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1.
Chem Biol Interact ; 315: 108869, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31682803

RESUMO

Spermatogenic dysfunction is one of the major secondary complications of male diabetes. Salidroside (SAL) is the important active ingredients isolated from Herba Cistanche, which exhibits numerous pharmacological activities such as antioxidant, anti-diabetic, and anti-inflammatory effects. The present study was designed to determine whether SAL contributes to the recovery from spermatogenic dysfunction in streptozotocin (STZ) induced type-1 diabetic mice. SAL (25, 50, or 100 mg/kg) and Clomiphene citrate (CC, 5 mg/kg) were orally administered to male type-1 diabetic mice for 10 weeks. Testis tissues were collected for histopathological and biochemical analysis. Moreover, reproductive organ weight, sperm parameters, and testicular cell DNA damage were estimated. The results revealed that SAL significantly improved the weight of the reproductive organs, sperm parameters and testicular morphology to different degrees in type-1 diabetic mice. Furthermore, reactive oxygen species (ROS) and malondialdehyde (MDA) levels were significantly reduced, and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), markedly increased in the testicular tissue after SAL treatment. In addition, our data also showed a marked downregulation the fluorescence expressions of p38 MAPK phosphorylation and upregulation the protein expressions of ZO-1, Occludin, Claudin-11 and N-cadherin after SAL administration (100 mg/kg) compared with the type-1 diabetic group. In conclusion, these results demonstrated that SAL exerts protective effects on type-1 diabetes-induced male spermatogenic dysfunction, which is likely mediated by inhibiting oxidative stress-mediated blood testis barrier damage.


Assuntos
Barreira Hematotesticular/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucosídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Substâncias Protetoras/farmacologia , Espermatogênese/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Barreira Hematotesticular/metabolismo , Catalase/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Contagem de Espermatozoides/métodos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Estreptozocina/farmacologia , Superóxido Dismutase/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo
2.
Chem Biol Interact ; 315: 108897, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31726037

RESUMO

Type 2 diabetes mellitus (T2DM) is a disease with a drastically growing worldwide prevalence. It is usually associated with numerous complications of which; diabetic nephropathy (DN); is a main complication of microvasculature and more seriously, a common cause of end-stage renal disease (ESRD). Unfortunately, both the lack of a definitive remedy alongside the economic and the social burden on DN patients enforces considerable impetus for developing alternative therapies. IL-33 is a newly discovered member of the IL-1 cytokine family. IL33/ST2 signaling plays a crucial role in acute and chronic kidney diseases. Calycosin is an isoflavone with reported IL33 signaling inhibitory activity. The present study aimed to investigate if calycosin possess renal protective effect in high-fat diet/STZ-induced T2DM model and to clarify the potential underlying mechanisms. HFD-STZ control rats showed functional and structural renal damage confirmed by increased serum creatinine, blood urea nitrogen and albuminuria associated with marked renal glomerulosclerosis and interstitial fibrosis. Initiation of inflammation, oxidative stress, and fibrosis was evident as depicted by elevated renal levels of IL33/ST2 mRNA as well as increased renal NF-κBp65, TNF-α, IL-1ß, MDA, and TGF-ß contents with suppressed Nrf2 and TAC. Calycosin treatment markedly improved the aforementioned makers of renal injury and dysfunction, modulated IL33/ST2 signaling, inflammatory cytokines, oxidative stress and fibrotic processes. This was accompanied by improvement of T2DM-induced renal ultramicroscopic and histopathological alterations.


Assuntos
Fibrose/tratamento farmacológico , Interleucina-33/metabolismo , Isoflavonas/farmacologia , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Receptores de Interleucina-1/metabolismo , Animais , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fibrose/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia
3.
J Biochem Mol Toxicol ; 34(2): e22430, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31833155

RESUMO

The aim of this study was to investigate the effect of melatonin (MT) and its metabolite N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) on Alzheimer-like learning and memory impairment in rats intracerebroventricularly injected with streptozotocin (STZ). The results showed that the escape latency of the STZ group was longer than that of the control (CON), MT, and AFMK groups. Increased levels of hyperphosphorylated tau, neurofilament proteins, and malondialdehyde and decreased superoxide dismutase levels were observed in the brains of the rats from the STZ group compared with the brains of the rats from the CON, MT, AFMK high and low group. These results suggest that exogenous MT and AFMK can improve memory impairment and downregulate AD-like hyperphosphorylation induced by STZ, most likely through their antioxidation function. Meanwhile, we found that an equal dose of AFMK had a stronger effect than that of MT. Our results indicate that MT and its metabolite AFMK represent novel treatment strategies for Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/uso terapêutico , Cinuramina/análogos & derivados , Melatonina/uso terapêutico , Memória Espacial/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Animais , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Glutationa Peroxidase/metabolismo , Cinuramina/farmacologia , Cinuramina/uso terapêutico , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Melatonina/farmacologia , Proteínas de Neurofilamentos/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/efeitos adversos , Estreptozocina/farmacologia , Superóxido Dismutase/metabolismo , Proteínas tau/metabolismo
4.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 72-83, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31844893

RESUMO

Type 2 diabetes increases the risk for cancer. Centrosome amplification can initiate tumorigenesis. We have described that type 2 diabetes increases the centrosome amplification of peripheral blood mononuclear cells, with high glucose, insulin, and palmitic acid as the triggers, which suggests that centrosome amplification is a candidate biological mechanism linking diabetes to cancer. In this study, we aimed to further investigate the signaling pathways of the diabetes-associated centrosome amplification and to examine whether and how resveratrol inhibits the centrosome amplification. The results showed that treatment with high glucose, insulin, and palmitic acid, alone or in combination, could increase the protein levels of phospho-protein kinase C alpha (p-PKCα), phospho-p38 mitogen-activated protein kinases (p-p38), c-myc, and c-jun, as well as the mRNA levels of c-myc and c-jun. PKCα inhibitor could inhibit the treatment-induced increase in the protein levels of p-p38, c-myc, and c-jun. Inhibitor or siRNA of p38 was also able to inhibit the treatment-induced increase in the levels of p-p38, c-myc, and c-jun. Meanwhile, knockdown of c-myc or c-jun did not alter the treatment-induced increase in the phosphorylation of PKCα or p38. Importantly, inhibition of the phosphorylation of PKCα or p38 and knockdown of c-myc or c-jun could attenuate the centrosome amplification. In diabetic mice, the levels of p-PKCα, p-p38, c-myc, and c-jun were all increased in the colon tissues. Interestingly, resveratrol, but not metformin, was able to attenuate the treatment-induced increase in the levels of p-PKCα, p-p38, c-myc, and c-jun, as well as the centrosome amplification. In conclusion, our results suggest that PKCα-p38 to c-myc/c-jun is the signaling pathway of the diabetes-associated centrosome amplification, and resveratrol attenuates the centrosome amplification by inhibiting this signaling pathway.


Assuntos
Centrossomo/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Proteína Quinase C-alfa/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Centrossomo/metabolismo , Colo/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Técnicas de Silenciamento de Genes , Glucose/farmacologia , Células HCT116 , Humanos , Insulina/farmacologia , Camundongos , Ácido Palmítico/farmacologia , Fosforilação/efeitos dos fármacos , Proteína Quinase C-alfa/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Interferente Pequeno/genética , Estreptozocina/efeitos adversos , Estreptozocina/farmacologia , Transfecção , Proteínas Quinases p38 Ativadas por Mitógeno/genética
5.
Bratisl Lek Listy ; 120(12): 887-893, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31855046

RESUMO

OBJECTIVE: We aimed to investigate the effects of recurrent sevoflurane anesthesia on cognitive functions in Alzheimer Disease. MATERIALS AND METHODS: Rats were divided into 4 groups as followed: control (Group C), sevoflurane (Group S), Alzheimer's (Group A) and Alzheimer's + sevoflurane (Group AS)]. Cognitive functions were evaluated with Radial Arm Maze Test (RAMT). Alzheimer model was created by administering 3 mg/kg (10 µl) STZ. Sevoflurane was administered to S and AS groups. Serum samples and hippocampus tissues were analyzed. RESULTS: In RAM test, the entry-exit data were significantly decreased in A and AS groups. After the 2nd and 3rd administration of anesthesia, the numbers were significantly decreased in Group S. Glial-fibrillary-acidic protein levels were significantly higher in AS compared to the C and S groups. The brain tissue caspase 3 activity was less than 1% in all rats in the Group C, 3 % in 2 rats and 1 % in 1 rat in the Group AS. In A and AS group, serum catalase, myeloperoxidase and ferroxidase activities were found to be higher than in the other groups and myeloperoxidase activity was higher in the AS than in the A Group. Serum native thiol, total thiol and disulfide levels were found to be significantly different in the A and AS groups. CONCLUSION: Sevoflurane anesthesia negatively affected the cognitive functions (Tab. 5, Fig. 10, Ref. 51).


Assuntos
Doença de Alzheimer/induzido quimicamente , Anestesia , Anestésicos Inalatórios , Cognição/efeitos dos fármacos , Éteres Metílicos/farmacologia , Sevoflurano/efeitos adversos , Estreptozocina/farmacologia , Animais , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Sevoflurano/administração & dosagem
6.
Life Sci ; 239: 117088, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31759039

RESUMO

AIMS: Diabetic nephropathy (DN) is a common chronic microvascular complication of both types of diabetes mellitus, which leads to renal dysfunction and subsequent need of dialysis and organ transplantation. Advanced glycation end products (AGEs) are metabolic consequence of hyperglycemia and are main contributory factor in the DN pathogenesis through mediating establishment of oxidative status and chronic inflammatory milieu. This study aimed to explore the impact of vanillin on preventing the progression of DN. MAIN METHODS: Experimental DN model was established in rats utilizing streptozotocin. Serum concentration of AGEs and Interleukin-6 (IL-6) and transforming growth factor ß1 (TGFß1) levels in kidney homogenate were assessed using ELISA technique. Also, we evaluated the expression of nuclear factor kappa B (NF-κB) using immunohistochemistry. KEY FINDINGS: Treatment with vanillin for 8 weeks significantly ameliorated DN. Vanillin significantly decreased hyperglycemia and improved kidney function reflected by decreased serum levels of blood urea nitrogen, creatinine, and decreased proteinuria. Also, vanillin significantly decreased malondialdehyde content and elevated superoxide dismutase activity in renal tissues. Moreover, vanillin decreased renal expression of NF-κB and renal concentrations of IL-6, TGFß1 and collagen. In addition, vanillin significantly decreased serum AGEs concentration. Also, vanillin attenuated histological abnormalities in kidney architecture. SIGNIFICANCE: Vanillin, which is a cheap and abundant natural product, exhibited anti-AGEs, antioxidant, anti-inflammatory and anti-fibrotic activities. These activities might be helpful and potent mechanisms in preventing the progression of DN.


Assuntos
Benzaldeídos/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Produtos Finais de Glicação Avançada/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Benzaldeídos/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Interleucina-6/análise , Interleucina-6/sangue , Rim/metabolismo , Masculino , NF-kappa B/análise , NF-kappa B/sangue , Estresse Oxidativo/efeitos dos fármacos , Proteinúria/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Estreptozocina/farmacologia , Fator de Crescimento Transformador beta1/análise , Fator de Crescimento Transformador beta1/sangue
7.
Drug Deliv ; 26(1): 849-859, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31524015

RESUMO

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus whose expand process is linked with the fibrosis, renal hypertrophy and inflammation. The current study was to formulate and optimize the nano-formulation of crocetin (CT-PLGA-NPs) against Streptozotocin-induced renal nephropathy in rats. Double emulsion evaporation technique was used for the preparation of CT-PLGA-NPs. CT-PLGA-NPs were scrutinized for polydispersity index, size, gastric stability, entrapment, drug-loading capacity and in-vitro drug release and in vivo preclinical study. Single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg) and rats were divided into different group. Renal function and metabolic parameters of urine and serum were estimated. Fibrotic protein, renal pro-inflammatory cytokines and degree of renal damage expression were also determined. We also estimated the fibronectin, type IV collagen and transforming growth factor-ß1 for a possible mechanism of action. Crocetin supplement (10 mg/kg) and CT-PLGA-NPs exhibited the accumulation of the drug in kidney and liver of diabetic rats. Crocetin reduced the BGL and enhanced plasma insulin and body weight. Dose dependent treatment of crocetin significantly (p < .001) down-regulated the expression of renal tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin (IL)-1ß (IL-1ß) and Monocyte Chemoattractant Protein-1 (MCP-1). Crocetin significantly (p < .001) altered the expression of fibronectin, type IV collagen, and transforming growth factor-ß1 (TGF-1ß). Crocetin significantly (p < .001) down-regulated the protein kinase C activity and the expression of nuclear factor κB (NF-κB) p65 activity and protein production in renal tissue. On the basis of the available result, we can conclude that nano-formulation of crocetin could attenuate the diabetic nephropathy via antifibrotic and anti-inflammatory effect.


Assuntos
Biomarcadores/metabolismo , Carotenoides/administração & dosagem , Carotenoides/química , Nefropatias Diabéticas/tratamento farmacológico , Inflamação/tratamento farmacológico , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia
8.
Molecules ; 24(16)2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430978

RESUMO

: The management of pain in patients affected by diabetic neuropathy still represents an unmet therapeutic need. Recent data highlighted the pain-relieving efficacy of glucosinolates deriving from Brassicaceae. The purpose of this study was to evaluate the anti-hyperalgesic efficacy of Eruca sativa defatted seed meal, along with its main glucosinolate, glucoerucin (GER), on diabetic neuropathic pain induced in mice by streptozotocin (STZ). The mechanism of action was also investigated. Hypersensitivity was assessed by paw pressure and cold plate tests after the acute administration of the compounds. Once bio-activated by myrosinase, both E. sativa defatted meal (1 g kg-1 p.o.) and GER (100 µmol kg-1 p.o., equimolar to meal content) showed a dose-dependent pain-relieving effect in STZ-diabetic mice, but the meal was more effective than the glucosinolate. The co-administration with H2S scavengers abolished the pain relief mediated by both E. sativa meal and GER. Their effect was also prevented by selectively blocking Kv7 potassium channels. Repeated treatments with E. sativa meal did not induce tolerance to the anti-hypersensitive effect. In conclusion, E. sativa meal can be suggested as a new nutraceutical tool for pain relief in patients with diabetic neuropathy.


Assuntos
Brassicaceae/química , Neuropatias Diabéticas/complicações , Glucose/análogos & derivados , Imidoésteres/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Glucose/farmacologia , Glucosinolatos/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sementes/química , Estreptozocina/farmacologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-31326961

RESUMO

Background Natural medicinal plants have been the focus of current research for developing neuroprotective agents to be used in the diabetes-linked cognitive dysfunction. Trigonella foenum-graecum seeds (known as fenugreek, methi in Hindi), is a well-known traditional medicinal herb and possesses anti-diabetic, anti-oxidant, and anti-inflammatory properties. Purpose This study was undertaken to explore the ameliorative effects of T. foenum-graecum seed extract on diabetes-induced cognitive dysfunction. Methods Experimental diabetes was induced by administering a single dose of streptozotocin (60 mg/kg) through intraperitoneal dose. Cognitive function was assessed using a T-maze and the Morris water maze. Lipid peroxidation levels and oxidative stress in the hippocampus was measured. Quantification of hippocampal CA1 and CA3 regions was done using cresyl violet stain. Results Diabetic rats demonstrated learning and memory impairment, which was evident from poor performance in behavioral tasks, i.e. T-maze and Morris water maze tasks. Learning and memory impairment in diabetic animals is associated with increased blood glucose levels, increased oxidative stress in the hippocampus and decreased number of neurons in the CA1 and CA3 regions of the hippocampus. The diabetic rats administered with T. foenum-graecum showed improved performance in behavioral tasks, and these changes were associated with decreased blood glucose levels, decreased oxidative stress in the hippocampus, and decreased neuronal loss from the CA1 and CA3 regions of the hippocampus. Conclusion In conclusion, administration of T. foenum-graecum seed extract ameliorates diabetes-linked cognitive dysfunction in rats by decreasing blood glucose levels, reducing lipid peroxidation and oxidative stress in the hippocampus, and preventing neuronal loss from the hippocampus.


Assuntos
Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Extratos Vegetais/farmacologia , Estreptozocina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Glicemia/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hipoglicemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Trigonella/química
10.
Int J Immunopathol Pharmacol ; 33: 2058738419866379, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337260

RESUMO

We aimed to analyze the action of berberine on the neuropathic pain and neuroglia activation in experimental diabetes mellitus (DM) model. Diabetes in mice was induced by intraperitoneal injection of streptozotocin (STZ) followed by the administration of berberine. Mechanical allodynia and thermal hyperalgesia and activations of microglia and astrocytes were evaluated. The levels of pro-inflammatory cytokines and protein expressions of inflammatory proteins were assessed by enzyme-linked immunosorbent assay (ELISA) and western blot, respectively. Our results revealed the anti-nociceptive effects of berberine in DM mice, supported by the improved mechanical threshold and thermal latency. In addition, berberine suppressed the activations of microglia and astrocytes in the spinal cords of diabetic mice. Berberine inhibited the expression of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and interleukin-1ß (IL-1ß), along with inflammatory proteins including iNOS and COX-2. Berberine suppressed neuropathic pain in STZ-induced diabetic mice, and this effect is related to the reduction on the neuroglia activation and inflammation associated with DM.


Assuntos
Berberina/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Estreptozocina/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hiperalgesia/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31356180

RESUMO

We have recently demonstrated the antithrombotic effect of eplerenone on the arterial thrombotic process in diabetic rats associated with suppression of coagulation and enhancement of fibrinolysis. The aim of this study was to evaluate the role of platelets and endothelium in the mechanism of eplerenone antithrombotic action. Diabetes was induced in male Wistar rats with a single injection of streptozotocin (65 mg/kg). On the 25th day, treatment with eplerenone (100 mg/kg) was initiated for 10 days. Eplerenone did not change hemodynamic parameters (blood pressure, carotid blood flow, and heart rate), however, improved endothelium-dependent vasorelaxation in aortas and small mesenteric arteries, enhanced the aortic amounts of mRNA of endothelial nitric oxide synthase (eNOS), and reduced mRNA of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase 2. A prolongation of bleeding time and decrease in platelet adhesion to collagen ex vivo was also observed. These changes were accompanied by prolonged time to occlusion and increased blood flow, and finally reduced thrombus mass in diabetic rats. The inhibition of NOS with L-NAME reduced the eplerenone antithrombotic effect. Our study provides evidence that the antithrombotic effect of eplerenone in diabetic rats is nitric oxide-dependent and associated with inhibiting the adhesion of platelets, as well as normalizing endothelial function. The mechanism of eplerenone antithrombotic action in diabetes is a result of improved endothelial nitric oxide bioavailability that leads to the improvement vascular and platelet function.


Assuntos
Plaquetas/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Eplerenona/farmacologia , Fibrinolíticos/farmacologia , Óxido Nítrico/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Plaquetas/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Endotélio Vascular/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Wistar , Estreptozocina/farmacologia , Vasodilatação/efeitos dos fármacos
12.
Life Sci ; 231: 116584, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220527

RESUMO

Taurine is a key functional amino acid with many functions in the nervous system. The effects of taurine on cognitive function have aroused increasing attention. First, the fluctuations of taurine and its transporters are associated with cognitive impairments in physiology and pathology. This may help diagnose and treat cognitive impairment though mechanisms are not fully uncovered in existing studies. Then, taurine supplements in cognitive impairment of different physiologies, pathologies and toxicologies have been demonstrated to significantly improve and restore cognition in most cases. However, elevated taurine level in cerebrospinal fluid (CSF) by exogenous administration causes cognition retardations only in physiologically sensitive period between the perinatal to early postnatal period. In this review, taurine levels are summarized in different types of cognitive impairments. Subsequently, the effects of taurine supplements on cognitions in physiology, different pathologies and toxication of cognitive impairments (e.g. aging, Alzheimer' disease, streptozotocin (STZ)-induced brain damage, ischemia model, mental disorder, genetic diseases and cognitive injuries of pharmaceuticals and toxins) are analyzed. These data suggest that taurine can improve cognition function through multiple potential mechanisms (e.g. restoring functions of taurine transporters and γ-aminobutyric acid (GABA) A receptors subunit; mitigating neuroinflammation; up-regulating Nrf2 expression and antioxidant capacities; activating Akt/CREB/PGC1α pathway, and further enhancing mitochondria biogenesis, synaptic function and reducing oxidative stress; increasing neurogenesis and synaptic function by pERK; activating PKA pathway). However, more mechanisms still need explorations.


Assuntos
Cognição/efeitos dos fármacos , Taurina/metabolismo , Taurina/farmacologia , Doença de Alzheimer/fisiopatologia , Animais , Antioxidantes/farmacologia , Cognição/fisiologia , Disfunção Cognitiva/fisiopatologia , Suplementos Nutricionais , Feminino , Humanos , Masculino , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Receptores de GABA , Receptores de GABA-A/efeitos dos fármacos , Estreptozocina/farmacologia , Taurina/fisiologia
13.
Int J Neurosci ; 129(11): 1053-1065, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31215291

RESUMO

Aim: Alzheimer's disease (AD) is characterized by oxidative stress, neuroinflammation and progressive cognitive decline. Abscisic acid (ABA) is produced in a variety of mammalian tissues, including brain. It has anti-inflammatory and antioxidant effects and elicits a positive effect on spatial learning and memory performance. Here, the possible protective effect of ABA was evaluated in streptozotocin (STZ)-induced AD rat model which were injected intracerebroventriculary (i.c.v.) with STZ (3 mg/kg). Material and Methods: The STZ-treated animals received ABA (10 µg/rat, i.c.v.), ABA plus PPARß/δ receptor antagonist (GSK0660, 80 nM/rat) or ABA plus selective inhibitor of PKA (KT5720, 0.5 µg/rat) for 14 d. Learning and memory were determined using Morris water maze (MWM) and passive avoidance (PA) tests. Results: The data showed that STZ produced a significant learning and memory deficit in both MWM and PA tests. ABA significantly prevented the learning and memory impairment in STZ-treated rats. However, ABA effects were blocked by GSK0660 and KT5720. Conclusion: The data indicated that ABA attenuates STZ-induced learning and memory impairment and PPAR-ß/δ receptors and PKA signaling are involved, at least in part, in the ABA mechanism.


Assuntos
Ácido Abscísico/farmacologia , Doença de Alzheimer/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Aprendizagem/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , PPAR delta/antagonistas & inibidores , PPAR beta/antagonistas & inibidores , Reguladores de Crescimento de Planta/farmacologia , Ácido Abscísico/administração & dosagem , Doença de Alzheimer/induzido quimicamente , Animais , Antibióticos Antineoplásicos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Carbazóis/farmacologia , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Pirróis/farmacologia , Ratos , Ratos Wistar , Estreptozocina/farmacologia , Sulfonas/farmacologia , Tiofenos/farmacologia
14.
Int J Neurosci ; 129(11): 1145-1153, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31251091

RESUMO

Objectives: Recent evidences have shown the beneficial effects of natural products for treating of Alzheimer's disease (AD). Arbutin is derived from Pyrus biossieriana and exerts a wide range of pharmacological activities including anti-inflammatory and anti-oxidant effects. The present study was designed to examine the protective effects of arbutin on streptozotocin (STZ)-induced neurotoxicity in rats. Materials and methods: The spatial memory impairment was induced by intracerebroventricular (i.c.v) microinjection of STZ (3 mg/kg, 10 µL). Animals received the pretreatment of arbutin (50 mg/kg) for 21 days before STZ injection. The Morris Water maze (MWM) task was used to study the spatial learning and memory. The levels of oxidative stress markers including malondialdehyde (MDA), nitrite and carbonyl were measured in serum and hippocampus samples. In addition, antioxidant level was assessed by ferric reducing antioxidant power (FRAP) test. Results: The obtained result indicated that administration of STZ is led to memory impairment and increases the levels of oxidative stress markers in the hippocampus tissues. Conversely, arbutin improves spatial memory and reduces oxidative and nitrosative stress, as evidenced by a significant decrease in the amount of MDA and nitrite in the serum and hippocampus. In addition, an increase in FRAP levels of hippocampus was observed in arbutin receiving animals. The protein carbonyl content was not reduced in arbutin receiving animals. Conclusion: It could be concluded that arbutin protects the brain against STZ-induced memory impairment and oxidative damage in the hippocampus. The neuroprotective effect of arbutin might be mediated through its antioxidant and free radical scavenging effects.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Arbutina/farmacologia , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Antibióticos Antineoplásicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Ratos , Ratos Wistar , Memória Espacial/efeitos dos fármacos , Estreptozocina/farmacologia
15.
Pharmacology ; 104(3-4): 157-165, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31185481

RESUMO

AIMS: We sought to determine whether insulin can protect against type 1 diabetes mellitus (T1DM)-induced cardiac ultrastructural alterations in an animal model of the disease. This has not been investigated before. METHODS: Rats were either injected once with 65 mg/kg streptozotocin (STZ) before being sacrificed after 8 weeks or were treated with a daily injection of insulin 2 days by STZ and continued until being sacrificed. RESULTS: Harvested tissues obtained from left ventricles in the untreated T1DM rats showed substantial damage to the cardiomyocyte ultrastructure as demonstrated by disintegrated myofibrils and their sarcomeres, damaged mitochondria and lipid droplets, which was substantially protected by insulin. Insulin also significantly inhibited T1DM-induced hyperglycemia (p < 0.001), dyslipidemia (p < 0.0001), malondialdehyde (MDA; p < 0.0001), tumor necrosis factor-alpha (TNF-α; p < 0.001) and interleukin-6 (p < 0.001). We further demonstrated a significant (p ≤ 0.001) correlation between either sarcomere or mitochondrial injury scoring and the serum levels of glucose, dyslipidemia, and biomarkers of oxidative stress (OxS) and inflammation. CONCLUSIONS: These results indicate that insulin effectively suppresses left ventricular cardiomyocyte ultrastructural damage, which substantially slows down the progression of diabetic cardiomyopathy for 8 weeks in a rat model of T1DM, possibly due to the glycemic control and inhibition of dyslipidemia, OxS and inflammation.


Assuntos
Biomarcadores/metabolismo , Diabetes Mellitus Tipo 1/complicações , Ventrículos do Coração/efeitos dos fármacos , Inflamação/tratamento farmacológico , Insulina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Ventrículos do Coração/metabolismo , Hipoglicemiantes/farmacologia , Inflamação/metabolismo , Masculino , Malondialdeído/metabolismo , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
16.
Exp Anim ; 68(4): 417-428, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31155606

RESUMO

The changes in free amino acid (AA) levels in blood during the progression from non-alcoholic steatohepatitis (NASH) to hepatocellular carcinoma (HCC) are unclear. We investigated serum AA levels, along with biochemical and histological events, in a mouse model of NASH. We induced NASH in male C57BL/6J mice with a streptozotocin injection and high-fat diet after 4 weeks of age (STAM group). We chronologically (6, 8, 10, 12, and 16 weeks, n=4-12 mice/group) evaluated the progression from steatohepatitis to HCC by biochemical and histological analyses. The serum AA levels were determined using an AA analyzer. Serum aspartate aminotransferase and alanine aminotransferase levels were higher in the STAM group than in the normal group (non-NASH-induced mice). Histological analysis revealed that STAM mice had fatty liver, NASH, and fibrosis at 6, 8, and 10 weeks, respectively. Moreover, the mice exhibited fibrosis and HCC at 16 weeks. The serum branched-chain AA levels were higher in the STAM group than in the normal group, especially at 8 and 10 weeks. The Fischer ratio decreased at 16 weeks in the STAM group, with increasing aromatic AA levels. These results suggested that this model sequentially depicts the development of fatty liver, NASH, cirrhosis, HCC, and AA metabolism disorders within a short experimental period. Additionally, serum amyloid A was suggested to be a useful inflammation biomarker associated with NASH. We believe that the STAM model will be useful for studying AA metabolism and/or pharmacological effects in NASH.


Assuntos
Aminoácidos/sangue , Carcinoma Hepatocelular/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Soro/química , Animais , Biomarcadores/metabolismo , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/etiologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Estreptozocina/farmacologia , Fatores de Tempo
17.
Int J Mol Sci ; 20(10)2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100973

RESUMO

It is known that green tea helps prevent obesity and diabetes mellitus. In this study, we aimed to determine whether green tea ameliorates hyperglycemia and the mechanism involved in diabetic rodents. Green tea consumption reduced blood glucose and ameliorated glucose intolerance, which was assessed using an oral glucose tolerance test in both streptozotocin-induced type 1 diabetic rats and type 2 diabetic KK-Ay mice. Green tea also reduced the plasma fructosamine and glycated hemoglobin concentrations in both models. Furthermore, it increased glucose uptake into the skeletal muscle of both model animals, which was accompanied by greater translocation of glucose transporter 4 (GLUT4). Moreover, epigallocatechin gallate (EGCG), the principal catechin in green tea, also ameliorated glucose intolerance in high-fat diet-induced obese and diabetic mice. These results suggest that green tea can ameliorate hyperglycemia in diabetic rodents by stimulating GLUT4-mediated glucose uptake in skeletal muscle, and that EGCG is one of the effective compounds that mediate this effect.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Transportador de Glucose Tipo 4/metabolismo , Hiperglicemia/prevenção & controle , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Extratos Vegetais/farmacologia , Chá/química , Animais , Catequina/análogos & derivados , Catequina/farmacologia , Dieta Hiperlipídica , Frutosamina/sangue , Glucose/metabolismo , Intolerância à Glucose/metabolismo , Intolerância à Glucose/prevenção & controle , Teste de Tolerância a Glucose , Hemoglobina A Glicada , Hiperglicemia/metabolismo , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/prevenção & controle , Ratos , Ratos Wistar , Roedores , Estreptozocina/farmacologia
18.
J Mol Model ; 25(6): 159, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089817

RESUMO

The adsorption of the anticancer drugs sorafenib (SF), streptozotocin (STZ), and sunitinib (STB) on pristine and functionalized carbon nanotubes (FCNTs, functionalized with valine or phenylalanine moieties) was investigated using molecular dynamics simulation. Descriptors such as the van der Waals (vdW) energy, the number of hydrogen bonds, and the radial distribution function were considered. It was found that the type of functional group on the nanotube is a key influence on the vdW interaction energy between a drug molecule and a nanotube. In addition, the positions of the functional groups on a nanotube are a key influence on the adsorption of drug molecules on its surface. Our study indicated that the adsorption of STZ on CNT/FCNTs involves a partial π-π interaction and hydrogen bonding, whereas SF and STB are adsorbed on CNT/FCNTs through π-π stacking and hydrogen bonding. Our results suggest that altering the functionalization of the nanotube surface can affect the drug-nanotube interaction. The results reported here should aid attempts to optimize the design of novel CNT-based drug carriers.


Assuntos
Antineoplásicos/química , Simulação de Dinâmica Molecular , Nanotubos de Carbono/química , Sorafenibe/química , Estreptozocina/química , Sunitinibe/química , Antineoplásicos/farmacologia , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Conformação Molecular , Sorafenibe/farmacologia , Análise Espectral , Estreptozocina/farmacologia , Sunitinibe/farmacologia , Água/química
19.
J Am Soc Nephrol ; 30(6): 929-945, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31040190

RESUMO

BACKGROUND: Evidence of a protective role of autophagy in kidney diseases has sparked interest in autophagy as a potential therapeutic strategy. However, understanding how the autophagic process is altered in each disorder is critically important in working toward therapeutic applications. METHODS: Using cultured kidney proximal tubule epithelial cells (PTECs) and diabetic mouse models, we investigated how autophagic activity differs in type 1 versus type 2 diabetic nephropathy. We explored nutrient signals regulating starvation-induced autophagy in PTECs and used autophagy-monitoring mice and PTEC-specific autophagy-deficient knockout mice to examine differences in autophagy status and autophagy's role in PTECs in streptozotocin (STZ)-treated type 1 and db/db type 2 diabetic nephropathy. We also examined the effects of rapamycin (an inhibitor of mammalian target of rapamycin [mTOR]) on vulnerability to ischemia-reperfusion injury. RESULTS: Administering insulin or amino acids, but not glucose, suppressed autophagy by activating mTOR signaling. In db/db mice, autophagy induction was suppressed even under starvation; in STZ-treated mice, autophagy was enhanced even under fed conditions but stagnated under starvation due to lysosomal stress. Using knockout mice with diabetes, we found that, in STZ-treated mice, activated autophagy counteracts mitochondrial damage and fibrosis in the kidneys, whereas in db/db mice, autophagic suppression jeopardizes kidney even in the autophagy-competent state. Rapamycin-induced pharmacologic autophagy produced opposite effects on ischemia-reperfusion injury in STZ-treated and db/db mice. CONCLUSIONS: Autophagic activity in PTECs is mainly regulated by insulin. Consequently, autophagic activity differs in types 1 and 2 diabetic nephropathy, which should be considered when developing strategies to treat diabetic nephropathy by modulating autophagy.


Assuntos
Autofagia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/prevenção & controle , Lisossomos/metabolismo , Sirolimo/farmacologia , Aminoácidos/farmacologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Insulina/farmacologia , Túbulos Renais Proximais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sensibilidade e Especificidade , Estreptozocina/farmacologia
20.
Exp Eye Res ; 184: 213-220, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31028750

RESUMO

Diabetic retinopathy is a complication of diabetes and a leading cause of vision loss among working-age adults. To assess whether the Wistar rat with Streptozotocin (STZ)-induced diabetes is a suitable animal model of human proliferative diabetic retinopathy we evaluated the vascular changes to assess the diabetic retinopathy (DR) stages in this model. After two weeks of intraperitoneal STZ (55 mg/kg) injection in male Wistar rats (270-300 g), they were considered diabetic with persistent blood glucose levels ≥ 16.65 mmol/L. The diabetic and control rats were investigated after 1, 3, 6 and 9 months by electroretinography, Evans blue assay, dextran fluorescence retinal angiography, and retinal histopathological studies. Retinal vascular permeability in the diabetic groups increased significantly in all diabetic groups. The amplitude of a- and b-waves decreased significantly in all diabetic groups compared with the age-matched control groups. The latent time of a-waves in the diabetic groups was delayed at 3 months of diabetes and this delay remained relatively constant till 9 months following the onset of diabetes. Although the latent time of b-wave in the diabetic groups increased slightly, a significant difference was found right at 9 months of diabetes. Vascular density and branching point numbers significantly decreased in the diabetic eyes at 3 and 6 months while they increased at 9 months, which was not significant. Intraretinal hemorrhage and ischemic changes were detected in the half of diabetic rats after 6 months and considered as preproliferative stage of diabetic retinopathy. Although preproliferative changes were detected in all diabetic rats at 9 months, half of them showed vitreous neovascularization attached to retina and retinal folds which can be considered as proliferative stage of DR. Intraretinal hemorrhage, extensive leakage of fluorescein, retinal folds, and vitreous neovascularization were the most prominent findings of severe and proliferative diabetic retinopathy in a fraction of the STZ-induced diabetic rats which were comparable to that of the human patients. STZ-induced diabetic rats can be considered to be a potentially useful model for studies on pathogenesis and treatment of diabetic retinopathy in human.


Assuntos
Diabetes Mellitus Experimental/complicações , Retinopatia Diabética , Animais , Retinopatia Diabética/patologia , Retinopatia Diabética/fisiopatologia , Modelos Animais de Doenças , Eletrorretinografia , Masculino , Ratos , Ratos Wistar , Descolamento Retiniano/patologia , Estreptozocina/farmacologia , Corpo Vítreo/patologia
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