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1.
Exp Brain Res ; 240(12): 3259-3270, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36301335

RESUMO

Numerous studies have shown the deleterious effects of sleep deprivation (SD) on memory. However, SD in various durations may induce different effects. Studies have reported that short-term or acute SD can improve cognitive functions. In addition, streptozotocin (STZ) significantly impairs learning and memory, and induces inflammation and oxidative stress. In this study, we aimed to investigate the effect of two types of SD (short term: 6 h; long term: 24 h) on STZ-induced spatial memory impairment in rats, with respect to the serum level of catalase (CAT), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1ß). Morris water maze apparatus was used to assess spatial memory performance and STZ was injected i.c.v., twice, and at the dose of 3 mg/kg, at an interval of 48 h. The results showed that only 24 h SD impaired spatial learning and memory in rats. In addition, 24 h SD attenuated anti-oxidant activity and increased the level of pro-inflammatory markers in the serum. STZ impaired spatial learning and memory, and attenuated anti-oxidant activity and increased the level of pro-inflammatory markers in the serum of rats. Furthermore, 6 h SD slightly and partially improved spatial memory and significantly improved anti-oxidant activity in rats, with no effect on STZ-induced inflammation. We suggest that STZ has more important mechanisms that are involved in its memory impairment effect, and maybe, STZ-induced inflammation has a more important role. We also suggest more detailed studies to investigate the potential therapeutic effect of SD (in different durations) on memory function, oxidative stress, and inflammation.


Assuntos
Doença de Alzheimer , Animais , Ratos , Estreptozocina/toxicidade , Doença de Alzheimer/tratamento farmacológico , Aprendizagem em Labirinto , Antioxidantes/efeitos adversos , Privação do Sono/complicações , Hipocampo , Ratos Wistar , Transtornos da Memória/induzido quimicamente , Estresse Oxidativo , Biomarcadores , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico
2.
Neurochem Int ; 160: 105417, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36067928

RESUMO

BACKGROUND: The incidence of cognitive dysfunction in diabetes is increasing yearly, which severely affects the quality of life of patients and places a heavy burden on families and society. It has been demonstrated that impaired clearance of cerebral amyloid ß-protein (Aß) is a central event in the initiation and progression of Aß deposition and cognitive impairment in diabetic patients. However, until now, the molecular mechanism by which diabetes mellitus induces impaired clearance of Aß has remained unclear. OBJECTIVE: To investigate the role and mechanism of lipoprotein receptor-related protein 1 (LRP1) in Aß clearance impairment and cognitive function damage caused by diabetes. METHODS: SPF male C57BL/6 mice were bred, and streptozotocin (STZ) (60 mg/kg/d) was intraperitoneally injected for 5 days to establish a diabetes model. The novel object recognition test and fear conditioning test were used to assess the cognitive function of mice in each group. Western blotting, qRT-PCR, ELISAs, and immunofluorescence staining were used to detect the expression levels of Aß and Aß clearance-related proteins in mouse brains. HBMECs were cultured in vitro to establish the blood-brain barrier model. The clearance rate of Aß and the expression levels of LRP1 were measured under different glucose concentration culture conditions. HBMECs were transfected with lentivirus to overexpress or knock down the LRP1, and then, the changes in Aß clearance were detected again. We injected adeno-associated virus AAV9-SP-A-LRP1 shRNA into the tail vein of DM mice to selectively knock down LRP1 gene expression in cerebral vascular endothelial cells. Then, the cognitive function and the expression levels of Aß and Aß clearance-related proteins in the brains of normal, DM and LRP1 knockdown mice were detected. RESULTS: Compared with the controls, diabetic mice showed impaired cognitive performance, increased deposition of Aß in the brain and decreased expression of LRP1 in the brain microvasculature. In vitro experiments showed that high glucose can downregulate the expression of LRP1 in HBMECs and damage the Aß clearance across the blood-brain barrier (BBB). The reduction in the clearance rate of Aß induced by high glucose was reversed by LRP1 overexpression but further substantially decreased when LRP1 was knocked down. CONCLUSION: Hyperglycemia can impair Aß efflux in the brain by downregulating the expression of LRP1 in the brain microvasculature, eventually resulting in cognitive impairment.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Diabetes Mellitus Experimental , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais/metabolismo , Glucose/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/metabolismo , Qualidade de Vida , RNA Interferente Pequeno , Receptores de LDL/genética , Receptores de LDL/metabolismo , Estreptozocina/toxicidade , Proteínas Supressoras de Tumor/metabolismo
3.
Neurotox Res ; 40(5): 1440-1454, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36029454

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder clinically manifested by a gradual cognitive decline. Intracerebroventricular injection (ICV) of streptozotocin (STZ), a model of sporadic AD (sAD), shows many aspects of sAD abnormalities (i.e., neuroinflammation, oxidative stress, protein aggregation), resulting in memory impairment. Andrographolide (ANDRO), a natural diterpene lactone, has numerous bioactivities including anti-inflammatory and antioxidant properties. Studies in rodents revealed that ANDRO has neuroprotective properties and restores cognitive impairment. In the present study, we investigated the effects of ANDRO in the ICV-STZ model relative to short-term spatial memory (object location test (OLT) and Y maze test), short-term recognition memory (object recognition test (ORT)), locomotor activity (open field test (OFT)), expression of amyloid precursor protein (APP), and activation of astrocytes (glial fibrillary acidic protein (GFAP) expression) and microglia (ionized calcium-binding adapter molecule-1 (Iba-1) immunohistochemistry) in the prefrontal cortex (PFC) and hippocampus (HIP). Wistar rats were injected ICV with STZ (3 mg/kg) or vehicle and treated with ANDRO (2 mg/kg, i.p.; three times per week). After four weeks, ANDRO attenuated the impairments of the Y maze and ORT performances, and the increase of astrocyte activation in the PFC induced by the ICV-STZ model. In addition, ANDRO decreased the number of activated microglia cells in the HIP of STZ-injected rats. The APP expression was not altered, neither by the STZ nor ANDRO. ANDRO showed a beneficial effect on memory impairment and neuroinflammation in the STZ model of AD.


Assuntos
Doença de Alzheimer , Diterpenos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/farmacologia , Animais , Antioxidantes/farmacologia , Cálcio , Modelos Animais de Doenças , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Proteína Glial Fibrilar Ácida , Lactonas/efeitos adversos , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Doenças Neuroinflamatórias , Agregados Proteicos , Ratos , Ratos Wistar , Estreptozocina/toxicidade
4.
Molecules ; 27(15)2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35956936

RESUMO

Molineria recurvata (MR) has been traditionally used to manage diabetes mellitus in India. However, the molecular mechanism of MR on the diabetic-induced nephropathy has not been clearly investigated. Thus, this study investigates the protective effects of the MR extract on nephropathy in streptozotocin (STZ)-induced diabetic rats. Diabetes was instigated by a single intraperitoneal injection of STZ (45 mg/kg) in male Sprague-Dawley rats. Once the diabetes was successfully induced, the MR extract (200 mg/kg/day) or metformin (200 mg/kg/day) was orally administered for 14 days. Renal function, morphology changes and levels of inflammatory cytokines were measured. Blood glucose concentrations were considerably reduced in STZ-induced diabetic rats following treatment with the MR extract. The administration of the MR extract substantially restored the abnormal quantity of the oxidative DNA damage marker 8-hydroxy-2'-deoxy-guanosine (8-OHdG), malondialdehyde, glutathione, oxidized glutathione, superoxide dismutase, catalase, interleukin (IL)-1ß, IL-6, IL-10, and transforming growth factor-ß (TGF-ß). The urinary excretion of kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), selenium binding protein 1 (SBP1), and pyruvate kinase M2 (PKM2) was significantly reduced in diabetes rats after administration of the MR extracts. In the kidneys of STZ-induced diabetic rats, the MR extracts markedly downregulated the expression of fibronectin, collagen-1, and α-smooth muscle actin (α-SMA). In particular, the MR extracts markedly increased the level of SIRT1 and SIRT3 and reduced claudin-1 in the kidney. These results suggest that the MR extracts exhibits therapeutic activity in contrast to renal injury in STZ-induced diabetic rats through repressing inflammation and oxidative stress.


Assuntos
Anti-Inflamatórios , Antioxidantes , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Hypoxidaceae , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Glicemia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Hypoxidaceae/química , Rim , Masculino , Estresse Oxidativo , Extratos Vegetais/uso terapêutico , Ratos , Ratos Sprague-Dawley , Estreptozocina/farmacologia , Estreptozocina/toxicidade
5.
Medicina (Kaunas) ; 58(8)2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35893108

RESUMO

Background and Objectives: To assess the antioxidant and neuroprotective role of rosinidin on rat memory impairment that is induced by streptozotocin. Materials and Methods: Wistar rats were given an intraperitoneal (i.p) injection of streptozotocin (60 mg/kg) followed by treatment with rosinidin at selective doses (10 and 20 mg/kg) for 30 days. The behavioral parameters were estimated by Y-maze test and Morris water test. Biochemical parameters such as acetylcholinesterase (AChE), choline aacetyltransferase (ChAT), and nitric oxide, and antioxidants such as glutathione transferase (GSH), superoxide dismutase (SOD) IL-6, IL-10, Nrf2, and BDNF, were determined. Results: The study results revealed that rosinidin improved cognition by reverting the behavioral parameters. The treatment with rosinidin restored the antioxidant enzymes and inflammatory cytokines. Conclusions: From the results, it has been proven that rosinidin possesses antioxidant, anti-amnesic, and anti-inflammatory activity. Rosinidin improved the cognitive and behavioral deficits that were induced by streptozotocin. Furthermore, 20 mg/kg rosinidin was found to have strong protective action against streptozotocin-induced toxicity.


Assuntos
Fármacos Neuroprotetores , Síndromes Neurotóxicas , Acetilcolinesterase , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Mediadores da Inflamação , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Ratos , Ratos Wistar , Estreptozocina/uso terapêutico , Estreptozocina/toxicidade
6.
Metab Brain Dis ; 37(7): 2533-2543, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35900690

RESUMO

DPP-4 inhibitors have been shown to reverse amyloid deposition in Alzheimer's disease (AD) patients with cognitive impairment. Ocimum sanctum L. leaves reported the presence of important phytoconstituents which are reported to have DPP-4 inhibitory activity. To investigate the effects of petroleum ether extract of Ocimum sanctum L. (PEOS) in Intracerebroventricular streptozotocin (ICV-STZ) induced AD rats. ICV-STZ (3 mg/kg) was injected bilaterally into male Wistar rats, while sham animals received the artificial CSF. The ICV-STZ-induced rats were administered with three doses of PEOS (100, 200, and 400 mg/kg, p.o.) for thirty days. All experimental rats were subjected to behaviour parameters (radial arm maze task and novel object recognition test), neurochemical parameters such as GLP-1, Aß42, and TNF-α levels, and histopathological examination (Congo red staining) of the left brain hemisphere. PEOS significantly reversed the spatial learning and memory deficit exhibited by ICV-STZ-induced rats. Furthermore, PEOS also shows promising results in retreating Aß deposition, TNF α, and increasing GLP-1 levels. The histopathological study also showed a significant dose-dependent reduction in amyloid plaque formation and dense granule in PEOS -treated rats as compared to the ICV-STZ induced rats (Negative control). The results show that extract of Ocimum sanctum L. attenuated ICV-STZ-induced learning and memory deficits in rats and has the potential to be employed in the therapy of AD.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Inibidores da Dipeptidil Peptidase IV , Peptídeo 1 Semelhante ao Glucagon , Extratos Vegetais , Animais , Masculino , Ratos , Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Vermelho Congo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/análise , Inflamação/induzido quimicamente , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Ocimum sanctum/química , Ratos Wistar , Estreptozocina/toxicidade , Fator de Necrose Tumoral alfa , Extratos Vegetais/farmacologia
7.
Behav Brain Res ; 433: 113984, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-35780960

RESUMO

Intracerebroventricularly (icv) injected streptozotocin (STZ) model of Alzheimer's disease (AD) is used to explore the effect of intermittent theta burst stimulation (iTBS) on astrocyte and microglia reactivity in selectively vulnerable brain regions and answer the question whether these changes are in the context of cognitive capacity. The iTBS is a non-invasive approach for stimulating neuronal and glial activity with the ability to induce long-term potentiation-like plasticity and represents a promising treatment for different neurological diseases, including AD. Male Wistar rats were assigned to five groups: 1. Control subjected to icv saline solution, 2. STZ subjected to icv-STZ (bilaterally, 3 mg/kg), 3. STZ+iTBS subjected to iTBS therapy after icv-STZ, 4. STZ+iTBS placebo subjected to noise artifact after icv-STZ and 5. Control+iTBS subjected to iTBS therapy after icv- saline solution. The RotaRod result showed that STZ did not alter motor function in rats. Eight arm radial maze test results showed that iTBS significantly improved cognitive impairment induced by STZ intoxication. Reactive gliosis in the hippocampus and periventricular area, manifested through elevated levels of Iba1+ and GFAP+/VIM+ following icv-STZ, was ameliorated after iTBS treatment. Our research identifies iTBS as an effective therapeutic candidate against STZ-induced neurotoxicity and AD-like changes. The beneficial effects of iTBS on cognitive dysfunction might be due to targeting microglia and astrocytes, as they exert a protective role in neurodegenerative and neuroinflammatory diseases. The results could provoke translation into clinical practice as an early/add-on non-invasive therapeutic intervention for cognitive impairment in AD.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/psicologia , Doença de Alzheimer/terapia , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/terapia , Modelos Animais de Doenças , Gliose , Hipocampo , Masculino , Aprendizagem em Labirinto , Ratos , Ratos Wistar , Solução Salina/farmacologia , Estreptozocina/toxicidade , Estimulação Magnética Transcraniana
8.
Neurochem Int ; 159: 105385, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35843421

RESUMO

Resveratrol (RES) is a polyphenol with diverse beneficial pharmacological activities, and our previous results have demonstrated its neuroprotective potential. The purpose of this study was to investigate the therapeutic effect of RES in Alzheimer's disease (AD)-like behavioral dysfunction induced by streptozotocin (STZ) and explore it's potential mechanism of action. STZ was microinjected bilaterally into the dorsal hippocampus of C57BL/6J mice at a dose of 3 mg/kg, and RES was administered intragastrically at a dose of 25 mg/kg for 5 weeks. Neurobehavioral performance was observed, and serum concentrations of insulin and Nesfatin-1 were measured. Moreover, the protein expression of amyloid beta 1-42 (Aß1-42), Tau, phosphorylated Tau (p-Tau) (Ser396), synaptic ras GTPase activation protein (SynGAP), postsynaptic density protein 95 (PSD95), synapsin-1, synaptogomin-1, and key molecules of the Wnt/ß-catenin signaling pathway in the hippocampus and prefrontal cortex (PFC) were assessed. Finally, pathological damage to hippocampal tissue was examined by Nissl and immunofluorescence staining. The results showed that compared with the controls, bilateral hippocampal microinjections of STZ induced task-specific learning and memory impairments, as indicated by the disadvantaged performances in the novel object recognition test (NOR) and Morris water maze (MWM), but not the contextual fear conditioning test (CFC). Treatment with RES could improve these behavioral disadvantages. The serum concentrations of insulin and Nesfatin-1 in the model group were remarkably higher than those of the control group. In addition, protein expression of Aß1-42, Tau, and p-Tau (Ser396) was increased but expression of SynGAP, PSD95, brain-derived neurotrophic factor (BDNF), and p-GSK-3ß/GSK-3ß were decreased in the hippocampus. Although the protein expression of BDNF and SynGAP was also markedly decreased in the PFC of the model mice, there was no significant difference among groups in the protein expression of PSD95, BDNF, synapsin-1, synaptogomin-1, and p-GSK-3ß/GSK-3ß. RES (25 mg/kg) reversed the enhanced insulin level, the abnormal protein expression of Aß1-42, Tau, and p-Tau (Ser396) in the hippocampus and PFC, and the hippocampal protein expression of SynGAP, PSD95 and BDNF. In addition, RES reversed the STZ-induced decrease in the number of Nissl bodies and the increase in fluorescence intensity of IBA1 in the hippocampal CA1 region. These findings indicate that RES could ameliorate STZ-induced AD-like neuropathological injuries, the mechanism of which could be partly related to its regulation of BDNF expression and synaptic plasticity-associated proteins in the hippocampus.


Assuntos
Doença de Alzheimer , Insulinas , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/metabolismo , Insulinas/efeitos adversos , Insulinas/metabolismo , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Estreptozocina/toxicidade , Sinapsinas/metabolismo , Sinapsinas/farmacologia , Sinapsinas/uso terapêutico
9.
Braz J Biol ; 84: e260189, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35703627

RESUMO

The antidiabetic and hepato-renal protective effects of Citrullus colocynthis and Momordica charantia ethanol extracts were investigated in streptozotocin (STZ) induced diabetic male albino rats. Diabetic rats were treated with C. colocynthis, M. charantia or C. colocynthis + M. charantia mixed extract at a dose of 250 mg /kg body weight per oral per day for 21 days. The mean body weight of all the diabetic rat groups on day 1 of treatment (day 10 of diabetes) was significantly lower than the normal control rat group (P<0.05). The blood glucose level of all the diabetic rat groups on day 1 of treatment (day 10 of diabetes) was significantly (P<0.05) higher (> 200 mg/dl) than the normal control rat group (95.5 ± 2.7). At the end of treatment (day 21), the diabetic rats treated with plant extracts showed significant increase (P<0.05) in body weight and significant (P<0.05) reduction in blood glucose level when compared to diabetic control animals. Significant increase (< 0.05) was observed in the serum bilirubin, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), urea and creatinine levels of diabetic control rat group. The serum levels of these liver and kidney-related parameters of diabetic rats treated with plant extract were significantly lower when compared to diabetic control rat group (p < 0.05). Photomicrographs of liver and kidney microsections from diabetic rats treated with these plant extracts showed amelioration in the hepato-renal histoarchitectures. It was concluded that the C. colocynthis and M. charantia methanol extracts are antidiabetic and hepato-renal protective in STZ induced diabetic male rats. Treatment of the diabetic rats with C. colocynthis + M. charantia mixed extract is more effective in the amelioration of diabetes and hepato-renal injuries in STZ induced diabetic male rats.


Assuntos
Diabetes Mellitus Experimental , Plantas Medicinais , Animais , Glicemia , Peso Corporal , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Fígado , Masculino , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Estreptozocina/uso terapêutico , Estreptozocina/toxicidade
10.
J Appl Toxicol ; 42(11): 1777-1786, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35665945

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease in elderly population. Pterostilbene (PTS) is a resveratrol analog with neuroprotective activity. However, the biological mechanisms of PTS in AD progression are largely uncertain. An animal model of AD was established using streptozotocin (STZ)-treated C57BL/6J mice. Monoamine oxidase B (MAOB) expression was analyzed by bioinformatics analysis and detected by western blotting assay. The memory impairment was investigated by Morris water maze test. The levels of Tau hyperphosphorylation and death-related proteins were detected by western blotting analysis. The levels of amyloid ß (Aß)1-42 accumulation, oxidative stress-related markers (ROS, MDA, SOD, and GSH), and inflammation-relative markers (TNF-α, IL-1ß, IL-6, and p-NF-κB) were measured by ELISA. MAOB expression was increased in hippocampus of AD mice, and it was decreased by PTS. PTS attenuated STZ-induced body weight loss and memory impairment by regulating MAOB. PTS mitigated Aß1-42 accumulation and Tau hyperphosphorylation by regulating MAOB in STZ-treated mice. PTS attenuated neuronal death by decreasing cleaved caspase-3 and Bax levels and increasing Bcl2 expression in hippocampus by regulating MAOB in STZ-treated mice. PTS weakened STZ-induced oxidative stress in hippocampus by decreasing ROS and MDA levels and increasing SOD and GSH levels by regulating MAOB. PTS protected against STZ-induced neuroinflammation in hippocampus by inhibiting TNF-α, IL-1ß, IL-6, and p-NF-κB levels through regulating MAOB. In conclusion, PTS alleviates STZ-induced memory impairment, Aß1-42 accumulation, Tau hyperphosphorylation, neuronal death, oxidative stress, and inflammation by decreasing MAOB in AD mice, proving anti-AD potential of PTS.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Idoso , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Animais , Caspase 3 , Modelos Animais de Doenças , Humanos , Inflamação , Interleucina-6 , Camundongos , Camundongos Endogâmicos C57BL , Monoaminoxidase , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio , Resveratrol , Estilbenos , Estreptozocina/toxicidade , Superóxido Dismutase , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2
11.
Respir Physiol Neurobiol ; 303: 103923, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35654367

RESUMO

PURPOSE: To evaluate the phrenic nerve compound muscle action potential (CMAP) in rats after diabetes mellitus (DM) induction. METHODS: Twenty DM animals (intravenous streptozotocin, 45 mg.kg-1) and 25 controls underwent CMAP analysis before and 30, 60 and 90 days after DM induction. RESULTS: Amplitude (mV) progressively declined in DM group after 30 (Mean difference (MD): -0.915, 95 % Confidence interval (CI) -1.580 to -0.250, p < 0.01), 60 (MD: -1.122, 95 % CI -1.664 to -0.581, p < 0.001) and 90 days (MD: -2.226, 95 % CI -3.059 to -1.393, p < 0.001); as well as the area (mV.ms) after 30 (MD: -3.19, 95 % CI -5.94 to -0.44, p < 0.05), 60 (MD: -3.94, 95 % CI -6.24 to -1.64, p < 0.001) and 90 days (MD: -8.64, 95 % CI -12.08 to -5.21, p < 0.001). Transient differences were observed in latency and duration at 60 days. CONCLUSIONS: The progressive changes in phrenic nerve CMAP observed during DM suggest a decrement in axonal function rather than substantial demyelination.


Assuntos
Diabetes Mellitus Experimental , Nervo Frênico , Potenciais de Ação , Animais , Músculos , Condução Nervosa/fisiologia , Nervo Frênico/fisiologia , Ratos , Estreptozocina/toxicidade
12.
Sci Prog ; 105(2): 368504221102751, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35619568

RESUMO

This study tested the protective effect of Rumex nervous (R. nervosus) methanol extract against streptozotocin (STZ)-mediated type 1 diabetes mellitus (T1DM)-induced nephropathy in rats and examined if this protection involves activating the nuclear factor erythroid 2 related factor-2 (Nrf2). Rats were divided into control, R. nervous (300 mg), STZ (T1DM), STZ + R. nervosus (100, 200, or 300 mg/kg), and STZ + R. nervosus (300 mg/kg) + brusatol (an Nrf2 inhibitor). With no effect on fasting glucose and insulin levels, R. nervosus methanol extract preserved kidney histological structure and alterations kidney function markers (e.g. albumin, creatinine, and urine volume) in the STZ-diabetic rats. R. nervosus also reduced levels of reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and interleukine-6 (IL-6), nuclear levels of the nuclear factor kappa beta (NF-κB), and mRNA of caspase-3 and Bax in the kidneys of these diabetic rats. Concomitantly, it stimulated renal mRNA levels of Bcl2 and Nrf2, cytoplasmic and nuclear levels of Nrf2, and levels of glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). All these effects were dose-dependent, with the maximum effect seen with the 300 mg/kg dose, all prevented by brusatol. Also, these effects occurred without any alteration in the transcription of the Kelch-like ECH-associated protein 1 (keap-1). Similar effects on levels of GSH, SOD, CAT, and NF-κB, as well as expression of Nrf2, were also observed in the kidney of control + R. nervous-treated rats. In conclusion, R. nervosus prevents diabetic nephropathy in rats by upregulating and activating Nrf2.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Nefropatias Diabéticas , Rumex , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Fator de Transcrição de Proteínas de Ligação GA , Glutationa , Metanol , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , RNA Mensageiro , Ratos , Estreptozocina/toxicidade , Superóxido Dismutase
13.
J Cell Mol Med ; 26(12): 3343-3363, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35502486

RESUMO

Since ancient times, plants have been used as green bioresources to ensure a healthier life by recovering from different diseases. Kattosh (Lasia spinosa L. Thwaites) is a local plant with various traditional uses, especially for arthritis, constipation and coughs. This research investigated the effect of Kattosh stem extract (LSES) on streptozotocin-induced damage to the pancreas, kidney, and liver using in vitro, in vivo and in silico methods. In vitro phytochemical, antioxidative and anti-inflammatory effects of LSES were accomplished by established methods followed by antidiabetic actions in in vivo randomized controlled intervention in STZ-induced animal models for four weeks. In an in silico study, LSES phytocompounds interacted with antidiabetic receptors of peroxisome proliferator-activated receptor-gamma (PPAR, PDB ID: 3G9E), AMP-activated protein kinase (AMPK, PDB ID: 4CFH) and α-amylase enzyme (PDB ID: 1PPI) to verify the in vivo results. In addition, LSES showed promising in vitro antioxidative and anti-inflammatory effects. In contrast, it showed a decrease in weekly blood glucose level, normalized lipid profile, ameliorated liver and cardiac markers, managed serum AST and ALT levels, and increased glucose tolerance ability in the animal model study. Restoration of pancreatic and kidney damage was reflected by improving histopathological images. In ligand-receptor interaction, ethyl α-d-glucopyranoside of Kattosh showed the highest affinity for the α-amylase enzyme, PPAR, and AMPK receptors. Results demonstrate that the affinity of Kattosh phytocompounds potentially attenuates pancreatic and kidney lesions and could be approached as an alternative antidiabetic source with further clarification.


Assuntos
PPAR gama , Extratos Vegetais , Proteínas Quinases Ativadas por AMP , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Rim/patologia , PPAR gama/metabolismo , Pâncreas/patologia , Extratos Vegetais/farmacologia , Estreptozocina/toxicidade , alfa-Amilases/farmacologia
14.
J Alzheimers Dis ; 88(1): 57-74, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35527550

RESUMO

BACKGROUND: With advancements in periodontal medicine, the relationship between periodontitis and systemic diseases has garnered increasing attention. Recently, emerging evidence has indicated that periodontitis may be involved in the pathogenesis of Alzheimer's disease (AD). OBJECTIVE: To assess the impact of experimental periodontitis on cognitive function deficits in a rat model of streptozotocin-induced AD and determine the mechanisms underlying these effects. METHODS: Rats were randomly assigned to the control (C), experimental periodontitis (P), Alzheimer's disease (AD), and experimental periodontitis with streptozotocin-induced AD (AD-P) groups. Experimental periodontitis was induced using ligation and coating with Porphyromonas gingivalis. In the AD-P group, AD was induced by intracerebroventricular injection of streptozotocin after 6 weeks of experimental periodontitis induction. RESULTS: Compared with the group C rats, those in group P exhibited alveolar bone resorption, learning and memory function impairment, and decreased insulin sensitivity and insulin signaling-related protein expression. Glial cell activation and cognitive impairment in streptozotocin-induced groups with significantly increased phosphorylated tau levels were more pronounced relative to the C group. The number of neurons and insulin sensitivity and insulin signaling-related protein expression in group AD-P rats were lower than those in the AD alone group, while the expressions of glial fibrillary acidic protein, tau phosphorylation, interleukin-6, and cyclooxygenase-2 were significantly increased. CONCLUSION: Periodontitis may be a risk factor exacerbating cognitive deficits in an AD-like neurodegenerative context, possibly by impairing the insulin signaling pathway and stimulating gliosis and neuroinflammation.


Assuntos
Doença de Alzheimer , Resistência à Insulina , Periodontite , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Animais , Cognição , Modelos Animais de Doenças , Insulina/metabolismo , Periodontite/complicações , Ratos , Transdução de Sinais , Estreptozocina/toxicidade
15.
Cell Rep Med ; 3(4): 100598, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35492248

RESUMO

We study the efficacy of a glucagon-like peptide-1 (GLP-1) and estrogen dual agonist (GLP1-E2) in pancreatic islet protection. GLP1-E2 provides superior protection from insulin-deficient diabetes induced by multiple low-dose streptozotocin (MLD-STZ-diabetes) and by the Akita mutation in mice than a GLP-1 monoagonist. GLP1-E2 does not protect from MLD-STZ-diabetes in estrogen receptor-α (ERα)-deficient mice and fails to prevent diabetes in Akita mice following GLP-1 receptor (GLP-1R) antagonism, demonstrating the requirement of GLP-1R and ERα for GLP1-E2 antidiabetic actions. In the MIN6 ß cell model, GLP1-E2 activates estrogen action following clathrin-dependent, GLP-1R-mediated internalization and lysosomal acidification. In cultured human islet, proteomic bioinformatic analysis reveals that GLP1-E2 amplifies the antiapoptotic pathways activated by monoagonists. However, in cultured mouse islets, GLP1-E2 provides antiapoptotic protection similar to monoagonists. Thus, GLP1-E2 promotes GLP-1 and E2 antiapoptotic signals in cultured islets, but in vivo, additional GLP1-E2 actions in non-islet cells expressing GLP-1R are instrumental to prevent diabetes.


Assuntos
Diabetes Mellitus , Ilhotas Pancreáticas , Animais , Diabetes Mellitus/metabolismo , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Insulina/metabolismo , Insulina Regular Humana/metabolismo , Ilhotas Pancreáticas/metabolismo , Camundongos , Proteômica , Estreptozocina/toxicidade
16.
Toxicol Mech Methods ; 32(9): 695-704, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35414346

RESUMO

Long-term diabetes mellitus results in neuronal damage by increased intracellular glucose leading to oxidative stress. This condition is known as diabetic encephalopathy. Morin is a bioflavonoid, has significant antidiabetic, antioxidant and anti-inflammatory activities. The present study investigated whether the antioxidant properties of morin has beneficial effects on structural brain damage, neuronal apoptosis and dysregulation of TrkB/Akt signaling associated with diabetes. Adult male Sprague Dawley rats were induced diabetes by an intraperitoneal injection of 40 mg/kg of streptozotocin and kept untreated for 30 days to induce DE. Cognitive performance was assessed using the Morris water maze test followed by morin and metformin administration at the doses of 50 and 100 mg/kg, respectively, for 60 days. After 60 days of treatment, animals were subjected to the behavioral test and sacrificed to collect blood and brain and checked biochemical parameters. The treatment with morin could significantly reduce the escape latency time in Morris water maze test, blood glucose level, HbA1c, toxicity markers, lipid peroxidation products and protein carbonyl content, downregulated the expression of Bax, Caspase - 3 and Cytochrome C and upregulated Bcl-2, Bcl-XL, Akt, BDNF and TrkB expressions. Besides, enhanced the activities of antioxidant enzymes, and plasma insulin level. Histomorphological observations also confirmed the protective effect of morin on neuronal degeneration. Morin 50 mg once daily for 60 days was the most effective dose with a significant reduction in diabetes mediated complications in the brain associated with neuronal apoptosis and dysregulation of TrkB/Akt signaling.


Assuntos
Diabetes Mellitus , Insulinas , Metformina , Fármacos Neuroprotetores , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose , Glicemia , Fator Neurotrófico Derivado do Encéfalo , Citocromos c/metabolismo , Diabetes Mellitus/tratamento farmacológico , Flavonas , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Hemoglobina A Glicada , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulinas/metabolismo , Insulinas/farmacologia , Masculino , Metformina/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Carbonilação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina/toxicidade , Proteína X Associada a bcl-2/metabolismo
17.
Eur J Clin Invest ; 52(9): e13807, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35488737

RESUMO

BACKGROUND: Diabetes mellitus (DM) induces cardiac and cerebral microvascular dysfunction via increased glycation, oxidative stress and endothelial activation. Liraglutide, a glucagon-like peptide-1 analogue, inhibited NOX2 and adhesion molecules in isolated endothelial cells. Here, we have studied how Liraglutide affects advanced glycation, NOX expression and inflammation of the cardiac, cerebral and renal microvasculature in diabetic rats. METHODS: DM was induced in Sprague-Dawley rats (n = 15) via intraperitoneal streptozotocin (STZ) injection (60 mg/kg bodyweight). Ten control rats remained nondiabetic. From day 9 post-STZ injection, Liraglutide (200 µg/kg bodyweight; n = 7) or vehicle (n = 8) was injected subcutaneously daily until termination on day 29. The advanced glycation endproduct N-ε-(carboxymethyl)lysine (CML), NOX2, NOX4, ICAM-1 and VCAM-1 were subsequently immunohistochemically analysed and quantified to compare Liraglutide treatment with placebo. RESULTS: In the heart, Liraglutide treatment significantly reduced the DM-increased scores/cm2 for CML in both ventricles (from 253 ± 53 to 72 ± 12; p = .003) and atria (343 ± 29 to 122 ± 8; p = .0001) and for NOX2, ICAM-1 and VCAM-1, but not for NOX4. Also in the cerebrum and cerebellum of the brain, Liraglutide significantly reduced the scores/cm2 for CML (to 60 ± 7 (p = .0005) and 47 ± 13 (p = .02), respectively), and for NOX2 and NOX4. In the kidney, the DM-induced expression of ICAM-1 and VCAM-1 was decreased in the blood vessels and glomeruli by Liraglutide treatment. Liraglutide did not affect blood glucose levels or bodyweight. CONCLUSIONS: Our study implies that Liraglutide protects the cardiac, cerebral and renal microvasculature against diabetes-induced dysfunction, independent of lowering blood glucose in a type 1 diabetes rat model.


Assuntos
Diabetes Mellitus Experimental , Liraglutida , Animais , Glicemia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Inflamação/tratamento farmacológico , Molécula 1 de Adesão Intercelular , Rim/metabolismo , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Microvasos , Ratos , Ratos Sprague-Dawley , Estreptozocina/toxicidade , Molécula 1 de Adesão de Célula Vascular
18.
Curr Drug Discov Technol ; 19(5): e080422203277, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35400345

RESUMO

BACKGROUND: Individual extracts of Garcinia kola and Kigelia africana have been shown to have therapeutic effects against a variety of variables linked to the development of diabetes mellitus. However, there is still a lack of information about the combined effects of these extracts on Insulin and Paraoxonase 1 (PON-1) in Streptozotocin-Nicotinamide-induced type-2 diabetic Wistar rats. METHODS: Forty-two young male rats (180-200g) were randomly divided into six groups (n = 7/group). Diabetes was intraperitoneally induced with 110 mg/kg of nicotinamide constituted in distilled water and fifteen minutes later with 65 mg/kg of streptozocin freshly prepared in 0.1M citrate buffer (pH of 4.5) and treated for six weeks as follows: the control rats received either 0.9% normal saline (NS) or 250 mg/kg extract by gavage. The remaining animals were diabetes induced and subsequently treated with either NS, graded doses of the extract (250 mg/kg and 500 mg/kg), or 5 mg/kg Glibenclamide + 100mg/kg Metformin. Gas chromatography-mass spectrometry (GCMS) of the combined extracts was also analyzed to identify the bioactive compounds present in it. Insulin, PON-1 levels, lipid profiles, and atherogenic index were assessed. RESULTS: Our findings show that Insulin and PON-1 levels in the plasma of diabetic rats treated with the combined extracts were significantly increased when compared to the control rats. Moreover, the GCMS of the extract shows the presence of both monounsaturated (oleic acid) and polyunsaturated (linoleic acid) fatty acids. CONCLUSION: The current findings suggest that the extract may help improve glucose homeostasis and prevent atherosclerosis through the established mechanism of the identified bioactive compounds.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Garcinia kola , Extratos Vegetais , Animais , Arildialquilfosfatase/uso terapêutico , Glicemia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Garcinia kola/química , Glibureto , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Metformina , Niacinamida/toxicidade , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Estreptozocina/toxicidade
19.
Oxid Med Cell Longev ; 2022: 3716609, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35464765

RESUMO

Takeda G protein-coupled receptor 5 (TGR5) is the first known G protein-coupled receptor specific for bile acids and is recognized as a new and critical target for type 2 diabetes and metabolic syndrome. It is expressed in many brain regions associated with memory such as the hippocampus and frontal cortex. Here, we hypothesize that activation of TGR5 may ameliorate streptozotocin- (STZ-) induced cognitive impairment. The mouse model of cognitive impairment was established by a single intracerebroventricular (ICV) injection of STZ (3.0 mg/kg), and we found that TGR5 activation by its agonist INT-777 (1.5 or 3.0 µg/mouse, ICV injection) ameliorated spatial memory impairment in the Morris water maze and Y-maze tests. Importantly, INT-777 reversed STZ-induced downregulation of TGR5 and glucose usage deficits. Our results further showed that INT-777 suppressed neuronal apoptosis and improved neurogenesis which were involved in tau phosphorylation and CREB-BDNF signaling. Moreover, INT-777 increased action potential firing of excitatory pyramidal neurons in the hippocampal CA3 and medial prefrontal cortex of ICV-STZ groups. Taken together, these findings reveal that activation of TGR5 has a neuroprotective effect against STZ-induced cognitive impairment by modulating apoptosis, neurogenesis, and neuronal firing in the brain and TGR5 might be a novel and potential target for Alzheimer's disease.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Doença de Alzheimer/metabolismo , Animais , Apoptose , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Aprendizagem em Labirinto , Camundongos , Neurogênese , Receptores Acoplados a Proteínas G/metabolismo , Estreptozocina/toxicidade
20.
Comput Math Methods Med ; 2022: 9212116, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35295199

RESUMO

Objective: DNA methylation played a vital role in the progression of diabetic retinopathy. In this study, we aimed to explore the role of DNA cytosine-5-methyltransferase 1 (DNMT1) in the development of early diabetic retinopathy and its potential underlying mechanism. Methods: Eight-week-old healthy Mongolian gerbils were used to establish type 1 diabetes using streptozotocin (STZ). Alteration of weight, fasting blood glucose, density of RGCs (Tuj1-labeled), and H&E-stained retinal cross sections were applied to evaluate the diabetic retinopathy mouse model. The global DNA methylation level of the retina at different time points after STZ injection was measured using the global methylation assay. Western blot was used to detect the protein expression of DNMT1, DNA methyltransferase 3A (DNMT3A), and 3B (DNMT3B). Quantitative reverse transcription-polymerase chain reactions (qRT-PCR) and western blot were used to determine the expression of CDKN2B. Cell proliferation and cell cycle were evaluated by the MTS assay and flow cytometry. Results: STZ injection caused the increased global DNA methylation level, which reached a maximum at 6 weeks after injection. Moreover, STZ injection caused the damage of RGCs. At 6 weeks after STZ injection, the expression levels of DNMT1 and DNMT3B were significantly increased in the STZ group. DNMT1-induced DNA hypermethylation inhibited the expression of CDKN2B (a negative regulator of cell cycle). DNMT1-mediated DNA methylation facilitated RGC proliferation via regulating the expression of CDKN2B. Conclusion: DNMT1-mediated DNA methylation played an important role in STZ-induced diabetic retinopathy via modulating CDKN2B expression.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Retinopatia Diabética/metabolismo , Células Ganglionares da Retina/metabolismo , Animais , Proliferação de Células , Biologia Computacional , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/etiologia , Retinopatia Diabética/patologia , Técnicas de Silenciamento de Genes , Gerbillinae , Masculino , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Estreptozocina/toxicidade
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