RESUMEN
Fenestrations are pores within the liver sinusoidal endothelial cells (LSECs) that line the sinusoids of the highly vascularized liver. Fenestrations facilitate the transfer of substrates between blood and hepatocytes. With pseudocapillarization of the hepatic sinusoid in old age, there is a loss of fenestrations. LSECs are uniquely exposed to gut-derived dietary and microbial substrates delivered by the portal circulation to the liver. Here we studied the effect of 25 diets varying in content of macronutrients and energy on LSEC fenestrations using the Geometric Framework method in a large cohort of mice aged 15 mo. Macronutrient distribution rather than total food or energy intake was associated with changes in fenestrations. Porosity and frequency were inversely associated with dietary fat intake, while fenestration diameter was inversely associated with protein or carbohydrate intake. Fenestrations were also linked to diet-induced changes in gut microbiome, with increased fenestrations associated with higher abundance of Firmicutes and reduced abundance of Bacteroidetes Diet-induced changes in levels of several fatty acids (C16:0, C19:0, and C20:4) were also significantly inversely associated with fenestrations, suggesting a link between dietary fat and modulation of lipid rafts in the LSECs. Diet influences fenestrations and these data reflect both the key role of the LSECs in clearing gut-derived molecules from the vascular circulation and the impact these molecules have on LSEC morphology.
Asunto(s)
Alimentación Animal , Senescencia Celular , Carbohidratos de la Dieta/metabolismo , Proteínas en la Dieta/metabolismo , Células Endoteliales/metabolismo , Hígado/irrigación sanguínea , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Biomarcadores/sangre , Forma de la Célula , Carbohidratos de la Dieta/administración & dosificación , Proteínas en la Dieta/administración & dosificación , Células Endoteliales/ultraestructura , Ingestión de Energía , Femenino , Microbioma Gastrointestinal , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/microbiología , Masculino , Ratones Endogámicos C57BL , Estado Nutricional , Valor Nutritivo , PorosidadRESUMEN
Decrease in muscle mass and performance with ageing is one of the main factors of frailty in the elderly. Maintenance of muscle performance by involving in physical activities is essential to increase independence and quality of life among elderly. The use of natural compounds with ergogenic activity in old people would increase the effect of moderate exercises in the maintenance of physiological muscle capacity. Resveratrol (RSV), a polyphenol found in walnuts, berries and grapes, shows this ergogenic activity. By using young, mature and old mice as models, we have found that RSV improves muscle performance in mature and old animals but not in young animals. Without showing significant effect by itself, RSV primed the effect of exercise by increasing endurance, coordination and strength in old animals. This effect was accompanied by a higher protection against oxidative damage and an increase in mitochondrial mass. RSV increased catalase and superoxide dismutase protein levels in muscle and primed exercise to reverse the decrease in their activities during ageing. Furthermore, RSV increased the level of mitochondrial mass markers such as cytochrome C, mitochondrial transcription factor A and nuclear respiratory factor-1 in muscle in exercised animals. Our results indicate that RSV can be considered an ergogenic compound that helps maintain muscle performance during ageing and subsequently reduces frailty and increases muscle performance in old individuals practising moderate exercise.
Asunto(s)
Envejecimiento/fisiología , Antiinflamatorios no Esteroideos/farmacología , Condicionamiento Físico Animal , Estilbenos/farmacología , Animales , Peroxidación de Lípido , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Resistencia Física , ResveratrolRESUMEN
BACKGROUND: Oxidative stress has been considered one of the causes of aging. For this reason, treatments based on antioxidants or those capable of increasing endogenous antioxidant activity have been taken into consideration to delay aging or age-related disease progression. AIM: In this paper, we determine if resveratrol and exercise have similar effect on the antioxidant capacity of different organs in old mice. METHODS: Resveratrol (6 months) and/or exercise (1.5 months) was administered to old mice. Markers of oxidative stress (lipid peroxidation and glutathione) and activities and levels of antioxidant enzymes (SOD, catalase, glutathione peroxidase, glutathione reductase and transferase and thioredoxin reductases, NADH cytochrome B5-reductase and NAD(P)H-quinone acceptor oxidoreductase) were determined by spectrophotometry and Western blotting in different organs: liver, kidney, skeletal muscle, heart and brain. RESULTS: Both interventions improved antioxidant activity in the major organs of the mice. This induction was accompanied by a decrease in the level of lipid peroxidation in the liver, heart and muscle of mice. Both resveratrol and exercise modulated several antioxidant activities and protein levels. However, the effect of resveratrol, exercise or their combination was organ dependent, indicating that different organs respond in different ways to the same stimulus. CONCLUSIONS: Our data suggest that physical activity and resveratrol may be of great importance for the prevention of age-related diseases, but that their organ-dependent effect must be taken into consideration to design a better intervention.
Asunto(s)
Envejecimiento/fisiología , Actividad Motora/efectos de los fármacos , Especificidad de Órganos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estilbenos/farmacología , Inhibidores de la Angiogénesis/farmacología , Animales , Antioxidantes/farmacología , Masculino , Ratones , Oxidación-Reducción/efectos de los fármacos , Condicionamiento Físico Animal/métodos , Condicionamiento Físico Animal/fisiología , Resveratrol , Ribonucleótido Reductasas/antagonistas & inhibidoresRESUMEN
Coenzyme Q (Q) is a key lipidic compound for cell bioenergetics and membrane antioxidant activities. It has been shown that also has a central role in the prevention of oxidation of plasma lipoproteins. Q has been associated with the prevention of cholesterol oxidation and several aging-related diseases. However, to date no clear data on the levels of plasma Q during aging are available. We have measured the levels of plasmatic Q10 and cholesterol in young and old individuals showing different degrees of physical activity. Our results indicate that plasma Q10 levels in old people are higher that the levels found in young people. Our analysis also indicates that there is no a relationship between the degree of physical activity and Q10 levels when the general population is studied. However, very interestingly, we have found a different tendency between Q10 levels and physical activity depending on the age of individuals. In young people, higher activity correlates with lower Q10 levels in plasma whereas in older adults this ratio changes and higher activity is related to higher plasma Q10 levels and higher Q10/Chol ratios. Higher Q10 levels in plasma are related to lower lipoperoxidation and oxidized LDL levels in elderly people. Our results highlight the importance of life habits in the analysis of Q10 in plasma and indicate that the practice of physical activity at old age can improve antioxidant capacity in plasma and help to prevent cardiovascular diseases.
Asunto(s)
Envejecimiento/sangre , Actividad Motora/fisiología , Ubiquinona/análogos & derivados , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antioxidantes/metabolismo , Proteínas Sanguíneas/metabolismo , Colesterol/sangre , Estudios Transversales , Femenino , Humanos , Peroxidación de Lípido , Lipoproteínas LDL/sangre , Masculino , Persona de Mediana Edad , Carbonilación Proteica , Ubiquinona/sangre , Adulto JovenRESUMEN
OBJECTIVES: Alzheimer's disease (AD) is a lingering progressive neurodegenerative disorder that causes patients to lose cognitive function. The enzyme Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Monoamine oxidase A (MAO A), Beta-secretase cleavage enzyme (BACE 1) and N-methyl-D-aspartate (NMDA) receptors play an important role in the pathogenesis of Alzheimer's disease. Therefore, inhibiting enzymes is an effective method to treat Alzheimer disease. In this study, we evaluated in silico inhibitory effects of AChE, BuChE, MAO A, BACE 1 and NMDA enzyme of Huperzia squarrosa's compounds. METHODS: The three-dimensional (3D) of N-methyl-D-aspartate receptor (PDB ID: 1PBQ), enzyme ß-secretase 1 (PDB ID: 4X7I), enzyme monoamine oxidase A (PDB ID: 2Z5X), enzyme butyrylcholinesterase (PDB ID: 4BDS) and enzyme acetylcholinesterase (PDB ID: 1EVE) were retrieved from the Protein Data Bank RCSB. Molecular docking was done by Autodock vina software and molecular dynamics (MD) simulation of the ligand-protein complex with the least binding energy pose was perfomed by MOE. Lipinski Rule of Five is used to compare compounds with drug-like and non-drug-like properties. Pharmacokinetic parameters of potential compounds were evaluated using the pkCSM tool. RESULTS: Based on previous publication of Huperzia squarrosa, we have collected 15 compounds. In these compounds, huperzine B, huperzinine, lycoposerramine U N-oxide, 12-epilycodine N-oxide showed strongly inhibit the five AChE, BuChE, MAO A, BACE 1 and NMDA targets for Alzheimer's treatment. Lipinski rule of five and ADMET predict have shown that four above compounds have drug-likeness properties, good absorption ability and cross the blood-brain barrier, which have the most potential to become drugs for the treatment of Alzheimer's in the future. Furthermore, MD study showed that huperzine B and huperzinine have stability of the docking pose with NMDA target. CONCLUSIONS: In this study, we found two natural compounds in Huperzia squarrosa including Huperzine B and Huperzinine have drug-likeness properties, good absorption ability and cross the blood-brain barrier, which have potential to become drugs for the treatment of Alzheimer's in the future.
Asunto(s)
Enfermedad de Alzheimer , Simulación de Dinámica Molecular , Humanos , Simulación del Acoplamiento Molecular , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide , Butirilcolinesterasa , Acetilcolinesterasa , MonoaminooxidasaRESUMEN
This paper reports the theoretical and experimental investigations on the strain sensing effect of a two dimensions (2D) photonic crystal (PhC) nanocavity resonator. By using the finite element method (FEM) and finite difference time domain (FDTD) simulations, the strain sensitivity of a high quality factor PhC nanocavity was calculated. Linear relationships between the applied strain and the shift in the resonant wavelength of the cavity were obtained. A single-defect silicon (Si) PhC cavity was fabricated, and measurements of the strain sensitivity were performed. Good agreement between the experimental and simulation results was observed.
Asunto(s)
Nanotecnología/instrumentación , Refractometría/instrumentación , Transductores , Elasticidad , Diseño de Equipo , Análisis de Falla de Equipo , Estrés MecánicoRESUMEN
As part of an ongoing study focused on the discovery of anti-influenza agents from plants, four new (1-4) and 10 known (5-14) C-methylated flavonoids were isolated from a methanol extract of Cleistocalyx operculatus buds using an influenza H1N1 neuraminidase inhibition assay. Compounds 4, 7, 8, and 14, with a chalcone skeleton, showed significant inhibitory effects on the viral neuraminidases from two influenza viral strains, H1N1 and H9N2. Compound 4 showed the strongest inhibitory activity against the neuraminidases from novel influenza H1N1 (WT) and oseltamivir-resistant novel H1N1 (H274Y mutant) expressed in 293T cells with IC50 values of 8.15 ± 1.05 and 3.31 ± 1.34 µM, respectively. Compounds 4, 7, 8, and 14 behaved as noncompetitive inhibitors in the kinetic studies. These results indicate that C-methylated flavonoids from C. operculatus have the potential to be developed as neuraminidase inhibitors for novel influenza H1N1.
Asunto(s)
Antivirales/aislamiento & purificación , Antivirales/farmacología , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Myrtaceae/química , Neuraminidasa/antagonistas & inhibidores , Antivirales/química , Flavonoides/química , Células HEK293 , Humanos , Subtipo H9N2 del Virus de la Influenza A , Gripe Humana/tratamiento farmacológico , Concentración 50 Inhibidora , Cinética , Estructura Molecular , Oseltamivir/farmacologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Huperzia squarrosa (Forst.) Trevis is used in traditional medicine for improving memory deficits. Alkaloids, triterpenoids, flavonoids are main bioactive compounds of Huperzia squarrosa (Forst.) Trevis. AIM OF THE STUDY: This study aimed to investigate the antioxidant, AChE inhibitory activities in vitro of differents fraction of Huperzia squarrosa (Forst.) Trevis extract and neuroprotective effects of EtOAc fraction on scopolamine-induced cognitive impairment in mice. MATERIALS AND METHODS: Antioxidant activity was measured by DPPH assay. AChE inhibitory effect in vitro and detail kinetic inhibition mechanism was evaluated by Ellman's assay. For in vivo assay, mice were administrated orally EtOAc fraction (150 and 300mg/kg) for fourteen days, and injected scopolamine at a dose of 1mg/kg intraperitoneally for four days to induce memory injured. The memory behaviors were evaluated using the Morris water maze. ACh levels were measured in brain tissue. Superoxide dismutase (SOD), glutathione peroxidase (GPx) activities, malondialdehyde and protein thiol groups were also evaluated in the brains. RESULTS: Our data also demonstrated that EtOAc fraction had the strongest antioxidant with an IC50 value of 9.35±1.68µg/mL and AChE inhibitory activity with an IC50 value of 23.44±3.14µg/mL in a concentration-dependent manner. Kinetic inhibition analysis indicated that EtOAc fraction was mixed inhibition type with Ki (representing the affinity of the enzyme and inhibitor) was 34.75±1.42µg/mL. Scopolamine significantly increased the escape latency time, reduced the crossings number, and swimming time in the target quadrant, while EtOAc fraction reversed these scopolamine-induced effects. EtOAc fraction significantly increased levels of acetylcholine in the brain. EtOAc fraction also significantly decreased oxidative stress in mice. CONCLUSION: Our data suggest that EtOAc fraction of Huperzia squarrosa extract exhibited a strong neuroprotective effect on cognitive impairment, and may be a potential candidate for the treatment of Alzheimer.
Asunto(s)
Antioxidantes/farmacología , Inhibidores de la Colinesterasa/farmacología , Disfunción Cognitiva/tratamiento farmacológico , Huperzia , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacología , Animales , Disfunción Cognitiva/inducido químicamente , Peroxidación de Lípido/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Escopolamina/farmacologíaRESUMEN
Background Zingiber officinale Roscoe has been used in traditional medicine for the treatment of neurological disorder. This study aimed to investigate the phenolic contents, antioxidant, acetylcholinesterase enzyme (AChE) inhibitory activities of different fraction of Z. officinale root grown in Vietnam. Methods The roots of Z. officinale are extracted with ethanol 96â% and fractionated with n-hexane, ethyl acetate (EtOAc) and butanol (BuOH) solvents. These fractions evaluated the antioxidant activity by 1,1-Diphenyl -2-picrylhydrazyl (DPPH) assay and AChE inhibitory activity by Ellman's colorimetric method. Results Our data showed that the total phenolic content of EtOAc fraction was highest equivalents to 35.2±1.4âmg quercetin/g of fraction. Our data also demonstrated that EtOAc fraction had the strongest antioxidant activity with IC50 was 8.89±1.37âµg/mL and AChE inhibitory activity with an IC50 value of 22.85±2.37 µg/mL in a dose-dependent manner, followed by BuOH fraction and the n-hexane fraction is the weakest. Detailed kinetic analysis indicated that EtOAc fraction was mixed inhibition type with Ki (representing the affinity of the enzyme and inhibitor) was 30.61±1.43âµg/mL. Conclusions Our results suggest that the EtOAc fraction of Z. officinale may be a promising source of AChE inhibitors for Alzheimer's disease.
Asunto(s)
Acetilcolinesterasa/metabolismo , Antioxidantes/farmacología , Inhibidores de la Colinesterasa/farmacología , Fenoles/farmacología , Extractos Vegetales/farmacología , Zingiber officinale/química , Acetatos , Antioxidantes/análisis , Compuestos de Bifenilo/metabolismo , Inhibidores de la Colinesterasa/análisis , Concentración 50 Inhibidora , Fenoles/análisis , Picratos/metabolismo , Extractos Vegetales/química , VietnamRESUMEN
BACKGROUND: Curcumin has been shown to possess strong cytotoxic effect against various cancer cell lines. However, curcumin has not applied as a drug for treatment of cancer yet due to low solubility in water and low bioavailability. The aims of this study were to prepare a new polyethylene glycol (PEG) conjugated curcumin and to evaluate its antitumor activity in vitro. METHODS: PEG-CUR was prepared by the reaction between curcumin and PEG. PEG-CUR which was characterized by SEM, TEM, FTIR, DSC and 1H NMR analysis. The physicochemical parameters of PEG-CUR such as zeta potential, size distribution, solubility and percentage of curcumin were also investigated. RESULTS: Our results showed that the percentage of curcumin in PEG-CUR was 13.26 ± 1.25 %. PEG-CUR has nanosize values of 96.3 nm and the zeta potential values of - 48.4 mV. The PEG-CUR showed significantly increasing curcumin's solubility in water and another medium such as in 0,1 N HCl, phosphate buffer pH 4.5 and pH 6.8 solution and n-octanol. Our data also have shown cytotoxicity effect of PEG-CUR was much greater than curcumin-free in two different HepG2 and HCT116 cancer cell lines. CONCLUSION: It could be concluded from our results that the PEG-CUR may be a potential candidate for cancer treatment. Further studies are needed to evaluate the antitumor efficacy of PEG-CUR in vivo.
Asunto(s)
Curcumina , Portadores de Fármacos , Nanopartículas , Polietilenglicoles , Supervivencia Celular/efectos de los fármacos , Curcumina/administración & dosificación , Curcumina/química , Curcumina/farmacología , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Células HCT116 , Células Hep G2 , Humanos , Nanopartículas/administración & dosificación , Nanopartículas/química , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Polietilenglicoles/farmacología , Solubilidad , Agua/químicaRESUMEN
Inflammation is a hallmark of aging. Caloric restriction and resveratrol (RSV) have shown important effects on prevention of oxidative stress and inflammation. Here, we investigate the progression of proinflammatory markers in liver during aging and the effect of RSV on inflammation markers in the liver of old male C57BL/6J mice. Young (2 months), mature (12 months) and old (18 months) mice were fed during 6 months with RSV. Levels of IL-1ß, IL-6, IL-10, IL-17 and TNF-α were evaluated by ELISA in mice liver. Levels of pro-inflammatory cytokines, IL-1ß, IL-6, IL-17 and TNF-α and also their respective mRNA increased in the liver from old mice. However, RSV decreased these levels in the case of IL-1ß and TNF-α but only in old mice showing no effect on young and mature animals. This reduction was also found at the mRNA level. Levels of mRNA of the components of NALP-3 inflammasome, ASC, CASP-1, NALP-1 and NALP-3, also showed an age-dependent increase that was reversed by RSV. Furthermore, cyclooxygenase 2 levels, a marker of proinflammatory innate immune activity, were also upregulated in aged liver and reversed again by RSV. In conclusion, our study confirms that aging is accompanied by an increase in the proinflammatory pattern in the liver and that RSV reduces this pattern in old mice liver.
Asunto(s)
Envejecimiento , Antiinflamatorios no Esteroideos/uso terapéutico , Inflamación/tratamiento farmacológico , Hígado/efectos de los fármacos , Estilbenos/uso terapéutico , Animales , Biomarcadores/metabolismo , Citocinas/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/genética , ResveratrolRESUMEN
Aging is a multifactorial process in which oxidative damage plays an important role. Resveratrol (RSV) and exercise delay some of the damages occurring during aging and increase life span and health span. We treated mice at different ages with RSV during 6 months and trained them during the last 6 weeks to determine if RSV and exercise induce changes in endogenous antioxidant activities in liver and if their effects depend on the age of the animal at the beginning of the intervention. Aging was accompanied by the increase in oxidative damage in liver especially affecting the glutathione-dependent system. Both RSV and exercise reversed the effect of aging and maintained high activities of glutathione, glutathione peroxidase, and glutathione transferase activities in old animals. NAD(P)H: quinone acceptor oxidoreductase activity was also increased. Modulation of antioxidant activities was not completely accompanied by changes at the protein level. Whereas glutathione peroxidase 1 protein increased in parallel to the higher activity in old animals, NAD(P)H: quinone acceptor oxidoreductase protein decreased by RSV although the activity was enhanced. Our results indicate that RSV and exercise revert the effect of aging in liver of old animals maintaining higher antioxidant activities and decreasing oxidative damage. Short-term interventions are enough to produce beneficial effects of RSV or exercise at later ages.
Asunto(s)
Envejecimiento/metabolismo , Antioxidantes/farmacocinética , Hígado/metabolismo , Condicionamiento Físico Animal , Estilbenos/farmacocinética , Animales , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidación-Reducción , ResveratrolRESUMEN
Abstract Curcuma longa, which contains curcumin as a major constituent, has been shown many pharmacological effects, but it is limited using in clinical due to low bioavailability. In this study, we developed a phytosome curcumin formulation and evaluated the hepatoprotective effect of phytosome curcumin on paracetamol induced liver damage in mice. Phytosome curcumin (equivalent to curcumin 100 and 200 mg/kg body weight) and curcumin (200 mg/kg body weight) were given by gastrically and toxicity was induced by paracetamol (500 mg/kg) during 7 days. On the final day animals were sacrificed and liver function markers (ALT, AST), hepatic antioxidants (SOD, CAT and GPx) and lipid peroxidation in liver homogenate were estimated. Our data showed that phytosome has stronger hepatoprotective effect compared to curcumin-free. Administration of phytosome curcumin effectively suppressed paracetamol-induced liver injury evidenced by a reduction of lipid peroxidation level, and elevated enzymatic antioxidant activities of superoxide dismutase, catalase, glutathione peroxidase in mice liver tissue. Our study suggests that phytosome curcumin has strong antioxidant activity and potential hepatoprotective effects.