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1.
Lipids Health Dis ; 18(1): 128, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31153380

RESUMO

BACKGROUND: Polygonum Multiflorum Thunb(PMT) has multiple biological effects, such as anti-inflammatory, lipid-lowering, anti-aging and so on. Therefore, D-galactose-induced aging mice were used to study the effect of PMT on fatty acid metabolism and its underlying mechanism. METHODS: C57BL/6 male mice were randomly divided into normal group, aging model group, PMT intragastrical administration group (high, Medium, low); model group and PMT intragastrical administration group Daily intraperitoneal injection D-galactose 800 mg·ml- 1·Kg- 1 to establish subacute aging model; PMT intragastrical administration group at the same time to intragastrical PMT extract (1 g·ml- 1·Kg- 1, 0.6 g·ml- 1·Kg- 1, 0.3 g·ml- 1·Kg- 1), normal group injection and intragastrical equivalent saline for 60 consecutive days. By detecting the oxidation index of liver to judge the efficacy of PMT, gas chromatography-mass spectrometry (GC-MS) analysis was used to quantitatively analyze the fatty acid content in liver. RESULTS: Finally, we found that PMT improved the enzyme activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in aging mice, and reduce the enzyme activity of malondialdehyde (MDA), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The content of fatty acids such as C18:1, C18:2, C18:3 N3, C20:2 and C20:3 N3 decreased significantly in senescent mice (P < 0.05) as evidenced by GC-MS analysis, whereas, these fatty acids increased significantly after treatment of PMT (P < 0.05). CONCLUSION: PMT improves the content of liver fatty acids in aging mice induced by D-galactose through, enhancing the activity of anti-oxidant enzymes.


Assuntos
Envelhecimento/efeitos dos fármacos , Ácidos Graxos/metabolismo , Extratos Vegetais/farmacologia , Polygonum/química , Envelhecimento/patologia , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Modelos Animais de Doenças , Ácidos Graxos/química , Ácidos Graxos/classificação , Galactose/toxicidade , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Malondialdeído/metabolismo , Camundongos , Oxirredução/efeitos dos fármacos , Extratos Vegetais/química
2.
Int J Mol Sci ; 20(8)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-31014012

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder more prevalent among the elderly population. AD is characterised clinically by a progressive decline in cognitive functions and pathologically by the presence of neurofibrillary tangles (NFTs), deposition of beta-amyloid (Aß) plaque and synaptic dysfunction in the brain. Centella asiatica (CA) is a valuable herb being used widely in African, Ayurvedic, and Chinese traditional medicine to reverse cognitive impairment and to enhance cognitive functions. This study aimed to evaluate the effectiveness of CA in preventing d-galactose/aluminium chloride (d-gal/AlCl3) induced AD-like pathologies and the underlying mechanisms of action were further investigated for the first time. Results showed that co-administration of CA to d-gal/AlCl3 induced AD-like rat models significantly increased the levels of protein phosphatase 2 (PP2A) and decreased the levels of glycogen synthase kinase-3 beta (GSK-3ß). It was further observed that, CA increased the expression of mRNA of Bcl-2, while there was minimal effect on the expression of caspase 3 mRNA. The results also showed that, CA prevented morphological aberrations in the connus ammonis 3 (CA 3) sub-region of the rat's hippocampus. The results clearly demonstrated for the first time that CA could alleviate d-gal/AlCl3 induced AD-like pathologies in rats via inhibition of hyperphosphorylated tau (P-tau) bio-synthetic proteins, anti-apoptosis and maintenance of cytoarchitecture.


Assuntos
Doença de Alzheimer/prevenção & controle , Centella/química , Hipocampo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Cloreto de Alumínio/química , Cloreto de Alumínio/toxicidade , Doença de Alzheimer/etiologia , Doença de Alzheimer/veterinária , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Centella/metabolismo , Galactose/química , Galactose/toxicidade , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Triterpenos/química , Triterpenos/uso terapêutico
3.
J Ethnopharmacol ; 234: 44-56, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30610932

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Chrysanthemum indicum Linne (C. indicum), a healthy food and folk medicine in China for thousands of years, has been reported to exert heat-clearing and detoxifying effects and extensively applied to treat various symptoms such as inflammation diseases, hepatitis and headache. AIM OF THIS STUDY: The purpose of the present study was to investigate the protective effect of the supercritical carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) on D-galactose-induced brain and liver damage during aging process and to illuminate the underlying mechanisms. MATERIALS AND METHODS: Mice were orally administrated with CISCFE (100, 150 and 300 mg/kg) after injection with D-galactose. 24 h after the last administration, the blood samples, whole brain and liver tissues were collected for biochemical analysis, histological examination and western blot analysis. The body weight, spleen and thymus indexes, alanine transaminase (ALT), aspartate transaminase (AST), total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), malondialdehyde (MDA) in brain and liver, interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and necrosis factor-α (TNF-α) were detected. Besides, the expressions of Bax, Bcl-2 and cleaved caspase-3 were determined by western blot assay. RESULTS: The results indicated that CISCFE effectively increased the suppressed body weight, attenuated the decline of thymus and spleen indexes, and reduced the elevated levels of ALT and AST induced by D-gal. Furthermore, CISCFE might notably alleviate D-gal-induced abnormal alterations in structure and function of brain and liver dose-dependently via renewing normal antioxidant enzymes activities (SOD, CAT, GSH-Px), reducing MDA accumulation, decreasing inflammatory cytokines productions (IL-1ß, IL-6, TNF-α), as well as attenuating the increase of Bax/Bcl-2 ratio and cleaved caspase-3 activation in the liver and brain. CONCLUSIONS: Taken together, our present results suggested that CISCFE treatment could effectively mitigate the D-gal-induced hepatic and cerebral injury, and the underlying mechanism might be tightly related to the decreased oxidative stress, inflammation and apoptosis, indicating CISCFE might be an alternative and promising agent for the treatment of aging and age-associated brain and liver diseases.


Assuntos
Chrysanthemum/química , Inflamação/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Envelhecimento/patologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Dióxido de Carbono/química , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Flores , Galactose/toxicidade , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Extratos Vegetais/administração & dosagem , Superóxido Dismutase/metabolismo
4.
Neurochem Int ; 124: 31-40, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30578839

RESUMO

Presbycusis has become a common sensory deficit in humans. Oxidative damage to mitochondrial DNA and mitochondrial dysfunction is strongly associated with the aging of the auditory system. A previous study established a mimetic rat model of aging using D-galactose (D-gal) and first reported that NADPH oxidase-dependent mitochondrial oxidative damage and apoptosis in the ventral cochlear nucleus (VCN) might contribute to D-gal-induced central presbycusis. In this study, we investigated the effects of apocynin, an NADPH oxidase inhibitor, on mitochondrial dysfunction and mitochondria-dependent apoptosis in the VCN of D-gal-induced aging model in rats. Our data showed that apocynin decreased NADPH oxidase activity, H2O2 levels, mitochondrial DNA common deletion, and 8-hydroxy-2-deoxyguanosine (8-OHdG) expression and increased total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) activity in the VCN of D-gal-induced aging model in rats. Moreover, apocynin also decreased the protein levels of phospho-p47phox (p-p47phox), tumor necrosis factor alpha (TNFα), and uncoupling protein 2 (UCP2) in the VCN of D-gal-induced aging model in rats. Meanwhile, apocynin alleviated mitochondrial ultrastructure damage and enhanced ATP production and mitochondrial membrane potential (MMP) levels in the VCN of D-gal-induced aging model in rats. Furthermore, apocynin inhibited cytochrome c (Cyt c) translocation from mitochondria to the cytoplasm and suppressed caspase 3-dependent apoptosis in the VCN of D-gal-induced aging model in rats. Consequently, our findings suggest that neuronal survival promoted by an NADPH oxidase inhibitor is a potentially effective method to enhance the resistance of neurons to central presbycusis.


Assuntos
Acetofenonas/farmacologia , Envelhecimento/efeitos dos fármacos , Núcleo Coclear/efeitos dos fármacos , Galactose/toxicidade , Mitocôndrias/efeitos dos fármacos , NADPH Oxidases/antagonistas & inibidores , Envelhecimento/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Núcleo Coclear/metabolismo , Inibidores Enzimáticos/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Mitocôndrias/metabolismo , NADPH Oxidases/metabolismo , Ratos , Ratos Sprague-Dawley
5.
Theriogenology ; 125: 157-167, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30447495

RESUMO

In this study, effects of icariin (Ica) on were examined in a mouse model of d-galactose (D-gal)-induced ovarian aging. Kunming white mice were divided into three groups: aging group induced with D-gal, experiment group treated with Ica at low (50 mg/kg), middle (100 mg/kg) and high (200 mg/kg) concentrations, and control group with no treatment. Ovarian histomorphology, serum FSH, LH and E2 levels, and reproductive function were compared among the groups. Ovarian expression of Amh, Bax and Bcl-2 was examined by qPCR and western blotting. Our results showed that diameters of secondary and tertiary follicles were significantly reduced in the aging group when compared with control group (P < 0.01), and were restored to normal in Ica 100 and Ica 200 treatment groups. The diameter of atretic follicles was significantly smaller in the aging group compared with control group and Ica 200 treatment group (P < 0.05). The proportion of secondary and atretic follicles was higher in the aging group compared with control group, Ica 100 and 200 treatment groups, whereas the proportion of tertiary and mature follicles was reduced in the aging group versus control, Ica 100 and 200 groups. The aging group lacked mature follicles, whereas Ica treatment induced mature follicle development. Primary and secondary follicles exhibited similar theca cell numbers and theca interna and externa cell layers in all groups examined, whereas theca interna and externa cell layers were decreased and increased, respectively, in tertiary follicles of aging group compared with control and I 200 groups. In the aging group, FSH and LH levels were significantly higher than those in control and Ica 200 groups (P < 0.05), and the E2 level was significantly reduced compared with control (P < 0.01), Ica 200 (P < 0.01), and Ica 100 (P < 0.05) groups. Serum hormone levels were equivalent in the control, Ica 100 and Ica 200 groups. The pregnancy rate was reduced in the aging group compared with other groups. The average litter size per birth, birth litter weight, and weaning weight of litters were all significantly lower in the aging group compared with control, Ica 100 and 200 groups (P < 0.05). The ovarian expression of AMH and Bcl-2 mRNA was significantly reduced in the aging group compared with those in control and Ica-treated groups (P < 0.01). In contrast, Bax expression was significantly higher in the aging group compared with all other groups (P < 0.01), and the Bcl-2/Bax ratio was markedly reduced in aging group compared with control, Ica 100 and 200 groups (P < 0.01), and Ica 50 group (P < 0.05). Ovarian expression of AMH protein was elevated in the Ica 100 group compared with the aging, control and Ica 50 groups (P < 0.01) and Ica 200 group (P < 0.05). Ovarian Bcl-2 protein levels and the Bcl-2/Bax ratio were significantly higher in the Ica 100 group than those in the Ica 50, 200 and aging groups (P < 0.05), and were similar or reduced (P < 0.05), respectively, compared to those in control group. Ovarian Bax expression was similar in each group. These findings suggest that Ica can improve ovarian follicular development, inhibit follicular atresia, decrease FSH and LH levels and increase E2, upregulate ovarian AMH expression and increase the Bcl-2/Bax ratio in aging mice. Therefore, Ica can partially restore ovarian function of aging mice and enhance their fertility. Optimal reproductive effects were obtained with the Ica 100 group.


Assuntos
Flavonoides/farmacologia , Ovário/efeitos dos fármacos , Envelhecimento , Animais , Hormônio Antimülleriano/genética , Hormônio Antimülleriano/metabolismo , Feminino , Galactose/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Ovário/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Organismos Livres de Patógenos Específicos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
6.
Biomed Pharmacother ; 109: 853-864, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551539

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder and the commonest cause of dementia among the aged people. D-galactose (D-gal) is a senescence agent, while aluminium is a known neurotoxin linked to pathogenesis of AD. The combined administration of rats with d-gal and aluminium chloride (AlCl3) is considered to be an easy and a cheap method to obtain an animal model of AD. The plant Centella asiatica (CA) is reported to exert neuroprotective effects both in vitro and in vivo. Therefore, this study explored the protective effects of CA on cognition and brain ultrastructure in d-gal and AlCl3 induced rats. MATERIALS AND METHODS: Rats were exposed to d-gal 60 mg/kg/b.wt/day + AlCl3 200 mg/kg/b.wt/day and CA (200, 400 and 800 mg/kg/b.wt/day) and 1 mg/kg/b.wt/day of donepezil for 70 days. Different cognitive paradigms viz. T maze spontaneous alternation, modified elevated plus maze and novel object recognition test, were used to evaluate full lesions of the hippocampus, spatial learning and memory and non-spatial learning and memory respectively. Nissl's staining was used to determine the survival of hippocampus CA1 pyramidal cells, while transmission electron microscopy was used to check the ultrastructural changes. RESULTS: The results revealed that d-gal and AlCl3 could significantly impair behavior and cognitive functions, besides causing damage to the hippocampal CA1 pyramidal neurons in rats. In addition, it also caused ultrastructural morphological alterations in rat hippocampus. Conversely, co-administration o;f CA, irrespective of the dosage used, alleviated the cognitive impairments and pathological changes in the rats comparable to donepezil. CONCLUSION: In conclusion the results suggest that CA could protect cognitive impairments and morphological alterations caused by d-gal and AlCl3 toxicity in rats. Biochemical and molecular studies are ongoing to elucidate the probable pharmacodynamics of CA.


Assuntos
Cloreto de Alumínio/toxicidade , Disfunção Cognitiva/prevenção & controle , Galactose/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/ultraestrutura , Triterpenos/uso terapêutico , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/patologia , Relação Dose-Resposta a Droga , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar , Resultado do Tratamento , Triterpenos/farmacologia
7.
Int J Med Sci ; 15(14): 1658-1666, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30588189

RESUMO

In a previous study, we reported the positive effects of extremely low frequency electromagnetic field (ELF-MF) exposure on Alzheimer's disease (AD) rats; however, the underlying mechanism remains unclear. In addition, we found that Raf-1 kinase inhibitor protein (RKIP) was downregulated by microwave exposure in the rat hippocampus. Our hypothesis was that RKIP-mediated NF-κB pathway signaling is involved in the effect of ELF-MF on the AD rat. In this study, D-galactose intraperitoneal (50 mg/kg/d for 42 d) and Aß25-35 hippocampal (5 µL/unilateral, bilateral, single-dose) injection were implemented to establish an AD rat model. Animals were exposed to 50 Hz and 400 µT ELF-MF for 60 continuous days. The spatial memory ability of the rat was then tested using the Morris water maze. Protein expression and interaction were detected by western blotting and co-immunoprecipitation for RKIP-mediated NF-κB pathway factors. The results showed that ELF-MF exposure partially improved the cognitive disorder, upregulated the levels of RKIP, TAK1, and the RKIP/TAK1 interaction, but downregulated p-IKK levels in AD rats. These results indicated that RKIP-mediated NF-κB pathway signaling plays an important role in the ELF-MF exposure-mediated improvements in the AD rat. Our study suggested that ELF-MF exposure might have a potential therapeutic value for AD. Further in depth studies are required in the future.


Assuntos
Doença de Alzheimer/terapia , Hipocampo/metabolismo , Terapia de Campo Magnético/métodos , NF-kappa B/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/administração & dosagem , Peptídeos beta-Amiloides/toxicidade , Animais , Comportamento Animal , Modelos Animais de Doenças , Regulação para Baixo , Galactose/administração & dosagem , Galactose/toxicidade , Humanos , Masculino , Aprendizagem em Labirinto , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/toxicidade , Ratos , Ratos Wistar , Transdução de Sinais , Resultado do Tratamento
8.
Aging (Albany NY) ; 10(12): 4166-4174, 2018 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-30582744

RESUMO

Exercise is known to be beneficial in controlling aging associated disorders however, the consequence of long-term exercise on cardiac health among aging population is not much clear. In this study the protective effect of exercise on aging associated cardiac disorders was determined using a D-galactose-induced aging model. Eight weeks old Sprague Dawley rats were given intraperitoneal injection of 150 mL/kg D-galactose. Swimming exercise was provided in warm water for 60 min/day for five days per week. Hematoxylin and eosin staining of cardiac tissue sections revealed cardiomyocyte disarrangements in the aging rat hearts but long-term exercise training showed improvements in the cardiac histology. Exercise training also enhanced the expression levels of proteins such as SIRT1, PGC-1α and AMPKα1 that are associated with energy homeostasis and further suppressed aging associated inflammatory cytokines. Our results show that long-term exercise training potentially enhances SIRT1 associated anti-aging signaling and provide cardio-protection against aging.


Assuntos
Envelhecimento/efeitos dos fármacos , Galactose/toxicidade , Cardiopatias/prevenção & controle , Inflamação/etiologia , Condicionamento Físico Animal , Sirtuína 1/metabolismo , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Sirtuína 1/genética , Natação
9.
Aging (Albany NY) ; 10(12): 4197-4212, 2018 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-30585174

RESUMO

The kidney is a typical organ undergoing age and injury. Hyperoside is reported to be useful for preventing aging induced by D-galactose (D-gal). However, therapeutic mechanisms remain unclear. We thereby aimed to verify whether hyperoside, compared to vitamin E (VE), could alleviate renal aging and injury by regulating autophagic activity and its related signaling pathways. In vivo, rats were administered with either hyperoside or VE after renal aging modeling induced by D-gal. Changes in renal aging and injury markers, autophagic activity and AMPK-ULK1 signaling pathway in the kidneys were analysed. In vitro, the NRK-52E cells exposed to D-gal were used to investigate regulative actions of hyperoside and VE on cell viability, renal tubular cellular aging markers, autophagic activity and its related signaling pathways by histomorphometry, immunohistochemistry, immunofluorescence, lentiviral transfection and Western blot. Aging and injury in the kidneys and renal tubular cells induced by D-gal were ameliorated by hyperoside and VE. Hyperoside and VE inhibited autophagic activity through mTOR-independent and AMPK-ULK1 signaling pathways. Hyperoside, as a component of phytomedicine similar to VE, attenuated renal aging and injury induced by D-gal via inhibiting AMPK-ULK1-mediated autophagy. This study provides the first evidence that hyperoside contributes to the prevention of age-associated renal injury.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Galactose/toxicidade , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Proteínas Quinases/metabolismo , Quercetina/análogos & derivados , Animais , Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Proteínas Quinases/genética , Quercetina/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
10.
Drug Dev Res ; 79(8): 426-436, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30375672

RESUMO

Preclinical Research & Development Several clinically useful anticancer drugs selectively kill cancer cells by inducing DNA damage; the genomic instability and DNA repair defects of cancer cells make them more vulnerable than normal cells to the cytotoxicity of DNA-damaging agents. Because epoxide-containing compounds can induce DNA damage, we have used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate the selective cytotoxicity of three epoxyalkyl galactopyranosides against A549 lung cancer cells and MRC-5 lung normal cells. Compound (2S,3S)-2,3-epoxydecyl 4,6-O-(S)-benzylidene-ß-d-galactopyranoside (EDBGP) showed the highest selective anticancer activity and was selected for mechanistic studies. After observing that EDBGP induced cellular DNA damage (comet assay), we found that cells deficient in nucleotide excision repair were hypersensitive to the cytotoxicity of this compound; this suggests that EDBGP may induce bulky DNA adducts. EDBGP did not inhibit glycolysis (glucose consumption and lactate production). Pretreatment of lung cancer cells with several antioxidants did not reduce the cytotoxicity of EDBGP, thereby indicating that reactive oxygen species do not participate in the anticancer activity of this compound. Finally, EDBGP was screened against a panel of cancer cells and normal cells from several tissues, including three genetically modified skin fibroblasts with increasing degree of malignancy. Our results suggest that epoxyalkyl galactopyranosides are promising lead compounds for the development of new anticancer agents.


Assuntos
Citotoxinas/química , Dano ao DNA/efeitos dos fármacos , Galactose/química , Galactose/toxicidade , Células A549 , Animais , Células CHO , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Cricetulus , Dano ao DNA/fisiologia , Relação Dose-Resposta a Droga , Feminino , Células HCT116 , Células HL-60 , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Masculino
11.
Pathol Res Pract ; 214(10): 1596-1605, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30093085

RESUMO

We investigated the effects of the intracerebroventricular infusion of galactose and the influence of pretreatment with antioxidants on oxidative stress parameters and acethylcholinesterase (AChE) activity in the brain of 60-day-old Wistar rats (6 per group). The animals were divided into naïve group (did not undergo surgery); procedure group (only underwent surgery); sham group (underwent surgery and received 5 µL saline) and galactose group (received 5 µL of galactose solution (5.0 mM) by intracerebroventricular injection), and were killed by decapitation after 1 h. Other groups were pretreated daily for 1 week with saline (sham and galactose groups) or antioxidants, α-tocopherol (40 mg/kg) plus ascorbic acid (100 mg/kg, i.p.) (antioxidants and galactose + antioxidants groups). Twelve hours after the last antioxidants injection, animals received an intracerebroventricular infusion of 5 µL of galactose solution (galactose and galactose + antioxidants groups) or saline (sham and antioxidants groups) and were sacrificed 1 h later. Galactose elevated thiobarbituric acid reactive substances (TBA-RS), protein carbonyl content and glutathione peroxidase (GSH-Px) activity and decreased total sulfhydryl content and catalase (CAT) activity in the cerebral cortex. In the hippocampus, galactose enhanced TBA-RS, decreased total sulfhydryl content and increased AChE activity, while in the cerebellum it decreased total sulfhydryl content and increased CAT and superoxide dismutase (SOD) activities. Pretreatment with antioxidants prevented the majority of these alterations, indicating the participation of free radicals in these effects. Thus, intracerebroventricular galactose infusion impairs redox homeostasis in the brain; the administration of antioxidants should be considered as an adjuvant therapy to specific diets in galactosemia.


Assuntos
Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Galactose/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Ácido Ascórbico/farmacologia , Galactosemias/metabolismo , Infusões Intraventriculares , Masculino , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , alfa-Tocoferol/farmacologia
12.
Sci Rep ; 8(1): 8894, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891841

RESUMO

Oxidative stress is known to be associated with various age-related diseases. D-galactose (D-gal) has been considered a senescent model which induces oxidative stress response resulting in memory dysfunction. Pyrroloquinoline quinone (PQQ) is a redox cofactor which is found in various foods. In our previous study, we found that PQQ may be converted into a derivative by binding with amino acid, which is beneficial to several pathological processes. In this study, we found a beneficial glutamate mixture which may diminish neurotoxicity by oxidative stress in D-gal induced mouse. Our results showed that PQQ may influence the generation of proinflammatory mediators, including cytokines and prostaglandins during aging process. D-gal-induced mouse showed increased MDA and ROS levels, and decreased T-AOC activities in the hippocampus, these changes were reversed by PQQ supplementation. Furthermore, PQQ statistically enhanced Superoxide Dismutase SOD2 mRNA expression. PQQ could ameliorate the memory deficits and neurotoxicity induced by D-gal via binding with excess glutamate, which provide a link between glutamate-mediated neurotoxicity, inflammation and oxidative stress. In addition, PQQ reduced the up-regulated expression of p-Akt by D-gal and maintained the activity of GSK-3ß, resulting in a down-regulation of p-Tau level in hippocampus. PQQ modulated memory ability partly via Akt/GSK-3ß pathway.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Galactose/toxicidade , Ácido Glutâmico/toxicidade , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteína Oncogênica v-akt/metabolismo , Cofator PQQ/administração & dosagem , Transdução de Sinais , Animais , Disfunção Cognitiva/induzido quimicamente , Citosol/química , Hipocampo/patologia , Fatores Imunológicos/administração & dosagem , Camundongos , Quinonas/análise , Espécies Reativas de Oxigênio/análise , Superóxido Dismutase/análise
13.
Biomed Pharmacother ; 103: 1602-1608, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29864948

RESUMO

Cognitive impairments and cholinergic dysfunctions have been well reported in old age disorders including Alzheimer's disease (AD). d-galactose (D-gal) has been reported as a senescence agent while aluminium act as a neurotoxic metal, but little is known about their combined effects at different doses. The aim of this study was to establish an animal model with cognitive impairments by comparing the effects of different doses of co-administrated D-gal and aluminium chloride (AlCl3). In this study male albino wistar rats were administered with D-gal 60 mg/kg.bwt intra peritoneally (I.P) injected and AlCl3 (100, 200, or 300 mg/kg.bwt.) was orally administered once daily for 10 consecutive weeks. Performance of the rats were evaluated through behavioural assessments; Morris water maze (MWM) and open field tests (OFT); histopathological examination was performed on the hippocampus; moreover biochemical measurements of acetylcholinesterase (AChE) and hyperphosphorylated tau protein (p-tau) were examined. The results of this experiment on rats treated with D-gal 60 + AlCl3 200 mg/kg.bwt showed near ideal cognitive impairments. The rats exhibited an obvious memory and learning deficits, marked neuronal loss in hippocampus, showed increase in AChE activities and high expression of p-tau within the tissues of the brain. This study concludes that D-gal 60 + AlCl3 200 mg/kg.bwt as the ideal dose for mimicking AD like cognitive impairments in albino wistar rats. It is also crucial to understand the pathogenesis of this neurodegenerative disease and for drug discovery.


Assuntos
Compostos de Alumínio/toxicidade , Cloretos/toxicidade , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/patologia , Galactose/toxicidade , Acetilcolinesterase/metabolismo , Cloreto de Alumínio , Compostos de Alumínio/administração & dosagem , Animais , Cloretos/administração & dosagem , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Galactose/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos Wistar , Tempo de Reação/efeitos dos fármacos
14.
Food Chem Toxicol ; 119: 141-149, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29751077

RESUMO

To elucidate the possible mechanisms for the preventive effect of procyanidin B2 on aging, a combined analysis of metabolic profile and gut microbiome was carried out in the present study. The mimetic aged mice induced by d-galactose injection (500 mg/kg, sc daily), and the preventive group was fed with the diet plus 0.2% procyanidin B2. After 7 weeks of treatment, the spatial memory was assayed using the Morris water maze test. Procyanidin B2 significantly ameliorated the impaired memory and antioxidant abilities induced by d-galactose. Furthermore, metabolomics analysis of plasma based on LC/Q-TOF-MS demonstrated that phosphatidyl cholines, oleic acid, linoleic acid, carnitine, pantothenic acid, and taurocholic acid were significantly increased in the mice treated with procyanidin B2, and pyruvic acid, hydroxybutyric acid, hippuric acid, and cholic acid were decreased significantly. Together, gut microbiome analysis using Illumina sequencing showed that there were significant differences in the Firmicutes/Bacteroidetes ratio and abundance of Roseburia, Lachnospiraceae, and Bifidobacterium between the aging and supplemental procyanidin B2 groups. In summary, procyanidin B2 possessed potential prevention of the cognitive and oxidative impairment via the metabolic pathway regulation related to citrate cycle, fatty acid, and bile acid in the aged mice, accompanied by remodeling the gut flora.


Assuntos
Envelhecimento/efeitos dos fármacos , Biflavonoides/farmacologia , Catequina/farmacologia , Galactose/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Proantocianidinas/farmacologia , Animais , Sequência de Bases , Biomarcadores , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Camundongos , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo
15.
Exp Gerontol ; 108: 77-86, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29649571

RESUMO

Changes in mitochondrial structure and function are the initial factors of cell aging. Spermidine has an antiaging effect, but its effect on neuronal aging and mitochondrial mechanisms is unclear. In this study, mouse neuroblastoma (N2a) cells were treated with d­galactose (d­Gal) to establish cell aging to investigate the antiaging effect and mechanisms of spermidine. Changes in the cell cycle and ß-galactosidase activity were analyzed to evaluate the extent of cell aging. Stabilities of mitochondrial mRNA and mitochondrial membrane potential (MMP) were evaluated in the process of cell aging under different treatments. The mitochondrial function was also evaluated using the Seahorse Metabolic Analysis System combined with ATP production. The unfolded protein response (UPR) of the N2a cells was analyzed under different treatments. Results showed that spermidine pretreatment could delay the cell aging and could maintain the mitochondrial stability during d­Gal treatment. Spermidine increased the proportion of cells in the S phase and maintained the MMP. The oxygen utilization and ATP production in the N2a cells were reduced by d­Gal treatment but were partially rescued by the spermidine pretreatment. Spermidine ameliorated the N2a cell aging by promoting the autophagy and inhibiting the apoptosis except the UPR. These results showed that spermidine could ameliorate the N2a cell aging by maintaining the mitochondrial mRNA transcription, MMP and oxygen utilization during the d­Gal treatment.


Assuntos
Senescência Celular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Espermidina/farmacologia , Envelhecimento/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Ciclo Celular , Linhagem Celular Tumoral , Galactose/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/fisiologia
16.
Biomed Pharmacother ; 103: 680-690, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29679909

RESUMO

Age-related neuronal injury and oxidative damage are the predominant factors for neurodegenerative diseases like Alzheimer's disease (AD). The aim of this study was to explore whether chronic administration of d-galactose (d-gal) can cause neuronal injury and oxidative damage, and to investigate the neuroprotective and antioxidative effects of the active components (UPNO-1) from Korean pine nut (Pinus koraiensis). Two dosing regimens were designed, one for the evaluation of preventive effects in which the rats were simultaneously administrated d-gal and UPNO-1/fishoil for 12 weeks, the other for the evaluation of therapeutic effects in which the rats were given d-gal for 8 weeks before treated with UPNO-1/selegiline for 8 weeks. The experimental results demonstrated that chronic administration of d-gal produced histopathological changes and increased neuronal apoptosis, and decreased significantly the activities of T-AOC, T-SOD and CAT. Additionally, a comprehensive metabolic profiling of d-gal-treated rats was performed for the first time to investigate the metabolic disorders in the hippocampus, cortex and plasma, and a total of 32 annotated metabolites were significantly increased or decreased in the modeled rats. Major disturbed metabolic pathways were fatty acid, glycerolphospholipid and arachidonic acid metabolic pathways. UPNO-1 significantly diminished neuronal apoptosis, ameliorated histopathological findings, and increased the activities of T-SOD and CAT but not T-AOC. Furthermore, UPNO-1 attenuated the decreased plasma levels of 3-oxooctanoic acid, l-tryptophan, 12-hydroxyheptadecanoic acid, lysophosphatidylcholine (16:0) (LPC(16:0)), LPC(18:3) and LPC(18:1) in the modeled rats. These results illustrated the mechanisms of d-gal induced neurotoxicity and oxidative stress and proved the positive effects of UPNO-1 on preventing and treating d-gal-induced-aging rats.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Galactose/toxicidade , Nozes , Pinus , Extratos Vegetais/farmacologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Antioxidantes/isolamento & purificação , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Masculino , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Sprague-Dawley
17.
Neurol Res ; 40(4): 324-333, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29464986

RESUMO

OBJECTIVES: Thymoquinone (TQ), the main active ingredient in Nigella sativa oil, exhibits various bioactivities. This study aimed to investigate the effect of TQ on neurobehavioral and neuropathological alterations induced by aluminum trichloride (AlCl3) and D-galactose (D-gal)-in male rats and to explore the related mechanisms. METHODS: D-gal (60 mg/kg day) and AlCl3 (10 mg/kg day) were given intraperitoneally (i.p.) once daily for 42 days and after 4 weeks TQ was concomitantly administered intragastrically (i.g.) (20 mg/kg/day) once daily for 14 days. Then, memory function was evaluated by Morris water maze test (MWM). Superoxide dismutase (SOD), Total antioxidant capacity (TAC), Acetylcholinesterase (AChE) activities, and malondialdehyde (MDA), nitric oxide (NO), brain-derived neurotrophic factor (BDNF), and B-cell lymphoma-2 (Bcl-2) levels in whole brain were assessed with the biochemical technique. Tumor necrosis factor-alpha (TNF-α) and Acetylcholine (ACh) were also assessed using an immunohistochemical technique. RESULTS: Administration of TQ significantly improved cognition. In addition, TQ significantly increased SOD and TAC and decreased AChE activities. It also decreased MDA and NO levels as well as TNF-α immunoreactivity and increased BDNF and Bcl-2 levels as well as ACh immunoreactivity. DISCUSSION: Our results indicate that TQ prevents D-gal/AlCl3-induced cognitive decline by enhancing cholinergic function and synaptic plasticity as well as attenuation of oxidative damage, neuronal apoptosis, and neuroinflammation. These results indicate that TQ holds potential for neuroprotection and may be a promising approach for the treatment of neurodegenerative disorders.


Assuntos
Compostos de Alumínio/toxicidade , Doença de Alzheimer/tratamento farmacológico , Benzoquinonas/administração & dosagem , Encéfalo/efeitos dos fármacos , Cloretos/toxicidade , Disfunção Cognitiva/tratamento farmacológico , Galactose/toxicidade , Fármacos Neuroprotetores/administração & dosagem , Cloreto de Alumínio , Doença de Alzheimer/induzido quimicamente , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/induzido quimicamente , Modelos Animais de Doenças , Masculino , Memória/efeitos dos fármacos , Ratos Sprague-Dawley
18.
Hum Exp Toxicol ; 37(10): 1092-1104, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29405769

RESUMO

Alzheimer's disease (AD) is characterized by a robust inflammatory response elicited by the accumulation and deposition of amyloid-ß (Aß) within the brain. Aß induces detrimental inflammatory responses through toll-like receptors (TLRs) signaling pathway. Thymoquinone (TQ), the main active constituent of Nigella sativa oil, has been reported by several previous studies for its potent anti-inflammatory effect. The aim of this study is to elucidate the effect of TQ in improving learning and memory, using a rat model of AD induced by a combination of aluminum chloride (AlCl3) and d-galactose (d-Gal). TQ was administered orally at doses of 10, 20, and 40 mg/kg/day for 14 days after AD induction. Memory functions were assessed using the step through passive avoidance test. Amyloid plaques were shown to be present using hematoxylin and eosin staining. Tumor necrosis factor-alpha (TNF-α) and Interleukin-1beta (IL-1ß) levels in brain were assessed via ELISA and profiling TLR-2, TLR-4, myeloid differential factor 88, toll-interleukin-1 receptor domain-containing adapter-inducing interferon-ß, interferon regulatory factor 3 (IRF-3), and nuclear factor-κB (NF-κB) expressions via real-time polymerase chain reaction. TQ improved AD rat cognitive decline, decreased Aß formation and accumulation, significantly decreased TNF-α and IL-1ß at all levels of doses and significantly downregulated the expression of TLRs pathway components as well as their downstream effectors NF-κB and IRF-3 mRNAs at all levels of doses ( p < 0.05). We concluded that TQ reduced the inflammation induced by d-Gal/AlCl3 combination. It is therefore reasonable to assign the anti-inflammatory responses to the modulation of TLRs pathway.


Assuntos
Doença de Alzheimer/prevenção & controle , Benzoquinonas/farmacologia , Inflamação/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Cloreto de Alumínio/toxicidade , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Galactose/toxicidade , Perfilação da Expressão Gênica , Inflamação/induzido quimicamente , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Aprendizagem , Masculino , Memória , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-29439546

RESUMO

The chemical composition of particles varies with space and time and depends on emission sources, atmospheric chemistry and weather conditions. Evidence suggesting that particles differ in toxicity depending on their chemical composition is growing. This in vitro study investigated the biological effects of PM10 in relation to PM-associated chemicals. PM10 was sampled in ambient air at an urban traffic site (Borgerhout) and a rural background location (Houtem) in Flanders (Belgium). To characterize the toxic potential of PM10, airway epithelial cells (Beas-2B cells) were exposed to particles in vitro. Different endpoints were studied including cell damage and death (cell viability) and the induction of interleukin-8 (IL-8). The mutagenic capacity was assessed using the Ames II Mutagenicity Test. The endotoxin levels in the collected samples were analyzed and the oxidative potential (OP) of PM10 particles was evaluated by electron paramagnetic resonance (EPR) spectroscopy. Chemical characteristics of PM10 included tracers for biomass burning (levoglucosan, mannosan and galactosan), elemental and organic carbon (EC/OC) and polycyclic aromatic hydrocarbons (PAHs). Most samples displayed dose-dependent cytotoxicity and IL-8 induction. Spatial and temporal differences in PM10 toxicity were seen. PM10 collected at the urban site was characterized by increased pro-inflammatory and mutagenic activity as well as higher OP and elevated endotoxin levels compared to the background area. Reduced cell viability (-0.46 < rs < -0.35, p < 0.01) and IL-8 induction (-0.62 < rs < -0.67, p < 0.01) were associated with all markers for biomass burning, levoglucosan, mannosan and galactosan. Furthermore, direct and indirect mutagenicity were associated with tracers for biomass burning, OC, EC and PAHs. Multiple regression analyses showed levoglucosan to explain 16% and 28% of the variance in direct and indirect mutagenicity, respectively. Markers for biomass burning were associated with altered cellular responses and increased mutagenic activity. These findings may indicate a role of biomass burning in the observed adverse health effect of particulate matter.


Assuntos
Poluentes Atmosféricos/toxicidade , Mutagênicos/toxicidade , Material Particulado/toxicidade , Poluentes Atmosféricos/análise , Bélgica , Carbono/análise , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Monitoramento Ambiental/métodos , Galactose/análogos & derivados , Galactose/análise , Galactose/toxicidade , Glucose/análogos & derivados , Interleucina-8/biossíntese , Manose/análogos & derivados , Manose/análise , Manose/toxicidade , Mutagênicos/análise , Material Particulado/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Saúde da População Rural , Saúde da População Urbana
20.
Curr Aging Sci ; 11(1): 10-15, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28676006

RESUMO

BACKGROUND: Chronic administration of D-galactose (GAL) induces changes that resemble natural aging in rodents. Oxidative stress and Advanced Glycation End products (AGE) formation play a role in GAL-induced aging. Carnosine (CAR; ß-alanyl-L-histidine) has antioxidant and anti-glycating actions and may be a potential therapeutic agent in aging due to these properties. The effect of CAR supplementation on AGE levels and oxidative stress parameters was investigated in serum, liver and brain tissues in GAL-treated rats. METHODS: GAL (300 mg/kg; s.c.; 5 days per week) alone or together with CAR (250 mg/kg/daily; i.p.; 5 days per week) was applied to male rats for two months. AGE, Advanced Oxidized Protein Products (AOPP), Protein Carbonyl (PC) and Malondialdehyde (MDA) levels together with Reactive Oxygen Species (ROS) formation and Ferric Reducing Antioxidant Power (FRAP) values were determined. RESULTS: GAL treatment elevated AGE levels, ROS formation and protein and lipid oxidation products in serum and examined tissues. CAR treatment was observed to decrease significantly glycooxidative stress in serum, liver and brain tissues of GAL-treated rats. CONCLUSION: Our results indicate that CAR may be useful for decreasing oxidative stress and glycation products in GAL-induced aging model in rats.


Assuntos
Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Carnosina/farmacologia , Galactose/toxicidade , Produtos Finais de Glicação Avançada/sangue , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Produtos da Oxidação Avançada de Proteínas/sangue , Fatores Etários , Envelhecimento/sangue , Animais , Biomarcadores/sangue , Encéfalo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/sangue , Carbonilação Proteica/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/sangue
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