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1.
PLoS One ; 15(7): e0228429, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722679

RESUMO

Diabetes mellitus (DM) causes ototoxicity by inducing oxidative stress, microangiopathy, and apoptosis in the cochlear sensory hair cells. The natural anti-oxidant pterostilbene (PTS) (trans-3,5-dimethoxy-4-hydroxystylbene) has been reported to relieve oxidative stress and apoptosis in DM, but its role in diabetic-induced ototoxicity is unclear. This study aimed to investigate the effects of dose-dependent PTS on the cochlear cells of streptozotocin (STZ)-induced diabetic rats. The study included 30 albino male Wistar rats that were randomized into five groups: non-diabetic control (Control), diabetic control (DM), and diabetic rats treated with intraperitoneal PTS at 10, 20, or 40 mg/kg/day during the four-week experimental period (DM + PTS10, DM + PTS20, and DM + PTS40). Distortion product otoacoustic emission (DPOAE) tests were performed at the beginning and end of the study. At the end of the experimental period, apoptosis in the rat cochlea was investigated using caspase-8, cytochrome-c, and terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin end labeling (TUNEL). Quantitative real-time polymerase chain reaction was used to assess the mRNA expression levels of the following genes: CASP-3, BCL-associated X protein (BAX), and BCL-2. Body weight, blood glucose, serum insulin, and malondialdehyde (MDA) levels in the rat groups were evaluated. The mean DPOAE amplitude in the DM group was significantly lower than the means of the other groups (0.9-8 kHz; P < 0.001 for all). A dose-dependent increase of the mean DPOAE amplitudes was observed with PTS treatment (P < 0.05 for all). The Caspase-8 and Cytochrome-c protein expressions and the number of TUNEL-positive cells in the hair cells of the Corti organs of the DM rat group were significantly higher than those of the PTS treatment and control groups (DM > DM + PTS10 > DM + PTS20 > DM + PTS40 > Control; P < 0.05 for all). PTS treatment also reduced cell apoptosis in a dose-dependent manner by increasing the mRNA expression of the anti-apoptosis BCL2 gene and by decreasing the mRNA expressions of both the pro-apoptosis BAX gene and its effector CASP-3 and the ratio of BAX/BCL-2 in a dose-dependent manner (P < 0.05 compared to DM for all). PTS treatment significantly improved the metabolic parameters of the diabetic rats, such as body weight, blood glucose, serum insulin, and MDA levels, consistent with our other findings (P < 0.05 compared to DM for all). PTS decreased the cochlear damage caused by diabetes, as confirmed by DPOAE, biochemical, histopathological, immunohistochemical, and molecular findings. This study reports the first in vivo findings to suggest that PTS may be a protective therapeutic agent against diabetes-induced ototoxicity.


Assuntos
Cóclea/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Ototoxicidade/prevenção & controle , Estilbenos/farmacologia , Acústica , Animais , Peso Corporal/efeitos dos fármacos , Caspase 3/genética , Cóclea/patologia , Diabetes Mellitus Experimental/complicações , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Substâncias Protetoras/farmacologia , Ratos Wistar , Estilbenos/administração & dosagem , Estreptozocina , Proteína X Associada a bcl-2/genética
2.
J Agric Food Chem ; 68(5): 1436-1446, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31927917

RESUMO

High fructose intake promotes hepatic lipid accumulation. Pterostilbene, a natural analogue of resveratrol found in diet berries, exhibits a hepatoprotective property. Here, we studied the protection by pterostilbene against fructose-induced hepatic lipid accumulation and explored its possible mechanism. We observed a high expression of microRNA-34a (miR-34a, P < 0.05) and a low expression of its target, sirtuin1 (Sirt1, mRNA: P < 0.01; protein: P < 0.001), with the overactivation of downstream sterol regulatory element-binding protein-1 (SREBP-1) lipogenic pathway (nuclear SREBP-1 protein: P < 0.05; FAS and SCD1 mRNA: P < 0.01), in rat livers, as well as BRL-3A and HepG2 cells, stimulated by fructose. More interestingly, pterostilbene recovered the fructose-disturbed miR-34a expression (0.3-0.5-fold vs fructose control, P < 0.05), Sirt1 protein level (1.2- to 1.5-fold vs fructose control, P < 0.05), and SREBP-1 lipogenic pathway, resulting in significant amelioration of hepatocyte lipid accumulation in animal [hepatic triglyceride and total cholesterol (TG&TC) mg/g·wet tissue: 4.90 ± 0.19, 5.23 ± 0.16, 5.20 ± 0.29 vs fructose control 9.73 ± 1.06, P < 0.001; 3.18 ± 0.30, 3.31 ± 0.39, 3.37 ± 0.47 vs 5.67 ± 0.28, P < 0.001] and cell models (BRL-3A TG&TC mmol/g·protein: 0.123 ± 0.011 vs 0.177 ± 0.004, P < 0.001; 0.169 ± 0.011 vs 0.202 ± 0.008, P < 0.05; HepG2: 0.257 ± 0.005 vs 0.303 ± 0.016, P < 0.05; 0.143 ± 0.004 vs 0.201 ± 0.008, P < 0.001). These results provide the experimental evidence supporting the anti-lipogenic effect of pterostilbene against fructose-induced hepatic lipid accumulation via modulating the miR-34a/Sirt1/SREBP-1 pathway.


Assuntos
Frutose/metabolismo , Fígado/efeitos dos fármacos , MicroRNAs/metabolismo , Sirtuína 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Estilbenos/administração & dosagem , Animais , Colesterol/metabolismo , Frutose/efeitos adversos , Fígado/metabolismo , Masculino , MicroRNAs/genética , Ratos , Ratos Sprague-Dawley , Sirtuína 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/metabolismo
3.
Molecules ; 25(1)2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31935877

RESUMO

Increasing studies have reported that cancer stem cells (CSCs) play critical roles in therapeutic resistance, recurrence, and metastasis of tumors, including cervical cancer. Pterostilbene, a dimethylated derivative of resveratrol, is a plant polyphenol compound with potential chemopreventive activity. However, the therapeutic effect of pterostilbene against cervical CSCs remains unclear. In this study, we compared the anticancer effects of resveratrol and pterostilbene using both HeLa cervical cancer adherent and stem-like cells. Pterostilbene more effectively inhibited the growth and clonogenic survival, as well as metastatic ability of HeLa adherent cells than those of resveratrol. Moreover, the superior inhibitory effects of pterostilbene compared to resveratrol were associated with the enhanced activation of multiple mechanisms, including cell cycle arrest at S and G2/M phases, induction of ROS-mediated caspase-dependent apoptosis, and inhibition of matrix metalloproteinase (MMP)-2/-9 expression. Notably, pterostilbene exhibited a greater inhibitory effect on the tumorsphere-forming and migration abilities of HeLa cancer stem-like cells compared to resveratrol. This greater effect was achieved through more potent inhibition of the expression levels of stemness markers, such as CD133, Oct4, Sox2, and Nanog, as well as signal transducer and activator of transcription 3 signaling. These results suggest that pterostilbene might be a potential anticancer agent targeting both cancer cells and cancer stem-like cells of cervical cancer via the superior bioavailability to resveratrol.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Resveratrol/farmacocinética , Estilbenos/administração & dosagem , Estilbenos/farmacocinética , Neoplasias do Colo do Útero/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Disponibilidade Biológica , Biomarcadores , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Feminino , Expressão Gênica , Humanos , Estrutura Molecular , Resveratrol/química , Estilbenos/química , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia
4.
Gynecol Oncol ; 156(3): 545-551, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31932108

RESUMO

OBJECTIVE: Vascular co-option is a resistance mechanism to anti-angiogenic agents, but combinations of anti-vascular agents may overcome this resistance. We report a phase 1b and randomised phase 2 trial to determine the safety and efficacy of pazopanib with fosbretabulin. METHODS: Eligible patients had recurrent, epithelial ovarian cancer with a platinum-free interval (PFI) of 3 to 12 months. Patients were stratified according to PFI (>6 versus ≤6 months) and prior bevacizumab use. RESULTS: Twelve patients were treated in the phase 1b. Commonest grade ≥ 2 adverse events (AEs) were hypertension (100%), neutropenia (50%), fatigue (50%), vomiting (50%). There was one DLT (grade 3 fatigue). The recommended phase 2 dose level was fosbretabulin 54 mg/m2 on days 1, 8 and 15 and pazopanib 600 mg once daily (od), every 28 days, which was then compared to pazopanib 800 mg od in a randomised phase 2 trial. Twenty-one patients were randomised (1:1) in the phase 2 trial. In phase 1b and phase 2, four patients treated with pazopanib and fosbretabulin developed reversible, treatment-related cardiac AEs, leading to premature discontinuation of the study. In the phase 2 trial, the median PFS was 7.6 months (95% CI 4.1-not estimated) versus 3.7 months (95% CI 1.0-8.1) in favour of the experimental arm (HR 0.30, 95% CI 0.09-1.03, P = .06). CONCLUSIONS: It remains unclear whether pazopanib with with fosbretabulin is an efficacious regimen to treat epithelial ovarian cancer. Effective cardiac risk mitigation is needed to increase the tolerability and maximize patient safety in future trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Epitelial do Ovário/sangue , Carcinoma Epitelial do Ovário/irrigação sanguínea , Cardiotoxicidade/etiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Recidiva Local de Neoplasia , Neovascularização Patológica/sangue , Neovascularização Patológica/tratamento farmacológico , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/irrigação sanguínea , Intervalo Livre de Progressão , Pirimidinas/efeitos adversos , Estilbenos/administração & dosagem , Estilbenos/efeitos adversos , Sulfonamidas/efeitos adversos , Taxa de Sobrevida
5.
Life Sci ; 243: 117274, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31927046

RESUMO

AIMS: 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-d-glucoside (TSG) is the key bioactive ingredient extracted from Polygonum multiflorum Thumb. Pharmacological studies suggest that it exerts numerous biological effects, including anti-oxidant, anti-aging, and anti-inflammation. This study aimed at investigating the effect of TSG on diethylnitrosamine (DEN)-induced acute hepatotoxicity and DNA damage. MAIN METHODS: Fifty male C57BL/6 mice were randomly divided into 5 groups (n = 10 each): control, DEN, DEN+TSG (low), DEN+TSG (high) and TSG (high) groups. DEN (100 mg/kg) was injected intraperitoneally (i.p.) alone or with TSG (30 or 60 mg/kg, i.p.) for 5 consecutive days. KEY FINDINGS: TSG inhibited liver injury and inflammatory cell infiltration in DEN-treated mice. It also attenuated DEN-induced accumulation of reactive oxygen species (ROS), proinflammatory cytokines, and DNA damage. Moreover, TSG promoted the expression of nuclear erythroid 2-related factor 2 (Nrf2) target antioxidant genes by enhancing Nrf2 protein phosphorylation and nuclear translocation. As major phase I detoxification enzymes, cytochrome P450 family 2 subfamily E member 1 (CYP2E1) and cytochrome P450 1 subfamily A member 1 (CYP1A1) are responsible for the metabolic activation of DEN. We found that TSG administration inhibited CYP2E1 and CYP1A1 induction in DEN-treated mice. SIGNIFICANCE: These results indicate that TSG can alleviate DEN-induced acute hepatotoxicity by modulating the Nrf2-related antioxidant system and metabolic activation of DEN. Therefore, TSG might be a promising medication for DEN-induced liver injury treatment.


Assuntos
Alquilantes/toxicidade , Dano ao DNA , Dietilnitrosamina/toxicidade , Glucosídeos/farmacologia , Fígado/efeitos dos fármacos , Estilbenos/farmacologia , Animais , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Citocinas/metabolismo , Dietilnitrosamina/administração & dosagem , Relação Dose-Resposta a Droga , Glucosídeos/administração & dosagem , Mediadores da Inflamação/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Estilbenos/administração & dosagem
6.
J Anim Sci ; 98(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31822918

RESUMO

The present study explored the potential effect of pterostilbene as a prophylactic treatment on the lipopolysaccharide (LPS)-induced intestinal injury of broiler chickens by monitoring changes in mucosal injury indicators, redox status, and inflammatory responses. In total, 192 one-day-old male Ross 308 broiler chicks were randomly divided into four groups. This trial consisted of a 2 × 2 factorial design with a diet factor (supplemented with 0 or 400 mg/kg pterostilbene from 1 to 22 d of age) and a stress factor (intraperitoneally injected with saline or LPS at 5.0 mg/kg BW at 21 da of age). The results showed that LPS challenge induced a decrease in BW gain (P < 0.001) of broilers during a 24-h period postinjection; however, this decrease was prevented by pterostilbene supplementation (P = 0.031). Administration of LPS impaired the intestinal integrity of broilers, as indicated by increased plasma diamine oxidase (DAO) activity (P = 0.014) and d-lactate content (P < 0.001), reduced jejunal villus height (VH; P < 0.001) and the ratio of VH to crypt depth (VH:CD; P < 0.001), as well as a decreased mRNA level of jejunal tight junction protein 1 (ZO-1; P = 0.002). In contrast, pterostilbene treatment increased VH:CD (P = 0.018) and upregulated the mRNA levels of ZO-1 (P = 0.031) and occludin (P = 0.024) in the jejunum. Consistently, pterostilbene counteracted the LPS-induced increased DAO activity (P = 0.011) in the plasma. In addition, the LPS-challenged broilers exhibited increases in nuclear accumulation of nuclear factor kappa B (NF-κB) p65 (P < 0.001), the protein content of tumor necrosis factor α (P = 0.033), and the mRNA abundance of IL-1ß (P = 0.042) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3; P = 0.019). In contrast, pterostilbene inhibited the nuclear translocation of NF-κB p65 (P = 0.039) and suppressed the mRNA expression of IL-1ß (P = 0.003) and NLRP3 (P = 0.049) in the jejunum. Moreover, pterostilbene administration induced a greater amount of reduced glutathione (P = 0.017) but a lower content of malondialdehyde (P = 0.023) in the jejunum of broilers compared with those received a basal diet. Overall, the current study indicates that dietary supplementation with pterostilbene may play a beneficial role in alleviating the intestinal damage of broiler chicks under the conditions of immunological stress.


Assuntos
Galinhas/fisiologia , Suplementos Nutricionais/análise , Estilbenos/administração & dosagem , Estresse Fisiológico/imunologia , Animais , Biomarcadores/metabolismo , Galinhas/genética , Galinhas/imunologia , Dieta/veterinária , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Masculino , Malondialdeído/metabolismo , Ocludina/metabolismo , RNA Mensageiro/genética , Distribuição Aleatória
7.
Int J Nanomedicine ; 14: 8805-8818, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31806973

RESUMO

Purpose: The objective of the present study was to develop a liposomal drug delivery system based on combretastatin A4 (CA4) prodrugs modified with varying alkyl chains and investigate the in vitro drug conversion from prodrug and in vivo antitumor effect. Methods: The prodrug of CA4 was synthesized with stearyl chloride (18-carbon chain), palmitoyl chloride (16-carbon chain), myristoyl chloride (14-carbon chain), decanoyl chloride (10-carbon chain), and hexanoyl chloride (6-carbon chain) at the 3'-position of the CA4. Subsequently, it was encapsulated with liposomes through the thin-film evaporation method. Furthermore, the characteristics of prodrug-liposome were evaluated using in vitro drug release, conversion, and cytotoxicity assays, as well as in vivo pharmacokinetic, antitumor, and biodistribution studies. Results: The liposome system with loaded CA4 derivatives was successfully developed with nano-size and electronegative particles. The rate of in vitro drug release and conversion was reduced as the fatty acid carbon chain lengthened. On the contrary, in vivo antitumor effects were improved with the enlargement of the fatty acid carbon chain. The results of the in vivo pharmacokinetic and tissue distribution studies indicated that the reduced rate of CA4 release with a long carbon chain could prolong the circulation time and increase the drug concentration in the tumor tissue. Conclusion: These results suggested that the release or hydrolysis of the parent drug from the prodrug was closely related with the in vitro and in vivo properties. The slow drug release of CA4 modified with longer acyl chain could prolong the circulation time and increase the concentration of the drug in the tumor tissue. These effects play a critical role in increasing the antitumor efficacy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/administração & dosagem , Pró-Fármacos/química , Estilbenos/administração & dosagem , Acilação , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Lipossomos/química , Células MCF-7 , Masculino , Camundongos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacologia , Ratos Sprague-Dawley , Estilbenos/química , Estilbenos/farmacocinética , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Biomed Res Int ; 2019: 7196535, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828124

RESUMO

Polydatin (PD), an active component of Chinese herbs, is reported to have many biological functions, such as cardioprotective actions, anti-inflammatory activities, and antitumor effects. In this study, we investigated the effects of PD on body weight control, glucose and lipid metabolic regulation, and anti-inflammation in a high-fat-diet- (HFD-) induced obese mice model. After treatment of PD (100 mg/kg/d for 4 weeks), HFD mice reduced body weight, retroperitoneal fat mass, and adipose cell sizes; significantly lowered serum total cholesterol triglyceride (TG) and low-density lipoprotein (LDL) levels; and increased high-density lipoprotein (HDL) levels compared with the HFD control mice. Further studies showed that PD downregulated the mRNA and protein expressions of peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor involving in the regulation of adipocyte differentiation, in the retroperitoneal fat of HFD mice. Additionally, PD significantly upregulated the mRNA and protein expressions of leptin, an adipocyte-derived anorexic hormone that regulates food intake and energy expenditure, in the adipose tissues of HFD mice. Moreover, PD reduced the expression levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) in the retroperitoneal and epididymal tissues of HFD mice, suggesting that PD prevented adipose tissue inflammation. In conclusion, PD may serve as a pharmaceutic candidate for obesity-related lipid metabolism, anti-inflammation, and body weight loss.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Dieta Hiperlipídica , Glucosídeos/farmacologia , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Estilbenos/farmacologia , Administração Oral , Animais , Metabolismo Energético/efeitos dos fármacos , Glucosídeos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , PPAR gama/metabolismo , Estilbenos/administração & dosagem
9.
Biomed Res Int ; 2019: 9828397, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828153

RESUMO

Aims: To assess the efficacy of a micronized-palmitoylethanolamide-polydatin (m-PEA-Pol) based product on chronic pelvic pain and severity of other symptoms in interstitial cystitis/bladder pain syndrome (IC/BPS) patients refractory to conventional therapies. Methods: A pilot, open-label bicentric study was carried out involving 32 IC/BPS patients. Chronic, oral m-PEA-Pol treatment lasted 6 months. Bladder pain was evaluated using the visual analog scale, while changes from baseline in other urinary symptoms were evaluated by means of the O'Leary-Sant Interstitial Cystitis Symptom and Problem Index and the Pelvic Pain and Urgency/Frequency (PUF) symptom scale questionnaires. The generalized linear mixed model was used to evaluate significant mean changes across time. Results: A significant and progressive reduction of pain intensity was observed during m-PEA-Pol treatment (p < 0.0001 for reduction over time). The effect was associated with a reduction in severity of patients' symptoms evaluated with the O'Leary-Sant questionnaire (p=0.0110 and p=0.0014 for cystitis symptoms and problem mean scores, respectively) and the PUF scale (p=0.0163 and p=0.0005 for symptom and bother mean scores, respectively). m-PEA-Pol therapy elicited a significant reduction over time in the urinary frequency evaluated with voiding diary (p=0.0005) and a small but not significant improvement of bladder capacity. Conclusions: These data highlight the potential benefit of m-PEA-Pol in patients with rare pathology such as IC/BPS and confirm the good safety profile of micronized PEA-based products.


Assuntos
Cistite Intersticial/tratamento farmacológico , Etanolaminas/administração & dosagem , Glucosídeos/administração & dosagem , Ácidos Palmíticos/administração & dosagem , Dor Pélvica/tratamento farmacológico , Estilbenos/administração & dosagem , Administração Oral , Adulto , Idoso , Dor Crônica/tratamento farmacológico , Dor Crônica/patologia , Cistite Intersticial/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Dor Pélvica/patologia , Projetos Piloto , Micção/efeitos dos fármacos
10.
J Agric Food Chem ; 67(46): 12752-12760, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31642668

RESUMO

Atherosclerosis, the major risk of cardiovascular events, is a chronic vascular inflammatory disease. Pterostilbene is a naturally occurring dimethylated analogue of resveratrol and has recently been demonstrated to be beneficial against cardiovascular diseases. However, the underlying mechanisms of pterostilbene on atherosclerosis remain elusive. Experimental atherosclerosis was induced by a high-fat diet (HFD) in apolipoprotein E knockout (ApoE-/-) mice. Pterostilbene was administered intragastrically for 16 weeks. We found that pterostilbene significantly attenuated thoracic and abdominal atherosclerotic plaque formation in HFD-fed ApoE-/-mice, accompanied by modulated lipid profiles and reduced production of proinflammatory cytokines (including IL-6, IFN-γ, and TNF-α). In addition, pterostilbene restored vascular redox balance in thoracic and abdominal aorta, evidenced by enhanced catalase (CAT) expression and activities, and decreased malondialdehyde and H2O2 production. Notably, pterostilbene specifically induced CAT expression and activities in the vascular smooth muscle cells (VSMCs) of thoracic and abdominal aorta. In vitro, pterostilbene markedly promoted the expression and activity of CAT and decreased ox-low-density lipoprotein (LDL)-mediated VSMC proliferation and intracellular H2O2 production, which was abolished by CAT siRNA knockdown or inhibition. Pterostilbene-induced CAT expression was associated with inhibition of Akt, PRAS40, and GSK-3ß signaling activation and upregulation of PTEN. Our data clearly demonstrated that pterostilbene exerted an antiatherosclerotic effect by inducing CAT and modulating the VSMC function.


Assuntos
Aterosclerose/tratamento farmacológico , Catalase/metabolismo , Músculo Liso Vascular/enzimologia , Estilbenos/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Catalase/genética , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Oxirredução
11.
Food Funct ; 10(11): 7308-7314, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626263

RESUMO

Pterostilbene (PTE) is broadly found in berries and has antioxidant and anti-inflammatory properties. To examine the effect of PTE on acute liver injury, mice were administrated PTE prior to concanavalin A (ConA). The mice were divided into the following groups: (i) vehicle control, (ii) ConA alone, (iii) ConA with PTE at 10 mg kg-1 (PTE low dose, PTL), and (iv) ConA with PTE at 40 mg kg-1 (PTE high dose, PTH). After the ConA challenge, the mice showed prompt induction of intrahepatic IFN-γ and TNF-α, followed by tissue factor (TF), which aggravated the fibrin deposition and massive liver necrosis. However, these effects were significantly counteracted by the PTE pretreatment. Furthermore, PTE reversed the phosphorylation of ConA-induced intrahepatic inflammatory kinases including JNK, ERK1/2, p38 and p65. Interestingly, PTE did not directly act on the hepatocytes, but inhibited intrahepatic macrophage accumulation and TF generation by inhibiting the activation of inflammatory p38 MAPK. These results suggest a promising avenue for the exploration of pterostilbene in improving acute liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Macrolídeos/toxicidade , Estilbenos/farmacologia , Animais , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Fibrina/genética , Fibrina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Organismos Livres de Patógenos Específicos , Estilbenos/administração & dosagem , Tromboplastina/genética , Tromboplastina/metabolismo
12.
Biomater Sci ; 7(12): 5283-5291, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31603448

RESUMO

Inhibition of tumor growth and metastasis simultaneously is an important issue for tumor therapy. The CXCR4/CXCL12 axis plays a crucial role in cancer metastasis, and the blocking of the CXCR4/CXCL12 axis is an effective way of inhibiting cancer metastasis. Combretastatin A4 nanodrug (CA4-NPs), a neogenesis blood vascular disrupting agent, can accumulate around blood vessels and disrupt tumor neogenesis of blood vessels more efficaciously than typical small molecular drug combretastatin A4 phosphate (CA4P). However, in this work, we find that the CXCR4 expression is significantly enhanced in CA4-NPs-treated tumor tissues in a metastatic orthotopic 4T1 mammary adenocarcinoma mouse model. Considering that the overexpression of CXCR4 can promote tumor cell metastasis, a novel cooperative strategy that utilizes plerixafor (PLF, CXCR4 antagonist) with CA4-NPs for inhibiting tumor growth and metastasis simultaneously is developed. The combination of CA4-NPs (60 mg kg-1 on CA4 basis) + PLF shows remarkably enhanced antitumor efficacy. The tumor growth inhibition rate of the combination group reaches 91.3%, significantly higher than those of non-cooperative groups. In addition, the number of lung metastasis foci of the combination group is least among all groups. This cooperative strategy provides a useful method for inhibiting tumor growth and metastasis simultaneously, and gives the evidence to support the clinical use of the combination of vascular disruption agents and CXCR4 antagonists.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Compostos Heterocíclicos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Receptores CXCR4/genética , Estilbenos/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Humanos , Neoplasias Pulmonares/genética , Camundongos , Estilbenos/farmacologia , Nanomedicina Teranóstica , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
13.
BMC Complement Altern Med ; 19(1): 235, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477089

RESUMO

BACKGROUND: Oxyresveratrol is a major bioactive component derived from the heartwood of Artocarpus lacucha. This compound exerts several biological activities, including neuroprotective effects in vitro and in vivo. However, there is limited pharmacokinetic information on this compound, especially its distribution in neuronal tissue and its route of excretion. The aim of this study was to investigate the pharmacokinetic profiles of oxyresveratrol alone and in combination with piperine as a bioenhancer in rats. METHODS: Male Wistar rats were administered with oxyresveratrol 10 mg/kg, oxyresveratrol 10 mg/kg plus piperine 1 mg/kg via intravenous or oxyresveratrol 100 mg/kg, oxyresveratrol 100 mg/kg plus piperine 10 mg/kg via oral gavage. Plasma, internal organs, urine, and feces were collected. Determination of the oxyresveratrol concentration in biological samples was performed by liquid chromatography tandem mass spectrometry. RESULTS: The combination with piperine had shown a significantly higher maximum concentration in plasma approximately 1500 µg/L within 1-2 h after oral dosing, and could increase oral bioavailability of oxyresveratrol approximately 2-fold. Oxyresveratrol could widely distributed most of the internal organs with a tissue to plasma ratio of 10-100 fold within 5 min after dosing. Urinary excretion of oxyresveratrol glucuronide was the major route of excretion after administration of oxyresveratrol alone and in combination with piperine. CONCLUSION: The addition of piperine could enhance some of the pharmacokinetic properties of oxyresveratrol via both intravenous and oral administration. This pharmacokinetic information will be useful for appropriate strategies to develop oxyresveratrol as a phytopharmaceutical product.


Assuntos
Alcaloides , Benzodioxóis , Piperidinas , Extratos Vegetais , Alcamidas Poli-Insaturadas , Estilbenos , Administração Intravenosa , Administração Oral , Alcaloides/administração & dosagem , Alcaloides/sangue , Alcaloides/farmacocinética , Alcaloides/urina , Animais , Artocarpus , Benzodioxóis/administração & dosagem , Benzodioxóis/sangue , Benzodioxóis/farmacocinética , Benzodioxóis/urina , Interações Medicamentosas , Masculino , Piperidinas/administração & dosagem , Piperidinas/sangue , Piperidinas/farmacocinética , Piperidinas/urina , Extratos Vegetais/administração & dosagem , Extratos Vegetais/sangue , Extratos Vegetais/farmacocinética , Extratos Vegetais/urina , Alcamidas Poli-Insaturadas/administração & dosagem , Alcamidas Poli-Insaturadas/sangue , Alcamidas Poli-Insaturadas/farmacocinética , Alcamidas Poli-Insaturadas/urina , Ratos , Ratos Wistar , Estilbenos/administração & dosagem , Estilbenos/sangue , Estilbenos/farmacocinética , Estilbenos/urina
14.
Food Funct ; 10(9): 6009-6019, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31482900

RESUMO

The major bioactive ingredient THSG of Polygonum multiflorum is well established for its anti-oxidation, anti-aging and anti-inflammation properties. Increasing evidence supports the capacity of THSG to ameliorate the biochemistry of neurotrophins and their downstream signaling axis in mouse models to attenuate neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In this study, the neuroprotective effects of THSG were studied in vitro and in vivo. In cultured mesencephalic dopamine neurons and SH-SY5Y cell line, it was found that THSG protected the integrity of the cell body and neurite branching from MPP+-induced toxicity by restoring the expression of FGF2 and BDNF and their downstream signaling pathways to inhibit apoptosis and promote cell survival. The inhibition of Akt signaling by LY294002 or TrkB activity by K252a eliminated the neuroprotective effects of THSG. In the MPTP-induced mouse models of Parkinson's disease, THSG ameliorated the animal behaviors against MPTP-induced neurotoxicity, which was demonstrated by the pole test and the tail suspension test. Biochemical and immunohistochemical analysis verified the THSG-mediated restoration of the FGF2-Akt and BDNF-TrkB signaling axis in the substantia nigra and corpus striatum and the recovery of dopaminergic neurons. These results establish the neuroprotective effects of THSG in vitro and in vivo and unravel the underlying mechanism against toxin-induced neural atrophy, providing a new avenue for the use and pharmacological research of edible medicine for anti-neurodegenerative diseases.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Fator 2 de Crescimento de Fibroblastos/metabolismo , Glucosídeos/administração & dosagem , Glicoproteínas de Membrana/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estilbenos/administração & dosagem , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , 1-Metil-4-fenilpiridínio/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Sobrevivência Celular/efeitos dos fármacos , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Fallopia multiflora/química , Fator 2 de Crescimento de Fibroblastos/genética , Humanos , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos
15.
Drug Des Devel Ther ; 13: 2811-2824, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496657

RESUMO

Background: Cadmium (Cd) is considered a heavy metal and potential pollutant to the environment. Purpose: The purpose of this study was to evaluate the protective potential of piceatannol (PT; 10 mg/kg body weight/day) against cadmium (Cd; 5 mg/kg body weight/day)-induced testicular dysfunction in Wistar rats. Materials and methods: Rats were randomly divided into four groups: control, PT, Cd, and Cd + PT. Results: Treatment with Cd resulted in a significant decrease in body, testicular, and epididymal weights, sperm quantity and quality, steroidogenic marker-enzyme activities, mRNA- and protein-expression levels of SF1, StAR, and P450 side chain-cleaving enzyme, and serum male sex hormonal levels when compared to controls. Testicular malondialdehyde levels were significantly increased, with a significant reduction in enzymatic and nonenzymatic antioxidants in Cd-treated rats compared to control rats. Testicular histomorphometric results supported the biochemical and molecular alterations observed in the study. In addition, significant downregulation in mRNA- and protein-expression levels of cytosolic Nrf2, HO1, γGCS, GPx, and NQO1, as well as significant upregulation in mRNA- and protein-expression levels of Nrf2 and Keap1 in testicular tissue, were noticed in rats administered Cd. PT treatment inCd-treated rats caused marked alleviation in body and organ weights, sperm analysis, steroidogenesis, serum hormonal levels, histomorphometric changes, and oxidative and antioxidative status in testes when compared to Cd alone-treated rats. Further, treatment of rats with PTl showed a marked improvement in mRNA- and protein-expression levels of Nrf2 and its regulated genes and proteins. Conclusion: The present study provides compelling evidence that PT treatment results in significant protection against Cd-induced testicular dysfunctions, such as spermatogenesis, steroidogenesis, and oxidative stress in rats, possibly through modification of the Nrf2-Keap1 signalling pathway.


Assuntos
Cádmio/toxicidade , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Esteroides/antagonistas & inibidores , Estilbenos/farmacologia , Testículo/efeitos dos fármacos , Administração Intravenosa , Administração Oral , Animais , Cádmio/administração & dosagem , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Esteroides/metabolismo , Estilbenos/administração & dosagem , Testículo/metabolismo
16.
Food Funct ; 10(8): 5115-5123, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31364649

RESUMO

Both as a food and an herbal plant, Polygonum multiflorum (PM) has long been used in food and prescriptions for several centuries in Southeast Asia. trans-2,3,5,4'-tetrahydroxystilbene 2-O-ß-d-glucopyranoside (trans-THSG) is one of the major compounds derived from PM and has been reported to exhibit multiple biological activities such as antioxidation and anti-obesity activities among others. The current study was aimed at investigating the effects of trans-THSG on liver fibrosis and renal injury in a carbon tetrachloride (CCl4) induced rodent model via oral feeding. Research results have demonstrated that administration of trans-THSG (100 and 300 mg kg-1) significantly ameliorated liver fibrosis, manifested by reduced expression of desmin and α-smooth muscle actin (α-SMA) plus collagen deposition. Specifically, treatment with trans-THSG effectively decreased the levels of transforming growth factor-ß (TGF-ß) and reduced the phosphorylation of Smad1/2 (p-Smad1/2) and extracellular signal-regulated kinases 1/2 (p-ERK1/2). Furthermore, we found that trans-THSG significantly down-regulated CCl4-induced excessive collagen secretion and increased the levels of desmin, MMP2 and MMP9 in rat liver tissues, suggesting that trans-THSG prevents liver fibrosis by attenuating the activation of hepatic stellate cells (HSCs) through the inhibition of Smad and ERK signaling pathways. Hence, the present findings demonstrate that trans-THSG is an effective antifibrotic agent in protecting liver from CCl4-induced toxicity.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Fallopia multiflora/química , Glucosídeos/administração & dosagem , Nefropatias/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Estilbenos/administração & dosagem , Animais , Tetracloreto de Carbono/efeitos adversos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/lesões , Rim/metabolismo , Nefropatias/etiologia , Nefropatias/genética , Nefropatias/metabolismo , Fígado/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Smad1/genética , Proteína Smad1/metabolismo , Proteína Smad2/genética , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
17.
J Med Food ; 22(8): 833-840, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268397

RESUMO

Piceatannol (PIC) is a natural hydroxylated analog of resveratrol (RSV) and considered as a potential metabolic regulator. The purpose of this study was to compare the effects of PIC and RSV on parameters affecting inflammation, oxidative stress, and sirtuins (Sirt). Male C57BL/6J mice, 20 weeks old, were assigned to the following groups; (1) lean control, (2) high-fat diet control (HF), (3) HF_PIC, and (4) HF_RSV. Oral administration of PIC and RSV (10 mg/kg/day) for 4 weeks improved glucose control as shown by decreasing levels of area under the curve (AUC) during the oral glucose tolerance test compared with HF group. PIC improved glycemic control by increasing hepatic levels of insulin receptor and AMP-activated protein kinase. PIC increased the levels of Sirt1, Sirt3, and Sirt6 and also increased two downstream targets of Sirt, peroxisome proliferator-activated receptor gamma coactivator 1-alpha and forkhead box O1, in the liver. The inflammatory markers, interleukin (IL)-1 and IL-6, in the liver were downregulated by RSV treatment. Exposure to PIC and RSV significantly lowered hepatic levels of tumor necrosis factor-alpha. However, PIC and RSV treatments showed minimal effects on hepatic markers of oxidative stress. The levels of antioxidant enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), were only increased in livers of RSV-treated mice compared with HF control mice. In conclusion, PIC was superior to an equal concentration of RSV in the regulation of Sirt and its downstream targets as well as insulin signaling-related parameters, while RSV potentially suppressed levels of proinflammatory markers and increased NQO1 protein levels.


Assuntos
Hepatopatias/tratamento farmacológico , Fígado/imunologia , Resveratrol/administração & dosagem , Sirtuínas/genética , Estilbenos/administração & dosagem , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Fígado/efeitos dos fármacos , Hepatopatias/etiologia , Hepatopatias/genética , Hepatopatias/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/imunologia , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/imunologia , Sirtuínas/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
18.
Immunol Med ; 42(2): 84-93, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31318324

RESUMO

Atopic dermatitis (AD) is the most common inflammatory skin disease driven by both terminal keratinocyte differentiation defects and type 2 immune responses, and this condition causes psychological and social morbidity. Although patients with severe AD require systemic immunotherapy, conventional agents including ciclosporin could not be used for several years due to side effects such as nephrotoxicity, hypertension and long-term risks of malignancy. It is well known that dupilumab, which blocks receptor binding of both IL-4 and IL-13, is remarkably efficacious in the treatment of AD. We have entered a new era when many novel topical and systemic agents that may have great potential in AD treatment are emerging through clinical trials. The purpose of this article is to summarize the efficacy and safety of the current topical and systemic therapies in AD by reviewing recently published papers regarding phase II/III clinical trials. It is revealed that topical phosphodiesterase 4 inhibitors and Janus kinase (JAK) inhibitors are promising treatments for AD. Moreover, systemic therapies such as biologics targeting IL-13 and oral JAK inhibitors show strong efficacy in AD.


Assuntos
Dermatite Atópica/tratamento farmacológico , Inibidores de Janus Quinases/administração & dosagem , Inibidores da Fosfodiesterase 4/administração & dosagem , Acrilamidas/administração & dosagem , Administração Tópica , Anticorpos Monoclonais Humanizados/administração & dosagem , Produtos Biológicos/administração & dosagem , Compostos de Boro/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Dermatite Atópica/etiologia , Dermatite Atópica/imunologia , Humanos , Imunoterapia , Interleucina-13 , Terapia de Alvo Molecular , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Resorcinóis/administração & dosagem , Estilbenos/administração & dosagem , Canais de Cátion TRPV/antagonistas & inibidores
19.
Nutrients ; 11(6)2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234376

RESUMO

Gnetin-C is a naturally occurring stilbene derived from the seeds of Gnetum gnemon L., an edible plant native to Southeast Asia that is called melinjo. Although the biological properties and safety of G. gnemon extract, which contains nearly 3% Gnetin-C, have been confirmed in various human studies, whether or not pure Gnetin-C is safe for humans is unclear at present. We conducted a randomized, double-blind, placebo-controlled trial. Healthy subjects were randomly divided into two groups. The interventional group (n = 6) was given Gnetin-C, and the control group (n = 6) was provided a placebo, for 14 days. Lipid profiles, biomarkers of oxidative stress and circulating blood cells were assessed before and after the intervention. All subjects completed the study, with no side effects reported across the study duration. Gnetin-C supplementation demonstrated a statistically significant increase in the absolute number of circulating natural killer (NK) cells expressing the activating receptors NKG2D and NKp46. NK cells derived from subjects who received Gnetin-C for two weeks showed higher cytotoxicity against K562 target cells than those before receiving Gnetin-C. In addition, Gnetin-C also resulted in a significant decrease in the absolute neutrophil count in the blood compared with the placebo. Furthermore, Gnetin-C significantly reduced the levels of uric acid, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total adiponectin, and high-molecular-weight adiponectin. These data indicate that Gnetin-C has biological effects of enhancing the NK activity on circulating human immune cells. The immunomodulatory effects are consistent with a putative improvement in cancer immunosurveillance via the upregulation of the NKG2D receptor. The study was registered with UMIN-CTR, number 000030364, on 12 December 2017.


Assuntos
Benzofuranos/administração & dosagem , Suplementos Nutricionais , Metabolismo Energético/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Células Matadoras Naturais/efeitos dos fármacos , Estilbenos/administração & dosagem , Adulto , Benzofuranos/efeitos adversos , Benzofuranos/farmacocinética , Biomarcadores/sangue , Técnicas de Cocultura , Citotoxicidade Imunológica/efeitos dos fármacos , Suplementos Nutricionais/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacocinética , Japão , Células K562 , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Subfamília K de Receptores Semelhantes a Lectina de Células NK/sangue , Receptor 1 Desencadeador da Citotoxicidade Natural/sangue , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Estresse Oxidativo/efeitos dos fármacos , Estilbenos/efeitos adversos , Estilbenos/farmacocinética , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
20.
Nutrients ; 11(5)2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31035507

RESUMO

Excessive fat accumulation within the liver is known as "simple hepatic steatosis", which is the most benign form of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to determine whether pterostilbene improves this hepatic alteration in Zucker (fa/fa) rats. Animals were distributed in two experimental groups (n = 10) and fed a standard laboratory diet. Rats in the pterostilbene group were given a dose of 30 mg/kg body weight/d for six weeks. After sacrifice, serum glucose, transaminase, and insulin concentrations were quantified and the liver triacylglycerol content and fatty acid profile was analyzed. Different pathways of triacylglycerol metabolism in liver were studied, including fatty acid synthesis and oxidation, triglyceride assembly, fatty acid uptake, and glucose uptake. With pterostilbene administration, a reduction in insulin concentrations (consequently in the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)) and hepatic triacylglycerol content were observed. No effects were observed in pterostilbene-treated rats in the activity of de novo lipogenesis enzymes. An improvement in the fatty acid profile was observed in pterostilbene-treated rats. In conclusion, pterostilbene is a useful molecule to reduce liver steatosis. Its delipidating effect is due, at least in part, to reduced fatty acid availability and triacylglycerol synthesis, as well as to an increased very low-density lipoprotein assembly and fatty acid oxidation.


Assuntos
Fígado Gorduroso/prevenção & controle , Fígado/metabolismo , Obesidade/metabolismo , Estilbenos/uso terapêutico , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/enzimologia , RNA/genética , RNA/metabolismo , Distribuição Aleatória , Ratos , Ratos Zucker , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estilbenos/administração & dosagem
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