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This study investigated the therapeutic effects of transplanting human mesenchymal stem cells (hMSCs) into wild-type mice that were intraperitoneally administered cytosine arabinoside (Ara-C) to develop cerebellar ataxia (CA) during the first three postnatal days. hMSCs were intrathecally injected into 10-week-old mice once or thrice at 4-week intervals. Compared to the nontreated mice, the hMSC-treated mice showed improved motor and balance coordination, as measured using the rotarod, open-field, and ataxic scoring assessments, and increased protein levels in Purkinje and cerebellar granule cells, as measured using calbindin and NeuN protein markers. Multiple hMSC injections preserved Ara-C-induced cerebellar neuronal loss and improved cerebellar weight. Furthermore, the hMSC implantation significantly elevated the levels of neurotrophic factors, including brain-derived and glial cell line-derived neurotrophic factors, and suppressed TNF-α-, IL-1ß-, and iNOS-mediated proinflammatory responses. Collectively, our results demonstrate that hMSCs exhibit therapeutic potential for Ara-C-induced CA by protecting neurons through the stimulation of neurotrophic factors and inhibition of cerebellar inflammatory responses, which can improve motor behavior and alleviate ataxia-related neuropathology. In summary, this study suggests that hMSC administration, particularly multiple treatments, can effectively treat ataxia-related symptoms with cerebellar toxicity.
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Sinapic acid (SA), a hydroxycinnamic acid, is known to confer protection against oxidative stress, inflammation, diabetes, and liver disease. However, the effectiveness of SA in improving obesity remains obscure. Therefore, this study evaluated anti-obesity efficacy of SA and to elucidate its mechanism of action. Male mice were maintained for 16 weeks on high-fat diet (HFD) alone or with SA (0.004%, w/w) and bodyweight, fat mass, adipocyte size, food intake, and biochemical and molecular markers were evaluated. SA-supplemented mice demonstrated markedly decreased fat mass and adipocyte size compared to unsupplemented group, without any changes in bodyweight and food intake between the two groups. Plasma adipocytokines levels including leptin, resistin, monocyte chemoattractant protein (MCP)-1 and interleukin-6 were also markedly reduced by SA supplementation. SA tended to lower plasma insulin level and improved homeostatic index of insulin resistance and intraperitoneal glucose tolerance test in HFD-induced obese mice. The anti-adiposity effect of SA was maybe owing to down-regulation of the mRNA expression of lipogenic genes, including acetyl coenzyme A (CoA) carboxylase, fatty acid synthesis, stearoyl-CoA desaturase 1, and phosphatidate phosphatase, and peroxisome proliferator-activated receptor γ, a transcription factor responsible for governing lipid metabolism, in adipose tissues. SA significantly down-regulated pro-inflammatory nuclear factor kappa B, MCP-1, tumor necrosis factor-α, and Toll-like receptor 4 mRNA expression in adipose tissue. Thus, SA could be beneficial for the development of functional foods or herbal medications to combat obesity.
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p-Coumaric acid (PC), a naturally occurring phytochemical, possesses antioxidant and anti-inflammatory properties; however, the mechanisms underlying its protective effects against obesity-related metabolic dysfunction are largely unknown. Here, we treated C57BL/6J mice to a high-fat diet (HFD) with or without PC (10 mg/kg body weight/day) for 16 weeks to determine whether PC ameliorates HFD-induced obesity, insulin resistance, inflammation, and non-alcoholic fatty liver disease (NAFLD). We found no significant differences in food intake and body weight between the groups. However, PC-treated mice showed significantly lower white adipose tissue (WAT) weight, adipocyte size, and plasma leptin level, which were associated with decreased lipogenic enzyme activity and mRNA expression of their genes in the epididymal WAT. Moreover, hepatic lipogenic enzymes activities and expression of their genes and proteins were decreased with concomitant increases in hepatic fatty acid oxidation and mRNA expression of its gene; fecal lipid excretion was significantly increased, resulting in decreased liver weight, hepatic lipid levels, lipid droplet accumulation, and plasma aspartate aminotransferase and lipid levels. Additionally, PC-treated mice showed lower fasting blood glucose, plasma resistin, and MCP-1 levels, HOMA-IR, and mRNA expression of inflammatory genes in the epididymal WAT and liver. Our findings reveal potential mechanisms underlying the action of PC against HFD-induced adiposity, NAFLD, and other metabolic disturbances.
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Ácidos Cumáricos/farmacologia , Inflamação/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/prevenção & controle , Adiposidade/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Resistina/sangueRESUMO
Epilepsy is a chronic neurological disorder that affects many people worldwide. Temporal lobe epilepsy is the most common and most studied type of epilepsy, but the pathological mechanisms underlying this condition are poorly understood. More than 20 antiepileptic drugs (AEDs) have been developed and used for the treatment of epilepsy; however, 30% of patients still experience uncontrolled epilepsy and associated comorbidities, which impair their quality of life. In addition, various side effects have been reported for AEDs, such as drowsiness, unsteadiness, dizziness, blurred or double vision, tremor (shakiness), greater risk of infections, bruising, and bleeding. Thus, critical medical needs remain unmet for patients with uncontrolled epilepsy. Flavonoids belong to a subclass of polyphenols that are widely present in fruits, vegetables, and certain beverages. Recently, many studies have reported that some flavonoids elicit various beneficial effects in patients with epilepsy without causing the side effects associated with conventional medical therapies. Moreover, flavonoids may have a property of regulating microRNA expression associated with inflammation and cell survival. These findings suggest that flavonoids, which are more effective but impose fewer adverse effects than conventional AEDs, could be used in the treatment of epilepsy.
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Anticonvulsivantes/uso terapêutico , Terapias Complementares/métodos , Epilepsia/terapia , Flavonoides/uso terapêutico , HumanosRESUMO
Parkinson's disease (PD) and Alzheimer's disease exhibit common features of neurodegenerative diseases and can be caused by numerous factors. A common feature of these diseases is neurotoxic inflammation by activated microglia, indicating that regulation of microglial activation is a potential mechanism for preserving neurons in the adult brain. Recently, we reported that upregulation of prothrombin kringle-2 (pKr-2), one of the domains that make up prothrombin and which is cleaved and generated by active thrombin, induces nigral dopaminergic (DA) neuronal death through neurotoxic microglial activation in the adult brain. In this study, we show that silibinin, a flavonoid found in milk thistle, can suppress the production of inducible nitric oxide synthase and neurotoxic inflammatory cytokines, such as interleukin-1ß and tumor necrosis factor-α, after pKr-2 treatment by downregulating the extracellular signal-regulated kinase signaling pathway in the mouse substantia nigra. Moreover, as demonstrated by immunohistochemical staining, measurements of the dopamine and metabolite levels, and open-field behavioral tests, silibinin treatment protected the nigrostriatal DA system resulting from the occurrence of pKr-2-triggered neurotoxic inflammation in vivo. Thus, we conclude that silibinin may be beneficial as a natural compound with anti-inflammatory effects against pKr-2-triggered neurotoxicity to protect the nigrostriatal DA pathway and its properties, and thus, may be applicable for PD therapy.
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Dopamina/metabolismo , Doença de Parkinson/tratamento farmacológico , Protrombina/toxicidade , Silibina/administração & dosagem , Animais , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Kringles , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Protrombina/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The role of astrocyte elevated gene-1 (AEG-1) in nigral dopaminergic (DA) neurons has not been studied. Here we report that the expression of AEG-1 was significantly lower in DA neurons in the postmortem substantia nigra of patients with Parkinson's disease (PD) compared to age-matched controls. Similarly, decreased AEG-1 levels were found in the 6-hydroxydopamine (6-OHDA) mouse model of PD. An adeno-associated virus-induced increase in the expression of AEG-1 attenuated the 6-OHDA-triggered apoptotic death of nigral DA neurons. Moreover, the neuroprotection conferred by the AEG-1 upregulation significantly intensified the neurorestorative effects of the constitutively active ras homolog enriched in the brain [Rheb(S16H)]. Collectively, these results demonstrated that the sustained level of AEG-1 as an important anti-apoptotic factor in nigral DA neurons might potentiate the therapeutic effects of treatments, such as Rheb(S16H) administration, on the degeneration of the DA pathway that characterizes PD.
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Apoptose , Astrócitos/metabolismo , Neurônios Dopaminérgicos/metabolismo , Glicoproteínas de Membrana/biossíntese , Substância Negra/metabolismo , Regulação para Cima , Animais , Astrócitos/patologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Humanos , Glicoproteínas de Membrana/genética , Camundongos , Oxidopamina/efeitos adversos , Oxidopamina/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Substância Negra/patologiaRESUMO
This study evaluated whether long-term supplementation with dietary yerba mate has beneficial effects on adiposity and its related metabolic dysfunctions in diet-induced obese mice. C57BL/6J mice were randomly divided into two groups and fed their respective experimental diets for 16 weeks as follows: (1) control group fed with high-fat diet (HFD) and (2) mate group fed with HFD plus yerba mate. Dietary yerba mate increased energy expenditure and thermogenic gene mRNA expression in white adipose tissue (WAT) and decreased fatty acid synthase (FAS) mRNA expression in WAT, which may be linked to observed decreases in body weight, WAT weight, epididymal adipocyte size, and plasma leptin level. Yerba mate also decreased levels of plasma lipids (free fatty acids, triglycerides, and total cholesterol) and liver aminotransferase enzymes, as well as the accumulation of hepatic lipid droplets and lipid content by inhibiting the activities of hepatic lipogenic enzymes, such as FAS and phosphatidate phosphohydrolase, and increasing fecal lipid excretion. Moreover, yerba mate decreased the levels of plasma insulin as well as the homeostasis model assessment of insulin resistance, and improved glucose tolerance. Circulating levels of gastric inhibitory polypeptide and resistin were also decreased in the mate group. These findings suggest that long-term supplementation of dietary yerba mate may be beneficial for improving diet-induced adiposity, insulin resistance, dyslipidemia, and hepatic steatosis.
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Metabolismo Energético/efeitos dos fármacos , Ilex paraguariensis/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Doenças Metabólicas/tratamento farmacológico , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais/análise , Humanos , Masculino , Doenças Metabólicas/metabolismo , Doenças Metabólicas/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologiaRESUMO
This study investigated the biological and molecular mechanisms underlying the antiobesity effect of omija fruit ethanol extract (OFE) in mice fed a high-fat diet (HFD). C57BL/6J mice were fed an HFD (20% fat, w/w) with or without OFE (500 mg/kg body weight) for 16 weeks. Dietary OFE significantly increased brown adipose tissue weight and energy expenditure while concomitantly decreasing white adipose tissue (WAT) weight and adipocyte size by up-regulating the expression of brown fat-selective genes in WAT. OFE also improved hepatic steatosis and dyslipidemia by enhancing hepatic fatty acid oxidation-related enzymes activity and fecal lipid excretion. In addition to steatosis, OFE decreased the expression of pro-inflammatory genes in the liver. Moreover, OFE improved glucose tolerance and lowered plasma glucose, insulin and homeostasis model assessment of insulin resistance, which may be linked to decreases in the activity of hepatic gluconeogenic enzymes and the circulating level of gastric inhibitory polypeptide. These findings suggest that OFE may protect against diet-induced adiposity and related metabolic disturbances by controlling brown-like transformation of WAT, fatty acid oxidation, inflammation in the liver and fecal lipid excretion. Improved insulin resistance may be also associated with its antiobesity effects.
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Adiposidade , Fármacos Antiobesidade/uso terapêutico , Suplementos Nutricionais , Resistência à Insulina , Sobrepeso/prevenção & controle , Extratos Vegetais/uso terapêutico , Schisandra/química , Tecido Adiposo Bege/imunologia , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Bege/patologia , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Biomarcadores/sangue , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético , Etanol/química , Frutas/química , Regulação Enzimológica da Expressão Gênica , Fígado/enzimologia , Fígado/imunologia , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Sobrepeso/imunologia , Sobrepeso/metabolismo , Sobrepeso/patologia , Distribuição Aleatória , Solventes/química , Aumento de PesoRESUMO
Granule cell dispersion (GCD) in the dentate gyrus (DG) of the hippocampus is a morphological alteration characteristic of temporal lobe epilepsy. Recently, we reported that treatment with naringin, a flavonoid found in grapefruit and citrus fruits, reduced spontaneous recurrent seizures by inhibiting kainic acid (KA)-induced GCD and neuronal cell death in mouse hippocampus, suggesting that naringin might have beneficial effects for preventing epileptic events in the adult brain. However, it is still unclear whether the beneficial effects of naringin treatment are mediated by the metabolism of naringin into naringenin in the KA-treated hippocampus. To investigate this possibility, we evaluated whether intraperitoneal injections of naringenin could mimic naringin-induced effects against GCD caused by intrahippocampal KA injections in mice. Our results showed that treatment with naringenin delayed the onset of KA-induced seizures and attenuated KA-induced GCD by inhibiting activation of the mammalian target of rapamycin complex 1 in both neurons and reactive astrocytes in the DG. In addition, its administration attenuated the production of proinflammatory cytokines such as tumor necrosis tumor necrosis factor-α (TNFα) and interleukin-1ß (IL-1ß) from microglial activation in the DG following KA treatment. These results suggest that naringenin may be an active metabolite of naringin and help prevent the progression of epileptic insults in the hippocampus in vivo; therefore, naringenin may be a beneficial metabolite of naringin for the treatment of epilepsy.
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Anticonvulsivantes/uso terapêutico , Giro Denteado/efeitos dos fármacos , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/patologia , Flavanonas/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Citocinas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Epilepsia do Lobo Temporal/induzido quimicamente , Fatores de Iniciação em Eucariotos , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Caínico/toxicidade , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Fosfoproteínas/metabolismoRESUMO
We compared metabolic biomarkers in the blood and peripheral blood mononuclear cell (PBMC) gene expression profiles among normal weight (BMI, 18·5-23 kg/m2), mildly obese (BMI, 25-27·5 kg/m2) and moderately obese Korean adult men (BMI, 27·5-30 kg/m2). High leptin, lipids (except LDL- and HDL-cholesterol) and apoB levels and low adiponectin and HDL-cholesterol levels were present in the plasma of both mildly and moderately obese subjects. Circulating levels of inflammatory cytokines and markers of insulin resistance, oxidative stress and liver damage were altered in moderately obese subjects but not in mildly obese subjects. PBMC transcriptome data showed enrichment of pathways involved in energy metabolism, insulin resistance, bone metabolism, cancer, inflammation and fibrosis in both mildly and moderately obese subjects. Signalling pathways involved in oxidative phosphorylation, TAG synthesis, carbohydrate metabolism and insulin production; mammalian target of rapamycin, forkhead box O, ras-proximate-1, RAS and transforming growth factor-ß signalling; as well as extracellular matrix-receptor interaction were enriched only in moderately obese subjects, indicating that changes in PBMC gene expression profiles, according to metabolic disturbances, were associated with the development and/or aggravation of obesity. In particular, fourteen and fifteen genes differentially expressed only in mildly obese subjects and in both mildly and moderately obese subjects, respectively, could be used as early or stable biomarkers for diagnosing and treating obesity-associated metabolic disturbance. We characterised BMI-associated metabolic and molecular biomarkers in the blood and provided clues about potential blood-based targets for preventing or treating obesity-related complications.
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Biomarcadores , Leucócitos Mononucleares/fisiologia , Obesidade , Transcriptoma , Adulto , Antioxidantes , Eritrócitos/metabolismo , Regulação da Expressão Gênica , Humanos , Peróxido de Hidrogênio/sangue , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos/fisiologia , Pessoa de Meia-Idade , Transaminases , Adulto JovemRESUMO
Parkinson's disease (PD) is a chronic and progressive movement disorder, resulting from the degeneration of the nigrostriatal dopaminergic (DA) pathway. The cause of DA neuronal loss in PD is still unclear; however, accumulating evidence suggests that treatment with certain flavonoids can induce neuroprotective properties, such as activation of mammalian target of rapamycin complex 1 (mTORC1) and anti-inflammatory activities in animal models of PD. The bioflavonoid myricitrin is well known for its anti-inflammatory and antioxidant properties. However, it is unclear whether systemic treatment with myricitrin can protect neurons against neurotoxin-induced DA degeneration in vivo via the preservation of tyrosine hydroxylase (TH) activity and the induction of mTORC1 activation. Our results found no significant neuroprotective effect of 30 mg/kg myricitrin on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in the substantia nigra (SN) of mice. However, myricitrin treatment with 60 mg/kg protected DA neurons against 6-OHDA-induced neurotoxicity. Moreover, myricitrin treatment preserved TH enzyme activity and mTORC1 activation in nigral DA neurons in the SN of 6-OHDA-treated mice, and its treatment suppressed an increase in tumor necrosis factor-α expression in activated microglia. These results suggest that myricitrin may have neuroprotective properties linked to mTORC1 activation, preservation of TH enzyme activity, and anti-neuroinflammation for preventing DA neuronal degeneration in vivo.
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Neurônios Dopaminérgicos/citologia , Flavonoides/farmacologia , Fármacos Neuroprotetores/farmacologia , Oxidopamina/toxicidade , Doença de Parkinson/tratamento farmacológico , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Substância Negra/citologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Obesity, along with its related complications, is a serious health problem worldwide. Many studies reported the anti-diabetic effect of phlorizin, while little is known about its anti-obesity effect. We investigated the beneficial effects of phlorizin on obesity and its complications, including diabetes and inflammation in obese animal. Male C57BL/6J mice were divided into three groups and fed their respective experimental diets for 16 weeks: a normal diet (ND, 5% fat, w/w), high-fat diet (HFD, 20% fat, w/w), or HFD supplemented with phlorizin (PH, 0.02%, w/w). The findings revealed that the PH group had significantly decreased visceral and total white adipose tissue (WAT) weights, and adipocyte size compared to the HFD. Plasma and hepatic lipids profiles also improved in the PH group. The decreased levels of hepatic lipids in PH were associated with decreased activities of enzymes involved in hepatic lipogenesis, cholesterol synthesis and esterification. The PH also suppressed plasma pro-inflammatory adipokines levels such as leptin, adipsin, tumor necrosis factor-α, monocyte chemoattractant protein-1, interferon-γ, and interleukin-6, and prevented HFD-induced collagen accumulation in the liver and WAT. Furthermore, the PH supplementation also decreased plasma glucose, insulin, glucagon, and homeostasis model assessment of insulin resistance levels. In conclusion, phlorizin is beneficial for preventing diet-induced obesity, hepatic steatosis, inflammation, and fibrosis, as well as insulin resistance.
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Tecido Adiposo/efeitos dos fármacos , Suplementos Nutricionais , Hiperglicemia/tratamento farmacológico , Inflamação/tratamento farmacológico , Fígado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Florizina/uso terapêutico , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Dieta Hiperlipídica , Hiperglicemia/sangue , Hiperglicemia/etiologia , Inflamação/etiologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Malus/química , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/complicações , Obesidade/metabolismo , Florizina/farmacologia , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
SCOPE: A number of findings suggest that zero-calorie d-allulose, also known as d-psicose, has beneficial effects on obesity-related metabolic disturbances. However, it is unclear whether d-allulose can normalize the metabolic status of diet-induced obesity without having an impact on the energy density. We investigated whether 5% d-allulose supplementation in a high fat diet(HFD) could normalize body fat in a diet-induced obesity animal model under isocaloric pair-fed conditions. METHODS AND RESULTS: Mice were fed an HFD with or without various sugar substitutes (d-glucose, d-fructose, erytritol, or d-allulose, n = 10 per group) for 16 wk. Body weight and fat-pad mass in the d-allulose group were dramatically lowered to that of the normal group with a simultaneous decrease in plasma leptin and resistin concentrations. d-allulose lowered plasma and hepatic lipids while elevating fecal lipids with a decrease in mRNA expression of CD36, ApoB48, FATP4, in the small intestine in mice. In the liver, activities of both fatty acid synthase and ß-oxidation were downregulated by d-allulose to that of the normal group; however, in WAT, fatty acid synthase was decreased while ß-oxidation activity was enhanced. CONCLUSION: Taken together, our findings suggest that 5% dietary d-allulose led to the normalization of the metabolic status of diet-induced obesity by altering lipid-regulating enzyme activities and their gene-expression level along with fecal lipids.
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Peso Corporal/efeitos dos fármacos , Frutose/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/tratamento farmacológico , Adiposidade/efeitos dos fármacos , Animais , Apolipoproteína B-48/genética , Apolipoproteína B-48/metabolismo , Glicemia/metabolismo , Antígenos CD36/genética , Antígenos CD36/metabolismo , Dieta Hiperlipídica , Suplementos Nutricionais , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Regulação da Expressão Gênica , Glucose/administração & dosagem , Leptina/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Resistina/sangue , Edulcorantes/administração & dosagemRESUMO
The aim of this study was to examine the efficacy of combined grape pomace and omija fruit ethanol extracts (GO) on metabolic disorders in overweight or obese subjects. Seventy-six subjects (30-70 years, body mass index ≥23.0 kg/m2) were divided into control (starch, 4 g/day, n = 24), low-GO (low dose GO, grape pomace extract [342.5 mg/day] + omija fruit extract [57.5 mg/day], n = 26), and high-GO (high dose GO, grape pomace extract [685 mg/day] + omija fruit extract [115 mg/day], n = 26) groups. Body composition, nutrient intake, plasma lipid profiles, inflammation, antioxidant capacity, and hepatotoxicity markers were assessed in all subjects at the baseline and 10 weeks after taking the supplements. The body weight and body fat of overweight or obese subjects was not significantly altered in the low-GO and high-GO groups. However, the high-GO supplement significantly decreased the baseline-adjusted final plasma total-cholesterol, low-density lipoprotein (LDL)-cholesterol, and non-high-density lipoprotein (HDL)-cholesterol levels and increased the baseline-adjusted final plasma apolipoprotein (apo) A-1 level compared with that of the control group. In addition, the high-GO supplement significantly lowered apo B, apo B/apo A-1, lipoprotein a (Lp[a]), atherogenic index, interleukin (IL)-1ß, tumor necrosis factor-α, and elevated erythrocyte antioxidant capacity compared with the control group or the baseline levels. The low-GO supplement decreased the plasma IL-1ß level and elevated erythrocyte superoxide dismutase activity compared with that at baseline. However, in general, high-GO exerted a greater effect than low-GO. There were no significant differences in activities of plasma glutamate oxaloacetate transaminase and glutamate pyruvate transaminase between the groups. This study is a preliminary clinical study to verify that GO could be beneficial for amelioration of obesity-related dyslipidemia, inflammation, and oxidative stress without side effect in the overweight or obese subjects.
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Composição Corporal/efeitos dos fármacos , Suplementos Nutricionais , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Extratos Vegetais/farmacologia , Vitis/química , Adulto , Idoso , Antioxidantes/metabolismo , Apolipoproteína A-I/sangue , Apolipoproteínas B/sangue , Biomarcadores/sangue , Índice de Massa Corporal , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Frutas/química , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
Kainic acid (KA) is well known as a chemical compound to study epileptic seizures and neuronal excitotoxicity. KA-induced excitotoxicity causes neuronal death by induction of autophagic stress and microglia-derived neuroinflammation, suggesting that the control of KA-induced effects may be important to inhibit epileptic seizures with neuroprotection. Naringin, a flavonoid in grapefruit and citrus fruits, has anti-inflammatory and antioxidative activities, resulting in neuroprotection in animal models from neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. In the present study, we examined its beneficial effects involved in antiautophagic stress and antineuroinflammation in the KA-treated hippocampus. Our results showed that naringin treatment delayed the onset of KA-induced seizures and decreased the occurrence of chronic spontaneous recurrent seizures (SRS) in KA-treated mice. Moreover, naringin treatment protected hippocampal CA1 neurons in the KA-treated hippocampus, ameliorated KA-induced autophagic stress, confirmed by the expression of microtubule-associated protein light chain 3 (LC3), and attenuated an increase in tumor necrosis factor-α (TNFα) in activated microglia. These results suggest that naringin may have beneficial effects of preventing epileptic events and neuronal death through antiautophagic stress and antineuroinflammation in the hippocampus in vivo.
RESUMO
BACKGROUND/OBJECTIVES: We investigated the effects of a combination of grape pomace (Vitis labrusca, Campbell Early) and Omija fruit (Schizandra chinensis, Baillon) ethanol extracts on lipid metabolism and antioxidant defense system in diet-induced obese mice. MATERIALS/METHODS: Forty male C57BL/6J mice were divided into four groups and fed high-fat diet (control group, CON) or high-fat diet added 0.5% grape pomace extract (GPE), 0.05% Omija fruit extract (OFE) or 0.5% GPE plus 0.05% OFE (GPE+OFE) for 12 weeks. RESULTS: In contrast to the GPE- or OFE-supplemented groups, the GPE+OFE group showed significantly lower body weight and white adipose tissue weights than the CON group. Moreover, GPE+OFE supplementation significantly decreased plasma total cholesterol and increased the plasma HDL-cholesterol/total-cholesterol ratio (HTR) compared to the control diet. The hepatic triglyceride level was significantly lower in the GPE+OFE and GPE groups by increasing ß-oxidation and decreasing lipogenic enzyme compared to the CON group. Furthermore, GPE+OFE supplementation significantly increased antioxidant enzyme activities with a simultaneous decrease in liver H2O2 content compared to the control diet. CONCLUSIONS: Together our results suggest that supplementation with the GPE+OFE mixture may be more effective in improving adiposity, lipid metabolism and oxidative stress in high-fat diet-fed mice than those with GPE and OFE alone.
RESUMO
The transduction of dopaminergic (DA) neurons with human ras homolog enriched in brain, which has a S16H mutation [hRheb(S16H)] protects the nigrostriatal DA projection in the 6-hydroxydopamine (6-OHDA)-treated animal model of Parkinson's disease (PD). However, it is still unclear whether the expression of active hRheb induces the production of neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), which are involved in neuroprotection, in mature neurons. Here, we show that transduction of nigral DA neurons with hRheb(S16H) significantly increases the levels of phospho-cyclic adenosine monophosphate (cAMP) response element-binding protein (p-CREB), GDNF, and BDNF in neurons, which are attenuated by rapamycin, a specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1). Moreover, treatment with specific neutralizing antibodies for GDNF and BDNF reduced the protective effects of hRheb(S16H) against 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity. These results show that activation of hRheb/mTORC1 signaling pathway could impart to DA neurons the important ability to continuously produce GDNF and BDNF as therapeutic agents against PD.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/biossíntese , Modelos Animais de Doenças , Fator Neurotrófico Derivado de Linhagem de Célula Glial/biossíntese , Proteínas Monoméricas de Ligação ao GTP/farmacologia , Neurônios/metabolismo , Neuropeptídeos/farmacologia , Doença de Parkinson/metabolismo , Animais , Humanos , Proteínas Monoméricas de Ligação ao GTP/uso terapêutico , Neurônios/efeitos dos fármacos , Neuropeptídeos/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/prevenção & controle , Proteína Enriquecida em Homólogo de Ras do Encéfalo , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismoRESUMO
Recent evidence has shown that Ras homolog enriched in brain (Rheb) is dysregulated in Alzheimer's disease (AD) brains. However, it is still unclear whether Rheb activation contributes to the survival and protection of hippocampal neurons in the adult brain. To assess the effects of active Rheb in hippocampal neurons in vivo, we transfected neurons in the cornu ammonis 1 (CA1) region in normal adult rats with an adeno-associated virus containing the constitutively active human Rheb (hRheb(S16H)) and evaluated the effects on thrombin-induced neurotoxicity. Transduction with hRheb(S16H) significantly induced neurotrophic effects in hippocampal neurons through activation of mammalian target of rapamycin complex 1 (mTORC1) without side effects such as long-term potentiation impairment and seizures from the alteration of cytoarchitecture, and the expression of hRheb(S16H) prevented thrombin-induced neurodegeneration in vivo, an effect that was diminished by treatment with specific neutralizing antibodies against brain-derived neurotrophic factor (BDNF). In addition, our results showed that the basal mTORC1 activity might be insufficient to mediate the level of BDNF expression, but hRheb(S16H)-activated mTORC1 stimulated BDNF production in hippocampal neurons. These results suggest that viral vector transduction with hRheb(S16H) may have therapeutic value in the treatment of neurodegenerative diseases such as AD.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/biossíntese , Região CA1 Hipocampal/metabolismo , Proteínas Monoméricas de Ligação ao GTP/genética , Neurônios/metabolismo , Neuropeptídeos/genética , Transdução Genética/métodos , Animais , Anticorpos Neutralizantes/farmacologia , Fator Neurotrófico Derivado do Encéfalo/agonistas , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/genética , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Dependovirus/genética , Dependovirus/metabolismo , Expressão Gênica , Vetores Genéticos/administração & dosagem , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Complexos Multiproteicos/agonistas , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neuropeptídeos/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo , Ratos , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Trombina/antagonistas & inibidores , Trombina/toxicidadeRESUMO
Recently, we have demonstrated the ability of naringin, a well-known flavanone glycoside of grapefruits and citrus fruits, to prevent neurodegeneration in a neurotoxin model of Parkinson's disease. Intraperitoneal injection of naringin protected the nigrostriatal dopaminergic projection by increasing glial cell line-derived neurotrophic factor expression and decreasing the level of tumor necrosis factor-alpha in dopaminergic neurons and microglia, respectively. These results suggest that naringin can impart to the adult dopaminergic neurons the ability to produce glial cell line-derived neurotrophic factor against Parkinson's disease with anti-inflammatory effects. Based on these results, we would like to describe an important perspective on its possibility as a therapeutic agent for Parkinson's disease.
RESUMO
This study investigated the effects of combined grape pomace and omija fruit extracts (GO) on diabetes-related metabolic changes in type 2 diabetic db/db mice. The effects of GO were compared with those of a resveratrol and schizandrin mixture (RS), which is a mixture of major components of GO. Mice were fed a normal diet with RS (0.005% resveratrol and 0.02% schizandrin in diet, w/w) or GO (0.3% grape pomace ethanol extract and 0.05% omija fruit ethanol extract in diet, w/w) for seven weeks. RS and GO not only lowered the levels of blood and plasma glucose, HbA1c, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) with a simultaneous decrease in hepatic gluconeogenic enzymes activities and adiposity, but also improved preservation of the pancreatic ß-cells. Plasma leptin and resistin levels were lower while the plasma adiponectin level was higher in the RS and GO groups than in the control group. Especially, GO increased hepatic glucokinase activity and gene expression and improved hepatic steatosis by elevating fatty acid oxidation compared to RS. These findings suggest that GO ameliorates hyperglycemia, adiposity and hepatic steatosis in type 2 diabetic mice.