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1.
IET Nanobiotechnol ; 15(5): 473-483, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34694755

RESUMO

This study examines the effect of nanoparticles with zinc oxides (ZnONPs) on diabetic nephropathy, which is the primary cause of mortality for diabetic patients with end-stage renal disease. Diabetes in adult male rats was induced via intraperitoneal injection of streptozotocin. ZnONPs were intraperitoneally administered to diabetic rats daily for 7 weeks. Diabetes was associated with increases in blood glucose level, 24-h urinary albumin excretion rate, glomerular basement membrane thickness, renal oxidative stress markers, and renal mRNA or protein expression of transforming growth factor-ß1, fibronectin, collagen-IV, tumour necrosis factor-α and vascular endothelial growth factor-A. Moreover, the expression of nephrin and podocin, and the mRNA expression of matrix metalloproteinase-9 were decreased in the diabetic group. These changes were not detected in the control group and were significantly prevented by ZnONP treatment. These results provide evidence that ZnONPs ameliorate the renal damage induced in a diabetic rat model of nephropathy through improving renal functionality; inhibiting renal fibrosis, oxidative stress, inflammation and abnormal angiogenesis; and delaying the development of podocyte injury. The present findings may help design the clinical application of ZnONPs for protection against the development of diabetic nephropathy.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Nefropatias Diabéticas , Nanopartículas , Óxido de Zinco , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Humanos , Rim , Masculino , Ratos , Estreptozocina/toxicidade , Fator A de Crescimento do Endotélio Vascular
2.
ACS Chem Neurosci ; 12(20): 3818-3828, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34491720

RESUMO

The pathogenesis of Alzheimer's disease (AD), the most prevalent form of dementia, remains unclear. Over the past few years, evidence has accumulated indicating that perturbed cerebral bioenergetics and neuroinflammation may compromise cognitive functions and precedes the onset of AD and that impaired function of glial cells can likely contribute to the development of the disease. Recently, N6-methyladenosine (m6A) modification of RNA has been implicated in the regulation of different processes in the brain and to play a potential role in neurodegeneration. In the present study, we investigated the potential role of the m6A machinery enzymes in a streptozotocin (STZ) model of AD in human astrocytoma CCF-STTG1 cells. We observed that STZ-treated astrocytes expressed significantly higher levels of m6A demethylase fat mass and obesity-associated protein (FTO) and m6A reader YTHDF1 (YTH domain-containing family protein 1). Our experiments revealed that MO-I-500, a novel pharmacological inhibitor of FTO, can strongly reduce the adverse effects of STZ. Inhibition of FTO enhanced the survival of cells exposed to STZ and suppressed oxidative stress, apoptosis, elevated expression of glial fibrillary acidic protein, mitochondrial dysfunction, and bioenergetic disturbances induced by this compound. Overall, the results of this study indicate that perturbed m6A signaling may be contributing to AD pathogenesis, likely by compromising astrocyte bioenergetics.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato , Astrócitos , Adenosina , Humanos , Mitocôndrias , Estreptozocina/toxicidade
3.
Physiol Behav ; 241: 113592, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34534530

RESUMO

RATIONALE: Vascular dementia (VaD) is the second leading cause of dementia worldwide. It is very important to find the possible pharmacological agents which may be useful in management and therapy of VaD. OBJECTIVES: The present study investigates the effect of ozagrel, a selective thromboxane A2 (TXA2) synthase inhibitor, in a rat model of VaD. METHODS: Single intraperitoneal injection of streptozotocin [STZ, (50 mg/kg)] was administered to Wistar rats to induced diabetes-associated vascular endothelial dysfunction and memory impairment. Morris water maze (MWM) test was employed to assess learning and memory. Endothelial dysfunction was assessed in the isolated aorta by observing endothelial-dependent vasorelaxation and levels of serum nitrite. Various biochemical and histopathological estimations were also performed. RESULTS: STZ treatment produced endothelial dysfunction, impairment of learning and memory, reduction in body weight and serum nitrite/nitrate, and increase in serum glucose, brain oxidative stress (increased brain thiobarbituric acid reactive species and decreased reduced glutathione levels), brain acetylcholinesterase activity and brain myeloperoxidase activity. Further a significant rise in brain tumor necrosis factor-α & interleukin-6 levels and brain neutrophil infiltration were also observed. Treatment of ozagrel (10 & 20 mg/kg, p. o.)/donepezil (0. 5 mg/kg, i.p., serving as standard) ameliorated STZ induced endothelial dysfunction; memory deficits; biochemical and histopathological changes. CONCLUSIONS: It may be concluded that ozagrel markedly improved endothelial dysfunction; learning and memory; biochemical and histopathological alteration associated with STZ induced dementia and that TXA2 can be considered as an important therapeutic target for the management of VaD.


Assuntos
Demência Vascular , Diabetes Mellitus Experimental , Acetilcolinesterase/metabolismo , Animais , Encéfalo/metabolismo , Demência Vascular/complicações , Demência Vascular/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Aprendizagem em Labirinto , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Estresse Oxidativo , Ratos , Ratos Wistar , Estreptozocina/toxicidade , Tromboxano A2
4.
Neuroscience ; 473: 102-118, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34358633

RESUMO

Depression has huge social risks of high incidence, disability, and suicide. Its prevalence and harm in people with hyperglycemia are 2-3 times higher than in normal people. However, antidepressants with precise curative effects and clear mechanisms for patients with hyperglycemia are currently lacking. Prescriptions containing Radix Rehmannia glutinosa Libosch., a traditional medicinal herb with a wide range of nutritional and medicinal values, are often used as antidepressants in Chinese clinical medicine. Catalpol is one of the main effective compounds of Radix R. glutinosa, with multiple biological activities such as hypoglycemia. Here, the antidepressant effect of catalpol on the pathological state of streptozotocin (STZ)-induced hyperglycemia and the underlying molecular mechanisms were analyzed. Results showed that administering catalpol orally to hyperglycemic mice for 21 consecutive days significantly reversed the abnormalities in tail suspension, forced swimming, and open field tests. Catalpol also reversed the abnormal phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) and the abnormal levels of nuclear factor erythroid 2-related factor 2 (Nrf2) protein, heme oxygenase-1 (HO-1), and antioxidants, including superoxide dismutase, glutathione peroxidase, glutathione-s transferase, reduced glutathione, and malondialdehyde in the hippocampus and frontal cortex of STZ-induced hyperglycemic mice. Thus, catalpol attenuates depressive-like behavior in pathological hyperglycemic state, and the antidepressant mechanism could at least be partly attributed to the upregulation of the PI3K/AKT/Nrf2/HO-1 signaling pathway in both brain regions, thus restoring the balance between oxidative and antioxidant damage. These data expanded the scientific understanding of catalpol and provided preclinical experimental evidence for its application.


Assuntos
Hiperglicemia , Fosfatidilinositol 3-Quinase , Animais , Heme Oxigenase-1/metabolismo , Humanos , Hiperglicemia/tratamento farmacológico , Glucosídeos Iridoides , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Estreptozocina/toxicidade
5.
J Food Biochem ; 45(9): e13857, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34309046

RESUMO

Gestational diabetes mellitus (GDM) is the serious complication of pregnancy induced via dysfunction in glucose metabolism during the pregnancy. Crocetin already proved antidiabetic effect in streptozotocin (STZ)-induced diabetes mellitus in rats. In this protocol, we have investigated the potential effect of crocetin against STZ-induced GDM in rats. Wistar rats were used for the current protocol; STZ was used for the induction for DM and finally caused the GDM. Body weight and serum advanced glycation end products level were estimated at regular time intervals. We also estimated the fetus weight and placental weight. Biochemical, antioxidant, pro-inflammatory cytokines, inflammatory mediators, and apoptosis parameters were estimated. mRNA expression of NOX2, RAGE, MCP-1, VCAM-1, EGFR, and p65 were also estimated. Crocetin treatment significantly (p < .001) reduced the fetus weight and increased the placental weight and index. Crocetin significantly (p < .001) reduced the blood glucose level and increased the body weight. Crocetin significantly (p < .001) boosted the level of antioxidant enzymes and includes superoxide dismutase, glutathione peroxidase, glutathione, and catalase. Crocetin significantly (p < .001) altered the level of lipid parameters and pro-inflammatory cytokines. Crocetin significantly (p < .001) reduced the level of intercellular adhesion molecule 1, cyclooxygenase-2, and nuclear factor kappa B and increased the level of visfatin against GDM rats. Crocetin significantly (p < .001) altered the level of mRNA expression. Based on the result, we can say that crocetin is a protective drug against the GDM in pregnant rats via antioxidant, inflammatory, and apoptosis parameters. PRACTICAL APPLICATIONS: As we all know, gestational diabetes mellitus (GDM) cases rise all over the world. The current investigation showed the protective effect of crocetin on GDM in experimental rats. The current finding exhibited the protective effect of crocetin against STZ-induced GDM via suppression of inflammatory, oxidative, and apoptosis parameters. The result suggests the antioxidant and anti-inflammatory effect of crocetin. Crocetin can be used as a preventive medication in the treatment of gestational diabetes mellitus, according to the latest findings.


Assuntos
Diabetes Gestacional , Animais , Carotenoides , Diabetes Gestacional/tratamento farmacológico , Feminino , Placenta , Gravidez , Ratos , Ratos Wistar , Estreptozocina/toxicidade , Vitamina A/análogos & derivados
6.
PLoS One ; 16(7): e0254718, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34270619

RESUMO

Artificial pancreas system (APS) is an emerging new treatment for type 1 diabetes mellitus. The aim of this study was to develop a rat APS as a research tool and demonstrate its application. We established a rat APS using Medtronic Minimed Pump 722, Medtronic Enlite sensor, and the open artificial pancreas system as a controller. We tested different dilutions of Humalog (100 units/ml) in saline ranged from 1:3 to 1:20 and determined that 1:7 dilution works well for rats with ~500g bodyweight. Blood glucose levels (BGL) of diabetic rats fed with chow diet (58% carbohydrate) whose BGL was managed by the closed-loop APS for the total duration of 207h were in euglycemic range (70-180 mg/dl) for 94.5% of the time with 2.1% and 3.4% for hyperglycemia (>180mg/dl) and hypoglycemia (<70 mg/dl), respectively. Diabetic rats fed with Sucrose pellets (94.8% carbohydrate) for the experimental duration of 175h were in euglycemic range for 61% of the time with 35% and 4% for hyperglycemia and hypoglycemia, respectively. Heathy rats fed with chow diet showed almost a straight line of BGL ~ 95 mg/dl (average 94.8 mg/dl) during the entire experimental period (281h), which was minimally altered by food intake. In the healthy rats, feeding sucrose pellets caused greater range of BGL in high and low levels but still within euglycemic range (99.9%). Next, to study how healthy and diabetic rats handle supra-physiological concentrations of glucose, we intraperitoneally injected various amounts of 50% dextrose (2, 3, 4g/kg) and monitored BGL. Duration of hyperglycemia after injection of 50% dextrose at all three different concentrations was significantly greater for healthy rats than diabetic rats, suggesting that insulin infusion by APS was superior in reducing BGL as compared to natural insulin released from pancreatic ß-cells. Ex vivo studies showed that islets isolated from diabetic rats were almost completely devoid of pancreatic ß-cells but with intact α-cells as expected. Lipid droplet deposition in the liver of diabetic rats was significantly lower with higher levels of triacylglyceride in the blood as compared to those of healthy rats, suggesting lipid metabolism was altered in diabetic rats. However, glycogen storage in the liver determined by Periodic acid-Schiff staining was not altered in diabetic rats as compared to healthy rats. A rat APS may be used as a powerful tool not only to study alterations of glucose and insulin homeostasis in real-time caused by diet, exercise, hormones, or antidiabetic agents, but also to test mathematical and engineering models of blood glucose prediction or new algorithms for closed-loop APS.


Assuntos
Glicemia/análise , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Insulina/administração & dosagem , Pâncreas Artificial , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/diagnóstico , Hemoglobina A Glicada/análise , Humanos , Infusões Intravenosas/instrumentação , Infusões Intravenosas/métodos , Masculino , Ratos , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade
7.
Comput Biol Med ; 134: 104462, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34148008

RESUMO

BACKGROUND: Chlorogenic acid is amongst the well-known polyphenolic compounds being used in human food and beverages. Its presence has been reported in tea leaves, roasted green beans, coffee, cocoa, berry fruits, apples, citrus fruits, and pears. OBJECTIVE: The present study aims to elucidate the effectiveness of chlorogenic acid on in silico and in vitro inhibition of glucose metabolising enzymes (α-amylase and α-glucosidase) and on blood-based markers associated with diabetic complications in vivo. METHODS: Docking and molecular dynamics studies were performed using GLIDE (Schrodinger, LLC, NY, 2019-2) and Maestro-Desmond Interoperability Tools, version 4.1 (Schrödinger, NY, 2015), respectively. α-Amylase and α-glucosidase inhibitory activities of chlorogenic acid were measured in vitro. Diabetes was induced in adult Wistar rats by injecting streptozotocin (50 mg/kg). Biochemical assays were performed using standard kits. RESULT: The in silico studies for α-amylase and α-glucosidase with chlorogenic acid suggested that the ligand was stable and strongly bound with the above-mentioned proteins. During in vitro studies, chlorogenic acid inhibited both the enzymes in a dose-dependent manner (5-30 µg/mL). In addition, chlorogenic acid treatment for 28 days significantly suppressed the increase in blood glucose, total cholesterol, triglyceride, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, γ-glutamyl transferase, alkaline phosphatase, total bilirubin, creatinine, urea, uric acid, and feed intake levels in diabetic rats. Chlorogenic acid also caused significant improvement in body weight, serum HDL-cholesterol, total protein, and albumin levels leading to betterment in atherogenic indices related to diabetes-associated cardiovascular risks. CONCLUSION: The findings indicated that chlorogenic acid inhibited α-amylase and α-glucosidase and significantly decreased diabetes associated hyperglycemia, hyperlipidemia, and hepatorenal damage, making it a possible functional food ingredient and drug candidate for the management of diabetes and related complications.


Assuntos
Diabetes Mellitus Experimental , Hipoglicemiantes , Animais , Ácido Clorogênico/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Extratos Vegetais , Ratos , Ratos Wistar , Estreptozocina/toxicidade
8.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073747

RESUMO

ADAM17 is a disintegrin and metalloproteinase capable of cleaving the ectodomains of a diverse variety of molecules including TNF-α, TGF-α, L-selectin, and ACE2. We have previously demonstrated that renal ADAM17 is upregulated in diabetic mice. The role of endothelial (eAdam17) and proximal tubular (tAdam17) Adam17 deletion in renal histology, modulation of the renin angiotensin system (RAS), renal inflammation, and fibrosis was studied in a mouse model of type 1 Diabetes Mellitus. Moreover, the effect of Adam17 deletion in an in vitro 3D cell culture from human proximal tubular cells under high glucose conditions was evaluated. eAdam17 deletion attenuates renal fibrosis and inflammation, whereas tAdam17 deletion decreases podocyte loss, attenuates the RAS, and decreases macrophage infiltration, α-SMA and collagen accumulation. The 3D in vitro cell culture reinforced the findings obtained in tAdam17KO mice with decreased fibrosis in the Adam17 knockout spheroids. In conclusion, Adam17 deletion either in the endothelial or the tubular cells mitigates kidney injury in the diabetic mice by targeting different pathways. The manipulation of Adam17 should be considered as a therapeutic strategy for treating DN.


Assuntos
Proteína ADAM17/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/metabolismo , Rim/metabolismo , Proteína ADAM17/genética , Animais , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/patologia , Fibrose , Deleção de Genes , Inflamação , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Podócitos , Estreptozocina/toxicidade
9.
Front Immunol ; 12: 653088, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122410

RESUMO

Allogeneic islet transplantation is a promising cell-based therapy for Type 1 Diabetes (T1D). The long-term efficacy of this approach, however, is impaired by allorejection. Current clinical practice relies on long-term systemic immunosuppression, leading to severe adverse events. To avoid these detrimental effects, poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) were engineered for the localized and controlled release of immunomodulatory TGF-ß1. The in vitro co-incubation of TGF-ß1 releasing PLGA MPs with naïve CD4+ T cells resulted in the efficient generation of both polyclonal and antigen-specific induced regulatory T cells (iTregs) with robust immunosuppressive function. The co-transplantation of TGF-ß1 releasing PLGA MPs and Balb/c mouse islets within the extrahepatic epididymal fat pad (EFP) of diabetic C57BL/6J mice resulted in the prompt engraftment of the allogenic implants, supporting the compatibility of PLGA MPs and local TGF-ß1 release. The presence of the TGF-ß1-PLGA MPs, however, did not confer significant graft protection when compared to untreated controls, despite measurement of preserved insulin expression, reduced intra-islet CD3+ cells invasion, and elevated CD3+Foxp3+ T cells at the peri-transplantation site in long-term functioning grafts. Examination of the broader impacts of TGF-ß1/PLGA MPs on the host immune system implicated a localized nature of the immunomodulation with no observed systemic impacts. In summary, this approach establishes the feasibility of a local and modular microparticle delivery system for the immunomodulation of an extrahepatic implant site. This approach can be easily adapted to deliver larger doses or other agents, as well as multi-drug approaches, within the local graft microenvironment to prevent transplant rejection.


Assuntos
Diabetes Mellitus Tipo 1/terapia , Portadores de Fármacos/química , Rejeição de Enxerto/prevenção & controle , Fatores Imunológicos/administração & dosagem , Transplante das Ilhotas Pancreáticas/efeitos adversos , Fator de Crescimento Transformador beta1/administração & dosagem , Animais , Glicemia/análise , Técnicas de Cocultura , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Liberação Controlada de Fármacos , Estudos de Viabilidade , Teste de Tolerância a Glucose , Rejeição de Enxerto/imunologia , Humanos , Imunomodulação , Transplante das Ilhotas Pancreáticas/métodos , Masculino , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Cultura Primária de Células , Ratos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/farmacocinética , Transplante Homólogo/efeitos adversos
10.
J Pharmacol Toxicol Methods ; 112: 107090, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34175449

RESUMO

Previous data indicate that the diabetogenic substance streptozotocin might act in nociceptive neurons changing the sensory signal, regardless of hyperglycemia. In the present article the effects of streptozotocin were compared with another diabetogenic drug, alloxan, for diabetes induction in rats. A possible direct effect of these drugs was tested by means of in vivo experiments and in vitro assays using cultured primary nociceptive neurons. Streptozotocin (17.5 and 35 mg/kg), alloxan (15 and 30 mg/kg) or vehicle were injected in adult male rats and the animal groups were separated according to glycemic levels. Body mass, glycemia and paw mechanical sensitivity were evaluated for 5 weeks. Streptozotocin caused an increase in mechanical sensitivity in both hyperglycemic and normoglycemic rats, while alloxan induced mechanical sensitization only in hyperglycemic animals. Injection of both substances induced local inflammation at rat paws; however, only streptozotocin caused significant mechanical sensitization when injected near to sensory neurons at the dorsal root ganglia. Also, streptozotocin treatment induced a reduction in intracellular calcium levels and inhibited capsaicin induced calcium transients and membrane depolarization. Alloxan did not affect calcium levels or membrane potential in primary nociceptive neurons. These findings suggest that alloxan might be a better option for animal studies regarding painful diabetic neuropathy as streptozotocin directly affects nociceptive neurons, probably by modulating TRPV1 channel activation.


Assuntos
Diabetes Mellitus Experimental , Neuropatias Diabéticas , Aloxano/toxicidade , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Neuropatias Diabéticas/induzido quimicamente , Gânglios Espinais , Masculino , Ratos , Estreptozocina/toxicidade
11.
Sci Rep ; 11(1): 9852, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972638

RESUMO

Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the ryanodine receptor blocker dantrolene and the Ca2+ channel blocker nimodipine significantly reduces phenylephrine (PHE)-induced vascular contraction in both diabetic and nondiabetic rats, but the effectiveness of this drug combination in reducing 5-HT-induced contraction is unknown. Dose-response curves for the 5-HT-induced contraction (from 0.1 nM to 100 µM) were performed on aortic rings from diabetic and non-diabetic rats after a 30-min incubation period with dantrolene, nimodipine, and both drugs in combination. In diabetic rats, 10 µM of dantrolene alone failed to reduce 5-HT-induced maximal contraction (Emax), but 50 µM reduced this parameter by 34% (n = 7, p < 0.05). In non-diabetic rats, by contrast, dantrolene did not modify the vascular response to 5-HT. 50 nM of nimodipine alone, however, reduced this parameter by 57% in diabetic rats (n = 10, p < 0.05), and by 34% in non-diabetic rats (n = 10, p < 0.05). In addition, concomitant administration of dantrolene and nimodipine reduced vascular reactivity to a similar extent in both diabetic (~ 60% reduction, n = 10, p < 0.05) and non-diabetic rats (~ 70% reduction, n = 10, p < 0.05). Moreover, the combination of nimodipine with the higher concentration of dantrolene significantly increased the EC50 values for the 5-HT-induced contraction curves in both diabetics (from 10.31 ± 1.17 µM to 19.26 ± 2.82; n = 10, p < 0.05) and non-diabetic rats (5.93 ± 0.54 µM to 15.80 ± 3.24; n = 10, p < 0.05). These results suggest that simultaneous administration of dantrolene and nimodipine has a synergistic effect in reducing 5-HT-induced vascular contraction under both diabetic and non-diabetic conditions. If our findings with rats are applicable to humans, concomitant administration of these drugs may represent a promising alternative for the management of CVSP in both diabetics and non-diabetics.


Assuntos
Dantroleno/administração & dosagem , Diabetes Mellitus Experimental/complicações , Nimodipina/administração & dosagem , Vasoespasmo Intracraniano/tratamento farmacológico , Animais , Bloqueadores dos Canais de Cálcio/administração & dosagem , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Quimioterapia Combinada , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Relaxantes Musculares Centrais/administração & dosagem , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Serotonina/metabolismo , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade , Hemorragia Subaracnóidea/etiologia , Hemorragia Subaracnóidea/prevenção & controle , Vasoespasmo Intracraniano/etiologia
12.
Sci Rep ; 11(1): 10418, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001961

RESUMO

Cryopreservation offers the potential to increase the availability of pancreatic islets for treatment of diabetic patients. However, current protocols, which use dimethyl sulfoxide (DMSO), lead to poor cryosurvival of islets. We demonstrate that equilibration of mouse islets with small molecules in aqueous solutions can be accelerated from > 24 to 6 h by increasing incubation temperature to 37 °C. We utilize this finding to demonstrate that current viability staining protocols are inaccurate and to develop a novel cryopreservation method combining DMSO with trehalose pre-incubation to achieve improved cryosurvival. This protocol resulted in improved ATP/ADP ratios and peptide secretion from ß-cells, preserved cAMP response, and a gene expression profile consistent with improved cryoprotection. Our findings have potential to increase the availability of islets for transplantation and to inform the design of cryopreservation protocols for other multicellular aggregates, including organoids and bioengineered tissues.


Assuntos
Criopreservação/métodos , Crioprotetores/farmacocinética , Diabetes Mellitus Tipo 1/terapia , Transplante das Ilhotas Pancreáticas/métodos , Ilhotas Pancreáticas , Animais , Sobrevivência Celular , Células Cultivadas , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/induzido quimicamente , Humanos , Masculino , Camundongos , Modelos Animais , Cultura Primária de Células , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade
13.
Aging (Albany NY) ; 13(8): 12143-12159, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33902006

RESUMO

Increased accumulation of advanced glycation end products (AGEs) in diabetic skin is closely related to delayed wound healing. Studies have shown that the concentration of AGEs is elevated in the skin tissues and not subcutaneous tissues in refractory diabetic wounds, which suggests there may be a causal relationship between the two. In the present study, in vitro experiments revealed that AGEs activated neutrophils, and the migratory and adhesive functions of neutrophils decreased once AGE levels reached a certain threshold. Different levels of AGE expression differentially affected the function of neutrophils. Messenger RNA (mRNA) sequencing analysis combined with real-time polymerase chain reaction (PCR) showed that poliovirus receptor (PVR/CD155) and CTNND1, which play a role in migration- and adhesion-related signaling pathways, were decreased following AGE stimulation. Consequently, neutrophils cannot effectively stimulate the formation of the inflammatory belt needed to remove necrotic tissues and defend against foreign microorganisms within diabetic chronic wounds. In addition, this phenomenon may be related to the differential accumulation of AGEs in different layers of the skin.


Assuntos
Complicações do Diabetes/imunologia , Diabetes Mellitus Experimental/complicações , Produtos Finais de Glicação Avançada/metabolismo , Neutrófilos/imunologia , Pele/patologia , Animais , Cateninas/metabolismo , Agregação Celular/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Complicações do Diabetes/patologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Humanos , Masculino , Ratos , Receptores Virais/metabolismo , Pele/citologia , Pele/imunologia , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade , Cicatrização/imunologia
14.
Biochemistry (Mosc) ; 86(2): 179-189, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33832416

RESUMO

Polydatin (PD) has a broad range of pharmacological activities; however, its effects on diabetic liver damage are poorly studies. This work is aimed to explore possible protective effects of polydatin-loaded chitosan nanoparticles (PD-CSNPs) or PD against liver damage associated with diabetes. Diabetes was induced in rats using nicotinamide/streptozotocin treatment. Diabetic rats were then divided into six groups: normal control rats, diabetic control rats, and rats orally treated with PD, PD-CSNPs, equivalent unloaded CSNPs, or metformin daily for 4 weeks. Treatment with PD and PD-CSNPs significantly reduced the blood glucose content, lipid peroxidation in the liver, and activities of serum transaminases and carbohydrate metabolism enzymes (including succinate dehydrogenase and pyruvate kinase); by contrast, liver glycogen content, glutathione concentration, and activities of the antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase, and glucose-6-phosphate dehydrogenase) were markedly increased compared with the control diabetic rats. Furthermore, expression of the tumor necrosis factor α and interleukin-1ß mRNAs was significantly downregulated, while expression of glucose transporter 2 and glucokinase mRNAs was strongly upregulated vs. control diabetic rats. We concluded that PD-CSNPs and PD ameliorate diabetic liver damage by modulating glucose transporter 2 expression, affecting the activity of carbohydrate metabolism enzymes, and suppressing oxidative stress and inflammation, PD-CSNPs being more efficient than PD, probably due to higher bioavailability and prolonged release.


Assuntos
Quitosana , Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/farmacologia , Fígado/efeitos dos fármacos , Nanopartículas/química , Estilbenos/farmacologia , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Glucose/metabolismo , Glucosídeos/uso terapêutico , Inflamação , Peroxidação de Lipídeos , Fígado/metabolismo , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Niacinamida , Estresse Oxidativo , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Estilbenos/uso terapêutico , Estreptozocina/toxicidade
15.
Nat Commun ; 12(1): 2368, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888696

RESUMO

Endothelial cells play a key role in the regulation of disease. Defective regulation of endothelial cell homeostasis may cause mesenchymal activation of other endothelial cells or neighboring cell types, and in both cases contributes to organ fibrosis. Regulatory control of endothelial cell homeostasis is not well studied. Diabetes accelerates renal fibrosis in mice lacking the endothelial glucocorticoid receptor (GR), compared to control mice. Hypercholesterolemia further enhances severe renal fibrosis. The fibrogenic phenotype in the kidneys of diabetic mice lacking endothelial GR is associated with aberrant cytokine and chemokine reprogramming, augmented Wnt signaling and suppression of fatty acid oxidation. Both neutralization of IL-6 and Wnt inhibition improve kidney fibrosis by mitigating mesenchymal transition. Conditioned media from endothelial cells from diabetic mice lacking endothelial GR stimulate Wnt signaling-dependent epithelial-to-mesenchymal transition in tubular epithelial cells from diabetic controls. These data demonstrate that endothelial GR is an essential antifibrotic molecule in diabetes.


Assuntos
Nefropatias Diabéticas/patologia , Endotélio/patologia , Hipercolesterolemia/complicações , Túbulos Renais/patologia , Receptores de Glucocorticoides/deficiência , Adrenalectomia , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Células Endoteliais/patologia , Endotélio/citologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Ácidos Graxos/metabolismo , Fibrose , Glucocorticoides/metabolismo , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/etiologia , Hipercolesterolemia/patologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Túbulos Renais/citologia , Masculino , Camundongos , Camundongos Knockout para ApoE , Oxirredução , Receptores de Glucocorticoides/genética , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética
16.
Nutrients ; 13(4)2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33920401

RESUMO

Diabetes is a disease with an inflammatory component that courses with an anemic state. Vanadium (V) is an antidiabetic agent that acts by stimulating insulin signaling. Hepcidin blocks the intestinal absorption of iron and the release of iron from its deposits. We aim to investigate the effect of V on hepcidin mRNA expression and its consequences on the hematological parameters in streptozotocin-induced diabetic Wistar rats. Control healthy rats, diabetic rats, and diabetic rats treated with 1 mgV/day were examined for five weeks. The mineral levels were measured in diet and serum samples. Hepcidin expression was quantified in liver samples. Inflammatory and hematological parameters were determined in serum or whole blood samples. The inflammatory status was higher in diabetic than in control rats, whereas the hematological parameters were lower in the diabetic rats than in the control rats. Hepcidin mRNA expression was significantly lower in the V-treated diabetic rats than in control and untreated diabetic rats. The inflammatory status remained at a similar level as the untreated diabetic group. However, the hematological profile improved after the V-treatment, reaching similar levels to those found in the control group. Serum iron level was higher in V-treated than in untreated diabetic rats. We conclude that V reduces gene expression of hepcidin in diabetic rats, improving the anemic state caused by diabetes.


Assuntos
Anemia/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Hepcidinas/genética , Hipoglicemiantes/administração & dosagem , Vanádio/administração & dosagem , Anemia/sangue , Anemia/diagnóstico , Anemia/etiologia , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Regulação da Expressão Gênica/efeitos dos fármacos , Hepcidinas/metabolismo , Humanos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Ferro/sangue , Ferro/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade
17.
Adv Exp Med Biol ; 1308: 273-281, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33861450

RESUMO

Crocin has been shown to have potent antioxidant properties, but its potential antioxidative effects on testicular tissue during uncontrolled diabetes is unknown. Wistar rats were randomly divided into four separate groups; normal, normal-treated, diabetic and diabetic treated (n = 6 per group). Diabetes was induced by a single intravenous injection of streptozotocin (45 mg/kg). Two treated groups of animals (diabetic and non-diabetic) received Crocin daily for 56 days (40 mg/kg/intraperitoneally). At the end of the 56th day, animals were sacrificed and blood and testicular tissue obtained. The level of nitrate, malondialdehyde, glutathione, and the activities of superoxide dismutase and catalase enzymes were determined. Crocin therapy moderated the increased oxidative stress in testicular tissue induced by diabetes with a significant reduction in nitrate and malondialdehyde, whilst reducing superoxide dismutase and catalase enzyme activities in diabetes (p < 0.001), though glutathione was unaffected. Treatment by Crocin in normal rats also modestly improved parameters of oxidative stress (p < 0.05). Crocin has a protective effect on diabetes induced oxidative stress in testicular tissue in an animal model, though it is unclear if this is a direct antioxidant effect.


Assuntos
Diabetes Mellitus Experimental , Animais , Antioxidantes/farmacologia , Carotenoides , Catalase/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Malondialdeído , Estresse Oxidativo , Ratos , Ratos Wistar , Estreptozocina/toxicidade , Superóxido Dismutase/metabolismo
18.
J Endocrinol ; 249(3): 163-175, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33764312

RESUMO

The ß-cell response to injury may be as critical for the development of diabetes as the specific insult. In the current study, we used streptozotocin (STZ) to injure the ß-cell in order to study the response with a focus on NFκB. MIN6 cells were exposed to STZ (0.5-8 mM, 0-24h) ±TNFα (100 ng/mL) and ±IκBß siRNA to lower the threshold to NFκB activation. Cell viability was determined by trypan blue exclusion. NFκB activation was determined by the expression of the target genes Nos2 and Cxcl10, localization of the NFκB proteins p65 and p50, and expression and localization of the NFκB inhibitors, IκBß and IκBα. There was no NFκB activation in MIN6 cell exposed to STZ (2 mM) alone. However, knocking down IκBß expression using siRNA resulted in STZ-induced expression of NFκB target genes and increased cell death, while co-incubation with STZ and TNFα enhanced cell death compared to either exposure alone. Adult male IκBß-/- and WT mice were exposed to STZ and monitored for diabetes. The IκBß-/- mice developed hyperglycemia and diabetes more frequently than controls following STZ exposure. Based on these results we conclude that STZ exposure alone does not induce NFκB activity. However, lowering the threshold to NFκB activation by co-incubation with TNFα or lowering IκBß levels by siRNA sensitizes the NFκB response to STZ and results in a higher likelihood of developing diabetes in vivo. Therefore, increasing the threshold to NFκB activation through stabilizing NFκB inhibitory proteins may prevent ß-cell injury and the development of diabetes.


Assuntos
Células Secretoras de Insulina/efeitos dos fármacos , NF-kappa B/metabolismo , Estreptozocina/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Diabetes Mellitus Experimental , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Células Secretoras de Insulina/metabolismo , Insulinoma/metabolismo , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
19.
Photochem Photobiol Sci ; 20(2): 293-301, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33721255

RESUMO

There is no effective treatment to halt peripheral nervous system damage in diabetic peripheral neuropathy. Mitochondria have been at the center of discussions as important factors in the development of neuropathy in diabetes. Photobiomodulation has been gaining clinical acceptance as it shows beneficial effects on a variety of nervous system disorders. In this study, the effects of photobiomodulation (904 nm, 45 mW, 6.23 J/cm2, 0.13 cm2, 60 ns pulsed time) on mitochondrial dynamics were evaluated in an adult male rat experimental model of streptozotocin-induced type 1 diabetes. Results presented here indicate that photobiomodulation could have an important role in preventing or reversing mitochondrial dynamics dysfunction in the course of peripheral nervous system damage in diabetic peripheral neuropathy. Photobiomodulation showed its effects on modulating the protein expression of mitofusin 2 and dynamin-related protein 1 in the sciatic nerve and in the dorsal root ganglia neurons of streptozotocin-induced type 1 diabetes in rats.


Assuntos
Gânglios Espinais/efeitos da radiação , Lasers Semicondutores , Dinâmica Mitocondrial/efeitos da radiação , Nervo Isquiático/efeitos da radiação , Animais , Glicemia/análise , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Gânglios Espinais/metabolismo , Masculino , Ratos , Ratos Wistar , Nervo Isquiático/metabolismo , Estreptozocina/toxicidade
20.
Psychopharmacology (Berl) ; 238(7): 1991-2009, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33774703

RESUMO

RATIONALE: Intracerebroventricular (ICV) streptozotocin (STZ) mimics sporadic Alzheimer's disease (SAD) characterized by tau pathology and neurodegeneration arising from oxidative stress, mitochondrial dysfunction, and insulin resistance. 7,8-Dihydroxyflavone (7,8-DHF) is a flavonoid having antioxidant property interlinked with mitochondrial functioning and insulin actions. OBJECTIVES: To evaluate the neuroprotective and cognitive enhancement properties of 7,8-DHF in an ICV-STZ rat model of SAD. METHODS: ICV-STZ (3 mg/kg) was injected into male Wistar rats. Cognitive functions were evaluated by Morris water maze (MWM) and novel object recognition (NOR). 7,8-DHF (5 mg/kg, 10 mg/kg, and 20 mg/kg) and rivastigmine (2 mg/kg) were given orally for 21 days. Reduced glutathione (GSH), catalase, superoxide dismutase (SOD), glutathione peroxidase (GPX), lipid peroxidation (LPO), protein carbonylation (PCO), and nitrite assays were performed. Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were determined. ELISA for the insulin-degrading enzyme (IDE) and p-tau was done. Histopathology was investigated by hematoxylin and eosin staining. RESULTS: 7,8-DHF treatment attenuated ICV-STZ-induced cognitive deficit in MWM and NOR. Moreover, in the cortex and hippocampus regions of the brain, GSH, catalase, SOD, GPX, LPO, PCO, and nitrite levels were reversed. Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were also normalized. IDE and p-tau protein were found to be significantly altered. 7,8-DHF provided protection from neuronal cell death examined in histopathology. CONCLUSIONS: Conclusively, 7,8-DHF was found to be neuroprotective in the ICV-STZ rat model by ameliorating oxidative stress, mitochondrial dysfunction, and insulin resistance, thereby improving cognitive functions evident with the behavioral results.


Assuntos
Doença de Alzheimer/metabolismo , Flavonas/uso terapêutico , Resistência à Insulina/fisiologia , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Estreptozocina/toxicidade , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Animais , Cognição/efeitos dos fármacos , Cognição/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Flavonas/farmacologia , Injeções Intravenosas , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
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