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1.
Cell Rep ; 42(4): 112400, 2023 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-37071536

RESUMEN

Dysregulated amino acid increases the risk for heart failure (HF) via unclear mechanisms. Here, we find that increased plasma tyrosine and phenylalanine levels are associated with HF. Increasing tyrosine or phenylalanine by high-tyrosine or high-phenylalanine chow feeding exacerbates HF phenotypes in transverse aortic constriction and isoproterenol infusion mice models. Knocking down phenylalanine dehydrogenase abolishes the effect of phenylalanine, indicating that phenylalanine functions by converting to tyrosine. Mechanistically, tyrosyl-tRNA synthetase (YARS) binds to ataxia telangiectasia and Rad3-related gene (ATR), catalyzes lysine tyrosylation (K-Tyr) of ATR, and activates the DNA damage response (DDR) in the nucleus. Increased tyrosine inhibits the nuclear localization of YARS, inhibits the ATR-mediated DDR, accumulates DNA damage, and elevates cardiomyocyte apoptosis. Enhancing ATR K-Tyr by overexpressing YARS, restricting tyrosine, or supplementing tyrosinol, a structural analog of tyrosine, promotes YARS nuclear localization and alleviates HF in mice. Our findings implicate facilitating YARS nuclear translocation as a potential preventive and/or interfering measure against HF.


Asunto(s)
Insuficiencia Cardíaca , Tirosina-ARNt Ligasa , Animales , Ratones , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Daño del ADN , Lisina/genética , Fenilalanina , Tirosina/metabolismo , Tirosina-ARNt Ligasa/química , Tirosina-ARNt Ligasa/genética , Tirosina-ARNt Ligasa/metabolismo
2.
Food Chem ; 375: 131848, 2022 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-34924255

RESUMEN

Theaflavin-3,3'-digallate (TFDG) in black tea possesses several health benefits. However, low TFDG yields limit its application. Herein, tyrosinases from Bacillus megaterium (Bmtyrc) were used to synthesize TFDG. To improve the catalytic efficiency of tyrosinase, a directed evolution strategy and a high-throughput screening method was employed. Compared with the wild type, mutant Bmtyrc-3 (N205D/D166E/D167G/F197W) showed 6.46 and 4.91-folds higher specific activity and 51.97- and 1.95-folds higher Vmax values towards epigallocatechin gallate (EGCG) and epicatechin gallate (ECG), respectively. Moreover, Bmtyrc-3 displayed significantly enhanced catalytic efficiencies, and the space-time yield of TFDG was 35.35 g L-1d-1. Bmtyrc-3 presents a broader substrate binding area, caused by a mutation (N205D) encompassing the active site. Changes in the potential of the substrate binding site and hydrogen bonds, and the electrostatic effect on the protein surface resulted in an increased activity of the substrates EGCG and ECG.


Asunto(s)
Bacillus megaterium , Biflavonoides , Camellia sinensis , Catequina , Catequina/análogos & derivados , Monofenol Monooxigenasa ,
3.
Front Immunol ; 12: 679897, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34367139

RESUMEN

Intestinal microbiota dysbiosis is an established characteristic of ulcerative colitis (UC). Regulating the gut microbiota is an attractive alternative UC treatment strategy, considering the potential adverse effects of synthetic drugs used to treat UC. Kaempferol (Kae) is an anti-inflammatory and antioxidant flavonoid derived from a variety of medicinal plants. In this study, we determined the efficacy and mechanism of action of Kae as an anti-UC agent in dextran sulfate sodium (DSS)-induced colitis mice. DSS challenge in a mouse model of UC led to weight loss, diarrhea accompanied by mucous and blood, histological abnormalities, and shortening of the colon, all of which were significantly alleviated by pretreatment with Kae. In addition, intestinal permeability was shown to improve using fluorescein isothiocyanate (FITC)-dextran administration. DSS-induced destruction of the intestinal barrier was also significantly prevented by Kae administration via increases in the levels of ZO-1, occludin, and claudin-1. Furthermore, Kae pretreatment decreased the levels of IL-1ß, IL-6, and TNF-α and downregulated transcription of an array of inflammatory signaling molecules, while it increased IL-10 mRNA expression. Notably, Kae reshaped the intestinal microbiome by elevating the Firmicutes to Bacteroidetes ratio; increasing the linear discriminant analysis scores of beneficial bacteria, such as Prevotellaceae and Ruminococcaceae; and reducing the richness of Proteobacteria in DSS-challenged mice. There was also an evident shift in the profile of fecal metabolites in the Kae treatment group. Serum LPS levels and downstream TLR4-NF-κB signaling were downregulated by Kae supplementation. Moreover, fecal microbiota transplantation from Kae-treated mice to the DSS-induced mice confirmed the effects of Kae on modulating the gut microbiota to alleviate UC. Therefore, Kae may exert protective effects against colitis mice through regulating the gut microbiota and TLR4-related signaling pathways. This study demonstrates the anti-UC effects of Kae and its potential therapeutic mechanisms, and offers novel insights into the prevention of inflammatory diseases using natural products.


Asunto(s)
Antiinflamatorios/farmacología , Colitis/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Quempferoles/farmacología , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Animales , Biomarcadores , Colitis/etiología , Colitis/patología , Colitis/terapia , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , Trasplante de Microbiota Fecal , Femenino , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Lipopolisacáridos/efectos adversos , Ratones , Permeabilidad , ARN Ribosómico 16S
4.
Phytomedicine ; 38: 90-97, 2018 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-29425659

RESUMEN

BACKGROUND: Oxidative stress is concomitant with acetaminophen (APAP)-induced hepatotoxicity, which has been highlighted as therapeutic targets for such diseases. The berries of Seabuckthorn (Hippophae rhamnoides L.) have been traditionally used in Tibetan medicine for thousands of years. The effect of Seabuckthorn berry polysaccharide on drug- induced liver injury (DILI) has not yet been elucidated. PURPOSE: This study aims to investigate the protective effects and mechanisms of Seabuckthorn polysaccharide (SP) against APAP-induced hepatotoxicity. STUDY DESIGN: Sixty C57BL/6 mice were randomly divided into six groups (n = 10 per group), namely the control group (Ctrl), APAP-induced-liver injury group (APAP), NAC pretreated group (NAC), 100 mg/kg SP pretreated group (APAP/SP100), 200 mg/kg SP pretreated group (APAP/SP200) and 200 mg/kg SP pretreated group without APAP challenge (SP200). SP was given orally to mice for 30 consecutive days prior to APAP exposure (300 mg/kg). NAC (150 mg/kg) was administrated 1 h before APAP challenge. METHODS: ALT and AST were detected 16 h after APAP treatment; Hepatic expression of GSH, SOD, NO, iNOS and GSH-Px were examined. The expression of p-JNK, Bcl-2/Bax, p62, Keap-1 and SOD-2 was detected by Western blotting. The expression of Nrf-2 and its target genes HO-1, GCLC and NQO-1 were analyzed by RT-PCR and Western blotting. RESULTS: Pretreatment with SP led to decreased levels of ALT and AST in APAP mice, without affecting APAP metabolism. This was accompanied by diminished liver injuries, increased levels of GSH and GSH-Px, reduced NO and iNOS expression. SP increased the activity of SOD as well as SOD-2 expression in APAP mice. SP suppressed APAP-induced JNK phosphorylation and increased the ratio of Bcl-2/Bax. Furthermore, SP decreased the expression of Keap-1 and increased the nuclear expression of Nrf-2. The expression of Nrf-2 target gene HO-1 was increased by SP pretreatment in APAP mice. CONCLUSION: SP alleviates APAP-induced hepatotoxicity. The protective effects of SP are associated with the activation of the Nrf-2/HO-1-SOD-2 signaling pathway.


Asunto(s)
Acetaminofén/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Hippophae/química , Polisacáridos/farmacología , Sustancias Protectoras/farmacología , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Frutas/química , Glutatión/metabolismo , Hemo-Oxigenasa 1/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Extractos Vegetales/química , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/metabolismo
5.
Food Funct ; 8(9): 3130-3138, 2017 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-28766672

RESUMEN

The berries of Seabuckthorn (Hippophae rhamnoides L.) are traditional medicinal foods that have been used by Tibetans and Mongolians for thousands of years. The polysaccharides are the main components of Seabuckthorn berries, possessing immune stimulating, anti-cancer and anti-fatigue activities. The present study focused on evaluating the protective effects and mechanisms of Seabuckthorn berry polysaccharide (SP) against carbon tetrachloride (CCl4)-induced hepatotoxicity. Mice were orally administrated with 50, 100 and 200 mg kg-1 of SP once daily for 14 consecutive days prior to CCl4 challenge. Pretreatment with SP significantly decreased alanine transaminase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) levels, while increasing the levels of prealbumin (PALB) in the CCl4-challenged mice, which were accompanied by diminished liver injuries, increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, increased GSH levels, and reduced malondialdehyde (MDA) content. The pretreatment with SP also markedly reduced the CCl4-induced expression of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), inducible nitric oxide synthase (iNOS) and nitric oxide (NO). Furthermore, the pretreatment with SP decreased hepatic Toll-like receptor 4 (TLR4) expression and inhibited the phosphorylation of p38 MAPK, extracellular signal-regulated kinase (p-ERK), c-Jun N-terminal kinase (p-JNK) and nuclear factor-kappa B (NF-κB) in the CCl4-challenged mice. These results suggest that the pretreatment with SP protected against CCl4-induced liver damage via its anti-oxidative and anti-inflammatory activities. SP might be suitable for functional foods and natural drugs in preventing CCl4-induced hepatotoxicity.


Asunto(s)
Antiinflamatorios/administración & dosificación , Antioxidantes/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Hippophae/química , Extractos Vegetales/administración & dosificación , Polisacáridos/administración & dosificación , Alanina Transaminasa/genética , Alanina Transaminasa/metabolismo , Animales , Aspartato Aminotransferasas/genética , Aspartato Aminotransferasas/metabolismo , Tetracloruro de Carbono/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Frutas/química , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
6.
J Clin Invest ; 126(9): 3192-206, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27500489

RESUMEN

A rise in the occurrence of obesity has driven exploration of its underlying genetic basis and potential targets for intervention. GWAS studies have identified obesity susceptibility pathways involving several neuropeptides that control energy homeostasis, suggesting that variations in the genes that regulate food intake and energy expenditure may contribute to obesity. In this study, we identified 5 additional obesity loci, including a neuronal orphan GPCR called Gpr45, in a forward genetic screen of mutant mice generated by piggyBac insertional mutagenesis. Disruption of Gpr45 led to increased adiposity at the time of weaning and increases in body mass, fat content, glucose intolerance, and hepatic steatosis with advancing age. Mice with disruptions in Gpr45 also displayed a reduction in expression of the metabolic regulator POMC and less energy expenditure prior to the onset of obesity. Mechanistically, we determined that GPR45 regulates POMC expression via the JAK/STAT pathway in a cell-autonomous manner. Consistent with this finding, intraventricular administration of melanotan-2, an analog of the POMC derivative α-MSH, suppressed adult obesity in Gpr45 mutants. These results reveal that GPR45 is a regulator of POMC signaling and energy expenditure, which suggests that it may be a potential intervention target to combat obesity.


Asunto(s)
Regulación de la Expresión Génica , Hipotálamo/metabolismo , Obesidad/metabolismo , Proopiomelanocortina/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores del Ácido Lisofosfatídico/genética , Animales , Conducta Animal , Electrofisiología , Hígado Graso/metabolismo , Femenino , Glucosa/metabolismo , Hígado/metabolismo , Masculino , Ratones , Mutagénesis , Mutación , Neuropéptidos/metabolismo , Fenotipo , Receptores Acoplados a Proteínas G/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo
7.
Mol Cell ; 60(4): 661-75, 2015 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-26585387

RESUMEN

Elucidating the tumorigenic mechanism of R-2-hydroxyglutarate (R-2HG) is critical for determining how NADP(+)-IDH mutations cause cancer. Here we report that R-2HG induces cancerous metabolism and apoptosis resistance through promoting hypersuccinylation. By competitive inhibition of the mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH), R-2HG preferentially induced succinyl-CoA accumulation and hypersuccinylation in the mitochondria. IDH1 mutation-bearing glioma samples and cells were hypersuccinylated in the mitochondria. IDH1 mutation or SDH inactivation resulted in hypersuccinylation, causing respiration inhibition and inducing cancerous metabolism and mitochondrial depolarization. These mitochondrial dysfunctions induced BCL-2 accumulation at the mitochondrial membrane, leading to apoptosis resistance of hypersuccinylated cells. Relief of hypersuccinylation by overexpressing the desuccinylase SIRT5 or supplementing glycine rescued mitochondrial dysfunctions, reversed BCL-2 accumulation, and slowed the oncogenic growth of hypersuccinylated IDH1(R132C)-harboring HT1080 cells. Thus, R-2HG-induced hypersuccinylation contributes to the tumorigenicity of NADP(+)-IDH mutations, suggesting the potential of hypersuccinylation inhibition as an intervention for hypersuccinylation-related tumors.


Asunto(s)
Glutaratos/farmacología , Isocitrato Deshidrogenasa/genética , Mitocondrias/efectos de los fármacos , Mutación , Neoplasias Experimentales/metabolismo , Ácido Succínico/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Células HEK293 , Humanos , Ratones , Mitocondrias/metabolismo , Neoplasias Experimentales/genética , Succinato Deshidrogenasa/antagonistas & inhibidores
8.
J Ethnopharmacol ; 176: 69-78, 2015 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-26494508

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn (Hippophae rhamnoides L.) berries have been traditionally used to treat gastric disorders, cardiovascular problems, and liver injuries in oriental medicinal system. This study aimed to explore the protective effects and mechanisms of the polysaccharide extracts of Sea buckthorn (HRP) berries against lipopolysaccharide (LPS) and d-galactosamine hydrochloride (d-GalN)-induced acute liver failure in mice. MATERIALS AND METHODS: HRP was isolated by hot-water extraction and characterized by HPLC and infrared spectrum analysis. The total carbohydrate, uronic acid and protein contents of HRP were measured by a spectrophotometric method. Mice were orally administrated with HRP (50, 100, 200mg/kg) once daily for 14 consecutive days prior to the challenge with LPS (50 µg/kg) and d-GalN (300 mg/kg). Animals of positive control group were intraperitoneally injected with dexamethasone (10mg/kg). Mice were sacrificed at 8h after LPS/d-GalN injection. RESULTS: Pretreatment with HRP significantly inhibited LPS/d-GalN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, which were accompanied by alleviated liver injuries and reduced production of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). HRP was also found to reduce malondialdehyde (MDA) content and to restore superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities. Furthermore, HRP supplementation dose-dependently inhibited the expression of Toll-like receptor 4 (TLR4), phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated c-Jun N-terminal kinase (p-JNK), and phosphorylated mitogen activated protein kinase 38 (p-p38 MAPK) in the liver of LPS/d-GalN challenged mice. Pretreatment with HRP also inhibited LPS/d-GalN-induced activation and translocation of nuclear factor-κB (NF-κB). CONCLUSIONS: This study indicates that pretreatment with HRP protects against LPS/d-GalN-induced liver injury in mice via suppressing the TLR4-NF-κB signaling pathway. Sea buckthorn may be a hopeful drug for prevention of acute live injury.


Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Hippophae , Fallo Hepático Agudo/tratamiento farmacológico , Polisacáridos/uso terapéutico , Sustancias Protectoras/uso terapéutico , Alanina Transaminasa/sangre , Animales , Antiinflamatorios/análisis , Antiinflamatorios/farmacología , Antioxidantes/análisis , Antioxidantes/farmacología , Aspartato Aminotransferasas/sangre , Frutas , Galactosamina , Interleucina-1beta/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Fallo Hepático Agudo/inducido químicamente , Fallo Hepático Agudo/metabolismo , Fallo Hepático Agudo/patología , Masculino , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Extractos Vegetales/química , Polisacáridos/análisis , Polisacáridos/farmacología , Sustancias Protectoras/análisis , Sustancias Protectoras/farmacología , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/sangre , Superóxido Dismutasa/metabolismo , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/sangre
9.
Early Hum Dev ; 67(1-2): 113-21, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11893442

RESUMEN

Recent neuronal activation studies have demonstrated the presence of regional cerebral blood flow (rCBF) increases in response to neuronal activation in normal newborns. In the present study, using near infrared spectroscopy (NIRS), we evaluated the evoked cerebral blood oxygenation (CBO) changes in hypoxic-ischemic encephalopathy (HIE) of newborns. We studied 20 normal newborns and 22 HIE newborns; mild HIE (n=9), moderate HIE (n=7), and severe HIE (n=6). The babies were from 1 to 3 days postdelivery. We measured the concentration changes of deoxyhemoglobin (Deoxy-Hb), oxyhemoglobin (Oxy-Hb), and total hemoglobin (Total-Hb) induced by auditory stimulation in the frontal lobes. The normal and HIE groups showed different Oxy-Hb and Total-Hb responses. In normal newborns, 19 out of 20 normal subjects showed increases of Oxy-Hb and Total-Hb, whereas 14 out of 22 subjects showed decreases of Oxy-Hb and Total-Hb during the stimulation (chi(2)=19.95, p<0.001). In addition, there was a strong negative correlation between HIE severity and changes of Total-Hb (r=-0.73, p<0.001). These results suggest that infants with HIE have decreased rCBF in the frontal lobes during auditory stimulation.


Asunto(s)
Estimulación Acústica , Hipoxia-Isquemia Encefálica/metabolismo , Oxígeno/metabolismo , Espectroscopía Infrarroja Corta/métodos , Telencéfalo/metabolismo , Circulación Cerebrovascular/fisiología , Femenino , Hemoglobinas/análisis , Hemoglobinas/metabolismo , Humanos , Recién Nacido , Masculino , Neuronas/metabolismo , Oxihemoglobinas/análisis , Oxihemoglobinas/metabolismo , Telencéfalo/irrigación sanguínea , Telencéfalo/citología
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