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1.
Photobiomodul Photomed Laser Surg ; 40(1): 13-24, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34941461

RESUMO

Objective: The difficulty in chronic diabetic wound healing remains the focus of clinical research. Photobiomodulation therapy (PBMT) with different wavelengths could exert different effects on wound healing, but the effects of combined red and blue light (BL) remained unclear. Methods: Diabetic rat wound model and diabetic wounded endothelial cell model were established to observe possible effects of PBMT using combined wavelengths for wound healing. Cells and animals were separated into four groups exposed to red and/or BL. Cell viability, apoptosis, and migration, as well as the expression level of nitric oxide (NO), vascular endothelial growth factor, interleukin-6, and tumor necrosis factor-α were measured in vitro. Diabetic rats were evaluated for wound closure rates, collagen deposition, inflammation intensity, and density of neovascularization after light irradiation. Results: PBMT using combined wavelengths significantly sped up the healing process with increasing angiogenesis density, collagen deposition, and alleviating inflammation in vivo. Moreover, combined wavelength irradiation promoted cell proliferation and migration, and NO production, as well as reduced reactive oxygen species and inflammation in vitro. Conclusions: PBMT using combined wavelengths performed a synergistic effect for promoting diabetic wound healing and would be helpful to explore a more efficient pattern toward chronic wound healing.


Assuntos
Diabetes Mellitus Experimental , Terapia com Luz de Baixa Intensidade , Animais , Colágeno , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/terapia , Ratos , Fator A de Crescimento do Endotélio Vascular , Cicatrização
2.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(6): 665-672, 2021 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-34821103

RESUMO

Objective: To investigate the effects of aerobic exercise plus spirulina polysaccharide(SP) supplement on the related protein expressions of p75NTR signal in hippocampal and the improvement of learning and memory of type 2 diabetes rats. Methods: The model of type 2 diabetic rats was established by fed high-fat diet for four weeks together with intraperitoneal injecting a low dose of STZ. The model rats were randomly divided into diabetic model group(B),diabetic exercise group(C),diabetic+SP group(D)and diabetic exercise+SP group(E), another normal control group(A)without any intervention was set up,12 rats in each group. The rats in Group C and E were treated with intervention of swimming training for six weeks. The rats in Group D and E were treated with SP intragastrically for 6 weeks. Learning and memory abilities were observed by Morris water maze test. The hippocampus cell apoptosis was observed by Tunnel staining, and BDNF content and the expressions of p75NTR, cleaved caspase-3 of hippocampus were tested by ELISA, Western blot and immunohistochemistry, respectively. At the same time, the changes of blood glucose and levels of serum insulin were examined. Results: ①Compared with Group A at different time points, the body weight of Group B was decreased significantly(P<0.01). Compared with Group B at different time points, the body weight of Group C,D and E had no difference (P>0.05). Compared with Group A, levels of the blood glucose and serum insulin Group B were increased significantly(P<0.01).Compared with Group B, the levels in the intervention groups were decreased significantly (P<0.01); ②Compared with Group A, the escape latencies of Group B were prolonged significantly(P<0.01), platform quadrant residence duration and the times of crossing platform were decreased (P<0.01). Compared with Group B, the escape latencies of the intervention groups were shortened (P<0.05 or P<0.01), and the times of crossing platform were increased (P<0.05 or P<0.01). ③Compared with Group B, the neural cells apoptosis of the intervention rats was decreased, and the protein expressions of p75NTR and cleaved caspase-3 were decreased (P<0.05 or P<0.01), however the expression of BDNF was increased significantly (P<0.05 or P<0.01). Conclusion: Aerobic exercise and SP supplement can improve the learning-memory ability of type 2 diabetes rats, and the improvement effect of exercise combined with SP is markedly better than that of exercise and SP alone, the mechanism might be related to better regulating p75NTR signal related protein expressions and then inhibiting apoptosis in hippocampus of rats with type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Spirulina , Animais , Diabetes Mellitus Experimental/terapia , Hipocampo , Polissacarídeos , Ratos , Ratos Sprague-Dawley , Natação
3.
Int J Mol Sci ; 22(19)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34638608

RESUMO

The delayed healing response of diabetic wounds is a major challenge for treatment. Negative pressure wound therapy (NPWT) has been widely used to treat chronic wounds. However, it usually requires a long treatment time and results in directional growth of wound healing skin tissue. We investigated whether nonthermal microplasma (MP) treatment can promote the healing of skin wounds in diabetic mice. Splint excision wounds were created on diabetic mice, and various wound healing parameters were compared among MP treatment, NPWT, and control groups. Quantitative analysis of the re-epithelialization percentage by detecting Ki67 and DSG1 expression in the extending epidermal tongue (EET) of the wound area and the epidermal proliferation index (EPI) was subsequently performed. Both treatments promoted wound healing by enhancing wound closure kinetics and wound bed blood flow; this was confirmed through histological analysis and optical coherence tomography. Both treatments also increased Ki67 and DSG1 expression in the EET of the wound area and the EPI to enhance re-epithelialization. Increased Smad2/3/4 mRNA expression was observed in the epidermis layer of wounds, particularly after MP treatment. The results suggest that the Smad-dependent transforming growth factor ß signaling contributes to the enhancement of re-epithelialization after MP treatment with an appropriate exposure time. Overall, a short-term MP treatment (applied for 30 s twice a day) demonstrated comparable or better efficacy to conventional NPWT (applied for 4 h once a day) in promoting wound healing in diabetic mice. Thus, MP treatment exhibits promise for treating diabetic wounds clinically.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/terapia , Tratamento de Ferimentos com Pressão Negativa/métodos , Gases em Plasma/uso terapêutico , Pele/lesões , Cicatrização/fisiologia , Animais , Desmogleína 1/metabolismo , Técnicas In Vitro , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Óxido Nítrico/metabolismo , Regeneração da Pele por Plasma/métodos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reepitelização/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Transdução de Sinais , Pele/patologia , Pele/fisiopatologia , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Cicatrização/genética
4.
J Appl Physiol (1985) ; 131(4): 1219-1229, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34570639

RESUMO

To clarify the preventive effects of low-current electrical stimulation (ES) under blood flow restriction (Bfr) on diabetes-associated capillary regression in skeletal muscles, we assessed the changes in three-dimensional capillary architecture and angiogenic factors. Twenty-four Goto-Kakizaki rats were randomly divided into four groups: the sedentary diabetes mellitus (DM), Bfr (DM + Bfr), electrical stimulation (DM + ES), and Bfr plus ES (DM + Bfr + ES) groups. Six healthy Wistar rats were used as age-matched controls. Bfr was performed using pressure cuffs (80 mmHg) around the thighs of the rats, and low-current ES was applied to the calf muscles of the rats. The current intensity was set at 30% of the maximal isometric contraction (24-30 mA). The treatments were delivered three times a week for 8 wk. In the DM group, the capillary diameter and volume of the soleus muscle decreased, and, the antiangiogenic factor level increased. Furthermore, DM caused an increase in the hypoxia-inducible factor. Individually, Bfr or ES treatments failed to inhibit the DM-associated capillary regression and increase in antiangiogenic factor. However, combined treatment with Bfr and ES prevented DM-associated capillary regression via inhibition of the increased antiangiogenic factor and enhancement of interleukin-15 expression, mitochondrial biogenesis factors, and a proangiogenic factor. Therefore, DM-associated capillary regression inhibited by the combined treatment may prevent the effects of the increased antiangiogenic factor and enhance the proangiogenic factor.NEW & NOTEWORTHY The combined treatment of blood flow restriction and low intensity electrical stimulation attenuated type 2 diabetes (T2D)-associated capillary regression in the skeletal muscles. The treatment inhibits the T2D-associated increase in antiangiogenic factors via inhibition of intramuscular chronic hypoxia; it can inhibit intramuscular chronic hypoxia by enhancing proangiogenic factors. These results suggest that the combined treatment may be an effective therapeutic intervention for the prevention of T2D-associated capillary regression in the skeletal muscles.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Treinamento de Força , Animais , Diabetes Mellitus Experimental/terapia , Estimulação Elétrica , Humanos , Músculo Esquelético , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional
5.
Life Sci ; 285: 119973, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34560083

RESUMO

AIMS: Hyperglycemia occurring in the diabetic condition can cause apoptosis via the mitochondrial pathway with higher pro-apoptotic protein expression. Probiotics are viable microorganisms that have anti-diabetic and antioxidant effects. Also, exercise may affect the signaling pathways of skeletal muscle apoptosis. This study examined the aerobic exercise training and probiotic supplementation effects on some apoptotic indices of the soleus muscle in diabetic rats-induced by streptozotocin. MAIN METHODS: We examined 32 male Wistar rats (weight: 250-270 g; age: eight weeks old) and divided them into four groups: control, control + probiotics, aerobic training (AT), and AT + probiotics (ATS). The rats in the training groups aerobically exercised using a treadmill five days per week for five weeks. We evaluated the gene expression of Bax, Bcl2, and p53 using the RT-PCR. We also used a one-way ANOVA for statistical analysis and set the significance level at P ≤ 0.05. KEY FINDINGS: The results showed that the fasting blood sugar was significantly higher in the control and control + probiotics groups (P = 0.008). Moreover, the AT + probiotics group showed lower expression of p53 (P = 0.005), Bax (P = 0.001) and the Bax/Bcl2 ratio (P = 0.001). Conversely, Bcl2 expression was higher after aerobic training and receiving probiotics (P = 0.002). However, the groups revealed no significant difference regarding muscle weight (P = 0.053) and the muscle weight/final body weight ratio of the rats (P = 0.26). SIGNIFICANCE: It appears that aerobic exercise training with the use of probiotics prevents apoptosis in the muscle with the down-regulation of blood glucose.


Assuntos
Apoptose , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Músculo Esquelético/fisiopatologia , Condicionamento Físico Animal , Probióticos/administração & dosagem , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Glicemia , Masculino , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Estreptozocina
6.
Cells ; 10(9)2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34572086

RESUMO

INTRODUCTION: Primary bile acids (PBAs) are produced and released into human gut as a result of cholesterol catabolism in the liver. A predominant PBA is chenodeoxycholic acid (CDCA), which in a recent study in our laboratory, showed significant excipient-stabilizing effects on microcapsules carrying insulinoma ß-cells, in vitro, resulting in improved cell functions and insulin release, in the hyperglycemic state. Hence, this study aimed to investigate the applications of CDCA in bio-encapsulation and transplantation of primary healthy viable islets, preclinically, in type 1 diabetes. METHODS: Healthy islets were harvested from balb/c mice, encapsulated in CDCA microcapsules, and transplanted into the epididymal tissues of 6 syngeneic diabetic mice, post diabetes confirmation. Pre-transplantation, the microcapsules' morphology, size, CDCA-deep layer distribution, and physical features such as swelling ratio and mechanical strength were analyzed. Post-transplantation, animals' weight, bile acids', and proinflammatory biomarkers' concentrations were analyzed. The control group was diabetic mice that were transplanted encapsulated islets (without PBA). RESULTS AND CONCLUSION: Islet encapsulation by PBA microcapsules did not compromise the microcapsules' morphology or features. Furthermore, the PBA-graft performed better in terms of glycemic control and resulted in modulation of the bile acid profile in the brain. This is suggestive that the improved glycemic control was mediated via brain-related effects. However, the improvement in graft insulin delivery and glycemic control was short-term.


Assuntos
Cápsulas/administração & dosagem , Ácido Quenodesoxicólico/farmacologia , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Células Secretoras de Insulina/citologia , Transplante das Ilhotas Pancreáticas/métodos , Animais , Biotecnologia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/patologia , Fármacos Gastrointestinais/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
7.
Cells ; 10(9)2021 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-34572120

RESUMO

Dental pulp stem cells (DPSCs) are suitable for use in regenerative medicine. Cryopreserved human DPSCs (hDPSCs) ameliorate diabetic polyneuropathy, and the effects of hDPSC transplantation are related to VEGF and NGF secretion. This study evaluated the long-term effects of a single transplantation of hDPSCs on diabetic polyneuropathy. hDPSCs were obtained from human third molars extracted for orthodontic treatment, which were then transplanted into the unilateral hindlimb skeletal muscles 8 weeks after streptozotocin injection in nude mice. The effects of hDPSC transplantation were analyzed at 16 weeks post-transplantation. DPSC transplantation significantly improved delayed nerve conduction velocity, decreased blood flow, and increased sensory perception thresholds. Furthermore, the hDPSC-conditioned medium promoted the neurite outgrowth of dorsal root ganglion neurons. In conclusion, the therapeutic effects of hDPSC transplantation with a single injection last for prolonged periods and may be beneficial in treating long-term diabetic polyneuropathy.


Assuntos
Polpa Dentária/citologia , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Neuropatias Diabéticas/prevenção & controle , Neurônios/fisiologia , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Adolescente , Adulto , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/patologia , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Neurônios/citologia , Medicina Regenerativa , Adulto Jovem
8.
EMBO Mol Med ; 13(10): e11668, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34542937

RESUMO

Loss of ß-cell number and function is a hallmark of diabetes. ß-cell preservation is emerging as a promising strategy to treat and reverse diabetes. Here, we first found that Pdia4 was primarily expressed in ß-cells. This expression was up-regulated in ß-cells and blood of mice in response to excess nutrients. Ablation of Pdia4 alleviated diabetes as shown by reduced islet destruction, blood glucose and HbA1c, reactive oxygen species (ROS), and increased insulin secretion in diabetic mice. Strikingly, this ablation alone or in combination with food reduction could fully reverse diabetes. Conversely, overexpression of Pdia4 had the opposite pathophysiological outcomes in the mice. In addition, Pdia4 positively regulated ß-cell death, dysfunction, and ROS production. Mechanistic studies demonstrated that Pdia4 increased ROS content in ß-cells via its action on the pathway of Ndufs3 and p22phox . Finally, we found that 2-ß-D-glucopyranosyloxy1-hydroxytrideca 5,7,9,11-tetrayne (GHTT), a Pdia4 inhibitor, suppressed diabetic development in diabetic mice. These findings characterize Pdia4 as a crucial regulator of ß-cell pathogenesis and diabetes, suggesting Pdia4 is a novel therapeutic and diagnostic target of diabetes.


Assuntos
Diabetes Mellitus Experimental , Animais , Glicemia , Diabetes Mellitus Experimental/terapia , Camundongos , Isomerases de Dissulfetos de Proteínas , Espécies Reativas de Oxigênio
9.
Zhen Ci Yan Jiu ; 46(8): 642-8, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472748

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli"(ST36)-"Sanyinjiao"(SP6) on glucose and lipid metabolism and insulin resistance (IR) in obese diabetic rats, so as to explore its mechanism underlying improvement of obesity diabetes. METHODS: SPF male rats were randomly divided into normal control, model, meridian-acupoint EA (acupoint), non-meridian non-acupoint EA (non-acupoint), and medication (metformin) groups, with 10 rats in each group. The diabetes model was established by feeding the rats with high-fat diet for 8 weeks. EA (1.5 mA, 10 Hz/100 Hz) was applied to unilateral ST36 and SP6 for 20 min, once daily (except Sundays) for 4 weeks. Rats of the medication group were treated by gavage of metformin (300 mg/kg) once daily for 4 weeks (except Sundays). The body weight and length were measured and the Lee's index was calculated. The contents of total cholesterol (TC), triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C) in the plasma were detected by using a full-automatic biochemical analyzer. The content of fasting serum insulin (FINS) was assayed by using radioimmunoassay, the fasting blood glucose (FBG) was measured, and serum superoxide dismutase (SOD) activity by using xanthine oxidase method, serum malondialdehyde (MDA) by color method, serum glutathione peroxidase (GSH-Px) activity by indirect method, reactive oxygen species (ROS) by Dithio-bis-nitrobenzoic acid (DTNB) direct method, and the homeostasis model assessment of IR (HOMA-IR) and insulin sensitive index (ISI) were calculated. The expression levels of pancreatic tissue P66shc mRNA and PKCß mRNA were detected by using RT-PCR, and the histopathological changes of the liver and adipose tissues were observed after H.E. staining. RESULTS: Compared with the normal control group, the Lee's index, levels of FBG, FINS, HOMA-IR, TC, TG, LDL-C, MDA, ROS, and P66shc mRNA and PKCß mRNA expressions were significantly increased (P<0.05,P<0.01), and ISI, HDL-C, SOD, GSH-Px significantly decreased (P<0.05, P<0.01) in the model group. After the interventions, the levels of Lee's index,levels of FBG, FINS, HOMA-IR, TC, TG, LDL-C, MDA, ROS, and expressions of P66shc mRNA and PKCß mRNA were remarkably down-regulated (P<0.05, P<0.01), and those of ISI, HDL-C, SOD, and GSH-Px up-regulated (P<0.05, P<0.01) in both EA and medication groups. H.E. staining showed many white adipocytes in the adipose tissue, radial and cord-like arrangement of liver cells, and many of them with vacuoles in the cytoplasm of small vesicular lipid droplets in the model group; and relative reduction of white adipocytes in number, smaller in cell body, and no obvious abnormal changes of structure and arrangement of liver cells in the EA and medication groups. CONCLUSION: EA of ST36 and SP6 can improve glucose and lipid metabolism and IR in obese diabetic rats, which may be related to its function in suppressing PKCß/P66shc signaling and oxidative stress.


Assuntos
Terapia por Acupuntura , Diabetes Mellitus Experimental , Eletroacupuntura , Pontos de Acupuntura , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/terapia , Masculino , Obesidade/genética , Obesidade/terapia , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src
10.
Sci Rep ; 11(1): 16983, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417511

RESUMO

Obesity (Ob) poses a significant risk factor for the onset of metabolic syndrome with associated complications, wherein the Mesenchymal Stem Cell (MSC) therapy shows pre-clinical success. Here, we explore the therapeutic applications of human Placental MSCs (P-MSCs) to address Ob-associated Insulin Resistance (IR) and its complications. In the present study, we show that intramuscular injection of P-MSCs homed more towards the visceral site, restored HOMA-IR and glucose homeostasis in the WNIN/GR-Ob (Ob-T2D) rats. P-MSC therapy was effective in re-establishing the dysregulated cytokines. We report that the P-MSCs activates PI3K-Akt signaling and regulates the Glut4-dependant glucose uptake and its utilization in WNIN/GR-Ob (Ob-T2D) rats compared to its control. Our data reinstates P-MSC treatment's potent application to alleviate IR and restores peripheral blood glucose clearance evidenced in stromal vascular fraction (SVF) derived from white adipose tissue (WAT) of the WNIN/GR-Ob rats. Gaining insights, we show the activation of the PI3K-Akt pathway by P-MSCs both in vivo and in vitro (palmitate primed 3T3-L1 cells) to restore the insulin sensitivity dysregulated adipocytes. Our findings suggest a potent application of P-MSCs in  pre-clinical/Ob-T2D management.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Experimental/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Modelos Biológicos , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Células Cultivadas , Citocinas/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Diabetes Mellitus Tipo 2/terapia , Feminino , Transportador de Glucose Tipo 4/metabolismo , Homeostase , Humanos , Insulina/metabolismo , Macrófagos/metabolismo , Obesidade/complicações , Fosfatidilinositol 3-Quinases/metabolismo , Placenta/citologia , Gravidez , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais
11.
Transplantation ; 105(9): 1980-1988, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34416751

RESUMO

BACKGROUND: Type 1 diabetes (T1DM) is a chronic autoimmune disease characterized by T-cell-mediated destruction of insulin-producing beta cells. Evidence shows that patients with T1DM and mice used in specific diabetic models both exhibit changes in their intestinal microbiota and dysregulated microbiota contributes to the pathogenesis of T1DM. Islet transplantation (Tx) is poised to play an important role in the treatment of T1DM. However, whether treatment of T1DM with islet Tx can rescue dysregulated microbiota remains unclear. METHODS: In this study, we induced diabetic C57BL/6 mice with streptozotocin. Then treatment with either insulin administration, or homogenic or allogenic islet Tx was performed to the diabetic mice. Total DNA was isolated from fecal pellets and high-throughput 16S rRNA sequencing was used to investigate intestinal microbiota composition. RESULTS: The overall microbial diversity was comparable between control (nonstreptozotocin treated) and diabetic mice. Our results showed the ratio of the Bacteroidetes: Firmicutes between nondiabetic and diabetic mice was significant different. Treatment with islet Tx or insulin partially corrects the dysregulated bacterial composition. At the genus level, Bacteroides, Odoribacter, and Alistipes were associated with the progression and treatment efficacy of the disease, which may be used as a biomarker to predict curative effect of treatment for patients with T1DM. CONCLUSIONS: Collectively, our results indicate that diabetic mice show changed microbiota composition and that treatment with insulin and islet Tx can partially correct the dysregulated microbiota.


Assuntos
Bactérias/crescimento & desenvolvimento , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Microbioma Gastrointestinal , Controle Glicêmico , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Animais , Bactérias/classificação , Bactérias/genética , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/microbiologia , Disbiose , Fezes/microbiologia , Transplante das Ilhotas Pancreáticas , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ribotipagem , Estreptozocina , Técnicas de Cultura de Tecidos
12.
Nutrients ; 13(8)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34444919

RESUMO

Flaxseed is an oilseed (45-50% oil on a dry-weight basis) crop. Its oil has demonstrated multiple health benefits and industrial applications. The goal of this research was to evaluate the antidiabetic and anti-inflammatory potential of the free polyphenol fraction of flax (Linum usitatissimum L.) seeds (PLU), based on their use in traditional medicine. Mice with alloxan-induced diabetes were used to study the antidiabetic activity of PLU in vivo, with an oral administration of 25 and 50 mg/kg over 28 days. Measurements of body weight and fasting blood glucose (FBG) were carried out weekly, and biochemical parameters were evaluated. An oral glucose tolerance test was also performed. Inhibitory activities of PLU on α-amylase and α-glucosidase activities were evaluated in vitro. The anti-inflammatory was evaluated in vivo in Wistar rats using the paw edema induction Test by carrageenan, and in vitro using the hemolysis ratio test. PLU administration to diabetic mice during the study period improved their body weight and FBG levels remarkably. In vitro inhibitory activity of digestive enzymes indicated that they may be involved in the proposed mode of action of PLU extract. Qualitative results of PLU revealed the presence of 18 polyphenols. These findings support daily consumption of flaxseed for people with diabetes, and suggest that polyphenols in flaxseed may serve as dietary supplements or novel phytomedicines to treat diabetes and its complications.


Assuntos
Anti-Inflamatórios/farmacologia , Diabetes Mellitus Experimental/terapia , Linho/química , Hipoglicemiantes/farmacologia , Óleos Vegetais/farmacologia , Sementes/química , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Suplementos Nutricionais , Humanos , Camundongos , Polifenóis/farmacologia , Ratos , Ratos Wistar
13.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445075

RESUMO

Pre-weaned porcine islets (PPIs) represent an unlimited source for islet transplantation but are functionally immature. We previously showed that necrostatin-1 (Nec-1) immediately after islet isolation enhanced the in vitro development of PPIs. Here, we examined the impact of Nec-1 on the in vivo function of PPIs after transplantation in diabetic mice. PPIs were isolated from pancreata of 8-15-day-old, pre-weaned pigs and cultured in media alone, or supplemented with Nec-1 (100 µM) on day 0 or on day 3 of culture (n = 5 for each group). On day 7, islet recovery, viability, oxygen consumption rate, insulin content, cellular composition, insulin secretion capacity, and transplant outcomes were evaluated. While islet viability and oxygen consumption rate remained high throughout 7-day tissue culture, Nec-1 supplementation on day 3 significantly improved islet recovery, insulin content, endocrine composition, GLUT2 expression, differentiation potential, proliferation capacity of endocrine cells, and insulin secretion. Adding Nec-1 on day 3 of tissue culture enhanced the islet recovery, proportion of delta cells, beta-cell differentiation and proliferation, and stimulation index. In vivo, this leads to shorter times to normoglycemia, better glycemic control, and higher circulating insulin. Our findings identify the novel time-dependent effects of Nec-1 supplementation on porcine islet quantity and quality prior to transplantation.


Assuntos
Diabetes Mellitus Experimental/terapia , Imidazóis/farmacologia , Indóis/farmacologia , Transplante das Ilhotas Pancreáticas/métodos , Ilhotas Pancreáticas/efeitos dos fármacos , Técnicas de Cultura de Tecidos/métodos , Animais , Diabetes Mellitus Experimental/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/fisiologia , Camundongos Nus , Suínos , Transplante Heterólogo/métodos , Transplantes/efeitos dos fármacos , Transplantes/fisiologia
14.
Photobiomodul Photomed Laser Surg ; 39(7): 453-462, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34264768

RESUMO

Objective: To assess whether photobiomodulation therapy (PBMT) induces angiogenesis in diabetic mice with hindlimb ischemia (HLI). Background: Patients with diabetes mellitus (DM) are at high risk of developing peripheral arterial disease (PAD) in the lower extremities. PBMT has been shown to promote angiogenesis both in vitro and in vivo and could be a treatment for DM patients with PAD. Methods: Femoral artery ligation/excision in mice was performed to induce HLI as an animal model of PAD. PBMT at a dose of 660 nm and 1.91 J/cm2 was delivered for 10 min on 5 consecutive days after the HLI surgery. Control mice received HLI only. Mice in the DM group were injected with streptozocin to induce diabetes before HLI surgery. Mice in the laser and DM+ laser groups received both HLI and PBMT, and the latter group had induced DM. After the laser treatment, lower limb blood flow was evaluated by laser Doppler. The capillary density and CD31 were analyzed by immunofluorescence staining, and protein levels of vascular endothelial growth factor (VEGF)-A, hypoxia-inducible factor-1α (HIF-1α), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and extracellular signal-regulated kinases (ERK) were measured by Western blotting of tissue samples. Results: Compared with the control and DM mice, the laser and DM+ laser groups had more than double the capillary density and blood perfusion rate. Levels of CD31 and VEGF-A proteins in groups that received laser were increased by 1.9- to 3.2-fold compared with groups that did not undergo laser treatment. Animals treated with PBMT exhibited significantly increased HIF-1α expression and ERK phosphorylation compared with animals that did not receive this treatment, and the amount of phospho-eNOS and iNOS increased and decreased, respectively. Conclusions: PBMT can induce therapeutic angiogenesis, indicating that low intensity laser could be a novel treatment for PAD patients.


Assuntos
Diabetes Mellitus Experimental , Terapia com Luz de Baixa Intensidade , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/terapia , Membro Posterior , Humanos , Isquemia/radioterapia , Camundongos , Fator A de Crescimento do Endotélio Vascular
15.
Stem Cell Res Ther ; 12(1): 403, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266474

RESUMO

BACKGROUND: Diabetic limb ischemia is a clinical syndrome and refractory to therapy. Our previous study demonstrated that adipose-derived stem cells (ADSCs) overexpressing glyoxalase-1 (GLO-1) promoted the regeneration of ischemic lower limbs in diabetic mice, but low survival rate, difficulty in differentiation, and tumorigenicity of the transplanted cells restricted its application. Recent studies have found that exosomes secreted by the ADSCs have the advantages of containing parental beneficial factors and exhibiting non-immunogenic, non-tumorigenic, and strong stable characteristics. METHODS: ADSCs overexpressing GLO-1 (G-ADSCs) were established using lentivirus transfection, and exosomes secreted from ADSCs (G-ADSC-Exos) were isolated and characterized to coculture with human umbilical vein endothelial cells (HUVECs). Proliferation, apoptosis, migration, and tube formation of the HUVECs were detected under high-glucose conditions. The G-ADSC-Exos were injected into ischemic hindlimb muscles of type 2 diabetes mellitus (T2DM) mice, and the laser Doppler perfusion index, Masson's staining, immunofluorescence, and immunohistochemistry assays were adopted to assess the treatment efficiency. Moreover, the underlying regulatory mechanisms of the G-ADSC-Exos on the proliferation, migration, angiogenesis, and apoptosis of the HUVECs were explored. RESULTS: The G-ADSC-Exos enhanced the proliferation, migration, tube formation, and anti-apoptosis of the HUVECs in vitro under high-glucose conditions. After in vivo transplantation, the G-ADSC-Exo group showed significantly higher laser Doppler perfusion index, better muscle structural integrity, and higher microvessel's density than the ADSC-Exo and control groups by Masson's staining and immunofluorescence assays. The underlying mechanisms by which the G-ADSC-Exos protected endothelial cells both in vitro and in vivo might be via the activation of eNOS/AKT/ERK/P-38 signaling pathways, inhibition of AP-1/ROS/NLRP3/ASC/Caspase-1/IL-1ß, as well as the increased secretion of VEGF, IGF-1, and FGF. CONCLUSION: Exosomes derived from adipose-derived stem cells overexpressing GLO-1 protected the endothelial cells and promoted the angiogenesis in type 2 diabetic mice with limb ischemia, which will be a promising clinical treatment in diabetic lower limb ischemia.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Exossomos , Tecido Adiposo , Animais , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Células Endoteliais da Veia Umbilical Humana , Humanos , Isquemia/terapia , Camundongos , Neovascularização Fisiológica , Células-Tronco
16.
Stem Cell Res Ther ; 12(1): 385, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233739

RESUMO

BACKGROUND: The therapeutic efficacy of mesenchymal stem cells (MSCs) of different tissue origins on metabolic disorders can be varied in many ways but remains poorly defined. Here we report a comprehensive comparison of human MSCs derived from umbilical cord Wharton's jelly (UC-MSCs), dental pulp (PU-MSCs), and adipose tissue (AD-MSCs) on the treatment of glucose and lipid metabolic disorders in type II diabetic mice. METHODS: Fourteen-to-fifteen-week-old male C57BL/6 db/db mice were intravenously administered with human UC-MSCs, PU-MSCs, and AD-MSCs at various doses or vehicle control once every 2 weeks for 6 weeks. Metformin (MET) was given orally to animals in a separate group once a day at weeks 4 to 6 as a positive control. Body weight, blood glucose, and insulin levels were measured every week. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed every 2 weeks. All the animals were sacrificed at week 6 and the blood and liver tissues were collected for biochemical and histological examinations. RESULTS: UC-MSCs showed the strongest efficacy in reducing fasting glucose levels, increasing fasting insulin levels, and improving GTT and ITT in a dose-dependent manner, whereas PU-MSCs showed an intermediate efficacy and AD-MSCs showed the least efficacy on these parameters. Moreover, UC-MSCs also reduced the serum low-density lipoprotein cholesterol (LDL-C) levels with the most prominent potency and AD-MSCs had only very weak effect on LDL-C. In contrast, AD-MSCs substantially reduced the lipid content and histological lesion of liver and accompanying biomarkers of liver injury such as serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, whereas UC-MSCs and PU-MSCs displayed no or modest effects on these parameters, respectively. CONCLUSIONS: Taken together, our results demonstrated that MSCs of different tissue origins can confer substantially different therapeutic efficacy in ameliorating glucose and lipid metabolic disorders in type II diabetes. MSCs with different therapeutic characteristics could be selected according to the purpose of the treatment in the future clinical practice.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/terapia , Glucose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cordão Umbilical
17.
Stem Cell Res Ther ; 12(1): 392, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34256844

RESUMO

BACKGROUND: Diabetic foot ulceration is a serious chronic complication of diabetes mellitus characterized by high disability, mortality, and morbidity. Platelet-rich plasma (PRP) has been widely used for diabetic wound healing due to its high content of growth factors. However, its application is limited due to the rapid degradation of growth factors. The present study aimed to evaluate the efficacy of combined adipose-derived mesenchymal stem cells (ADSCs) and PRP therapy in promoting diabetic wound healing in relation to the Notch signaling pathway. METHODS: Albino rats were allocated into 6 groups [control (unwounded), sham (wounded but non-diabetic), diabetic, PRP-treated, ADSC-treated, and PRP+ADSCs-treated groups]. The effect of individual and combined therapy was evaluated by assessing wound closure rate, epidermal thickness, dermal collagen, and angiogenesis. Moreover, gene and protein expression of key elements of the Notch signaling pathway (Notch1, Delta-like canonical Notch ligand 4 (DLL4), Hairy Enhancer of Split-1 (Hes1), Hey1, Jagged-1), gene expression of angiogenic marker (vascular endothelial growth factor and stromal cell-derived factor 1) and epidermal stem cells (EPSCs) related gene (ß1 Integrin) were assessed. RESULTS: Our data showed better wound healing of PRP+ADSCs compared to their individual use after 7 and 14 days as the combined therapy caused reepithelialization and granulation tissue formation with a marked increase in area percentage of collagen, epidermal thickness, and angiogenesis. Moreover, Notch signaling was significantly downregulated, and EPSC proliferation and recruitment were enhanced compared to other treated groups and diabetic groups. CONCLUSIONS: These data demonstrated that PRP and ADSCs combined therapy significantly accelerated healing of diabetic wounds induced experimentally in rats via modulating the Notch pathway, promoting angiogenesis and EPSC proliferation.


Assuntos
Diabetes Mellitus Experimental , Células-Tronco Mesenquimais , Plasma Rico em Plaquetas , Animais , Diabetes Mellitus Experimental/terapia , Ratos , Fator A de Crescimento do Endotélio Vascular , Cicatrização
18.
PLoS One ; 16(7): e0254718, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34270619

RESUMO

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


Assuntos
Glicemia/análise , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Insulina/administração & dosagem , Pâncreas Artificial , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/diagnóstico , Hemoglobina A Glicada/análise , Humanos , Infusões Intravenosas/instrumentação , Infusões Intravenosas/métodos , Masculino , Ratos , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade
19.
Spectrochim Acta A Mol Biomol Spectrosc ; 262: 120157, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34271236

RESUMO

We studied the effects of photobiomodulation therapy (PBMT) on adipose-derived mesenchymal stem cells (ADSCs) which were extracted from streptozotocin (STZ) induced diabetic rats. Adipose tissue was extracted from the hypodermis of diabetic rats, and diabetic ADSCs were extracted, characterized, and cultured. There were two in vitro groups: control-diabetic ADSCs, and PBMT-diabeticADSCs. We used 630 nm and 810 nm laser at 1.2 J/cm2 with 3 applications 48 h apart. We measured cell viability, apoptosis, population doubling time (PDT), and reactive oxygen species (ROS) by flow cytometry. Gene expression of antioxidants, including cytosolic copper-zinc superoxide dismutase (SOD1), catalase (CAT), total antioxidant capacity (TAC), and oxidative stress biomarkers (NADPH oxidase 1 and 4) by quantitative real time (qRT) - PCR. In this study, data were analyzed using t-test. Viability of PBMT-diabetic- ADSC group was higher than control- diabetic-ADSC (p = 0.000). PDT and apoptosis of PBMT- diabetic-ADSC group were lower than control-diabetic -ADSC (p = 0.001, p = 0.02). SOD1 expression and TAC of PBMT- diabetic-ADSC group were higher than control -diabetic -ADSC (p = 0.018, p = 0.005). CAT of PBMT -diabetic-ADSC group was higher than control-diabetic -ADSC. ROS, NOX1, and NOX4 of PBMT- diabetic -ADSC group were lower than control-diabetic-ADSC (p = 0.002, p = 0.021, p = 0.017). PBMT may improve diabetic- ADSC function in vitro by increasing levels of cell viability, and gene expression of antioxidant agents (SOD1, CAT, and TAC), and significantly decreasing of levels of PDT, apoptosis, ROS, and gene expression of oxidative stress biomarkers (NOX1 and NOX4).


Assuntos
Diabetes Mellitus Experimental , Terapia com Luz de Baixa Intensidade , Células-Tronco Mesenquimais , Animais , Antioxidantes , Diabetes Mellitus Experimental/terapia , Estresse Oxidativo , Ratos
20.
Methods Mol Biol ; 2312: 35-57, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34228283

RESUMO

Diabetes mellitus is a complex metabolic disease characterized by chronically deregulated blood-glucose levels. To restore glucose homeostasis, therapeutic strategies allowing well-controlled production and release of insulinogenic hormones into the blood circulation are required. In this chapter, we describe how mammalian cells can be engineered for applications in diabetes treatment. While closed-loop control systems provide automated and self-sufficient synchronization of glucose sensing and drug production, drug production in open-loop control systems is engineered to depend on exogenous user-defined trigger signals. Rational, robust, and reliable manufacture practices for mammalian cell engineering are essential for industrial-scale mass-production in view of clinical and commercial applications.


Assuntos
Técnicas Biossensoriais , Glicemia/metabolismo , Engenharia Celular , Diabetes Mellitus Experimental/terapia , Terapia Genética , Peptídeo 1 Semelhante ao Glucagon/genética , Células Secretoras de Insulina/transplante , Insulina/genética , Biologia Sintética , Animais , Biomarcadores/sangue , Encapsulamento de Células , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/genética , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células HEK293 , Homeostase , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Transfecção
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