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1.
Int J Nanomedicine ; 15: 4393-4405, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606684

RESUMO

Aim: The effects of polyamidoamine (PAMAM) dendrimers on the mammalian heart are not completely understood. In this study, we have investigated the effects of a sixth-generation cationic dendrimer (G6 PAMAM) on cardiac function in control and diabetic rat hearts following ischemia-reperfusion (I/R) injury. Methods: Isolated hearts from healthy non-diabetic (Ctr) male Wistar rats were subjected to ischemia and reperfusion (I/R). LV contractility and hemodynamics data were computed digitally whereas cardiac damage following I/R injury was assessed by measuring cardiac enzymes. For ex vivo acute exposure experiments, G6 PAMAM was administered during the first 10 mins of reperfusion in Ctr animals. In chronic in vivo studies, nondiabetic rats (Ctr) received either vehicle or daily i.p. injections of G6 PAMAM (40 mg/kg) for 4 weeks. Diabetic (D) animals received either vehicle or daily i.p. injections of G6 PAMAM (10, 20 or 40 mg/kg) for 4 weeks. The impact of G6 PAMAM on pacing-postconditioning (PPC) was also studied in Ctr and D rats. Results: In ex vivo studies, acute administration of G6 PAMAM to isolated Ctr hearts during reperfusion dose-dependently impaired recovery of cardiac hemodynamics and vascular dynamics parameters following I/R injury. Chronic daily i.p. injections of G6 PAMAM significantly (P<0.01) impaired recovery of cardiac function following I/R injury in nondiabetic animals but this was not generally observed in diabetic animals except for CF which was impaired by about 50%. G6 PAMAM treatment completely blocked the protective effects of PPC in the Ctr animals. Conclusion: Acute ex vivo or chronic in vivo treatment with naked G6 PAMAM dendrimer can significantly compromise recovery of non-diabetic hearts from I/R injury and can further negate the beneficial effects of PPC. Our findings are therefore extremely important in the nanotoxicological evaluation of G6 PAMAM dendrimers for potential clinical applications in physiological and pathological settings.


Assuntos
Dendrímeros/toxicidade , Coração/fisiopatologia , Mamíferos/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nanopartículas/toxicidade , Poliaminas/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Pós-Condicionamento Isquêmico , Masculino , Contração Miocárdica/efeitos dos fármacos , Miocárdio/enzimologia , Ratos Wistar
2.
Braz J Med Biol Res ; 53(7): e8763, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520205

RESUMO

Upper limb performance is affected by diabetes mellitus (DM). Neuromuscular junction (NMJ) is a key structure to understand the relationship between performance and morphology in DM. The aim of the study was to analyze NMJ plasticity due to DM in an animal model and its relationship with the function of forelimbs in rats. Twelve Wistar rats were divided into control (C) and DM groups. Animals were trained to perform a grasping task, following procedures of habituation, shaping, and reaching task. DM was induced using streptozotocin. Forelimb neuromuscular performance for dexterity was evaluated one day before DM induction and five weeks following induction. After that, biceps, triceps, and finger flexors and extensors were removed. Connective tissue and muscle fiber cross-sectional area (CSA) were measured. NMJ was assessed by its morphometric characteristics (area, perimeter, and maximum diameter), using ImageJ software. Motor performance analyses were made using single pellet retrieval task performance test. Student's t-test was used for comparisons between groups. A significant decrease in all NMJ morphometric parameters was observed in the DM group compared with the C group. Results showed that DM generated NMJ retraction in muscles involved in a reaching task. These alterations are related to signs of muscular atrophy and to poor reaching task performance. In conclusion, induced DM caused NMJ retraction and muscular atrophy in muscles involved in reaching task performance. Induced DM caused significantly lower motor performance, especially in the final moments of evaluation, when DM compromised the tropism of the muscular tissue.


Assuntos
Adaptação Fisiológica/fisiologia , Diabetes Mellitus Experimental/patologia , Junção Neuromuscular/patologia , Análise e Desempenho de Tarefas , Animais , Diabetes Mellitus Experimental/fisiopatologia , Masculino , Camundongos , Junção Neuromuscular/fisiopatologia , Ratos , Ratos Wistar
3.
Invest Ophthalmol Vis Sci ; 61(5): 36, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32437549

RESUMO

Purpose: Retinal vasomotor activity can be regulated by two major endothelial enzymes, nitric oxide synthase (NOS) and cyclooxygenase (COX). The vascular arginase also consumes a NOS substrate and thus impedes NOS-mediated vasodilation. Diabetes mellitus exhibits vascular complications in the retina with elevated oxidative stress and compromised NOS-mediated vasodilation. However, the underlying molecular mechanisms remain unclear, and the effect of diabetes on COX-mediated vasodilation is unknown. Herein, we examined the relative impact of diabetes on retinal arteriolar dilations to COX and NOS activation and the roles of arginase and superoxide in diabetes-induced vasomotor dysfunction. Methods: Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2 weeks of hyperglycemia, 433 ± 27 mg/dL) or age-matched control pigs (97 ± 4 mg/dL). The vasodilations to bradykinin (NOS activator) and histamine (NOS/COX activator) were examined in vitro. Results: Retinal arteriolar dilations to histamine and bradykinin were significantly reduced after 2 weeks of diabetes. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) attenuated the dilations of control vessels, but not diabetic vessels, to histamine. In the presence of L-NAME and COX inhibitor indomethacin, histamine-induced dilations of control and diabetic vessels were reduced similarly. Treatment of diabetic vessels with arginase inhibitor nor-NOHA, but not superoxide dismutase mimetic TEMPOL, preserved both histamine- and bradykinin-induced dilations in an L-NAME-sensitive manner. Conclusions: Arginase, rather than superoxide, impairs endothelium-dependent NOS-mediated dilation of retinal arterioles during diabetes, whereas vasodilation mediated by COX remains intact. Blockade of vascular arginase may improve endothelial function of retinal arterioles during early onset of diabetes.


Assuntos
Arginase/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Endotélio Vascular/enzimologia , Óxido Nítrico Sintase Tipo III/metabolismo , Artéria Retiniana/fisiologia , Vasodilatação/fisiologia , Animais , Arteríolas/fisiologia , Glicemia/metabolismo , Bradicinina/farmacologia , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 1/enzimologia , Inibidores Enzimáticos/farmacologia , Histamina/farmacologia , Hiperglicemia/fisiopatologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Sus scrofa
4.
Life Sci ; 256: 117855, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32473245

RESUMO

OBJECTIVE: Subjects with type 2 diabetes (T2D) have lower circulating hydrogen sulfide (H2S) levels following myocardial ischemia and a higher risk of mortality. The aim of this study was to determine the dose-dependent favorable effects of sodium hydrosulfide (NaSH) on myocardial ischemia-reperfusion (IR) injury in rats with T2D. METHODS: T2D was induced using a high-fat diet (HFD) and low-dose of streptozotocin. Rats were divided into control, T2D, and T2D + NaSH groups. NaSH (0.28, 0.56, 1.6, 2.8, and 5.6 mg/kg) was administered intraperitoneally for 9 weeks. At the end of the study, heart from all rats were isolated and left ventricular developed pressure (LVDP) and the peak rates of positive and negative changes in LV pressure (±dp/dt) were recorded during baseline and following myocardial IR injury. In addition, infarct size as well as mRNA expression of H2S- and nitric oxide (NO)-producing enzymes were measured. RESULTS: In diabetic rats, NaSH only at doses of 0.56 and 1.6 mg/kg increased recovery of LVDP (16% and 42%), +dp/dt (25% and 35%) and -dp/dt (23% and 32%) as well as decreased infarct size (44% and 35%). At these doses, NaSH increased expressions of cystathionine γ-lyase (CSE) (440% and 271%) and endothelial NO synthase (eNOS) (232% and 148%) but it decreased the expressions of inducible NOS (iNOS) (55% and 71%). NaSH at 0.28, 2.8 and 5.6 mg/kg had no significant effects on these parameters. CONCLUSION: NaSH had a bell-shaped cardioprotective effect against myocardial IR injury in rats with T2D. Higher tolerance to IR injury in heart isolated from type 2 diabetic rats treated with intermediate doses of NaSH is associated with higher CSE-derived H2S and eNOS-derived NO as well as lower iNOS-derived NO.


Assuntos
Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Sulfetos/farmacologia , Animais , Cardiotônicos/administração & dosagem , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Dieta Hiperlipídica , Relação Dose-Resposta a Droga , Sulfeto de Hidrogênio/metabolismo , Masculino , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/complicações , Ratos , Ratos Wistar , Estreptozocina , Sulfetos/administração & dosagem
5.
Life Sci ; 255: 117724, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32360624

RESUMO

AIMS: Type 1 diabetes (T1D) is the most common autoimmune disease that affects a global scale. Accumulating evidence has indicated, nuclear factor kappa B (NF-κB) and some microRNAs (miRNAs) as important biomarkers participating in the development of T1D. Thus, we aimed to determine the role of NF-κB and miR-150 in the development of T1D and to unravel the molecular mechanism. MAIN METHODS: Non-obese diabetic mice were used for the T1D model establishment by injecting with streptozotocin. Besides, pancreatic islet ß cells, separated from T1D mice, were induced by interferon-γ and tumor necrosis factor-α for 3 days to mimic T1D damage. The expression of NF-κB p65, miR-150, and p53 up-regulated modulator of apoptosis (PUMA) was evaluated by RT-qPCR, while the expression of PUMA, p65, and apoptotic proteins in pancreatic islet ß cells were determined by western blot analysis. Besides, inflammatory factors IL-17A, IL-2, IFN-γ, and IL-4 were detected by ELISA. The relationship among NF-κB, miR-150, and PUMA was analyzed by the dual-luciferase reporter gene, chromatin- and RNA-immunoprecipitation assays, respectively. KEY FINDINGS: Restoration of NF-κB reduced the incidence of T1D in mice. Over-expressed NF-κB inhibited the release of inflammatory factors and apoptosis in pancreatic islet ß cells. PUMA was confirmed to be a potential target gene of miR-150. miR-150 suppressed PUMA to inhibit the T1D-induced inflammation and ß cell apoptosis whereas NF-κB activated the miR-150 expression by binding to the miR-150 promoter, thereby preventing the T1D-induced inflammation and ß cell apoptosis. SIGNIFICANCE: NF-κB/miR-150/PUMA may serve as potential therapeutic targets for T1D.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , MicroRNAs/genética , NF-kappa B/genética , Proteínas Supressoras de Tumor/genética , Animais , Apoptose/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/genética , Inflamação/genética , Inflamação/patologia , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Endogâmicos NOD , Regulação para Cima
6.
Life Sci ; 255: 117758, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32407845

RESUMO

AIMS: NLR family pyrin domain containing 3 (NLRP3) inflammasome activation contributes to the development of diabetic cardiovascular complications. CD38 regulates vascular inflammation through cyclic ADP-ribose (cADPR)-mediated Ca2+ signaling in vascular smooth muscle cells (VSMCs). Ca2+ mobilization may modulate inflammasome activation by impacting mitochondrial function. However, it remains unclear whether CD38 regulates NLRP3 inflammasome activation in VSMCs through cADPR-dependent Ca2+ release under diabetic condition. Main methods and key findings: In VSMCs, we observed that high glucose (HG, 30 mM) enhanced CD38 protein expression and ADP ribosyl cyclase activity. Moreover, along with less abundance of NLRP3, apoptosis-associated speck-like protein containing CARD (ASC) and their colocalization, the expression of active caspase-1(p20) and IL-1ß were significantly inhibited by CD38 gene deficiency with siRNA transfection in VSMCs. Further, CD38 regulated the release of intracellular cADPR-mediated Ca2+ and mitochondrial DNA (mtDNA) to the cytosol, which was associated with NLRP3 inflammasome activation and VSMCs proliferation and collagen I synthesis. Finally, we found that CD38 inhibitors, nicotinamide and telmisartan significantly improved the endothelium-independent contraction and vascular remodeling, which was also associated with the inhibition of NLRP3 inflammasome in the aorta media in the diabetic mice. SIGNIFICANCE: Our data suggested that CD38/cADPR-mediated Ca2+ signaling contributed to the mitochondrial damage, consequently released mtDNA to the cytosol, which was related with NLRP3 inflammasome activation and VSMCs remodeling in diabetic mice.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Cálcio/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Inflamassomos/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Sinalização do Cálcio/fisiologia , ADP-Ribose Cíclica/metabolismo , DNA Mitocondrial/metabolismo , Diabetes Mellitus Experimental/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/patologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia
7.
Life Sci ; 254: 117813, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32428597

RESUMO

AIMS: This study aimed to investigate the effect of lymphocytes in wound healing and the underlying mechanisms, in diabetic and non-diabetic mice, using Balb/c recombination activating gene (Rag)-2 and interleukin 2 receptor gamma (IL-2Rγ) double knockout (KO) (RAG2-/- IL-2Rγ-/-) mice. MAIN METHODS: Wound healing in vivo was performed in control and STZ-induced diabetic mice, in both KO and WT mice. Inflammation and ROS production were evaluated by immunofluorescence microscopy analysis, antioxidant enzymes and angiogenesis were evaluated by quantitative PCR and immunofluorescence microscopy analysis, and wound closure kinetics evolution was evaluated by measurement of acetate tracing of the wound area. KEY FINDINGS: Wound closure was significantly delayed in KO mice, where the M1/M2 macrophage ratio and basal ROS levels were significantly increased, while antioxidant defenses and angiogenesis were significantly decreased. Moreover, the expected increase in matrix metallopeptidase (MMP)-9 protein levels in diabetic conditions was not observed in KO mice, suggesting that the mechanisms leading to the increase in MMP-9 observed in diabetic wounds may in part be lymphocyte-dependent. SIGNIFICANCE: Our results indicate that lack of lymphocytes compromises wound healing independent of diabetes. The lack of these cells, even in non-diabetic mice, mimics the phenotype observed in wounds under diabetic conditions. Moreover, the combination of diabetes and the lack of lymphocytes, further impair the wound healing conditions, indicating that when the innate regulatory function is lost in these KO mice, excessive M1 polarization, poor angiogenesis and impaired wound healing are worsen.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Subunidade gama Comum de Receptores de Interleucina/fisiologia , Linfócitos/fisiologia , Neovascularização Fisiológica/fisiologia , Cicatrização/fisiologia , Animais , Proteínas de Ligação a DNA/genética , Inflamação/metabolismo , Subunidade gama Comum de Receptores de Interleucina/genética , Ativação de Macrófagos/fisiologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Pele/irrigação sanguínea , Pele/metabolismo
8.
Life Sci ; 255: 117856, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32473246

RESUMO

BACKGROUND: Ferulic acid (FA) is a phenolic phytochemical known to protect against various diabetic complications. However, its role in diabetic neuropathy is still unclear. The present study investigated the potential protective effects of FA alone and its combination with insulin against streptozotocin (STZ)-induced diabetic neuropathy in rats. METHODS: STZ (55 mg/kg) was injected in adult Sprague-Dawley rats to induce diabetes. Diabetic rats were treated with FA (25, 50, and 100 mg/kg, p.o), insulin (10 IU/kg, s.c.) and the combination of FA (100 mg/kg, p.o.) with insulin (10 IU/kg, s.c.) for four weeks. Body weight, blood glucose, insulin, glycosylated hemoglobin, nerve conduction velocity and pain parameters were measured. Moreover, oxidative stress, inflammatory (TNF-α, IL-1ß, COX-2) and apoptotic markers (Bcl-2, Bax, caspase 3) were assessed in the sciatic nerve tissue. Na+-K+-ATPase activity and nerve growth factor (NGF) levels were also determined. RESULTS: FA attenuated STZ induced alteration in metabolic parameters, nociceptive threshold, motor nerve conduction velocity, NGF levels and Na+-K+-ATPase activity. In addition, FA boosted anti-oxidant defenses and suppressed oxidative stress, pro-inflammatory mediators and apoptotic markers. Furthermore, diabetic rats treated with insulin-FA (100 mg/kg) combination demonstrated more pronounced beneficial effects as compared to either agent alone. CONCLUSIONS: Collectively, our results suggest that FA either alone or in combination with insulin therapy could serve as an efficacious agent for treating diabetic neuropathy.


Assuntos
Ácidos Cumáricos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Animais , Antioxidantes/metabolismo , Glicemia/efeitos dos fármacos , Ácidos Cumáricos/administração & dosagem , Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estreptozocina
9.
J Appl Oral Sci ; 28: e20190690, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348445

RESUMO

Objective To investigate the effects of intro-oral injection of parathyroid hormone (PTH) on tooth extraction wound healing in hyperglycemic rats. Methodology 60 male Sprague-Dawley rats were randomly divided into the normal group (n=30) and DM group (n=30). Type 1 diabetes mellitus (DM) was induced by streptozotocin. After extracting the left first molar of all rats, each group was further divided into 3 subgroups (n=10 per subgroup), receiving the administration of intermittent PTH, continuous PTH and saline (control), respectively. The intermittent-PTH group received intra-oral injection of PTH three times per week for two weeks. A thermosensitive controlled-release hydrogel was synthesized for continuous-PTH administration. The serum chemistry was determined to evaluate the systemic condition. All animals were sacrificed after 14 days. Micro-computed tomography (Micro-CT) and histological analyses were used to evaluate the healing of extraction sockets. Results The level of serum glucose in the DM groups was significantly higher than that in the non-DM groups (p<0.05); the level of serum calcium was similar in all groups (p>0.05). Micro-CT analysis showed that the DM group had a significantly lower alveolar bone trabecular number (Tb.N) and higher trabecular separation (Tb.Sp) than the normal group (p<0.05). The histological analyses showed that no significant difference in the amount of new bone (hard tissue) formation was found between the PTH and non-PTH groups (p>0.05). Conclusions Bone formation in the extraction socket of the type 1 diabetic rats was reduced. PTH did not improve the healing of hard and soft tissues. The different PTH administration regimes (continuous vs. intermittent) had similar effect on tissue healing. These results demonstrated that the metabolic characteristics of the hyperglycemic rats produced a condition that was unable to respond to PTH treatment.


Assuntos
Hormônios e Agentes Reguladores de Cálcio/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Hormônio Paratireóideo/farmacologia , Extração Dentária/métodos , Alvéolo Dental/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Glicemia/análise , Cálcio/sangue , Hidrogéis , Masculino , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Ferida Cirúrgica/tratamento farmacológico , Fatores de Tempo , Alvéolo Dental/diagnóstico por imagem , Resultado do Tratamento , Microtomografia por Raio-X
10.
PLoS One ; 15(4): e0231962, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32324828

RESUMO

Vascular deficits are a fundamental contributing factor of diabetes-associated diseases. Although previous studies have demonstrated that the pro-angiogenic phase of wound healing is blunted in diabetes, a comprehensive understanding of the mechanisms that regulate skin revascularization and capillary stabilization in diabetic wounds is lacking. Using a mouse model of diabetic wound healing, we performed microCT analysis of the 3-dimensional architecture of the capillary bed. As compared to wild type, vessel surface area, branch junction number, total vessel length, and total branch number were significantly decreased in wounds of diabetic mice as compared to WT mice. Diabetic mouse wounds also had significantly increased capillary permeability and decreased pericyte coverage of capillaries. Diabetic wounds exhibited significant perturbations in the expression of factors that affect vascular regrowth, maturation and stability. Specifically, the expression of VEGF-A, Sprouty2, PEDF, LRP6, Thrombospondin 1, CXCL10, CXCR3, PDGFR-ß, HB-EGF, EGFR, TGF-ß1, Semaphorin3a, Neuropilin 1, angiopoietin 2, NG2, and RGS5 were down-regulated in diabetic wounds. Together, these studies provide novel information about the complexity of the perturbation of angiogenesis in diabetic wounds. Targeting factors responsible for wound resolution and vascular pruning, as well those that affect pericyte recruitment, maturation, and stability may have the potential to improve diabetic skin wound healing.


Assuntos
Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Neovascularização Patológica , Cicatrização , Animais , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/metabolismo , Capilares/metabolismo , Capilares/fisiopatologia , Diabetes Mellitus Experimental/diagnóstico por imagem , Diabetes Mellitus Experimental/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Pericitos/patologia , Permeabilidade , Microtomografia por Raio-X
11.
Int J Nanomedicine ; 15: 1939-1950, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32256070

RESUMO

Introduction: Chronic trauma repair is an important issue affecting people's healthy lives. Thermo-sensitive hydrogel is injectable in situ and can be used to treat large-area wounds. In addition, antioxidants play important roles in promoting wound repair. Methods: The purpose of this research was to prepare a novel thermo-sensitive hydrogel-poly(N-isopropyl-acrylamide)/poly(γ-glutamic acid) (PP) loaded with superoxide dismutase (SOD) to improve the effect for trauma treatment. The micromorphology of the hydrogel was observed by scanning electron microscope and the physical properties were measured. The biocompatibility of hydrogel was evaluated by MTT experiment, and the effect of hydrogel on skin wound healing was evaluated by in vivo histological staining. Results: Gelling behavior and differential scanning calorimeter outcomes showed that the PP hydrogels possessed thermo-sensitivity at physiological temperature and the phase transformation temperature was 28.2°C. The high swelling rate and good water retention were conducive to wound healing. The activity of SOD in vitro was up to 85% at 10 h, which was advantageous to eliminate the superoxide anion. MTT assay revealed that this hydrogel possessed good biocompatibility. Dressings of PP loaded with SOD (SOD-PP) had a higher wound closure rate than other treatments in vivo in diabetic rat model. Discussion: The SOD-PP thermo-sensitive hydrogels can effectively promote wound healing and have good application prospects for wound repair.


Assuntos
Bandagens , Hidrogéis/química , Hidrogéis/farmacologia , Superóxido Dismutase/administração & dosagem , Superóxido Dismutase/farmacologia , Cicatrização/efeitos dos fármacos , Resinas Acrílicas/química , Animais , Materiais Biocompatíveis/química , Diabetes Mellitus Experimental/fisiopatologia , Masculino , Teste de Materiais , Ácido Poliglutâmico/química , Polímeros/química , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Temperatura
12.
Life Sci ; 249: 117537, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32165214

RESUMO

AIMS: To establish an animal model of diabetes mellitus (DM) with moderately elevated blood glucose levels, and to examine the nitric oxide (NO) mechanism controlling urethral function in streptozotocin (STZ)-induced DM rats. MAIN METHODS: Female Sprague-Dawley rats were used. DM was induced by intraperitoneal injection of STZ (65 mg/kg) and some of them received subcutaneous implantation of a low-dose insulin pellet. Voiding behavior was evaluated in metabolic cages. Isovolumetric cystometry and urethral perfusion pressure (UPP) were then evaluated under urethane anesthesia, during which L-arginine (100 mg/kg) and N-nitro-L-arginine methyl ester hydrochloride (L-NAME) (50 mg/kg) were administered intravenously. In vitro urethral activity was also tested by organ bath muscle strip studies. KEY FINDINGS: UPP changes and high-frequency oscillation (HFO) were significantly (P < 0.05) smaller in 8-weeks DM rats vs. normal control (NC) rats or insulin-treated DM rats, which showed reductions in urine overproduction and voided volume per micturition vs. untreated DM rats. UPP nadir was decreased by L-arginine in NC and insulin-treated DM groups, and decreased by L-NAME in all groups. Five of 6 untreated DM rats showed a detrusor-sphincter dyssynergia pattern after L-NAME. In in vitro studies, the relative ratio of L-NAME-induced reductions of urethral relaxation against pre-drug urethral relaxation was significantly smaller in DM vs. NC rats (P < 0.05). SIGNIFICANCE: Low-dose insulin-treated DM rats would be a useful model for studying natural progression of DM-induced lower urinary tract dysfunction. The impaired NO-mediated urethral relaxation mechanisms play an important role in DM-induced urethral dysfunction, which could contribute to DM-induced inefficient voiding.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Insulina/uso terapêutico , Óxido Nítrico/metabolismo , Uretra/fisiopatologia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Insulina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Estreptozocina
13.
Acta Diabetol ; 57(7): 883-890, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32124076

RESUMO

AIMS/HYPOTHESIS: Impaired wound healing significantly impacts morbidity and mortality in diabetic patients, necessitating the development of novel treatments to improve the wound healing process. We here investigated the topical use of acellular embryonic stem cell extracts (EXTs) in wound healing in diabetic db/db mice. METHODS: Wounds were induced in diabetic db/db mice, which were subsequently treated with EXTs, with 3T3 fibroblast cell line protein extracts (3T3XTs) or with saline as a control. Pathology and mechanistic assays were then performed. RESULTS: The in vivo topical administration of EXTs facilitates wound closure, contraction and re-epithelialization. Moreover, EXTs reduced the number of wound-infiltrating CD45+ inflammatory cells and increased the rate of repair and of angiogenesis as compared to controls. Interestingly, the EXT effect was partly enhanced by the use of a collagen-based biocompatible scaffold. In vivo, topical administration of EXTs increased the percentage of regulatory T cells in the wounded tissue, while in vitro EXT treatment reduced T cell-mediated IFN-γ production. Proteomic screening revealed 82 proteins differentially segregating in EXTs as compared to 3T3 extracts, with APEX1 identified as a key player for the observed immunomodulatory effect of EXTs. CONCLUSIONS: EXTs are endowed with immunoregulatory and anti-inflammatory properties; their use improves wound healing in diabetic preclinical models.


Assuntos
Extratos Celulares/farmacologia , Extratos Celulares/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Células-Tronco Embrionárias/química , Cicatrização/efeitos dos fármacos , Células 3T3 , Animais , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Células-Tronco Embrionárias/metabolismo , Imunidade Inata/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/fisiopatologia , Proteoma/análise , Proteoma/metabolismo , Proteômica , Cicatrização/fisiologia
14.
Diabetes Res Clin Pract ; 162: 108093, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32109518

RESUMO

AIMS: This study aimed to detect the effect of angiotensin-converting enzyme (ACE) 2-modified mesenchymal stem cells (MSCs) on glomerular fibrosis in vitro and in vivo and investigate the underlying molecular mechanism. METHODS: MSCs transduced with the ACE2 gene (MSCs-ACE2) were cocultured with glomerular mesangial cells (GMCs) following Ang II stimulation. MSCs-ACE2 were transplanted into streptozotocin-induced diabetic rats. Physical, biochemical and morphological parameters were measured, and fibrotic indicators and renin-angiotensin system (RAS) components in GMCs and kidney tissues were assessed. RESULTS: The transduction efficiency of MSCs was as high as 85%. The modified MSCs secreted soluble ACE2 protein into the culture medium. After transplantation into rats with diabetes, MSCs-ACE2 targeted injured kidneys and enhanced local expression of ACE2. Compared with MSC treatment alone, MSC-ACE2 treatment was superior in reducing albuminuria and improving glomerulosclerosis. In vitro and in vivo, MSCs-ACE2 were more beneficial than MSCs alone in decreasing Ang II and increasing Ang1-7, thereby inhibiting the detrimental effects of Ang II accumulation by downregulating collagen I and fibronectin (FN) expression and inhibiting the transforming growth factor (TGF-ß)/Smad pathway. CONCLUSIONS: MSCs modified with ACE2 therapy have additional benefits to the progression of diabetic nephropathy (DN) by inhibiting renal RAS activation and reducing glomerular fibrosis.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/complicações , Fibrose/terapia , Glomérulos Renais/patologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Peptidil Dipeptidase A/metabolismo , Animais , Fibrose/etiologia , Fibrose/patologia , Glomérulos Renais/metabolismo , Masculino , Células-Tronco Mesenquimais/química , Peptidil Dipeptidase A/genética , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
15.
Mol Med Rep ; 21(2): 583-588, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974606

RESUMO

Diabetes mellitus can exacerbate renal ischemia­reperfusion (I/R) injury (RI/RI) in diabetic rats. Previous studies have shown that Notch signaling is involved in renal disorders. The aim of the present study was to evaluate the protective effect of the Notch inhibitor γ­secretase N­[N­(3,5­difluorophenacetyl)­L­alanyl]­S­phenylglycine t­butyl ester (DAPT) on RI/RI in a streptozocin (STZ)­induced diabetic rat model. STZ­induced diabetic rats were randomly grouped for different treatments. Cisplatin was used to trigger the Notch signaling pathway and the animals were preconditioned with DAPT to block the signaling pathway. Renal function, oxidative stress and inflammatory factors were examined. DAPT­treated diabetic rats demonstrated mitigated renal injury and function, antioxidative activity was significantly improved and HIF­1a was upregulated. Notch inhibitor DAPT is a potential therapeutic target to improve the outcome of RI/RI in STZ­induced diabetic rats in part via the regulation of anti­oxidation and HIF­1a.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Dipeptídeos/uso terapêutico , Receptores Notch/antagonistas & inibidores , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Nitrogênio da Ureia Sanguínea , Cisplatino , Creatinina/sangue , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mediadores da Inflamação/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Oxirredução , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores Notch/genética , Receptores Notch/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Estreptozocina
16.
Plast Reconstr Surg ; 145(2): 433-443, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31985637

RESUMO

BACKGROUND: This study explored the effect of a single local intraosseous application of a small dose of simvastatin on the wound healing process in type 1 diabetic rats and related mechanisms. METHODS: The authors chose the streptozotocin-induced type 1 diabetic rat to establish a full-thickness dermal wound using a 12-mm-diameter sterile disposable punch. The rats (n = 32) were divided randomly into four groups: (1) normal control rats, (2) type 1 diabetic rats with intraosseous injection of hydrogel vehicle, (3) type 1 diabetic rats with intraosseous injection of simvastatin (0.5 mg), and (4) type 1 diabetic rats with intragastric administration of simvastatin (20 mg/kg per day). Wound closure was followed by digital planimetry. Mobilization of endothelial progenitor cells into the circulatory system was studied using fluorescence-activated cell sorting. Neovascularization was analyzed with immunofluorescence histochemical staining. The relative levels of adiponectin and stromal cell-derived factor 1 (SDF-1) in serum, bone, and wound tissues were examined by enzyme-linked immunosorbent assay and Western blot. RESULTS: Diabetic rats exhibited impaired wound healing. Intraosseous administration of simvastatin accelerated wound healing beginning at day 4, and angiogenesis was more obvious than in the control group. Enzyme-linked immunosorbent assay revealed that adiponectin concentrations in the diabetic rats with intraosseous injection of hydrogel vehicle plus simvastatin 0.5-mg group were significantly higher compared with the diabetic rats with intraosseous injection of hydrogel vehicle group beginning at day 4. Intraosseous administration of simvastatin decreased the expression of adiponectin and SDF-1 in bone tissue but enhanced the expression of adiponectin in wounded skin. CONCLUSIONS: A single local intraosseous application of simvastatin promotes wound healing in type 1 diabetic rat. The underlying mechanisms may be attributed to the regulation of the adiponectin/SDF-1 pathway, which plays a pivotal role in endothelial progenitor cell mobilization and angiogenesis.


Assuntos
Indutores da Angiogênese/farmacocinética , Células Progenitoras Endoteliais/efeitos dos fármacos , Sinvastatina/farmacologia , Cicatrização/efeitos dos fármacos , Adiponectina/metabolismo , Animais , Quimiocina CXCL12/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Combinação de Medicamentos , Hidrogéis , Injeções , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Poloxâmero/administração & dosagem , Ratos Sprague-Dawley , Sinvastatina/administração & dosagem , Pele/metabolismo
17.
Sci Rep ; 10(1): 1206, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31988386

RESUMO

In this study, we sought to investigate the impact of photobiomodulation and adipose-derived stem cells (ADS), alone and in combination, on the maturation step of wound healing in an ischemic infected delayed healing wound model in rats with type 2 diabetes mellitus (DM2). We randomly divided 24 adult male rats into 4 groups (n = 6 per group). DM2 plus an ischemic delayed healing wound were induced in all rats. The wounds were infected with methicillin-resistant Staphylococcus aureus. Group 1 was the control (placebo) group. Group 2 received only photobiomodulation (890 nm, 80 Hz, 0.324 J/cm2, and 0.001 W/cm2). Group 3 received only the allograft ADS. Group 4 received allograft ADS followed by photobiomodulation. On days 0, 4, 8, 12, and 16, we performed microbiological examination (colony forming units, [CFU]), wound area measurement, wound closure rate, wound strength, and histological and stereological examinations. The results indicated that at day 16, there was significantly decreased CFU (Analysis of variance, p = 0.001) in the photobiomodulation + ADS (0.0 ± 0.0), ADS (1350 ± 212), and photobiomodulation (0.0 ± 0.0) groups compared with the control group (27250 ± 1284). There was significantly decreased wound area (Analysis of variance, p = 0.000) in the photobiomodulation + ADS (7.4 ± 1.4 mm2), ADS (11 ± 2.2 mm2), and photobiomodulation (11.4 ± 1.4 mm2) groups compared with the control group (25.2 ± 1.7). There was a significantly increased tensiometeric property (stress maximal load, Analysis of variance, p = 0.000) in the photobiomodulation + ADS (0.99 ± 0.06 N/cm2), ADS (0.51 ± 0.12 N/cm2), and photobiomodulation (0.35 ± 0.15 N/cm2) groups compared with the control group (0.18 ± 0.04). There was a significantly modulated inflammatory response in (Analysis of variance, p = 0.049) in the photobiomodulation + ADS (337 ± 96), ADS (1175 ± 640), and photobiomodulation (69 ± 54) treatments compared to control group (7321 ± 4099). Photobiomodulation + ADS gave significantly better improvements in CFU, wound area, and wound strength compared to photobiomodulation or ADS alone. Photobiomodulation, ADS, and their combination significantly hastened healing in ischemic methicillin-resistant Staphylococcus aureus infected delayed healing wounds in rats with DM2. Combined application of photobiomodulation plus ADS demonstrated an additive effect.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Isquemia/microbiologia , Terapia com Luz de Baixa Intensidade , Staphylococcus aureus Resistente à Meticilina/efeitos da radiação , Infecções Estafilocócicas/radioterapia , Transplante de Células-Tronco , Infecção da Ferida Cirúrgica/radioterapia , Cicatrização/efeitos da radiação , Tecido Adiposo/citologia , Aloenxertos , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Infecções Estafilocócicas/microbiologia , Estreptozocina/farmacologia , Infecção da Ferida Cirúrgica/microbiologia , Resultado do Tratamento
18.
J Vasc Res ; 57(2): 76-85, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31968349

RESUMO

Diabetes mellitus (DM)-induced impairment of collateral formation has been demonstrated in subjects with coronary artery disease, which contributes to unfavorable prognosis among diabetic individuals. In our previous studies, thioredoxin1 (Trx1) activity was shown to be decreased in diabetic cardiac tissues, but the reason of Trx1 inactivation and whether it mediates the impaired angiogenesis in ischemic myocardium is still to be identified. As thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of Trx, is overexpressed in DM due to carbohydrate response element within its promoter, we hypothesized that inhibition of Trx1 by enhanced TXNIP expression in endothelial cells may play a role in hyperglycemia-induced impairment of angiogenesis. In the present study, we found that high glucose-mediated increase of TXNIP expression and TXNIP-Trx1 interaction induced the impairment in endothelial cell function and survival, since these detrimental effects are rescued by silencing TXNIP with small interfering RNA. In diabetic mice, TXNIP knockdown or recombinant human Trx1 treatment counteracted the impairment of angiogenesis, alleviated myocardial ischemic injury, and improved survival rate. All these data implicate that TXNIP upregulation and subsequently the increased formation of TXNIP-Trx1 complex is a novel pathologic pathway by which DM induces insufficient angiogenesis and thereby exacerbates myocardial ischemia injury.


Assuntos
Diabetes Mellitus Experimental/complicações , Isquemia Miocárdica/fisiopatologia , Neovascularização Fisiológica/fisiologia , Tiorredoxinas/fisiologia , Animais , Proteínas de Transporte/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Células Endoteliais/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
19.
Diabetes ; 69(4): 699-712, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31974141

RESUMO

Current therapeutic strategies for diabetic foot ulcer (DFU) have focused on developing topical healing agents, but few agents have controlled prospective data to support their effectiveness in promoting wound healing. We tested a stem cell mobilizing therapy for DFU using a combination of AMD3100 and low-dose FK506 (tacrolimus) (AF) in streptozocin-induced type 1 diabetic (T1DM) rats and type 2 diabetic Goto-Kakizaki (GK) rats that had developed peripheral artery disease and neuropathy. Here, we show that the time for healing back wounds in T1DM rats was reduced from 27 to 19 days, and the foot wound healing time was reduced from 25 to 20 days by treatment with AF (subcutaneously, every other day). Similarly, in GK rats treated with AF, the healing time on back wounds was reduced from 26 to 21 days. Further, this shortened healing time was accompanied by reduced scar and by regeneration of hair follicles. We found that AF therapy mobilized and recruited bone marrow-derived CD133+ and CD34+ endothelial progenitor cells and Ym1/2+ M2 macrophages into the wound sites, associated with enhanced capillary and hair follicle neogenesis. Moreover, AF therapy improved microcirculation in diabetic and neuropathic feet in GK rats. This study provides a novel systemic therapy for healing DFU.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Pé Diabético/fisiopatologia , Células Progenitoras Endoteliais/efeitos dos fármacos , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/farmacologia , Tacrolimo/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Feminino , Masculino , Ratos , Ratos Sprague-Dawley
20.
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
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