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1.
Eur J Med Chem ; 188: 111920, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901745

RESUMO

γ-Aminobutyric acid (GABA) uptake transporters are membrane transport proteins that are involved in the pathophysiology of a number of neurological disorders. Some types of chronic pain appear to result from the dysfunction of the GABAergic system. The deficiency of mouse GAT1 transporter (mGAT1) abolishes the nociceptive response, which means that mGAT1 inhibition is an appropriate medical approach to achieve analgesia. The mGAT4 transporter is the second most abundant GAT subtype in the brain; however, its physiological role has not yet been fully understood in the central nervous system. In this study, we examined whether the combination of mGAT1 and mGAT3/mGAT4 inhibition in a single molecule might lead to potentially synergistic effects improving analgesic activity to relieve neuropathic pain. To study this hypothesis, new GABA uptake inhibitors were designed, synthesized, and evaluated in terms of their activity and subtype selectivity for mGAT1-4. Among new functionalized amino acid derivatives of serine and GABA analogs, compounds with preferential mGAT3/4 inhibitory activity were discovered. Two selected hits (19b and 31c) were subjected to in vivo tests. We found a statistically significant antiallodynic activity in the von Frey test in diabetic and oxaliplatin-induced neuropathic pain model. The novel compounds (4-hydroxybutanoic, 4-hydroxypentanoic, and 4-aminobutanoic acid derivatives and serine analogs) provide new insights into the structure-activity relationship of mGAT3/mGAT4 inhibitors and indicate a new direction in the search for potential treatment of neuropathic pain of various origin.


Assuntos
Analgésicos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Analgésicos/síntese química , Analgésicos/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Proteínas da Membrana Plasmática de Transporte de GABA/química , Inibidores da Captação de GABA/síntese química , Inibidores da Captação de GABA/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuralgia/induzido quimicamente , Neuralgia/etiologia , Oxaliplatina , Ligação Proteica , Estreptozocina , Relação Estrutura-Atividade
2.
Food Chem Toxicol ; 135: 110953, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31707032

RESUMO

Edible Sonchus oleraceus Linn is a medicinal plant with many bioactivities such as anti-diabetic activity and anti-inflammatory activity. However, the main bioactive components such as polyphenols in S. oleraceus Linn are poorly absorbed in gastrointestinal tract and rapidly metabolized. Thereby, a self-emulsifying delivery system containing S. oleraceus Linn extracts (SSEDDS) was introduced to evade these problems. Herein, the anti-inflammatory effect of SSEDDS on streptozotocin-induced diabetic rats was investigated. The plasma glucose level was increased and plasma insulin level was decreased in diabetic rats. The levels of NF-κB, TNF-α, and IL-6 in the liver were significantly improved in diabetic rats (p < 0.05). Conversely, daily fed diabetic rats with 100, 200 and 400 mg/kg/day of SSEDS and 1 mg/kg/day metformin for 4 weeks, significantly (p < 0.05) restored all the above mentioned parameters to near normal levels. The immuno-histochemical studies confirmed the anti-inflammatory effects of SSEDDS.


Assuntos
Anti-Inflamatórios/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Emulsões/uso terapêutico , Extratos Vegetais/uso terapêutico , Sonchus/química , Animais , Glicemia/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Ratos Sprague-Dawley , Estreptozocina
3.
Food Chem Toxicol ; 135: 110965, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31743741

RESUMO

Perilla oil (PerO), a natural oil with a high unsaturated fatty acid content derived from the mature seeds of Perilla frutescens, is a homology of medicine and food. The type 2 diabetes mellitus (T2DM) model was successfully established using a high-fat and high-sugar diet combined with a single low-dose of streptozocin (STZ). PerO intervention reduced the levels of fasting blood glucose and the level, size and accumulation of lipid droplets, increased the insulin level and diminished the body weight loss. PerO pretreatment markedly promoted the serum levels of alanine transaminase (ALT) and aspartate transaminase alanine (AST) and inhibited the levels of glucose (GLU), glucose-6-phosphate dehydrogenase (G6PD), triglycerides (TGs) and total cholesterol (TC). Moreover, PerO treatment enhanced the expression of phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT) and activated the expression of glucose transporter 4 (Glut4) and phospho-AKT serine/threonine kinase (p-AS160) in the liver. Additionally, PerO treatment distinctly decreased the abundance of Aerococcus and facilitated the richness of Alloprevotella in the intestine, as well as accelerated the restoration of the gut microflora diversity. Thus, PerO regulates intestinal microbiota and alleviates insulin resistance through the PI3K/AKT signaling pathway in type-2 diabetic KKAy mice and may be a potential functional food for diabetic treatment.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Resistência à Insulina/fisiologia , Transdução de Sinais/efeitos dos fármacos , Ácido alfa-Linoleico/uso terapêutico , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/fisiopatologia , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Perilla/química , Fosfatidilinositol 3-Quinase/metabolismo , Óleos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estreptozocina
4.
Cell Physiol Biochem ; 53(6): 982-998, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31829530

RESUMO

BACKGROUND/AIMS: Diabetic cardiomyopathy (DCM) is characterized by structural and functional alterations that can lead to heart failure. Several mechanisms are known to be involved in the pathogenesis of DCM, however, the molecular mechanism that links inflammation to DCM is incompletely understood. To learn about this mechanism, we investigated the role of inflammatory serine proteases (ISPs) during the development of DCM. METHODS: Eight weeks old mice with deletion of dipeptidyl peptidase I (DPPI), an enzyme involved in the maturation of major ISPs, and wild type (WT) mice controls were injected with streptozotocin (50 mg/kg for 5 days intraperitoneally) and studied after 4, 8, 16, and 20 week after induction of type 1 diabetes mellitus (T1DM). Induction of diabetes was followed by echocardiographic measurements, glycemic and hemoglobulin A1c profiling, immunoblot, qPCR, enzyme activity assays, and immunohistochemistry (IHC) analysis of DPPI, ISPs, and inflammatory markers. Fibrosis was determined from left ventricular heart by Serius Red staining and qPCR. Apoptosis was determined by TUNEL assay and immunoblot analysis. RESULTS: In the diabetic WT mice, DPPI expression increased along with ISP activation, and DPPI accumulated abundantly in the left ventricle mainly from infiltrating neutrophils. In diabetic DPPI-knockout (DPPI-KO) mice, significantly decreased activation of ISPs, myocyte apoptosis, fibrosis, and cardiac function was improved compared to diabetic WT mice. In addition, DPPI-KO mice showed a decrease in overall inflammatory status mediated by diabetes induction which was manifested by decreased production of pro-inflammatory cytokines like TNF-α, IL-1ß and IL-6. CONCLUSION: This study elucidates a novel role of ISPs in potentiating the immunological responses that lead to the pathogenesis of DCM in T1DM. To the best of our knowledge, this is the first study to report that DPPI expression and activation promotes the inflammation that enhances myocyte apoptosis and contributes to the adverse cardiac remodeling that subsequently leads to DCM.


Assuntos
Catepsina C/metabolismo , Cardiomiopatias Diabéticas/patologia , Serina Proteases/metabolismo , Animais , Apoptose , Glicemia/análise , Catepsina C/genética , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/etiologia , Regulação para Baixo , Fibrose , Coração/fisiologia , Ventrículos do Coração/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/citologia , Neutrófilos/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo
5.
J Photochem Photobiol B ; 201: 111643, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31698218

RESUMO

Diabetes is a major emerging health consequence across the world which directly associated with the obesity. Contemporary anti-diabetic drugs have numeral limitations, and investigation of herbal remedies for diabetes give novel guide for the expansion of new drugs that can be used as harmonizing to present anti-diabetic allopathic medications. Gold nanoparticles (AuNPs) of 21 nm have been formerly well portrayed in vitro for their capability to intend active uptake in cell. Our present study was dealing with the synthesis of gold nanoparticles by means of Smilax glabra rhizome amend the anti-obesity constraints in high-fat diet by streptozotocin provoked obese diabetes in rat model. Characterization studies like UV -Spectroscopy, XRD analysis, SEM, TEM microscopy, Energy Dispersive X-Ray Spectroscopy, and FT-IR investigation confirms the availability of dimension, shape and size. Biochemical parameters like blood glucose and insulin sufferance and its release, lipid profile, aterogenic & coronary index, liver markers, inflammatory markers, hormones like leptin, resistin, adiponectin indicates the therapeutic effect of gold nanoparticles harvested from Smilax glabra on obese and diabetic rats. Histopathological examinations displayed the disturbed internal structures of obese and diabetic rats liver and heart tissues. Whereas, treatment with gold nanoparticles synthesized from Smilax glabra restored the internal membrane, nuclei and cytoplasm. All these findings confirmed the anti-obesity and anti-diabetic effect of synthesized gold nanoparticles from Smilax glabra.


Assuntos
Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica , Ouro/química , Nanopartículas Metálicas/química , Smilax/química , Animais , Glicemia/análise , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Coração/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Nanopartículas Metálicas/uso terapêutico , Nanopartículas Metálicas/toxicidade , Miocárdio/metabolismo , Miocárdio/patologia , Extratos Vegetais/química , Ratos , Ratos Wistar , Rizoma/química , Rizoma/metabolismo , Smilax/metabolismo , Estreptozocina/toxicidade
6.
Undersea Hyperb Med ; 46(5): 635-646, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31683362

RESUMO

We aimed to assess the effects of intermittent hyperbaric oxygenation (HBO2 at 2 bars for 120 minutes a day for four successive days) on acetylcholine-induced vasorelaxation (AChIR) in female Sprague-Dawley (SD) rats (N=80) that were randomized into four groups: healthy controls (CTR); diabetic rats (DM); and control and diabetic rats that underwent hyperbaric oxygenation (CTR+HBO and DM+HBO), respectively. AChIR was measured in vitro in aortic rings, with/without L-NAME, MS-PPOH, HET0016 or indomethacin. mRNA expression of eNOS, iNOS, COX-1, COX-2, thromboxane A synthase 1 (TBXAS1), CYP4A1, CYP4A3 and CYP2J3 was assessed by qPCR. Systemic oxidative stress and plasma antioxidative capacity were determined with the thiobarbituric acid-reactive substances (TBARS) and the ferric reducing ability of plasma (FRAP) assays, respectively. There was no significant difference in AChIR among experimental groups of rats. In CTR and DM group of rats, AChIR was mediated by NO and EETs pathway, while in the CTR+HBO and DM+HBO groups, NO-pathway prevailed. iNOS expression was upregulated in the DM group compared to CTR, while HBO2 upregulated eNOS in CTR group and TBXAS1 in DM group of rats. In both, CTR and DM group of rats, the sensitivity to ACh in the presence of L-NAME or in the presence of MSPPOH was significantly decreased compared to the response to ACh in the absence or presence of indomethacin or HET0016. DM and DM+HBO rats had increased TBARS compared to their respective controls. In conclusion, HBO2 presumably alters vasorelaxation in response to ACh from NO-EETs mediated pathways to solely NO-pathway, without affecting oxidative status of DM rats.


Assuntos
Acetilcolina/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Oxigenação Hiperbárica , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Análise de Variância , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Glicemia/análise , Peso Corporal , Sistema Enzimático do Citocromo P-450/fisiologia , Primers do DNA , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Oxigenação Hiperbárica/métodos , Estresse Oxidativo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina , Fatores de Tempo , Vasodilatação/fisiologia
7.
Chem Biodivers ; 16(12): e1900514, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31609067

RESUMO

Coreopsis tinctoria capitula (CTC) of the Compositae family has been used traditionally to treat various diseases in China, particularly type 2 diabetes mellitus (T2DM). This study evaluated the anti-lipid peroxidation, α-glucosidase and α-amylase inhibitory effects of CTC extracts, and analyzed its chemical composition by HPLC. Moreover, the antioxidant activity and protection effects of CTC extracts were investigated on high-fat/high-sugar and streptozotocin-induced T2DM mice. In vitro study, the ethyl acetate extract (EAE) and butanol extract (BE) of CTC exhibited anti-lipid peroxidation (IC50 : BHA>BE or EAE>ascorbic acid, p<0.05) and α-glucosidase inhibitory activity (IC50 : BE>EAE, p<0.05). In vivo, the BE at the dose of 600 mg/kg was intragastrically given to T2DM mice, which exhibited a certain extent of repair and improvement of the levels of CAT, GSH, GSH-PX , SOD, as well as plasma biomarkers, compared with those in the model group (p<0.05). These results demonstrated that CTC extracts have a positive effect to treat T2DM and it can be used for the treatment of T2DM in the future.


Assuntos
Coreopsis/química , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica , Extratos Vegetais/química , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/química , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Biomarcadores/sangue , Coreopsis/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/prevenção & controle , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Flores/química , Flores/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Estreptozocina/toxicidade , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo
8.
Chem Biodivers ; 16(12): e1900405, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31566891

RESUMO

The purpose of this study was to examine the neuroprotective effects of caffeic acid hexyl (CAF6) and dodecyl (CAF12) amide derivatives on the early stage of retinopathy in streptozotocin-induced diabetic rats. Animals were divided in five groups (n=8/group); one group consisted of non-diabetic rats as control, while the other four were diabetic animals either non-treated or treated with CAF6, CAF12 or resveratrol intravitreally for four weeks. Retinal superoxide dismutase (SOD) activity and 8-iso-prostaglandin F2α (iPF2α ) levels were evaluated by an ELISA assay. Phosphorylation of ERK1/2 and AKT was determined by immunoblotting in retinal homogenates. Retinal morphology was also examined using light microscopy. Treatment with CAF6 and CAF12 increased retinal SOD activity, while it decreased iPF2α levels in diabetic rats. Phosphorylation of ERK1/2 was increased, while AKT phosphorylation was decreased in diabetic rats compared to normal control and these alterations were significantly reversed in diabetic rats treated with CAF6 and CAF12. Furthermore, thickness of the whole retinal layer, outer nuclear layer, and ganglion cell count were decreased in diabetic rats compared to control and CAF6 and CAF12 treatments prevented these changes. CAF6 and CAF12 seem to be effective agents for treatment of diabetic retinopathy via attenuation of retinal oxidative stress and improvement of neuronal survival signaling.


Assuntos
Ácidos Cafeicos/química , Retinopatia Diabética/patologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/etiologia , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Retina/metabolismo , Retina/patologia , Superóxido Dismutase/metabolismo
9.
Vasc Health Risk Manag ; 15: 419-427, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632046

RESUMO

Introduction: The increasing blood glucose level due to insulin resistance which occurs in diabetes mellitus (DM) may cause vascular damage. This study aims to prove the effect of the polysaccharide peptide (PsP) Ganoderma lucidum on improving vascular damage through an increase of circulating endothelial cells and circulating endothelial cells (CEC) ratio, decreased H2O2, triglyceride (TG), total cholesterol (TC) and insulin resistance in type 2 DM. Methods: Our study is a true experimental study with randomized posttest control group design that used 35 Wistar rats divided into five groups: normal, control (+) and three groups of different variant PsP doses 50, 150 and 300 mg/kg BW (n=7). Results: By using one-way ANOVA and post-hoc Duncan test, the results show a significant increase of endothelial progenitor cell (EPC) concentration (p=0.000) and ratio EPC:CEC (0.000) by dose-dependent fashion and also reduced CEC concentration (p=0.001), H2O2 (p=0.03), TG (p=0.001), TC (p=0.01) and insulin resistance (p=0.003). Conclusion: In this study, PsP induced endothelial repairing process and reduced the risk factor with 300 mg/kg BW as optimum dose. However, further research on EPC and CEC detection markers is important. Further research on PsP and clinical trial for commercial uses is also needed.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Células Endoteliais/efeitos dos fármacos , Proteoglicanas/farmacologia , Reishi , Remodelação Vascular/efeitos dos fármacos , Animais , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/induzido quimicamente , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/induzido quimicamente , Angiopatias Diabéticas/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Peróxido de Hidrogênio/sangue , Resistência à Insulina , Lipídeos/sangue , Proteoglicanas/isolamento & purificação , Ratos Wistar , Reishi/química , Estreptozocina
10.
An Acad Bras Cienc ; 91(3): e20181330, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31508665

RESUMO

Type 1 diabetes (T1D) is the result of the selective destruction of the pancreatic ß-cells by T cells of the immune system. Although spleen is a secondary lymphoid organ, it is also involved in the T1D pathogenesis. However, the alterations in a variety of cellular processes of this disease need to be further understood. We aimed to analyze the benefits of resveratrol, and its complexed form on diabetic complications in the spleen of rats. To this end, we investigated important enzymes of phosphoryl transfer network, and Na+, K+-ATPase activity. Wistar rats were divided into non-diabetic groups: Control, Ethanol, Resveratrol, Hydroxypropyl-ß-cyclodextrin, Resveratrol-hydroxypropyl-ß-cyclodextrin, and diabetic groups with the same treatments. Diabetes was induced by a single dose of 60 mg/kg of streptozocin intraperitoneally, and treatments by intragastric gavage once daily for 60 days. Hyperglycemia reduced creatine kinase activity, which was reversed by the administration of resveratrol. Na+, K+-ATPase activity was greatly affected, but it was reversed by resveratrol and resveratrol-hydroxypropyl-ß-cyclodextrin. This suggest an energetic imbalance in the spleen of diabetic rats, and in case this also occurs in the diabetic patients, it is possible that resveratrol supplementation could be beneficial to the better functioning of the spleen in diabetic patients.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Antioxidantes/farmacologia , Diabetes Mellitus Experimental/metabolismo , Resveratrol/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Baço/metabolismo , Animais , Antioxidantes/metabolismo , Glicemia/análise , Peso Corporal , Creatina Quinase/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Metabolismo Energético/efeitos dos fármacos , Hiperglicemia/metabolismo , Masculino , Tamanho do Órgão , Ratos , Ratos Wistar , Estreptozocina
11.
Drug Deliv ; 26(1): 849-859, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31524015

RESUMO

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


Assuntos
Biomarcadores/metabolismo , Carotenoides/administração & dosagem , Carotenoides/química , Nefropatias Diabéticas/tratamento farmacológico , Inflamação/tratamento farmacológico , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia
12.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514311

RESUMO

Hypogonadism and oxidative stress are occurring commonly in men with diabetes and associated male infertility. This study aimed to investigate the capability of anti-oxidative and anti-inflammatory properties of fucoxanthin as well as to evaluate its protective effects on male reproduction in diabetic rats. The RAW 264.7 macrophage cells were used to evaluate the anti-oxidative and anti-inflammatory activity. Thirty male Sprague-Dawley rats were induced by streptozotocin-nicotinamide for a diabetes model and fed either with three different doses of fucoxanthin (13, 26, and 65 mg/kg) or rosiglitazone (0.571 mg/kg) for four weeks. The fucoxanthin significantly inhibited nitric oxide production and reduced reactive oxygen species level in lipopolysaccharide-induced RAW 264.7 cells. In the animal study, fucoxanthin administration improved insulin resistance, restored sperm motility, decreased abnormal sperm number, and inhibited lipid peroxidation. Moreover, it restored GPR54 and SOCS-3 mRNA expression in the hypothalamus and recovered luteinizing hormone level, as well as the testosterone level. In conclusion, fucoxanthin not only possessed antioxidant and anti-inflammatory properties but also decreased the diabetes signs and symptoms as well as improved spermatogenesis and male reproductive function.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Feófitas/química , Reprodução/efeitos dos fármacos , Xantofilas/uso terapêutico , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Insulina/sangue , Resistência à Insulina , Kisspeptinas/genética , Kisspeptinas/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Niacinamida , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptores de Kisspeptina-1/genética , Receptores de Kisspeptina-1/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Estreptozocina , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Testículo/efeitos dos fármacos , Testículo/patologia , Xantofilas/farmacologia
13.
Folia Histochem Cytobiol ; 57(3): 127-138, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31489604

RESUMO

INTRODUCTION: Diabetes mellitus (DM) is a serious, chronic metabolic disorder commonly complicated by diabetic foot ulcers with delayed healing. Metformin was found to have a wound healing effect through several mechanisms. The current study investigated the effect of both bone marrow-derived mesenchymal stem cells (BM-MSCs) and metformin, considered alone or combined, on the healing of an experimentally induced cutaneous wound injury in streptozotocin-induced diabetic rats. MATERIAL AND METHODS: Forty adult male albino rats were used. Diabetes was induced by single intravenous (IV) injection of streptozotocin (STZ). Next, two circular full thickness skin wounds were created on the back of the animals, then randomly assigned into 4 groups, ten rats each. BM-MSCs were isolated from albino rats, 8 weeks of age and labeled by PKH26 before intradermal injection into rats of Group III and IV. Groups I (diabetic positive control), II (metformin-treated, 250 mg/kg/d), III (treated with 2×106 BM-MSCs), and IV (wounded rats treated both with metformin and BM-MSCs cells). Healing was assessed 3, 7, 14, and 21 days post wound induction through frequent measuring of wound diameters. Skin biopsies were obtained at the end of the experiment. RESULTS: Gross evaluation of the physical healing of the wounds was done. Skin biopsies from the wound areas were processed for hematoxylin and eosin (H&E), Masson's trichrome staining and immunohistochemical staining for CD31. The results showed better wound healing in the combined therapy group (IV) as compared to monotherapy groups. CONCLUSIONS: Although both metformin and BM-MSCs were effective in the healing of experimentally induced skin wounds in diabetic rats, the combination of both agents appears to be a better synergistic option for the treatment of diabetic wound injuries.


Assuntos
Transplante de Células-Tronco Mesenquimais , Metformina/uso terapêutico , Cicatrização/efeitos dos fármacos , Ferimentos Penetrantes/tratamento farmacológico , Ferimentos Penetrantes/terapia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Masculino , Células-Tronco Mesenquimais/citologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos , Pele/lesões , Pele/patologia , Lesões dos Tecidos Moles/tratamento farmacológico , Lesões dos Tecidos Moles/terapia , Estreptozocina
14.
Molecules ; 24(16)2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430978

RESUMO

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


Assuntos
Brassicaceae/química , Neuropatias Diabéticas/complicações , Glucose/análogos & derivados , Imidoésteres/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Glucose/farmacologia , Glucosinolatos/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sementes/química , Estreptozocina/farmacologia
15.
DNA Cell Biol ; 38(10): 1134-1142, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433203

RESUMO

Diabetes mellitus is a complicated metabolic disease characterized by hyperglycemia. Diabetic nephropathy (DN) is a progressive kidney disease, which results in mortality in diabetic patients. The present study was designed to investigate the effect of applying spironolactone (S), captopril (C), and their combination (S+C) on some renal performance indices and microRNAs' (miRNAs) expression. A total of 35 two-month-old male Wistar rats were provided for the study. Intraperitoneal injection of freshly dissolved streptozotocin (60 mg/kg) in cold citrate buffer was used to induce diabetes. Blood samples were examined through calorimetry to assess serum concentrations of glucose, blood urea nitrogen (BUN), and creatinine. To measure the microalbuminuria and transforming growth factor-ß (TGF-ß) levels and to evaluate the miRNAs expression levels of the kidney tissue, the ELISA method and the real-time PCR were used. The obtained results serve as in vivo evidence for the positive relationship between miR-192 and TGF-ß levels in the DN rats. A significant increase and decrease were found for miR-29a/b/c and the miR-192 expression of DN after treatment with S, C, and S+C. TGF-ß levels and microalbuminuria of diabetic rats also increased. The results obtained from this research study suggest that S, C, and S + C can improve DN by targeting miR-192 and miR-29 family and changing their expression. These findings suggest that miR-192 and miRs-29a/b/c can be potential targets for DN remediation.


Assuntos
Captopril/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Espironolactona/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Diuréticos/farmacologia , Combinação de Medicamentos , Reposicionamento de Medicamentos , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Hiperglicemia/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
16.
J Diabetes Res ; 2019: 2813489, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467926

RESUMO

While the autoimmune character of T1D (type 1 diabetes) is being challenged, it is currently recognized that inflammation plays a key role in its development. We hypothesized that glucotoxicity could contribute to ß-cell mass destruction through participation in islet inflammation. We evaluated the potential of empagliflozin (EMPA) and GABA (gamma-aminobutyric acid) to protect ß-cell mass against glucotoxicity and to increase ß-cell mass after diagnosis of T1D. Empagliflozin is a SGLT2 (sodium-dependent glucose cotransporter) inhibitor which thereby blocks glucose recapture by the kidney and promotes glucose excretion in urine. GABA is an inhibitory neurotransmitter, which stimulates α-to-ß cell transdifferentiation. In streptozotocin-treated mice, empagliflozin and/or GABA were delivered for a period of five days or three weeks. As compared to untreated T1D mice, EMPA-treated T1D mice had decreased FFA (free fatty acid) levels and improved glucose homeostasis. EMPA-treated T1D mice had higher islet density, with preserved architecture, compared to T1D mice, and EMPA-treated T1D mice also differed from T1D mice by the total absence of immune cell infiltration within islets. Islets from EMPA-treated mice were also less subjected to ER (endoplasmic reticulum) stress and inflammation, as shown by qPCR analysis. Glucose homeostasis parameters and islet area/pancreas area ratio improved, as compared to diabetic controls, when T1D mice were treated for three weeks with GABA and EMPA. T1D EMPA+GABA mice had higher glucagon levels than T1D mice, without modifications of glucagon area/islet area ratios. In conclusion, empagliflozin and GABA, used in monotherapy in streptozotocin-induced diabetic mice, have positive effects on ß-cell mass preservation or proliferation through an indirect effect on islet cell inflammation and ER stress. Further research is mandatory to evaluate whether empagliflozin and GABA may be a potential therapeutic target for the protection of ß-cell mass after new-onset T1D.


Assuntos
Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Glucosídeos/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia , Animais , Compostos Benzidrílicos/administração & dosagem , Glicemia/metabolismo , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Esquema de Medicação , Quimioterapia Combinada , Intervenção Médica Precoce , Teste de Tolerância a Glucose , Glucosídeos/administração & dosagem , Injeções Intraperitoneais , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/fisiologia , Masculino , Camundongos , Estreptozocina , Fatores de Tempo , Ácido gama-Aminobutírico/administração & dosagem
17.
J Diabetes Res ; 2019: 5451038, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467927

RESUMO

Aims: Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. Materials and Methods: We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. Results: GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. Conclusion: Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.


Assuntos
Metabolismo dos Carboidratos/genética , Proteínas de Ligação a DNA/fisiologia , Glucose/metabolismo , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/fisiologia , Histona Desmetilases com o Domínio Jumonji/fisiologia , Animais , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Homeostase/genética , Resistência à Insulina/genética , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Estreptozocina
18.
Int J Mol Sci ; 20(16)2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31443143

RESUMO

Rehmanniae Radix Praeparata (RR, named as Shudihuang in traditional Chinese medicine), the steamed roots of Rehmannia glutinosa Libosch (Scrophulariaceae), has been demonstrated to have anti-diabetic and anti-osteoporotic activities. This study aimed to explore the protective effect and underlying mechanism of RR on diabetes-induced bone loss. It was found that RR regulated the alkaline phosphatase activity and osteocalcin level, enhanced bone mineral density, and improved the bone microarchitecture in diabetic rats. The catalpol (CAT), acteoside (ACT), and echinacoside (ECH) from RR increased the proliferation and differentiation of osteoblastic MC3T3-E1 cells injured by high glucose and promoted the production of IGF-1 and expression of related proteins in BMP and IGF-1/PI3K/mammalian target of rapamycin complex 1 (mTOR) signaling pathways. The verifying tests of inhibitors of BMP pathway (noggin) and IGF-1/PI3K/mTOR pathway (picropodophyllin) and molecular docking of IGF-1R further indicated that CAT, ACT, and ECH extracted from RR enhanced bone formation by regulating IGF-1/PI3K/mTOR signaling pathways. These findings suggest that RR may prove to be a promising candidate drug for the prevention and treatment of diabetes-induced osteoporosis.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/uso terapêutico , Rehmannia/química , Serina-Treonina Quinases TOR/metabolismo , Animais , Western Blotting , Densidade Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Diabetes Mellitus Experimental/induzido quimicamente , Feminino , Fator de Crescimento Insulin-Like I/genética , Masculino , Simulação de Acoplamento Molecular , Osteocalcina/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Fosfatidilinositol 3-Quinases/genética , Extratos Vegetais/química , Ratos , Ratos Wistar , Estreptozocina/toxicidade , Serina-Treonina Quinases TOR/genética , Microtomografia por Raio-X
19.
J Mater Sci Mater Med ; 30(8): 93, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31392433

RESUMO

To enhance the bioavailability of protein therapeutants and improve the stability of storage and delivery, a series of branched amphiphilic block copolymers consisting of cholic acid (CA) initiated poly(D,L-lactide-co-glycolide) (CA-PLGA) and water-soluble polyethyleneimine cross-linked polyethylene glycol (PEI-PEG) denoted as CA-PLGA-b-(PEI-PEG) were synthesized and characterized. CA-PLGA-b-(PEI-PEG) presented low cytotoxicity by MTT and cck-8 assay. The cationic CA-PLGA-b-(PEI-PEG) micelles (diameter about 100 nm and zeta potential 34-61 mV) were prepared through self-assembly method, and complexed with insulin via electrostatic interaction to obtain nanoscale micelle/insulin complexes. The micelle/insulin complexes-loaded CA-PLGA microspheres (MIC-MS, 10.4 ± 3.85 µm) were manufactured by employing a double emulsion (W1/O/W2) method. The in vitro insulin release behavior and in vivo hypoglycaemic effect of MIC-MS on streptozotocin (STZ) induced diabetic rats were compared with those of the insulin-loaded CA-PLGA microspheres (INS-MS, 7.8 ± 2.57 µm). The initial burst in vitro release of MIC-MS was markedly lower than that of INS-MS (P < 0.01), and the pharmacological availability of MIC-MS via subcutaneous administration was 148.9% relative to INS-MS. Therefore, the cationic CA-PLGA-b-(PEI-PEG) micelles can effectively increase the bioavailability of insulin in CA-PLGA microspheres and can be considered as a potential protein carrier.


Assuntos
Portadores de Fármacos , Microesferas , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Poliglactina 910/química , Animais , Cátions , Células Cultivadas , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Humanos , Células MCF-7 , Masculino , Micelas , Nanopartículas/química , Tamanho da Partícula , Polietilenoglicóis/síntese química , Polietilenoimina/síntese química , Polietilenoimina/química , Ácido Poliglicólico/química , Polímeros/síntese química , Polímeros/química , Ratos , Ratos Sprague-Dawley , Estreptozocina
20.
Orv Hetil ; 160(32): 1270-1278, 2019 Aug.
Artigo em Húngaro | MEDLINE | ID: mdl-31387373

RESUMO

Introduction: During recent decades, the perinatal mortality of extremely low-birth weight infants has decreased. An important task is to recognize complications of prematurity. Aim: We made an attempt to explore the relationship between complications of prematurity and neonatal hyperglycemia. Method: From 1 January 2014 to 31 December 2017, 188 infants with birth weight below 1000 g were admitted. For each infant, the frequencies of hyperglycemia (blood glucose >8.5 mmol/l), retinopathy of prematurity, intraventricular hemorrhage, and bronchopulmonary dysplasia were determined. Animal studies were performed in Sprague Dawley rats. Hyperglycemia was achieved by intraperitoneal injection of streptozotocin (100 mg/kg). On the 7th day of life, aorta sections were prepared and stained with hematoxylin eosin. Wall thickness was measured using QCapture Pro 7 image analysis software. Results: The mean ± SD gestational age and birth weight were 27.1 ± 2.2 weeks and 814.9 ± 151.9 g; 33 infants (17.5%) died. Hyperglycemia was confirmed in 62 cases (32.9%), and insulin treatment was given to 43 infants (22.8%). The gestational age and birth weight of the hyperglycemic infants were significantly lower (p<0.001), the incidence of severe retinopathy (p = 0.012) and the mortality of insulin-treated patients were higher (p = 0.02) than in normoglycemic infants. Among survivors (n = 155), we found by logistic regression analysis that hyperglycemia was a risk factor for severe retinopathy (p<0.001). In the rat model, neonatal hyperglycemia caused significant thickening of the aortic wall. Conclusion: Our studies indicate that hyperglycemia is common in extremely low birth-weight infants. Monitoring of these infants for retinopathy of prematurity, kidney dysfunction, and hypertension is recommended. Orv Hetil. 2019; 160(32): 1270-1278.


Assuntos
Diabetes Mellitus Experimental , Hiperglicemia , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Doenças do Prematuro , Retinopatia da Prematuridade/etiologia , Animais , Peso ao Nascer , Displasia Broncopulmonar/epidemiologia , Hemorragia Cerebral Intraventricular/epidemiologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Gravidez , Ratos , Ratos Sprague-Dawley , Retinopatia da Prematuridade/epidemiologia
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