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2.
Brain Res Bull ; 150: 160-167, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132419

RESUMO

OBJECTIVE: Diabetes-associated cognitive decline (DACD) is increasingly being concerned, and oxidative stress plays a vital role in the pathological process. AB-38b is a novel synthetic compound with two specific active groups of biphenyl dicarboxylate and α, ß unsaturated ketone, showing good antioxidant activity. The aim of this study was to investigate the ameliorative effects of AB-38b on DACD in mice, and to explore the possible mechanisms from glyoxylase 1 (Glo-1) enhancement and NF-E2-related factor-2 (Nrf2) activation. METHODS: Experimental type 2 mouse model of diabetes with C57BL/6 mice was made through high-fat diet combining with intraperitoneal streptozotocin. Diabetic mice were treated by gavage with AB-38b (0, 10, 20 and 40 mg/kg) or resveratrol (40 mg/kg), a typical inducer of Nrf2, for 8 weeks. Cognitive performances were evaluated by the novel object recognition task. Then brain tissues were collected to assess hippocampal damages, protein glycation, Glo-1 functions and protein expression, and the classic Nrf2/ARE pathway. RESULT: AB-38b markedly increased the preference index to novel object and the number of neurons in hippocampal CA1 area of diabetic mice. AB-38b significantly elevated the activity and protein of Glo-1, while reduced the levels of advanced glycation end products (AGEs) and protein expression of its receptor RAGE. Moreover, AB-38b raised Nrf2 expression and phosphorylation, as well as the protein expression and enzymatic activity of γ-glutamylcysteine synthetase, a well-known gene of Nrf2/ARE pathway, in hippocampus of the diabetic mice. CONCLUSION: AB-38b improved the cognitive performances of diabetic mice, which was achieved via up-regulation of Glo-1 and activation of Nrf2/ARE pathway.

3.
Biomed Pharmacother ; 111: 1166-1175, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841430

RESUMO

Diabetic nephropathy (DN) is one of the most common diabetic complications, and alpha-carbonyl aldehydes and their detoxicating enzyme glyoxalase 1 (Glo-1) play vital roles in pathogenesis of diabetic complications. The aim of this study was to evaluate the renoprotective effects of hesperetin against DN in rats, and to investigate mechanisms from the aspect of Nrf2/ARE/Glo-1 pathway. Streptozotocin-induced diabetic rats were treated orally with hesperetin (50 and 150 mg/kg), or nuclear factor erythroid-derived-2-like 2 (Nrf2) inducer tert-butylhydroquinone (tBHQ, 25 mg/kg) for 10 weeks. Then proteinuria, creatinine, urea nitrogen, and uric acid were assayed for renal functions, fibronectin and collagen IV levels by immunohistochemistry, as well as periodic acid-Schiff staining and electron microscope observation, were used to assess renal morphology. Glo-1 activity, protein, and mRNA levels and the classic Nrf2/ARE pathway were investigated. Moreover, advanced glycation endproducts (AGEs) and its receptor RAGE, interleukin-1ß and tumor necrosis factor-α levels were also examined in the kidney. Hesperetin markedly ameliorated the renal functions and structural changes of diabetic rats, accompanied by up-regulation of Glo-1 as well as inhibition of AGEs/RAGE axis and inflammation. Meanwhile, hesperetin caused significant increases in Nrf2 and p-Nrf2 levels, as well as up-regulation of γ-glutamylcysteine synthetase, a well-known target gene of Nrf2/ARE signaling. Our results demonstrated that hesperetin could slow down the pathological process of DN, and Glo-1 enhancement contributed to the beneficial effects, which was obtained by the activation of Nrf2/ARE pathway.


Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Hesperidina/farmacologia , Lactoilglutationa Liase/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Glutamato-Cisteína Ligase/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Estreptozocina/farmacologia , Regulação para Cima/efeitos dos fármacos
4.
Biomed Pharmacother ; 109: 2145-2154, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551472

RESUMO

Although dietary flavonoid quercetin alleviates diabetes-associated cognitive decline in rodents, the mechanisms are not clearly clarified. This study was designed to investigate whether quercetin showed neuroprotection on central neurons against chronic high glucose through the enhancement of Nrf2/ARE/glyoxalase 1 (Glo-1) pathway. SH-SY5Y cells were divided into 8 groups: normal glucose, high glucose (HG), osmotic pressure control, solvent control, HG plus low, middle, high concentrations of quercetin, or Nrf2 activator (sulforaphane). After treatment for 72 h, the associated parameters were measured. We found quercetin and sulforaphane increased cell viability, and enhanced Glo-1 functions (Glo-1 activity, the reduced glutathione and advanced glycation end-products levels) as well as Glo-1 protein and mRNA levels in SH-SY5Y cells cultured with HG. Meanwhile, quercetin and sulforaphane activated Nrf2/ARE pathway, reflected by the raised Nrf2 and p-Nrf2 levels, and the elevated protein and mRNA levels of γ-glutamycysteine synthase (γ-GCS), a known target gene of Nrf2/ARE signaling. Moreover, Nrf2/ARE pathway was activated after pretreatment with a PKC activator, p38 MAPK inhibitor, or GSK-3ß inhibitor under the condition of HG, and quercetin addition further strengthened this pathway; however, PKC inhibition or GSK-3ß activation pretreatment reversed the effects of quercetin on the protein expression of γ-GCS in the HG condition. In summary, quercetin exerts the neuroprotection by enhancing Glo-1 functions in central neurons under chronic HG condition, which may be mediated by activation of Nrf2/ARE pathway; furthermore, the increased Nrf2 phosphorylation mediated by PKC activation and/or GSK-3ß inhibition may involve in the activation of Nrf2/ARE pathway.


Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Glucose/toxicidade , Lactoilglutationa Liase/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neuroproteção/efeitos dos fármacos , Quercetina/farmacologia , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Fator 2 Relacionado a NF-E2/agonistas , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuroproteção/fisiologia , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
5.
Naunyn Schmiedebergs Arch Pharmacol ; 391(11): 1237-1245, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30062553

RESUMO

Glyoxalase 1 (Glo-1) is an ubiquitous cellular enzyme that participates in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis that induces protein modification (advanced glycation end products [AGEs]), oxidative stress, and inflammation. The concentration of MG is elevated under high-glucose conditions, such as diabetes. Therefore, Glo-1 and MG have been implicated in the pathogenesis of diabetic encephalopathy. We investigated the effect of quercetin on brain damage that was caused by diabetes in rats and the mechanisms associated with Glo-1. Streptozotocin-induced diabetic rats were treated orally with quercetin (30, 60, and 90 mg/kg) or distilled water for 14 weeks. The temporal cortex and hippocampus were harvested and analyzed for different indices assays. Quercetin, especially at a high dose, increased the levels of reduced glutathione and the activity of superoxide dismutase and decreased the levels of AGEs, the receptor for AGEs (RAGE), and malondialdehyde in the diabetic brain. Quercetin also significantly decreased the levels of inflammatory markers (cyclooxygenase-2, interleukin-1ß, and tumor necrosis factor α) in diabetic brains. Most importantly, Glo-1 activity and protein expression were increased in quercetin-treated diabetic rat brains compared with untreated diabetic brains. These results indicate that quercetin exerts beneficial effects by decreasing protein glycation, oxidative stress, and inflammation through the upregulation of Glo-1, which may ameliorate diabetic encephalopathy.

6.
Phytother Res ; 32(8): 1574-1582, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29682805

RESUMO

Rhizome of Anemarrhena asphodeloides Bunge (AA, family Liliaceae) has been widely used in China for thousands of years to treat febrile diseases and diabetes. Steroidal saponins from AA show good antidiabetes effects and ameliorate diabetic complications. This study was designed to investigate the effects of sarsasapogenin (Sar), a major sapogenin from AA, on diabetic nephropathy (DN) in rats, and to explore the possible mechanisms. Diabetic rats were divided into 3 groups treated orally with Sar (0, 20, or 60 mg/kg) and carboxymethylcellulose sodium, whereas normal rats for Sar (0 or 60 mg/kg) and carboxymethylcellulose sodium. We found that chronic treatment with Sar for 9 weeks significantly ameliorated renal dysfunction of diabetic rats, as evidenced by decreases in albuminuria, kidney weight index, serum uric acid, and morphologic changes such as extracellular matrix expansion and accumulation (fibronectin and collagen IV levels, etc.). Meanwhile, Sar treatment resulted in decreases in interleukin-18, NLRP3, and activated caspase 1 levels as well as advanced glycation endproducts (AGEs) and their receptor (RAGE) levels in the renal cortex of diabetic rats. However, Sar has no effects on the above indices in the normal rats. Therefore, Sar can markedly ameliorate diabetic nephropathy in rats via inhibition of NLRP3 inflammasome activation and AGEs-RAGE interaction.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Espirostanos/farmacologia , Anemarrhena/química , Animais , China , Diabetes Mellitus Experimental/complicações , Medicamentos de Ervas Chinesas/farmacologia , Produtos Finais de Glicação Avançada , Interleucina-18/metabolismo , Rim/efeitos dos fármacos , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Ratos Sprague-Dawley , Rizoma/química , Saponinas/farmacologia , Ácido Úrico/sangue
7.
Naunyn Schmiedebergs Arch Pharmacol ; 391(2): 159-168, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29275517

RESUMO

The aim of this study is to investigate effects and potential mechanisms of sarsasapogenin (Sar), an active component purified from Rhizoma Anemarrhenae, on high glucose-induced amyloid-beta (Aß) peptide overproduction in HT-22 cells. HT-22 cells were divided into normal glucose; high glucose (HG); HG co-treated with low, middle, and high concentration of Sar (1, 5, 25 µmol/L); and peroxisome proliferator-activated receptor γ (PPARγ) agonist (10 µmol/L pioglitazone). After treatment for 24 h, protein expression of Aß and ß-site Aß precursor protein cleaving enzyme 1 (BACE1) and activated PPARγ level were determined by Western blot; Aß42 levels were also measured by using both immunofluorescence and ELISA methods. BACE1 activity and mRNA level were assessed by fluorospectrophotometry and quantitative PCR, respectively. Cell viability was assayed with a CCK-8 kit. Elevated Aß expression and Aß42 level were found in HG-treated HT-22 cells, accompanied by increased BACE1 protein and mRNA levels as well as enzymatic activity, which was markedly attenuated by three concentrations of Sar and pioglitazone. Moreover, HG reduced nuclear PPARγ levels, which was reversed by middle and high concentrations of Sar as well as pioglitazone. PPARγ antagonist GW9662 (20 µmol/L) pretreatment reversed the effect of Sar on BACE1 protein expression in HG-cultured HT-22 cells. Additionally, Sar suppressed HG-induced decreases in cell viability of HT-22 cells. High glucose can induce an increase in Aß levels and a decrease in cell viability in HT-22 cells, while co-treatment with Sar improves these results, which is mediated likely through activation of PPARγ and subsequent downregulation of BACE1.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Medicamentos de Ervas Chinesas/farmacologia , Glucose/toxicidade , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/biossíntese , Espirostanos/farmacologia , Animais , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Camundongos
8.
Mol Neurobiol ; 54(6): 4060-4070, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-27318675

RESUMO

Mangiferin, a natural C-glucoside xanthone, has anti-inflammatory, anti-oxidative, neuroprotective actions. Our previous study showed that mangiferin could attenuate diabetes-associated cognitive impairment of rats by enhancing the function of glyoxalase 1 (Glo-1) in brain. The aim of this study was to investigate whether Glo-1 upregulation by mangiferin in central neurons exposed to chronic high glucose may be related to activation of Nrf2/ARE pathway. Compared with normal glucose (25 mmol/L) culture, Glo-1 protein, mRNA, and activity levels were markedly decreased in primary hippocampal and cerebral cortical neurons cultured with high glucose (50 mmol/L) for 72 h, accompanied by the declined Nrf2 nuclear translocation and protein expression of Nrf2 in cell nucleus, as well as protein expression and mRNA level of γ-glutamylcysteine synthetase (γ-GCS) and superoxide dismutase activity, target genes of Nrf2/ARE signaling. Nonetheless, high glucose cotreating with mangiferin or sulforaphane, a typical inducer of Nrf2 activation, attenuated the above changes in both central neurons. In addition, mangiferin and sulforaphane significantly prevented the formation of advanced glycation end-products (AGEs) reflecting Glo-1 activity, while elevated the level of glutathione, a cofactor of Glo-1 activity and production of γ-GCS, in high glucose cultured central neurons. These findings demonstrated that Glo-1 was greatly downregulated in central neurons exposed to chronic high glucose, which is expected to lead the formation of AGEs and oxidative stress damages. We also proved that mangiferin enhanced the function of Glo-1 under high glucose condition by inducing activation of Nrf2/ARE signaling pathway.


Assuntos
Elementos de Resposta Antioxidante/genética , Glucose/toxicidade , Lactoilglutationa Liase/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Xantonas/farmacologia , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Células Cultivadas , Glutamato-Cisteína Ligase/metabolismo , Glutationa/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Lactoilglutationa Liase/metabolismo , Neurônios/efeitos dos fármacos , Pressão Osmótica , Pressão , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Solventes , Superóxido Dismutase/metabolismo
9.
Mol Med Rep ; 13(6): 5326-34, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27109015

RESUMO

Ibuprofen, a commonly administered nonsteroidal anti­inflammatory therapeutic agent, is also a partial agonist of peroxisome proliferator­activated receptor Î³ (PPARγ). The present study investigated the effects of ibuprofen on type 1 diabetic nephropathy (DN) in rats, and the potential mechanisms associated with the activation of PPARγ. Diabetic rats were induced through a single intraperitoneal injection of streptozotocin before oral treatment with ibuprofen or pioglitazone for 8 weeks. The 24­h urine collection was performed for measurement of total protein content. The kidney was fixed in 10% formalin for periodic acid­Schiff and Masson's trichrome staining. Blood and residual kidney tissue samples were collected to measure the associated biochemical parameters. Chronic ibuprofen treatment decreased urinary protein excretion, blood urea nitrogen, glomerular basement membrane thickening and renal fibrosis, which were accompanied by increases in PPARγ protein expression, glutathione (GSH) level, and superoxide dismutase (SOD) activity, decreases in cyclooxygenase 2 and inducible nitric oxide synthase protein expressions, as well as a decreased interleukin 1ß (IL­1ß) level in the renal cortex of DN rats. Furthermore, the reduced IL­1ß level, increased GSH quantities and stronger SOD activity in the rat serum were evaluated in ibuprofen­treated diabetic rats and were compared with untreated diabetic rats. Regarding GSH and IL­1ß levels, ibuprofen was identified to be superior to the positive control, pioglitazone, while levels of the other indices were identified to be similar. Thus, ibuprofen was observed to prevent the development of DN, caused by type 1 diabetes, by anti­inflammatory and anti­oxidative action, potentially via PPARγ activation.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Ibuprofeno/farmacologia , Rim/metabolismo , Animais , Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Glutationa/metabolismo , Interleucina-1beta/metabolismo , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo
10.
Mol Neurobiol ; 53(7): 4972-80, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26374551

RESUMO

Acetylcholinesterase (AChE) is impaired in brain of diabetic animals, which may be one of the reasons for diabetes-associated cognitive decline. However, the mechanism is still unknown. The present study was designed to investigate whether the increased expression of AChE in central neurons under high glucose (HG) condition was due to activation of mammalian target of rapamycin (mTOR) signaling. It was found that more production of reactive oxygen species, and higher levels of phospho-Akt, phospho-mTOR, phospho-p70S6K, and AChE were detected in HT-22 cells in HG group than normal glucose group after culture for 24 h, which were all attenuated by an antioxidant N-acetyl-L-cysteine. A PI3K inhibitor LY294002 significantly decreased the levels of phospho-Akt, phospho-mTOR, phospho-p70S6K, and AChE protein expression in HG-cultured HT-22 cells, and an mTOR inhibitor rapamycin markedly reduced the levels of phospho-mTOR, phospho-p70S6K, and AChE expression. Furthermore, compared with normal rats, diabetic rats showed remarkable increases in levels of AChE activity and expression, malondialdehyde, phospho-mTOR, phospho-p70S6K, and a significant decrease in total superoxide dismutase activity in both hippocampus and cerebral cortex. However, much lower levels of phospho-mTOR, phospho-p70S6K, and AChE expression occurred in both brain regions of diabetic rats treated with rapamycin when compared with untreated ones. These results indicated that mTOR signaling was activated through the activation of PI3K/Akt pathway mediated by oxidative stress in HG-cultured HT-22 cells and diabetic rat brains, which contributed to the elevated protein expression of AChE in central neurons under the condition of HG.


Assuntos
Acetilcolinesterase/biossíntese , Diabetes Mellitus Experimental/metabolismo , Regulação Enzimológica da Expressão Gênica , Glucose/toxicidade , Serina-Treonina Quinases TOR/metabolismo , Acetilcolinesterase/genética , Animais , Linhagem Celular Transformada , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cromonas/farmacologia , Diabetes Mellitus Experimental/genética , Glucose/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Morfolinas/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Sirolimo/farmacologia
11.
Phytomedicine ; 22(12): 1071-8, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26547529

RESUMO

BACKGROUND: Recently, extract of Ginkgo biloba leaves (GbE) have become widely known phytomedicines and have shown various pharmacological activities, including improvement of blood circulation, protection of oxidative cell damage, prevention of Alzheimer's disease, treatment of cardiovascular disease and diabetes complications. This study was designed to investigate the effects of an ethanolic GbE on renal fibrosis in diabetic nephropathy (DN) and to clarify the possible mechanism by which GbE prevents renal fibrosis. STUDY DESIGN: We investigated the protective effects of GbE on renal fibrosis in STZ-induced diabetic rats. Rats were randomized into six groups termed normal control, diabetes mellitus, low dose of GbE (50 mg/kg/d), intermediate dose of GbE (100 mg/kg/d), high dose of GbE (200 mg/kg/d) and rapamycin (1 mg/kg/d). METHODS: After 12 weeks, the rats were sacrificed and then fasting blood glucose (FBG), creatinine (Cr), blood urea nitrogen (BUN), urine protein, relative kidney weight, glycogen and collagen accumulation, and collagen IV and laminin expression were measured by different methods. The amounts of E-cadherin, α-SMA and snail, as well as the phosphorylation of Akt, mTOR and p70S6K in the renal cortex of rats, were examined by western blotting. RESULTS: Compared with diabetic rats, the levels of Cr, BUN, urine protein, relative kidney weight, accumulation of glycogen and collagen, and expression of collagen IV and laminin in the renal cortex were all decreased in GbE treated rats. In addition, GbE reduced the expression of E-cadherin, α-SMA, snail and the phosphorylation of Akt, mTOR and p70S6K in diabetic renal cortex. CONCLUSION: GbE can prevent renal fibrosis in rats with diabetic nephropathy, which is most likely to be associated with its abilities to inhibit the Akt/mTOR signaling pathway.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Ginkgo biloba/química , Nefropatias/prevenção & controle , Extratos Vegetais/farmacologia , Transdução de Sinais , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Fibrose/prevenção & controle , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Fitoterapia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Serina-Treonina Quinases TOR/metabolismo
12.
Chem Commun (Camb) ; 51(42): 8880-3, 2015 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-25925958

RESUMO

A sensitive and selective strategy for the colorimetric visualization of the total monomeric Aß down to 40 pg mL(-1) based on dual-functionalized gold nanoplasmonic particles (GNPs) is developed and applied to evaluate Aß levels in the AD cerebral system.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/análise , Encéfalo/metabolismo , Colorimetria , Ouro/química , Nanopartículas Metálicas/química , Peptídeos beta-Amiloides/metabolismo , Animais , Nanopartículas Metálicas/análise , Estrutura Molecular , Tamanho da Partícula , Ratos , Propriedades de Superfície
13.
Phytother Res ; 29(2): 295-302, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25380391

RESUMO

This study was designed to investigate the effects of mangiferin on renal fibrosis, osteopontin production, and inflammation in the kidney of diabetic rats. Diabetes was induced through the single administration of streptozotocin (55 mg/kg, i.p.). Diabetic rats were treated with mangiferin (15, 30, and 60 mg/kg/day, i.g.) for 9 weeks. The kidney was fixed in 10% formalin for glomerulus fibrosis examination using Masson trichrome staining. Kidney and blood were obtained for assays of the associated biochemical parameters. Chronic mangiferin treatment prevented renal glomerulus fibrosis evidenced by decreases in Mason-stained positive area of glomeruli, protein expression of type IV collagen, and α-smooth muscle actin in the kidney of diabetic rats, in comparison with decreases in mRNA and protein expression of osteopontin as well as protein expression of cyclooxygenase 2 and NF-кB p65 subunit in the renal cortex of diabetic rats. Moreover, mangiferin reduced the levels of interleukin 1ß in both the serum and the kidney of diabetic rats. Our findings demonstrate that mangiferin prevents the renal glomerulus fibrosis of diabetic rats, which is realized through the suppression of osteopontin overproduction and inflammation likely via inactivation of NF-кB.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Glomérulos Renais/efeitos dos fármacos , Osteopontina/metabolismo , Xantonas/farmacologia , Actinas/metabolismo , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Colágeno Tipo IV/metabolismo , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo , Fibrose , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Nefropatias/patologia , Glomérulos Renais/patologia , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina , Fator de Transcrição RelA/metabolismo
14.
Pharmacol Biochem Behav ; 117: 128-36, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24291733

RESUMO

OBJECTIVE: Diabetic encephalopathy is characterised by cognitive impairment, neurochemical and structural abnormalities. The aim of the study was to investigate the effects of ibuprofen on diabetic encephalopathy and potential mechanisms. RESEARCH DESIGN AND METHOD: Diabetes was induced through a single intraperitoneal injection of streptozotocin (60 mg/kg). Diabetic rats were treated with ibuprofen (40 mg/kg) by gavage for 8 weeks. Cognitive performances were evaluated using Morris water maze. The temporal cortex and hippocampus were obtained to evaluate the levels of advanced glycation endproducts (AGEs) and their receptor (RAGE), the activity, protein expression, and mRNA levels of ß-amyloid precursor protein cleaving enzyme 1 (BACE1), the protein and mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ), and the protein expression of cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS). Blood was obtained for the evaluation of interleukin 1ß level. RESULTS: Chronic ibuprofen treatment significantly prevented the decline in learning and memory ability of diabetic rats and loss of neurons in the CA1 and CA3 areas of the hippocampus. Moreover, ibuprofen treatment markedly reduced the activity, protein, and mRNA levels of BACE1, AGE level, protein expression of RAGE, COX-2, and iNOS in the brain, and interleukin 1ß level in serum, while increasing the protein and mRNA expression of PPARγ in the brain of diabetic rats. However, ibuprofen had no effects on the hyperglycaemia and the body weight of diabetic rats. CONCLUSION: These findings demonstrated that ibuprofen markedly ameliorated diabetic encephalopathy, potentially reflecting the down-regulation of BACE1, the suppression of the AGE/RAGE axis, and the anti-inflammation in diabetic rat brain.


Assuntos
Encefalopatias/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Ibuprofeno/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Sequência de Bases , Peso Corporal/efeitos dos fármacos , Encefalopatias/complicações , Primers do DNA , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , PPAR gama/agonistas , PPAR gama/genética , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
Eur J Pharmacol ; 721(1-3): 355-64, 2013 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-24036348

RESUMO

Advanced glycation endproducts (AGEs) and its precursor methylglyoxal are associated with diabetic nephropathy (DN). Mangiferin has many beneficial biological activities, including anti-inflammatory, anti-oxidative and anti-diabetic effects. We investigated the effect of mangiferin on DN and its potential mechanism associated with glyoxalase 1 (Glo-1), a detoxifying enzyme of methylglyoxal, in streptozotocin-induced rat model of DN. Diabetic rats were treated orally with mangiferin (15, 30, and 60 mg/kg) or distilled water for 9 weeks. Kidney tissues were collected for morphologic observation and the determination of associated biochemical parameters. The cultured mesangial cells were used to measure the activity of Glo-1 in vitro. Chronic treatment with mangiferin significantly ameliorated renal dysfunction in diabetic rats, as evidenced by decreases in albuminuria, blood urea nitrogen, kidney weight index, periodic acid-schiff stain positive mesangial matrix area, glomerular extracellular matrix expansion and accumulation, and glomerular basement membrane thickness. Meanwhile, mangiferin treatment caused substantial increases in the enzymatic activity of Glo-1 in vivo and in vitro, and protein and mRNA expression of Glo-1, reduced levels of AGEs and the protein and mRNA expression of their receptor (RAGE) in the renal cortex of diabetic rats. Moreover, mangiferin significantly attenuated oxidative stress damage as reflected by the lowered malondialdehyde and the increased glutathione levels in the kidney of diabetic rats. However, mangiferin did not affect the blood glucose and body weight of diabetic rats. Therefore, mangiferin can remarkably ameliorate DN in rats through inhibiting the AGEs/RAGE aix and oxidative stress damage, and Glo-1 may be a target for mangiferin action.


Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/prevenção & controle , Progressão da Doença , Lactoilglutationa Liase/genética , Regulação para Cima/efeitos dos fármacos , Xantonas/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/metabolismo , Jejum/sangue , Produtos Finais de Glicação Avançada/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo
16.
Psychopharmacology (Berl) ; 228(4): 585-94, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23529380

RESUMO

RATIONALE: Evidences indicate that methylglyoxal, a highly reactive metabolite of hyperglycemia, can enhance protein glycation, oxidative stress, or inflammation. Mangiferin, a polyphenol compound of C-glucoside, has many beneficial biological activities, including anti-inflammation, anti-oxidation, neuroprotection, cognitive enhancement, etc. Whether mangiferin alleviates diabetes-associated cognitive impairment is still unclear. OBJECTIVES: The present study was designed to investigate the effects of mangiferin on the behavioral deficits of diabetic rats induced by streptozotocin; the mechanisms associated with methylglyoxal toxicity are especially investigated. METHODS: Diabetic rats were treated with mangiferin (15, 30, and 60 mg/kg, p.o.) for 9 weeks. Cognitive performances were evaluated with the Morris water maze. Hippocampus and blood were obtained for evaluation of the effects of mangiferin on protein glycation, oxidative stress, and inflammation in diabetic state. RESULTS: Mangiferin significantly improved the behavioral performances of diabetic rats, evidenced by a decrease in escape latency as well as increases in numbers of crossing the platform and percentage of time spent in the target quadrant, which were accompanied by decreases in the levels of advanced glycation end-products and their receptor (RAGE), interleukin-1ß, TNF-α, and malondialdehyde and increases in the activity and expression of glyoxalase 1 as well as glutathione level in the hippocampus of diabetic rats. Furthermore, mangiferin produced a significant decrease in malondialdehyde level and increased glutathione level and superoxide dismutase activity in the serum of diabetic rats. CONCLUSIONS: This study demonstrates that mangiferin can markedly ameliorate diabetes-associated cognitive decline in rats, which is done likely through suppressing methylglyoxal hyperactivity (promoting protein glycation, oxidative stress, and inflammation) mediated noxious effects.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Aldeído Pirúvico/metabolismo , Xantonas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Diabetes Mellitus Experimental/fisiopatologia , Relação Dose-Resposta a Droga , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Produtos Finais de Glicação Avançada/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/etiologia , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estreptozocina , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Xantonas/administração & dosagem
17.
Acta Pharmacol Sin ; 34(4): 507-14, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23524565

RESUMO

AIM: To investigate whether NO over-production in rat mesangial cells cultured in high glucose (HG) is related to activation of the TGF-ß1/PI3K/Akt pathway. METHODS: Rat mesangial cells line (HBZY-1) was exposed to HG (24.44 mmol/L) or H2O2 (10 µmol/L) for 16 h. NO release was quantified using the Griess assay. The TGF-ß1 level was measured using ELISA. The protein expression of p-Akt, t-Akt, Bim, and iNOS was examined by Western blotting. The mRNA levels of TGF-ß1 and Bim were measured using RT-PCR. The cell proliferation rate was estimated using a BrdU incorporation assay. RESULTS: Treatment of the cells with HG, H2O2, or TGF-ß1 (5 ng/mL) significantly increased the NO level that was substantially inhibited by co-treatment with the NADPH oxidase inhibitor diphenylene iodonium (DPI), TGF-ß1 inhibitor SB431542, or PI3K inhibitor LY294002. Both HG and H2O2 significantly increased the protein and mRNA levels of TGF-ß1 in the cells, and HG-induced increases of TGF-ß1 protein and mRNA were blocked by co-treatment with DPI. Furthermore, the treatment with HG or H2O2 significantly increased the expression of phosphorylated Akt and iNOS and cell proliferation rate, which was blocked by co-treatment with DPI, SB431542, or LY294002. Moreover, the treatment with HG or H2O2 significantly inhibited Bim protein and mRNA expression, which was reversed by co-treatment with DPI, SB431542, or LY294002. CONCLUSION: The results demonstrate that high glucose causes oxidative stress and NO over-production in rat mesangial cells in vitro via decreasing Bim and increasing iNOS, which are at least partially mediated by the TGF-ß1/PI3K/Akt pathway.


Assuntos
Glucose/metabolismo , Células Mesangiais/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Peróxido de Hidrogênio/farmacologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Células Mesangiais/efeitos dos fármacos , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Óxido Nítrico/genética , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , RNA Mensageiro/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Crescimento Transformador beta1/genética
18.
Pharmacol Biochem Behav ; 101(1): 93-8, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22197711

RESUMO

OBJECTIVE: This study was designed to investigate the effect of ginsenoside Re (Re) on cognitive functions, oxidative stress and inflammation in streptozotocin-induced diabetic rats. RESEARCH DESIGN AND METHOD: Diabetic rats were treated with Re (40mg/kg) for 8weeks, blood glucose and body weight were measured monthly and weekly, respectively. Cognitive performances were evaluated with Morris water maze. Brain was obtained for measurements of TNF-α and malondialdehyde (MDA) contents in both temporal cortex and hippocampus, blood was collected for assays of TNF-α, MDA and reduced glutathione (GSH) levels. RESULTS: Learning and memory abilities were significantly (both P<0.01) impaired in diabetic rats, accompanied by the marked (all P<0.01) elevations of TNF-α and MDA levels in temporal cortex and hippocampus. Increment of MDA and decrement of GSH in serum also occurred with significant differences (both P<0.01). Chronic treatment with Re markedly (P<0.05) improved the cognition of diabetic rats, evidenced by the decreased escape latency and the increased percentage of time spent in the target quadrant. Furthermore, Re treatment remarkably (P<0.05) reduced the levels of TNF-α and MDA in both brain areas of diabetic rats. Decline of MDA level and elevation of GSH level in serum were also seen in Re-treated diabetic rats, coupled with decrease in serum glucose level, all with statistically significant differences. CONCLUSIONS: Our findings firstly provide the first evidence that ginsenoside Re can remarkably attenuate diabetes-associated cognitive decline, secondly confirm the involvement of oxidative stress and inflammation in the development of cognitive impairment caused by diabetes, finally point toward the potential of ginsenoside Re as an adjuvant therapy to conventional anti-hyperglycemic regimens as well as diabetes-associated cognitive decline.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/psicologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/psicologia , Ginsenosídeos/farmacologia , Animais , Antioxidantes/farmacologia , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Glutationa/sangue , Inflamação/etiologia , Inflamação/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
19.
J Ethnopharmacol ; 139(1): 194-200, 2012 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-22101084

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: As a well-known Chinese Materia Medica Rhizoma Anemarrhenae has multiple pharmacological activities including antipyretic, anti-inflammatory, anti-diabetic actions, etc. This study was designed to investigate effects of total saponins from Rhizoma Anemarrhenae (TS) on diabetes-associated cognitive decline in rats and influence on amyloid-beta (Aß) levels in brain and inflammation. MATERIALS AND METHODS: Diabetic rats induced by intraperitoneal administration of streptozotocin, were randomized into two groups: diabetes and TS-treated diabetes. Blood glucose and body weight were measured monthly and weekly, respectively. After seven weeks, cognitive performances were evaluated with Morris water maze. Then, brain was obtained for assay of Aß and TNF-α levels, and blood was collected for TNF-α assay. RESULTS: Aß(1-40), Aß(1-42) and TNF-α levels were dramatically (all P<0.01) increased both in temporal cortex and hippocampus of diabetic rats, coupled with impairment of cognition, compared with those of the control. Chronic TS (200mg/kg) treatment markedly (P<0.05) improved the learning ability of diabetic rats, and significantly (all P<0.05) reduced Aß(1-40), Aß(1-42) and TNF-α levels in cortex as well as Aß(1-40) level in hippocampus, whereas showed a decreased tendency for Aß(1-42) and TNF-α levels in hippocampus. Moreover, eight-week treatment with TS remarkably (P<0.05) inhibited the elevation of TNF-α level in serum of diabetic rats, and significantly (both P<0.01) decrease the fasting blood glucose level and increase the body weight of diabectic rats. CONCLUSION: Our findings demonstrate that diabetes-associated cognitive decline is, at least in part, due to brain Aß accumulation in diabetic condition, and efficacy of TS to diabetes-associated cognitive decline in rats is a sum of reduction of Aß accumulation and inflammation in brain as well as attenuation of major symptoms of diabetes.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Anemarrhena , Transtornos Cognitivos/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Saponinas/uso terapêutico , Anemarrhena/química , Animais , Glicemia/análise , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/metabolismo , Fitoterapia , Ratos , Ratos Sprague-Dawley , Rizoma/química , Saponinas/isolamento & purificação , Saponinas/farmacologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
20.
Naunyn Schmiedebergs Arch Pharmacol ; 381(4): 371-81, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20229011

RESUMO

Clinical reports have demonstrated that berberine is a potential antidiabetic agent, but the underlying mechanism is unclear. The purpose of this study was to investigate if berberine exerts its hypoglycemic action via inhibiting intestinal disaccharidases using in vivo and in vitro experiments. Streptozotocin-induced diabetic rats received berberine (100 or 200 mg/kg) orally once daily or acarbose (40 mg/kg) orally twice daily for 5 weeks. Disaccharidase activities and sucrase-isomaltase (SI) complex messenger RNA (mRNA) expression in intestinal regions were assessed. The same treatment was operated in normal rats. Sucrose and maltose loading tests were also documented. In addition, Caco-2 cells were cultured in medium containing berberine or berberine plus chelerythrine. Compound C or H-89 for 5 days, disaccharidase activities, and SI complex mRNA levels were measured. The animal experiments showed that berberine significantly decreased the disaccharidase activities and SI complex mRNA expression both in diabetic rats and normal rats. Berberine can also significantly lower postprandial blood glucose levels induced by sucrose or maltose loading in normal rats. The cellular results showed that berberine may suppress disaccharidase activities and downregulate SI complex mRNA expression in a concentration-dependent manner. Only H-89, an inhibitor of protein kinase A (PKA), may reverse the decrease in disaccharidase activities and SI complex mRNA expression induced by berberine. In conclusion, berberine suppresses disaccharidase activities and SI complex mRNA expression with beneficial metabolic effects in diabetic states. The inhibitory effect, at least partly, involves the PKA-dependent pathway.


Assuntos
Berberina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Dissacaridases/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Acarbose/farmacologia , Animais , Berberina/administração & dosagem , Glicemia/efeitos dos fármacos , Células CACO-2 , Proteínas Quinases Dependentes de AMP Cíclico/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/enzimologia , Relação Dose-Resposta a Droga , Humanos , Hipoglicemiantes/administração & dosagem , Intestinos/enzimologia , Masculino , Maltose/administração & dosagem , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina , Complexo Sacarase-Isomaltase/metabolismo , Sacarose/administração & dosagem
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