last decade. Alterations of bile acid metabolism and gut microbiota have been reported to play vital roles in intestinal carcinogenesis. About trillions of bacteria have inhabited in the human gut and maintained the balance of host metabolism. Bile acids are one of numerous metabolites that are synthesized in the liver and further metabolized by the gut microbiota, and are essential in maintaining the normal gut microbiota and lipid digestion. Multiple receptors such as FXR, GPBAR1, PXR, CAR and VDR act as sensors of bile acids have been reported. In this review, we mainly discussed interplay between bile acid metabolism and gut microbiota in intestinal carcinogenesis. We then summarized the critical role of bile acids receptors involving in CRC, and also addressed the rationale of multiple interventions for CRC management by regulating bile acids-microbiota axis such as probiotics, metformin, ursodeoxycholic acid and fecal microbiota transplantation. Thus, by targeting the bile acids-microbiota axis may provide novel therapeutic modalities in CRC prevention and treatment.


Assuntos
Transformação Celular Neoplásica/metabolismo , Microbioma Gastrointestinal , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Animais , Ácidos e Sais Biliares/metabolismo , Terapia Biológica , Biomarcadores , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Disbiose , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Mucosa Intestinal/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Terapia de Alvo Molecular , Ligação Proteica , Receptores Citoplasmáticos e Nucleares/metabolismo
5.
Life Sci ; 241: 117086, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31756344

RESUMO

BACKGROUND/AIMS: Recent studies have found vitamin D deficiency promotes fat deposition into the hepatocytes, thus contributing to the development of nonalcoholic fatty liver disease (NAFLD), which is a hepatic manifestation of metabolic syndrome. This study aimed to investigate the potential effects of vitamin D on NAFLD with the involvement of the p53 pathway. METHODS: Initially, an in vivo high-fat diet (HFD)-induced NAFLD mouse model was established. Then the HFD-induced NAFLD mice were treated with vitamin D. Next, the serum levels of TNF-α, GSH-px and malondialdehyde (MDA) were assessed using ELISA and ROS content was evaluated by flow cytometry, followed by the measurement of expression of Duox1, Duox2, SOD1, SOD2, PRDX1 I, ACC, SREBP1c, MTTP, PPARα, p53, p21 and p16 using RT-qPCR and Western blot analysis. Positive expression of FAS and FASL proteins was measured using immunohistochemistry. TUNEL and Senescence-associated ß-galactosidase (SA-ß-Gal) staining were subsequently conducted to assess the senescence and apoptosis of hepatocytes. RESULTS: HFD-induced mice treated with vitamin D presented with significantly increased GSH-px levels, as well as protein expression of SOD1, SOD2, PRDX1, MTTP and PPARα, but decreased MDA and ROS levels, expression of Duox1, Duox2, ACC, SREBP1c, p53, p21 and p16, positive expression of FAS and FASL proteins as well as impaired senescence and apoptosis of hepatocytes. CONCLUSION: Active vitamin D supplementation could potentially impede hepatocyte senescence and apoptosis via suppression of the p53 pathway, thus preventing the progression of NAFLD. Our study provides available evidence on the potential clinical utility of vitamin D supplementation in NAFLD.


Assuntos
Hepatócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Vitamina D/farmacologia , Animais , Apoptose/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Proteína Ligante Fas/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas/metabolismo , Esteroide Hidroxilases/genética , Proteína Supressora de Tumor p53/genética , Receptor fas/metabolismo
6.
J Pharm Biomed Anal ; 177: 112837, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31493746

RESUMO

The ambiguity of dose-effect relationship of many traditional Chinese medicines (TCMs) has always influenced their rational use in TCM clinic. Rhubarb, a preferred representative of cathartic TCM, is currently widely used that results in a diversity of its dosage. The aim of this study was to use an integrated metabolomics strategy to simultaneously reveal dose-effect relationship and therapeutic mechanisms of different efficacy of rhubarb in constipation rats. Six doses of rhubarb (0.135, 0.27, 0.81, 1.35, 4.05, and 8.1 g/kg) were examined to elucidate the laxative and fire-purging effects by pathological sections and UPLC-Q-TOF/MSE. The results showed that there existed serious lesions in the stomach and colon of model rats. And conditions were basically improved to some extent in rhubarb-treated groups. Through relative distance calculation based on metabolomics score plots, it suggested that the effective dose threshold (EC20-EC80 range) of rhubarb was from 0.31 to 4.5 g/kg (corresponding to 3.44-50.00 g in the clinic) in rat serum and 0.29-2.1 g/kg (corresponding to 3.22-23.33 g in the clinic) in feces. Then, 33 potential biomarkers were identified in total. Functional pathway analysis revealed that the alterations of these biomarkers were associated with 15 metabolic pathways, mainly including arachidonic acid metabolism, glycerophospholipid metabolism, steroid biosynthesis, primary bile acid biosynthesis and sphingolipid metabolism. Of note, different doses of rhubarb could alleviate endogenous disorders to varying degrees through regulating multiple perturbed pathways to the normal state, which might be in a dose-dependent manner and involved in therapeutic mechanisms. To sum up, integrated serum and fecal metabolomics obtained that rhubarb ranging from 0.31 to 2.1 g/kg is safe and effective for constipation treatment. Also, our findings showed that the robust metabolomics techniques would be promising to be more accurately used in the dose-effect studies of complex TCM, and to clarify syndrome pathogenesis and action mechanisms in Chinese medicine.


Assuntos
Constipação Intestinal/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Laxantes/administração & dosagem , Redes e Vias Metabólicas/efeitos dos fármacos , Rheum/química , Animais , Ácido Araquidônico/análise , Ácido Araquidônico/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Constipação Intestinal/sangue , Constipação Intestinal/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Fezes/química , Glicerofosfolipídeos/análise , Glicerofosfolipídeos/metabolismo , Humanos , Laxantes/isolamento & purificação , Masculino , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Ratos
7.
Food Chem ; 311: 126009, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31887558

RESUMO

Proteomics and metabolomics were used to study the changes in proteins and metabolites in tomato fruits at different ripening stages and the effect of salt treatment on fruit quality. The results showed 2607 and 153 differentially expressed proteins in ripe fruits compared with mature green fruits and in NaCl-treated ripe fruits compared with control ripe fruits, respectively. KEGG analysis indicated that these proteins were mainly involved in photosynthesis, pentose and glucuronate interconversions in different ripening stages of fruits, and salt-induced proteins were involved in flavonoid biosynthesis and linoleic acid metabolism. A series of metabolites, including carbohydrates and amino acids showed significantly different accumulations between ripe and mature green fruits and between salt-treated and control fruits. Combined analysis explored glycine, L-alanine, D-xylose and sucrose and some proteins involved in multiple metabolic pathways under salt conditions. Their interactions might affect fruit development and fruit quality under salt treatment.


Assuntos
Lycopersicon esculentum/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica , Proteômica , Cloreto de Sódio/farmacologia , Aminoácidos/metabolismo , Ácidos Graxos/metabolismo , Frutas/efeitos dos fármacos , Frutas/metabolismo , Lycopersicon esculentum/efeitos dos fármacos , Proteínas de Plantas/metabolismo
8.
J Agric Food Chem ; 67(49): 13568-13576, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31709793

RESUMO

Astaxanthin (AST) is a fat-soluble and non-vitamin A source of carotenoid that can quench reactive oxygen species and it has strong antioxidant and anti-inflammatory abilities. Herein, we have used H2O2 to establish a model of oxidative damage to RAW 264.7 cells and cells treated with vitamin C as the positive control group. The changes in metabolome were examined using 1H NMR and the results demonstrated that H2O2 treatment and various metabolic pathways such as amino acid, glucose, and glycerolipid metabolism were downregulated, which in turn affected citric acid cycle and energy status. AST could reverse downregulation of some of these metabolic pathways to a certain extent, and reduce cellular oxidative stress and death. The AST group differed from the vitamin C group in regulating d-glutamine, d-glutamic acid, pyruvate, and glycerolipid metabolism. The experimental results help to further understand the antioxidant effects of AST.


Assuntos
Antioxidantes/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Animais , Peróxido de Hidrogênio/toxicidade , Macrófagos/química , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7 , Xantofilas/farmacologia
9.
Life Sci ; 239: 116999, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31654746

RESUMO

AIMS: The present study aimed to investigate the effects of cyclophosphamide (Cytoxan, CTX) on premature ovarian failure (POF) in mice and its regulatory mechanisms by transcriptome analysis. MAIN METHODS: Female C57BL/6 mice were treated with a single intraperitoneal injection of 70 mg/kg CTX. Serum levels of estradiol (E2) and follicle stimulating hormone (FSH) were measured by enzyme-linked immunosorbent assay (ELISA), and follicular structure differences were observed by hematoxylin and eosin (H&E) staining. The main mechanism of POF was investigated by RNA-seq data, protein-protein interaction (PPI) networks and qPCR analysis. KEY FINDINGS: The serum levels of E2 were significantly decreased and those of FSH were significantly increased compared to the control group. The ovarian weights of the mice in the CTX group were reduced, and abnormal follicular structures were also observed in the CTX group. The RNA-seq data show that the downregulated genes were related to the cholesterol biosynthesis pathway. The PPI network and qPCR analyses further confirm that the PPAR signaling pathway and the ovarian infertility genes were also involved in blocking the cholesterol biosynthesis pathway. The differences were statistically significant. SIGNIFICANCE: Our results indicate that CTX may exert its anti-tumor effects by inactivating the cholesterol biosynthesis pathway, and simultaneously reducing the supply of estrogen precursor materials, ultimately leading to the occurrence of POF. Our data provided a preliminary theoretical basis for resolving the clinical toxicity and side effects of CTX.


Assuntos
Antineoplásicos Alquilantes/toxicidade , Colesterol/biossíntese , Ciclofosfamida/toxicidade , Perfilação da Expressão Gênica , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/metabolismo , Animais , Regulação para Baixo/efeitos dos fármacos , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/biossíntese , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Receptores Ativados por Proliferador de Peroxissomo/genética , Insuficiência Ovariana Primária/genética , Mapas de Interação de Proteínas
10.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(9): 990-995, 2019 Sep 28.
Artigo em Chinês | MEDLINE | ID: mdl-31645487

RESUMO

OBJECTIVE: To explore the renal metabolic markers relavant to the renal toxicity of diethylnitrosamine and the metabolic pathways involved in the renal metabolic markers.
 Methods: Nineteen Sprague Dawley rats were assigned into 2 groups: A normal control group (n=9) and a diethylnitrosamine (DEN) administration group (n=10). The rats in the normal control group were given sterilized water for free drinking. The rats in the DEN administration group were given 0.1 mg/mL DEN solution for free drinking. After 18 weeks, the kidney tissues were collected and tested for nuclear magnetic resonance detection and pathological examination.
 Results: The content of kidneys metabolites in the rats with the DEN administration was changed significantly. The levels of alanine, taurine, pyruvate, acetate, and choline were significantly reduced compared with rat in the normal control group, while the levels of creatine, glycine, TMAO, methionine, proline, lactate, valine, leucine and isoleucine were significantly increased.
 Conclusion: Metabolicomics studies have revealed significant differences in five metabolic pathways, including valine, leucine and isoleucine biosynthesis, glycine serine and threonine metabolism, pyruvate metabolism, glycolysis or gluconeogenesis, cysteine and methionine metabolism.


Assuntos
Alquilantes/toxicidade , Dietilnitrosamina/toxicidade , Rim/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Animais , Glicina , Rim/fisiologia , Ratos , Ratos Sprague-Dawley
11.
J Exp Clin Cancer Res ; 38(1): 406, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519186

RESUMO

Iron, an indispensable element for life, is involved in all kinds of important physiological activities. Iron promotes cell growth and proliferation, but it also causes oxidative stress damage. The body has a strict regulation mechanism of iron metabolism due to its potential toxicity. As a cancer of the bone marrow and blood cells, leukemia threatens human health seriously. Current studies suggest that dysregulation of iron metabolism and subsequent accumulation of excess iron are closely associated with the occurrence and progress of leukemia. Specifically, excess iron promotes the development of leukemia due to the pro-oxidative nature of iron and its damaging effects on DNA. On the other hand, leukemia cells acquire large amounts of iron to maintain rapid growth and proliferation. Therefore, targeting iron metabolism may provide new insights for approaches to the treatment of leukemia. This review summarizes physiologic iron metabolism, alternations of iron metabolism in leukemia and therapeutic opportunities of targeting the altered iron metabolism in leukemia, with a focus on acute leukemia.


Assuntos
Ferro/metabolismo , Leucemia/etiologia , Leucemia/metabolismo , Animais , Gerenciamento Clínico , Suscetibilidade a Doenças , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Humanos , Ferro/química , Leucemia/terapia , Redes e Vias Metabólicas/efeitos dos fármacos , Nanopartículas Metálicas/química , Terapia de Alvo Molecular , Oxirredução/efeitos dos fármacos , Estresse Oxidativo
12.
Int J Mol Sci ; 20(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533365

RESUMO

Turmeric, a popular ingredient in the cuisine of many Asian countries, comes from the roots of the Curcuma longa and is known for its use in Chinese and Ayurvedic medicine. Turmeric is rich in curcuminoids, including curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Curcuminoids have potent wound healing, anti-inflammatory, and anti-carcinogenic activities. While curcuminoids have been studied for many years, not much is known about their effects on steroid metabolism. Since many anti-cancer drugs target enzymes from the steroidogenic pathway, we tested the effect of curcuminoids on cytochrome P450 CYP17A1, CYP21A2, and CYP19A1 enzyme activities. When using 10 µg/ml of curcuminoids, both the 17α-hydroxylase as well as 17,20 lyase activities of CYP17A1 were reduced significantly. On the other hand, only a mild reduction in CYP21A2 activity was observed. Furthermore, CYP19A1 activity was also reduced up to ~20% of control when using 1-100 µg/ml of curcuminoids in a dose-dependent manner. Molecular docking studies confirmed that curcumin could dock onto the active sites of CYP17A1, CYP19A1, as well as CYP21A2. In CYP17A1 and CYP19A1, curcumin docked within 2.5 Å of central heme while in CYP21A2 the distance from heme was 3.4 Å, which is still in the same range or lower than distances of bound steroid substrates. These studies suggest that curcuminoids may cause inhibition of steroid metabolism, especially at higher dosages. Also, the recent popularity of turmeric powder as a dilatory supplement needs further evaluation for the effect of curcuminoids on steroid metabolism. The molecular structure of curcuminoids could be modified to generate better lead compounds with inhibitory effects on CYP17A1 and CYP19A1 for potential drugs against prostate cancer and breast cancer.


Assuntos
Curcumina/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Esteroides/metabolismo , Curcumina/química , Ativação Enzimática , Humanos , Relação Estrutura-Atividade
13.
Int J Mol Sci ; 20(19)2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31557807

RESUMO

EPA, an omega-3 polyunsaturated fatty acid, exerts beneficial effects on human health. However, the molecular mechanisms underlying EPA function are poorly understood. The object was to illuminate molecular mechanism underlying EPA's role. Here, 1H-NMR-based metabolic analysis showed enhanced branched-chain amino acids (BCAAs) and lactate following EPA treatment in skeletal muscle cells. EPA regulated mitochondrial oxygen consumption rate. Furthermore, EPA induced calcium/calmodulin-dependent protein kinase kinase (CaMKK) through the generation of intracellular calcium. This induced the phosphorylation of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38 MAPK) that led to glucose uptake, and the translocation of glucose transporter type 4 (GLUT4) in muscles. In conclusion, EPA exerts benign effects on glucose through the activation of AMPK-p38 MAPK signaling pathways in skeletal muscles.


Assuntos
Ácido Eicosapentaenoico/farmacologia , Glucose/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Monofosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Metabolismo dos Carboidratos/efeitos dos fármacos , Regulação da Expressão Gênica , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Consumo de Oxigênio/efeitos dos fármacos
14.
World J Gastroenterol ; 25(34): 5134-5151, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31558862

RESUMO

BACKGROUND: Tong Xie Yao Fang is a representative traditional Chinese prescription for the treatment of liver and spleen deficiency, abdominal pain and diarrhea. It has a unique function in the treatment of gastrointestinal dysfunction including irritable bowel syndrome (IBS), is a common functional bowel disease. Its main symptoms are recurrent abdominal pain, diarrhea, constipation or alternations between diarrhea and constipation. There are obvious differences in metabolites between TCM syndromes. By comparing the body fluid metabolism maps of model animals, metabolomics can discover disease biomarkers, analyze the differences in metabolic pathways and understand the pathological process and the metabolic pathways of substances in the body. Thus, the evaluation of animal models tends to be comprehensive and objective. This may provide further understanding between the interaction between Tong Xie Yao Fang and the IBS model. AIM: To evaluate the effect of Tong Xie Yao Fang on IBS rats by using metabolomics method. METHODS: Wistar rats were used to establish IBS models, and then randomly divided into four groups: A model control group and three Tong Xie Yao Fang treatment groups (high, medium and low doses). A normal, non-IBS group was established. The rats were treated for 2 wk. On days 0 and 14 of the experimental model, urine was collected for 12 h and was analyzed by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry. Nine potential biomarkers were identified, and six major metabolic pathways were found to be related to IBS. RESULTS: In the study of metabonomics, nine potential biomarkers including L-serine, 4-methylgallic acid, L-threonine, succinylacetone, prolyl-hydroxyproline, valyl-serine, acetyl citrate, marmesin rutinoside and 5-hydroxy-L-tryptophan were identified in urine, which were assigned to amino acids, organic acids, succinyl and glycosides. Furthermore, the metabolic pathway of L-serine, L-threonine and 5-hydroxy-L-tryptophan was found in the Kyoto Encyclopedia of Genes and Genomes, which mainly involved the metabolism of cysteine and methionine, vitamin B6 metabolism, serotonin synapse, tryptophan metabolism, sphingolipid metabolism, digestion, absorption of protein and amino acid metabolism. These pathways are related to intestinal dysfunction, inflammatory syndrome, nervous system dysfunction and other diseases. CONCLUSION: Tong Xie Yao Fang has pharmacological effects on IBS, and its mechanism may be related to the metabolism of the nine potential biomarkers identified above in urine.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Síndrome do Intestino Irritável/tratamento farmacológico , Redes e Vias Metabólicas/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Biomarcadores/urina , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Síndrome do Intestino Irritável/metabolismo , Síndrome do Intestino Irritável/urina , Masculino , Metabolômica , Ratos , Ratos Wistar
15.
Int J Food Microbiol ; 310: 108313, 2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31476580

RESUMO

Aflatoxin production of Aspergillus flavus is affected by abiotic factors such as temperature, water activity, oxidative stress, etc. These factors likely affect different metabolic pathways and result in altered aflatoxin production. Aflatoxin was determined in liquid media at 28 °C, solid media at 28 °C and solid media at 37 °C. The proteomic method was used to elucidate the mechanism of aflatoxin production in A. flavus in liquid media at 28 °C, solid media at 28 °C and solid media at 37 °C. Potential factors affecting aflatoxin production were found by GO and KEGG analysis. A. flavus produces more aflatoxin at 28 °C compared to 37 °C. Our study also found that A. flavus cultured on solid media produced more aflatoxin than in liquid media. In this study, we identified 5029 proteins from A. flavus NRRL3357, in which 1547 differential proteins were identified between liquid media and solid-state media, while 546 differential proteins were identified between 28 °C and 37 °C. Biological informatics analysis showed that these differential proteins were widely involved in a variety of biological processes, molecular functions, and cellular components, and were associated with multiple metabolic pathways. Compared to the liquid media, extracellular hydrolase for nutrient uptake and proteins related to sclerotia development were differentially expressed on solid media (p < 0.05). Enzymes involved in oxidative stress showed significantly down-regulated in liquid media and up-regulated at 28 °C (p < 0.05). Furthermore, our research also revealed aflatoxin synthesis is a complex process that is affected by a variety of factors such as nutrient uptake, oxidative stress, sclerotia development, G protein signaling pathways and valine, leucine and isoleucine degradation, and a speculative model summarizing the regulation of aflatoxin biosynthesis in A. flavus is presented.


Assuntos
Aflatoxinas/biossíntese , Aspergillus flavus/metabolismo , Meios de Cultura/farmacologia , Proteoma , Temperatura Ambiente , Aflatoxinas/genética , Aspergillus flavus/efeitos dos fármacos , Aspergillus flavus/genética , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Estresse Oxidativo/genética , Proteômica , Água/metabolismo
16.
Molecules ; 24(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480258

RESUMO

Gouty arthritis (GA) is commonly caused by deposition of monosodium urate (MSU) crystals within the joint capsule, bursa, cartilage, bone, or other periarticular tissues after chronic hyperuricemia. Clinically, GA is characterized by acute episodes of joint inflammation, which is most frequently encountered in the major joints, and also has a significant impact on quality of life. Pulchinenoside b4(P-b4) has a wide range of biological activities, including antitumor, anti-inflammatory, antiviral and immunomodulatory activities. Currently, the anti-GA activity and metabolomic profiles after being treated by P-b4 have not been reported. In this paper, for the first time, we have performed a non-targeted metabolomics analysis of serum obtained from an MSU crystal-induced GA rat model intervened by P-b4, using ultra-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry. In this study, the main pharmacodynamics of different dosing methods and dosages of P-b4 was firstly investigated. Results have shown that P-b4 possesses high anti-inflammatory activity. These results demonstrated changes in serum metabolites with 32 potential biomarkers. Arachidonic acid, sphingolipid, and glycerophospholipid metabolism are considered to be the most relevant metabolic pathway with P-b4 treatment effect in this study. Moreover, the changes of metabolites and the self-extinction of model effects within 24 h reveals important information for GA diagnostic criteria: The regression of clinical symptoms or the decline of some biochemical indicators cannot be regarded as the end point of GA treatment. Furthermore, our research group plans to conduct further metabolomics research on the clinical course of GA.


Assuntos
Artrite Gotosa/sangue , Artrite Gotosa/tratamento farmacológico , Cromatografia Líquida/métodos , Metabolômica , Espectrometria de Massas em Tandem/métodos , Triterpenos/administração & dosagem , Triterpenos/uso terapêutico , Animais , Artrite Gotosa/induzido quimicamente , Biomarcadores/sangue , Cristalização , Análise Discriminante , Modelos Animais de Doenças , Feminino , Articulações/patologia , Análise dos Mínimos Quadrados , Redes e Vias Metabólicas/efeitos dos fármacos , Análise Multivariada , Limiar da Dor , Análise de Componente Principal , Ratos Sprague-Dawley , Triterpenos/química , Triterpenos/farmacologia , Ácido Úrico
17.
Ecotoxicol Environ Saf ; 184: 109602, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31493589

RESUMO

Given the wide applications of engineered nanomaterials (ENMs) in various fields, the ecotoxicology of ENMs has attracted much attention. The traditional plant physiological activity (e.g., reactive oxygen species and antioxidant enzymes) are limited in that they probe one specific process of nanotoxicity, which may result in the loss of understanding of other important biological reactions. Metabolites, which are downstream of gene and protein expression, are directly related to biological phenomena. Metabolomics is an easily performed and efficient tool for solving the aforementioned problems because it involves the comprehensive exploration of metabolic profiles. To understand the roles of metabolomics in phytotoxicity, the analytical methods for metabolomics should be organized and discussed. Moreover, the dominant metabolites and metabolic pathways are similar in different plants, which determines the universal applicability of metabolomics analysis. The analysis of regulated metabolism will globally and scientifically help determine the ecotoxicology that is induced by ENMs. In the past several years, great developments in nanotoxicology have been achieved using metabolomics. However, many knowledge gaps remain, such as the relationships between biological responses that are induced by ENMs and the regulation of metabolism (e.g., carbohydrate, energy, amino acid, lipid and secondary metabolism). The phytotoxicity that is induced by ENMs has been explored by metabolomics, which is still in its infancy. The detrimental and defence mechanisms of plants in their response to ENMs at the level of metabolomics also deserve much attention. In addition, owing to the regulation of metabolism in plants by ENMs affected by multiple factors, it is meaningful to uniformly identify the key influencing factor.


Assuntos
Metaboloma/efeitos dos fármacos , Nanoestruturas/toxicidade , Plantas/efeitos dos fármacos , Plantas/metabolismo , Antioxidantes/metabolismo , Ecotoxicologia , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica , Nanoestruturas/química , Espécies Reativas de Oxigênio/metabolismo
18.
Ecotoxicol Environ Saf ; 184: 109606, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31472382

RESUMO

Epidemiological and animal studies have revealed a possible linkage between 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) exposure and neurodegenerative disease such as Parkinson's disease (PD). However, whether or how BDE-47 would affect the PD progression remains unclear. Here, we carried out a metabolomics study based on liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) to investigate the possible contribution of BDE-47 exposure to PD progression in Drosophila (fly) model. Transgenic PD flies were exposed to BDE-47 through diet for 30 days. Global metabolomic analysis identified 48 altered metabolites after the exposure. These metabolites were mainly involved in tryptophan metabolism, phenylalanine metabolism, purine metabolism, and alanine, aspartate and glutamate metabolism. Further, by quantifying metabolites of interest using LC-MS/MS, we confirmed that the formation of neuro-protector kynurenic acid was slowed down while the formation of neurotoxin 3-hydroxy-kynurenine was speeded up on the 20th exposure day. Moreover, the levels of SAM/SAH (an index of methylation potential) and GSH/GSSG (an indicator of oxidative stress) were found to decrease on the 30th exposure day. Our results suggest that BDE-47 could induce imbalance of kynurenine metabolism and methylation potential, and oxidative stress, which might further accelerate PD progression.


Assuntos
Exposição Dietética , Drosophila/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Animais , Modelos Animais de Doenças , Drosophila/metabolismo , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica , Metilação/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
19.
Biomed Pharmacother ; 118: 109393, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545258

RESUMO

OBJECTIVE: Diabetes mellitus is associated with gut microbiota disturbance and intestinal mucosal injuries. This study investigated the influence of propolis on the gut microbiota and intestinal mucosa in rats with diabetes. METHODS: Sprague-Dawley (SD) rats were randomly assigned to the control group, model group, and three propolis groups (supplemented with 80, 160, and 240 mg/kg·bw propolis, respectively). A high-fat diet combined with a streptozotocin (STZ) abdominal injection were used to induce diabetes in the rats. After 4 weeks, the intestinal histopathological analysis of the ileum was observed by transmission electron microscopy. The fasting blood glucose (FBG), plasma insulin, glucose tolerance (OGTT) and glycosylated hemoglobin (HbA1c) levels were measured. The expression of tight junction (TJ) proteins in the ileum was measured using western blotting. The molecular ecology of the fecal gut microbiota was analyzed by 16S rDNA high-throughput sequencing. The contents of the short-chain fatty acids (SCFAs) in feces were measured using high-performance liquid chromatography (HPLC). RESULTS: After propolis treatment, compared to the model group, FBG and HbA1c levels declined, while the glucose tolerance and insulin sensitivity index (ISI) increased. The levels of TJ proteins in the ileum increased in the propolis groups. The tight junctions and gap junctions of the intestinal epithelium were also improved in the propolis groups. The contents of the feces acetic acid, propionic acid and butyrate were increased in the propolis groups. 16S rDNA high-throughput sequencing revealed that the composition of the gut microbiota of rats in the propolis supplement group was significantly improved. CONCLUSIONS: Compared to the model group, propolis exerted hypoglycemic effects in diabetic rats, and it repaired intestinal mucosal damage, benefited the communities of the gut microbiota and increased SCFA levels in diabetic rats.


Assuntos
Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Experimental/fisiopatologia , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/fisiopatologia , Própole/farmacologia , Animais , Biodiversidade , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Jejum/sangue , Ácidos Graxos/metabolismo , Fezes/química , Íleo/efeitos dos fármacos , Íleo/patologia , Íleo/ultraestrutura , Insulina/sangue , Mucosa Intestinal/efeitos dos fármacos , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Filogenia , Ratos Sprague-Dawley
20.
Molecules ; 24(15)2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31390847

RESUMO

Diabetic kidney disease develops in approximately 40% of diabetic patients and is a major cause of chronic kidney diseases (CKD) and end stage kidney disease (ESKD) worldwide. Hydrogen sulfide (H2S), the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), is synthesized in nearly all organs, including the kidney. Though studies on H2S regulation of renal physiology and pathophysiology are still in its infancy, emerging evidence shows that H2S production by renal cells is reduced under disease states and H2S donors ameliorate kidney injury. Specifically, aberrant H2S level is implicated in various renal pathological conditions including diabetic nephropathy. This review presents the roles of H2S in diabetic renal disease and the underlying mechanisms for the protective effects of H2S against diabetic renal damage. H2S may serve as fundamental strategies to treat diabetic kidney disease. These H2S treatment modalities include precursors for H2S synthesis, H2S donors, and natural plant-derived compounds. Despite accumulating evidence from experimental studies suggests the potential role of the H2S signaling pathway in the treatment of diabetic nephropathy, these results need further clinical translation. Expanding understanding of H2S in the kidney may be vital to translate H2S to be a novel therapy for diabetic renal disease.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Avaliação Pré-Clínica de Medicamentos , Fibrose , Humanos , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/metabolismo , Podócitos/metabolismo , Podócitos/patologia , Sistema Renina-Angiotensina
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