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1.
Braz J Med Biol Res ; 54(11): e11352, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34495249

RESUMO

Diabetes mellitus is associated with neural and micro- and macrovascular complications. Therapeutic options for these complications are limited and the delivery of mesenchymal stem cells into lesions have been reported to improve the healing process. In this work, the effects of the administration of a lineage of human bone marrow mesenchymal stem cells immortalized by the expression of telomerase (hBMSC-TERT) as a potential therapeutic tool for wound healing in diabetic rats were investigated. This is the first description of the use of these cells in diabetic wounds. Dorsal cutaneous lesions were made in streptozotocin-induced diabetic rats and hBMSC-TERT were subcutaneously administered around the lesions. The healing process was evaluated macroscopically, histologically, and by birefringence analysis. Diabetic wounded rats infused with hBMSC-TERT (DM-TERT group) and the non-diabetic wounded rats not infused with hBMSC-TERT (CW group) had very similar patterns of fibroblastic response and collagen proliferation indicating improvement of wound healing. The result obtained by birefringence analysis was in accordance with that obtained by the histological analysis. The results indicated that local administration of hBMSC-TERT in diabetic wounds improved the wound healing process and may become a therapeutic option for wounds in individuals with diabetes.


Assuntos
Diabetes Mellitus Experimental , Células-Tronco Mesenquimais , Telomerase , Animais , Humanos , Ratos , Estreptozocina , Cicatrização
2.
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
3.
Front Immunol ; 12: 650176, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512619

RESUMO

Diabetes-related cognitive dysfunction (DRCD) is a serious complication induced by diabetes. However, there are currently no specific remedies for DRCD. Here, we show that streptozotocin-induced DRCD can be prevented without causing side effects through oral administration of lipopolysaccharide (LPS) derived from Pantoea agglomerans. Oral administration of LPS (OAL) prevented the cerebral cortex atrophy and tau phosphorylation induced by DRCD. Moreover, we observed that neuroprotective transformation of microglia (brain tissue-resident macrophages) is important for preventing DRCD through OAL. These findings are contrary to the general recognition of LPS as an inflammatory agent when injected systemically. Furthermore, our results strongly suggest that OAL promotes membrane-bound colony stimulating factor 1 (CSF1) expression on peripheral leukocytes, which activates the CSF1 receptor on microglia, leading to their transformation to the neuroprotective phenotype. Taken together, the present study indicates that controlling innate immune modulation through the simple and safe strategy of OAL can be an innovative prophylaxis for intractable neurological diseases such as DRCD. In a sense, for modern people living in an LPS-depleted environment, OAL is like a time machine that returns microglia to the good old LPS-abundant era.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Complicações do Diabetes/tratamento farmacológico , Lipopolissacarídeos/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Pantoea/química , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/prevenção & controle , Diabetes Mellitus Experimental , Modelos Animais de Doenças , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Transdução de Sinais
4.
Life Sci ; 284: 119925, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34480933

RESUMO

AIMS: Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction and is frequent in people with type 2 diabetes mellitus. In diabetic patients, increased levels of the eicosanoid 12-hydroxyeicosatetraenoic acid (12-HETE) are linked to vascular dysfunction. Here, we aimed to identify the importance of 12-HETE in type 2 diabetic patients exhibiting diastolic dysfunction, and mice exhibiting HFpEF and whether targeting 12-HETE is a means to ameliorate HFpEF progression by improving vascular function in diabetes. MATERIAL AND METHODS: Subjects with diagnosed type 2 diabetes mellitus and reported diastolic dysfunction or healthy controls were recruited and 12(S)-HETE levels determined by ELISA. 12(S)-HETE levels were determined in type 2 diabetic, leptin receptor deficient mice (LepRdb/db) and HFpEF verified by echocardiography. Mitochondrial function, endothelial function and capillary density were assessed using Seahorse technique, pressure myography and immunohistochemistry in LepRdb/db or non-diabetic littermate controls. 12/15Lo generation was inhibited using ML351 and 12(S)-HETE action by using the V1-cal peptide. KEY FINDINGS: Endothelium-dependent vasodilation and mitochondrial functional capacity both improved in response to either application of ML351 or the V1-cal peptide. Correlating to improved vascular function, mice treated with either pharmacological agent exhibited improved diastolic filling and left ventricular relaxation that correlated with increased myocardial capillary density. SIGNIFICANCE: Our results suggest that 12-HETE may serve as a biomarker indicating endothelial dysfunction and the resulting cardiovascular consequences such as HFpEF in type 2 diabetic patients. Antagonizing 12-HETE is a potent means to causally control HFpEF development and progression in type 2 diabetes by preserving vascular function.


Assuntos
Vasos Sanguíneos/fisiopatologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Volume Sistólico/fisiologia , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Idoso , Animais , Diástole , Células Endoteliais/metabolismo , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Camundongos , Mitocôndrias/metabolismo , Canais de Cátion TRPV/metabolismo , Vasodilatação
5.
Life Sci ; 284: 119931, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34480934

RESUMO

AIMS: Retinal neovascularization is one of the visual disorders during the postmenopausal period or types two diabetes. Physical activities and also phytoestrogens with powerful antioxidant features have been widely considered to improve nervous system diseases. Therefore, this study investigated the effects of genistein, swimming exercise, and their co-treatment on retina angiogenesis, oxidative stress, and inflammation in diabetic-ovariectomized rats. MAIN METHODS: Wistar rats were randomly divided into six groups (n = 8 per group): sham, ovariectomized group (OVX), OVX + diabetes (OVX.D), OVX.D+ genistein (1 mg/kg, eight weeks; daily SC), OVX.D + exercise (eight weeks), and OVX.D+ genistein+exercise (eight weeks). At the end of 8 weeks, the retina was removed under anesthesia. The assessed effects of treatment were by measuring MiR-146a and miR-132 expression via RT-PCR, the protein levels of ERK, MMP-2, VEGF, and NF-κB via western blotting, inflammation, and oxidative stress markers levels via the Eliza. KEY FINDINGS: The results showed miR-132, miR-146b, and MMP-2, NF-κB, ERK, VEGF, TNF-α, IL-1ß proteins, and MDA factor in the OVX.D group were increased, but glutathione (GSH) was decreased in comparison with the sham and OVX groups. Both exercise and genistein treatment has reversed the disorder caused by diabetes. However, the combination of exercise and genistein was more effective than each treatment alone. SIGNIFICANCE: It can be concluded that the interaction of exercise and genistein on microRNAs and their target protein was affected in the inflammation, stress oxidative, and extracellular matrix metalloproteinase pathways, can leading to a decrease in impairment of retinal neovascularization of the ovariectomized diabetic rats.


Assuntos
Diabetes Mellitus Experimental/patologia , Genisteína/farmacologia , Inflamação/patologia , Ovariectomia , Estresse Oxidativo , Retina/patologia , Natação/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Biomarcadores/metabolismo , Diabetes Mellitus Experimental/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Genisteína/administração & dosagem , Glucose/metabolismo , Glutationa/metabolismo , Homeostase/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Malondialdeído/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Wistar , Retina/efeitos dos fármacos
6.
Life Sci ; 284: 119928, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34480937

RESUMO

AIMS: Berberine is effective for type 2 diabetes mellitus (T2DM), but has limited use in clinic. This study aims to evaluate the effect of berberine combined with stachyose on glycolipid metabolism and gut microbiota and to explore the underlying mechanisms in diabetic rats. MAIN METHODS: Zucker diabetic fatty (ZDF) rats were orally administered berberine, stachyose and berberine combined with stachyose once daily for 69 days. The oral glucose tolerance and levels of blood glucose, insulin, triglyceride and total cholesterol were determined. The gut microbial profile, colonic miRNA and gene expression were assayed using Illumina sequencing. The quantitative polymerase chain reaction was used to verify the expression of differentially expressed miRNAs and genes. KEY FINDINGS: Repeated treatments with berberine alone and combined with stachyose significantly reduced the blood glucose, improved the impaired glucose tolerance, and increased the abundance of beneficial Akkermansiaceae, decreased that of pathogenic Enterobacteriaceae in ZDF rats. Furthermore, combined treatment remarkably decreased the abundances of Desulfovibrionaceae and Proteobacteria in comparison to berberine. Combined treatment evidently decreased the expression of intestinal early growth response protein 1 (Egr1) and heparin-binding EGF-like growth factor (Hbegf), and significantly increased the expression of miR-10a-5p, but berberine alone not. SIGNIFICANCE: Berberine combined with stachyose significantly improved glucose metabolism and reshaped gut microbiota in ZDF rats, especially decreased the abundance of pathogenic Desulfovibrionaceae and Proteobacteria compared to berberine alone, providing a novel strategy for treating T2DM. The underlying mechanisms may be associated with regulating the expression of intestinal Egr1, Hbegf and miR-10a-5p, but remains further elucidation.


Assuntos
Berberina/farmacologia , Colo/metabolismo , Diabetes Mellitus Experimental/genética , Microbioma Gastrointestinal , Regulação da Expressão Gênica , Glucose/metabolismo , MicroRNAs/genética , Oligossacarídeos/farmacologia , Animais , Colo/efeitos dos fármacos , Colo/microbiologia , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , MicroRNAs/metabolismo , Análise de Componente Principal , Ratos Zucker , Reprodutibilidade dos Testes , Transcriptoma/genética
7.
Life Sci ; 284: 119935, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34508760

RESUMO

OBJECTIVE: Atherosclerotic vascular disease remains the principal cause of death and disability among patients with type 2 diabetes. Unfortunately, the problem is not adequately resolved by therapeutic strategies with currently available drugs or approaches that solely focus on optimal glycemic control. To identify the key contributors and better understand the mechanism of diabetic atherosclerotic vascular disease, we aimed to elucidate the key genetic characteristics and pathological pathways in atherosclerotic vascular disease through nonbiased bioinformatics analysis and subsequent experimental demonstration and exploration in diabetic atherosclerotic vascular disease. METHODS AND RESULTS: Sixty-eight upregulated and 23 downregulated genes were identified from the analysis of gene expression profiles (GSE30169 and GSE6584). A comprehensive bioinformatic assay further identified that ferroptosis, a new type of programmed cell death and HMOX1 (a gene that encodes heme oxygenase), were vital factors in atherosclerotic vascular disease. We further demonstrated that diabetes significantly increased ferroptosis and HMOX1 levels compared to normal controls. Importantly, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively attenuated diabetic atherosclerosis, suggesting the causative role of ferroptosis in diabetic atherosclerosis development. At the cellular level, Fer-1 ameliorated high glucose high lipid-induced lipid peroxidation and downregulated ROS production. More importantly, HMOX1 knockdown attenuated Fe2+ overload, reduced iron content and ROS, and alleviated lipid peroxidation, which led to a reduction in ferroptosis in diabetic human endothelial cells. CONCLUSIONS: We demonstrated that HMOX1 upregulation is responsible for the increased ferroptosis in diabetic atherosclerosis development, suggesting that HMOX1 may serve as a potential therapeutic or drug development target for diabetic atherosclerosis.


Assuntos
Aterosclerose/enzimologia , Aterosclerose/genética , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/genética , Ferroptose , Heme Oxigenase-1/genética , Regulação para Cima , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/complicações , Aterosclerose/patologia , Cicloexilaminas/farmacologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica , Progressão da Doença , Comportamento Alimentar , Feminino , Ferroptose/efeitos dos fármacos , Perfilação da Expressão Gênica , Glutationa/metabolismo , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Sobrecarga de Ferro/complicações , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos Knockout , NADP/metabolismo , Fenilenodiaminas/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
8.
Zhongguo Zhong Yao Za Zhi ; 46(17): 4462-4470, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34581051

RESUMO

This study explored the molecular mechanism underlying the Gegen Qinlian Decoction(GQD) promoting the differentiation of brown adipose tissue(BAT) to improve glucose and lipid metabolism disorders in diabetic rats. After the hypoglycemic effect of GQD on diabetic rats induced by high-fat diet combined with a low dose of streptozotocin was confirmed, the total RNA of rat BAT around scapula was extracted. Nuclear transcription genes Prdm16, Pparγc1α, Pparα, Pparγ and Sirt1, BAT marker genes Ucp1, Cidea and Dio2, energy expenditure gene Ampkα2 as well as BAT secretion factors Adpn, Fndc5, Angptl8, IL-6 and Rbp4 were detected by qPCR, then were analyzed by IPA software. Afterward, the total protein from rat BAT was extracted, and PRDM16, PGC1α, PPARγ, PPARα, SIRT1, ChREBP, AMPKα, UCP1, ADPN, NRG4, GLUT1 and GLUT4 were detected by Western blot. The mRNA expression levels of Pparγc1α, Pparα, Pparγ, Ucp1, Cidea, Ampkα2, Dio2, Fndc5, Rbp4 and Angptl8 were significantly increased(P<0.05) and those of Adpn and IL-6 were significantly decreased(P<0.05) in the GQD group compared with the diabetic group. In addition, Sirt1 showed a downward trend(P=0.104), whereas Prdm16 tended to be up-regulated(P=0.182) in the GQD group. IPA canonical pathway analysis and diseases-and-functions analysis suggested that GQD activated PPARα/RXRα and SIRT1 signaling pathways to promote the differentiation of BAT and reduce the excessive lipid accumulation. Moreover, the protein expression levels of PRDM16, PGC1α, PPARα, PPARγ, SIRT1, ChREBP, AMPKα, UCP1, GLUT1, GLUT4 and NRG4 were significantly decreased in the diabetic group(P<0.01), which were elevated after GQD intervention(P<0.05). Unexpectedly, the expression of ADPN protein in the diabetic group was up-regulated(P<0.01) as compared with the control group, which was down-regulated after the administration with GQD(P<0.01). This study indicated that GQD promoted BAT differentiation and maturity to increase energy consumption, which reduced the glucose and lipid metabolism disorders and thereby improved diabetes symptoms.


Assuntos
Diabetes Mellitus Experimental , Transtornos do Metabolismo dos Lipídeos , Tecido Adiposo Marrom , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Medicamentos de Ervas Chinesas , Fibronectinas , Glucose , Metabolismo dos Lipídeos , Ratos
9.
Zhongguo Zhong Yao Za Zhi ; 46(17): 4488-4496, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34581054

RESUMO

This study focused on the ameliorative effects of gypenosides(GPS) on insulin sensitivity and inflammatory factors in rats with type 2 diabetes mellitus(T2 DM) and explored their possible molecular mechanisms. After the successful establishment of T2 DM model, diabetic rats were randomly divided into four groups, including model group, GPS groups(200, 100 mg·kg~(-1)) and metformin group(100 mg·kg~(-1)), with healthy rats serving as the control. After 6-week intragastric administration, fasting blood glucose(FBG) and oral glucose tolerance were examined. The levels of insulin, C-peptide, tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), interleukin-6(IL-6) and C-reactive protein(CRP) in serum were examined. Then the homeostasis model assessment of insulin resistance(HOMA-IR) and insulin sensitivity index(ISI) were calculated. The protein expression levels of phosphorylated insulin receptor substrate-1(p-IRS-1) and phosphorylated protein kinase B(p-Akt) in skeletal muscle were measured by Western blot, as well as those of phosphorylated inhibitor of nuclear factor-κB(NF-κB) kinase ß(p-IKKß), phosphorylated alpha inhibitor of NF-κB(p-IκBα) and phosphorylated p65 subunit of NF-κB(p-p65) in adipose tissue. The relative expression levels of glucose transporter 4(GLUT4) mRNA in skeletal muscle and NF-κB mRNA in adipose tissue were measured by qRT-PCR, and the morphological changes of pancreatic tissue were observed. Compared with the model group, the GPS groups witnessed significant decrease in FBG, marked amelioration of impaired oral glucose tolerance and significant increase in ISI. Further, the high-dose GPS group saw significantly reduced HOMA-IR, TNF-α, IL-1ß and CRP, significantly increased expression levels of p-IRS-1(Tyr), p-Akt and GLUT4, and markedly inhibited p-IRS-1(Ser), p-IKKß, p-IκBα, p-p65 and NF-κB. The concentration of CRP and the expression levels of p-IRS-1(Ser), p-IKKß, p-IκBα and NF-κB were remarkably reduced in the low-dose GPS group. However, GPS was found less effective in the regulation of serum insulin, C-peptide and IL-6 levels and the alleviation of pancreatic islet injury. The results indicated that GPS can reduce FBG and improve insulin sensitivity in diabetic rats possibly by regulating the NF-κB signaling pathway, inhibiting inflammation, and thereby regulating the expression of key proteins in the insulin signaling pathway.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Gynostemma , Insulina , NF-kappa B/genética , NF-kappa B/metabolismo , Extratos Vegetais , Ratos , Transdução de Sinais
10.
Biomed Res Int ; 2021: 7202447, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497854

RESUMO

This study is aimed at comparing the antidiabetic and antioxidant potential of fenugreek and buckthorn which are commonly used in modulating diabetes in the Middle East. In this study, the antioxidant and antidiabetic activity of the aqueous extracts of the leaf and seed of fenugreek and buckthorn was tested in streptozotocin-induced diabetic male rats fed with a fat-rich diet for 8 weeks. Thirty-six male albino rats were divided into 6 groups (n = 6); the 1st group was the negative control. Diabetes was induced in the other 30 rats using streptozotocin, which were then divided into 5 groups; the 2nd was the untreated positive diabetic group, the 3rd was treated with fenugreek leaf aqueous extract, the 4th was treated with the fenugreek seed aqueous extract, the 5th was treated with buckthorn leaf aqueous extract, and the 6th was treated with buckthorn seed aqueous extract. The positive control group showed an increase in blood sugar, glycated hemoglobin, liver function enzymes, lactate dehydrogenase, kidney indices, total cholesterol, triglycerides, low- and very-low-density lipoprotein, immunoglobulins, and lipid peroxidation and a decrease in high-density lipoprotein, albumin, and antioxidant activity. The histology of the liver and testes showed severe histopathological alterations. Rats of groups 4-6 that were treated with the aqueous extract of the leaf and seed extract of fenugreek and buckthorn showed improvement of all biochemical and histopathological parameters. The seed extract of fenugreek and buckthorn showed more antioxidant activity than their leaves.


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Rhamnus/química , Trigonella/química , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/patologia , Masculino , Folhas de Planta/química , Ratos , Ratos Sprague-Dawley , Sementes/química
11.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443619

RESUMO

This study was designed to investigate the influence of dietary chitosan feeding-duration on glucose and lipid metabolism in diabetic rats induced by streptozotocin and nicotinamide [a non-insulin-dependent diabetes mellitus (NIDDM) model]. Male Sprague-Dawley rats were used as experimental animals and divided into short-term (6 weeks) and long-term (11 weeks) feeding durations, and each duration contained five groups: (1) control, (2) control + 5% chitosan, (3) diabetes, (4) diabetes + 0.8 mg/kg rosiglitazone (a positive control), and (5) diabetes + 5% chitosan. Whether the chitosan feeding was for 6 or 11 weeks, the chitosan supplementation decreased blood glucose and lipids levels and liver lipid accumulation. However, chitosan supplementation decreased plasma tumor necrosis factor (TNF)-α, insulin levels, alanine aminotransferase (ALT) activity, insulin resistance (HOMA-IR), and adipose tissue lipoprotein lipase activity. Meanwhile, it increased plasma high-density lipoproteins (HDL)-cholesterol level, plasma angiopoietin-like-4 protein expression, and plasma triglyceride levels (at 11-week feeding duration only). Taken together, 11-week (long-term) chitosan feeding may help to ameliorate the glucose and lipid metabolism in a NIDDM diabetic rat model.


Assuntos
Quitosana/farmacologia , Diabetes Mellitus Experimental/metabolismo , Carboidratos da Dieta/farmacologia , Glucose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
12.
Life Sci ; 283: 119870, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352258

RESUMO

OBJECTIVE: Increased renal and hepatic gluconeogenesis are important sources of fasting hyperglycemia in type 2 diabetes (T2D). The inhibitory effect of co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on hepatic but not renal gluconeogenesis has been reported in rats with T2D. The present study aimed to determine the effects of co-administration of sodium nitrite and NaSH on the expression of genes involved in renal gluconeogenesis in rats with T2D. METHODS: T2D was induced by a combination of a high-fat diet and low-dose streptozotocin (30 mg/kg). Male Wistar rats were divided into 5 groups (n = 6/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite and NaSH were administered for nine weeks at a dose of 50 mg/L (in drinking water) and 0.28 mg/kg (daily intraperitoneal injection), respectively. Serum levels of urea and creatinine, and mRNA expressions of PEPCK, G6Pase, FBPase, PC, PI3K, AKT, PGC-1α, and FoxO1 in the renal tissue, were measured at the end of the study. RESULTS: Nitrite decreased mRNA expression of PEPCK by 39%, G6Pase by 43%, FBPase by 41%, PC by 63%, PGC-1α by 45%, and FoxO1 by 27% in the renal tissue of rats with T2D; co-administration of nitrite and NaSH further decreases FoxO1, while had no additive effects on the tissue expression of the other genes. In addition, nitrite+NaSH decreased elevated serum urea levels by 58% and creatinine by 37% in rats with T2D. CONCLUSION: The inhibitory effect of nitrite on gluconeogenesis in T2D rats is at least in part due to decreased mRNA expressions of renal gluconeogenic genes. Unlike effects on hepatic gluconeogenesis, co-administration of nitrite and NaSH has no additive effects on genes involved in renal gluconeogenesis in rats with T2D.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gluconeogênese/efeitos dos fármacos , Rim/metabolismo , Nitrito de Sódio/farmacologia , Sulfetos/farmacologia , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Rim/patologia , Masculino , Ratos , Ratos Wistar
13.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445504

RESUMO

Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-Leprdb/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria.


Assuntos
Diabetes Mellitus Experimental/complicações , Perda Auditiva/fisiopatologia , Mitocôndrias/ultraestrutura , Receptores para Leptina/genética , Animais , Apoptose , Biomarcadores/metabolismo , Cóclea/irrigação sanguínea , Cóclea/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Regulação para Baixo , Perda Auditiva/etiologia , Perda Auditiva/genética , Perda Auditiva/metabolismo , Humanos , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo
14.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445586

RESUMO

Remote ischemic preconditioning (RIPC) protects hearts from ischemia-reperfusion (I/R) injury in experimental studies; however, clinical RIPC trials were unsatisfactory. This discrepancy could be caused by a loss of cardioprotection due to comorbidities in patients, including diabetes mellitus (DM) and hyperglycemia (HG). RIPC is discussed to confer protective properties by release of different humoral factors activating cardioprotective signaling cascades. Therefore, we investigated whether DM type 1 and/or HG (1) inhibit the release of humoral factors after RIPC and/or (2) block the cardioprotective effect directly at the myocardium. Experiments were performed on male Wistar rats. Animals in part 1 of the study were either healthy normoglycemic (NG), type 1 diabetic (DM1), or hyperglycemic (HG). RIPC was implemented by four cycles of 5 min bilateral hind-limb ischemia/reperfusion. Control (Con) animals were not treated. Blood plasma taken in vivo was further investigated in isolated rat hearts in vitro. Plasma from diseased animals (DM1 or HG) was administered onto healthy (NG) hearts for 10 min before 33 min of global ischemia and 60 min of reperfusion. Part 2 of the study was performed vice versa-plasma taken in vivo, with or without RIPC, from healthy rats was transferred to DM1 and HG hearts in vitro. Infarct size was determined by TTC staining. Part 1: RIPC plasma from NG (NG Con: 49 ± 8% vs. NG RIPC 29 ± 6%; p < 0.05) and DM1 animals (DM1 Con: 47 ± 7% vs. DM1 RIPC: 38 ± 7%; p < 0.05) reduced infarct size. Interestingly, transfer of HG plasma showed comparable infarct sizes independent of prior treatment (HG Con: 34 ± 9% vs. HG RIPC 35 ± 9%; ns). Part 2: No infarct size reduction was detectable when transferring RIPC plasma from healthy rats to DM1 (DM1 Con: 54 ± 13% vs. DM1 RIPC 53 ± 10%; ns) or HG hearts (HG Con: 60 ± 16% vs. HG RIPC 53 ± 14%; ns). These results suggest that: (1) RIPC under NG and DM1 induces the release of humoral factors with cardioprotective impact, (2) HG plasma might own cardioprotective properties, and (3) RIPC does not confer cardioprotection in DM1 and HG myocardium.


Assuntos
Cardiotônicos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Hiperglicemia/complicações , Imunidade Humoral , Precondicionamento Isquêmico Miocárdico/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/patologia , Ratos , Ratos Wistar , Transdução de Sinais
15.
Environ Pollut ; 287: 117671, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34435562

RESUMO

In humans and animal models, the kidneys and cardiovascular systems are negatively affected by BPA from the environment. It is considered that BPA have some potential estrogen-like and non-hormone-like properties. In this study, RNA-sequencing and its-related bioinformatics was used as the basic strategy to clarify the characteristic mechanisms of kidney-heart axis remodeling and dysfunction in diabetic male rats under BPA exposure. We found that continuous BPA exposure in diabetic rats aggravated renal impairment, and caused hemodynamic disorders and dysfunctions. There were 655 and 125 differentially expressed genes in the kidney and heart, respectively. For the kidneys, functional annotation and enrichment, and gene set enrichment analyses identified bile acid secretion related to lipid synthesis and transport, and MAPK cascade pathways. For the heart, these bioinformatics analyses clearly pointed to MAPKs pathways. A total of 12 genes and another total of 6 genes were identified from the kidney tissue and heart tissue, respectively. Western blotting showed that exposure to BPA activated MAPK cascades in both organs. In this study, the exacerbated remodeling of diabetic kidney-heart axis under BPA exposure and diabetes might occur through hemodynamics, metabolism disorders, and the immune-inflammatory response, as well as continuous estrogen-like stimulation, with focus on the MAPK cascades.


Assuntos
Diabetes Mellitus Experimental , Transcriptoma , Animais , Compostos Benzidrílicos , Biologia Computacional , Rim , Masculino , Fenóis , Ratos
16.
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
17.
Nutrients ; 13(8)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34445047

RESUMO

Sargassum fusiforme alginate (SF-Alg) possess many pharmacological activities, including hypoglycemic and hypolipidemic. However, the hypoglycemic mechanisms of SF-Alg remain unclear due to its low bioavailability. In this study, we evaluated the therapeutic effect of SF-Alg on high-fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetes (T2D) mice. SF-Alg intervention was found to significantly reduce fasting blood glucose (FBG), triglycerides (TG), and total cholesterol (TC), while increasing high-density lipoprotein cholesterol (HDL-c) and improving glucose tolerance. In addition, administrating SF-Alg to diabetic mice moderately attenuated pathological changes in adipose, hepatic, and heart tissues as well as skeletal muscle, and diminished oxidative stress. To probe the underlying mechanisms, we further analyzed the gut microbiota using 16S rRNA amplicon sequencing, as well as metabolites by non-targeted metabolomics. Here, SF-Alg significantly increased some benign bacteria (Lactobacillus, Bacteroides, Akkermansia Alloprevotella, Weissella and Enterorhabdus), and significantly decreased harmful bacteria (Turicibacter and Helicobacter). Meanwhile, SF-Alg dramatically decreased branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) in the colon of T2D mice, suggesting a positive benefit of SF-Alg as an adjvant agent for T2D.


Assuntos
Alginatos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Sargassum/química , Animais , Glicemia/efeitos dos fármacos , Colesterol/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Hiperglicemia/etiologia , Camundongos , Estreptozocina , Triglicerídeos/sangue
18.
Biomed Res Int ; 2021: 9920826, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34341763

RESUMO

Background: Abrus precatorius is used in folk medicine across Afro-Asian regions of the world. Earlier, glucose lowering and pancreato-protective effects of Abrus precatorius leaf extract (APLE) was confirmed experimentally in STZ/nicotinamide-induced diabetic rats; however, the underlying mechanism of antidiabetic effect and pancreato-protection remained unknown. Objective: This study elucidated antidiabetic mechanisms and pancreato-protective effects of APLE in diabetic rats. Materials and Methods: APLE was prepared by ethanol/Soxhlet extraction method. Total phenols and flavonoids were quantified calorimetrically after initial phytochemical screening. Diabetes mellitus (DM) was established in adult Sprague-Dawley rats (weighing 120-180 g) of both sexes by daily sequential injection of nicotinamide (48 mg/kg; ip) and Alloxan (120 mg/kg; ip) over a period of 7 days. Except control rats which had fasting blood glucose (FBG) of 4.60 mmol/L, rats having stable FBG (16-21 mmol/L) 7 days post-nicotinamide/Alloxan injection were considered diabetic and were randomly reassigned to one of the following groups (model, APLE (100, 200, and 400 mg/kg, respectively; po) and metformin (300 mg/kg; po)) and treated daily for 18 days. Bodyweight and FBG were measured every 72 hours for 18 days. On day 18, rats were sacrificed under deep anesthesia; organs (kidney, liver, pancreas, and spleen) were isolated and weighed. Blood was collected for estimation of serum insulin, glucagon, and GLP-1 using a rat-specific ELISA kit. The pancreas was processed, sectioned, and H&E-stained for histological examination. Effect of APLE on enzymatic activity of alpha (α)-amylase and α-glucosidase was assessed. Antioxidant and free radical scavenging properties of APLE were assessed using standard methods. Results: APLE dose-dependently decreased the initial FBG by 68.67%, 31.07%, and 4.39% compared to model (4.34%) and metformin (43.63%). APLE (100 mg/kg) treatment restored weight loss relative to model. APLE increased serum insulin and GLP-1 but decreased serum glucagon relative to model. APLE increased both the number and median crosssectional area (×106 µm2) of pancreatic islets compared to that of model. APLE produced concentration-dependent inhibition of α-amylase and α-glucosidase relative to acarbose. APLE concentration dependently scavenged DPPH and nitric oxide (NO) radicals and demonstrated increased ferric reducing antioxidant capacity (FRAC) relative to standards. Conclusion: Antidiabetic effect of APLE is mediated through modulation of insulin and GLP-1 inversely with glucagon, noncompetitive inhibition of α-amylase and α-glucosidase, free radical scavenging, and recovery of damaged/necro-apoptosized pancreatic ß-cells.


Assuntos
Abrus/química , Diabetes Mellitus Experimental/metabolismo , Peptídeo 1 Semelhante ao Glucagon/sangue , Glucagon/sangue , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo , Aloxano , Animais , Antioxidantes/metabolismo , Compostos de Bifenilo/química , Glicemia/metabolismo , Peso Corporal , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Feminino , Flavonoides/análise , Sequestradores de Radicais Livres/farmacologia , Cobaias , Concentração Inibidora 50 , Insulina/sangue , Ferro/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Cinética , Masculino , Niacinamida , Fenóis/análise , Compostos Fitoquímicos/análise , Picratos/química , Extratos Vegetais/farmacologia , Ratos Sprague-Dawley
19.
Int J Pharm ; 607: 120963, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34363919

RESUMO

Chitosan and alginate are natural bioactive polymers with wound healing properties, in addition to chitosan's anti-bacterial properties. In this study, these two polymers were combined in a drug-free nanosystem with positive or negative surface charges, for the treatment of non-diabetic and diabetic pressure ulcers. Chitosan alginate nanoparticles (CA NPs) were prepared by a modified ionic gelation method. Interaction between the polymers and formation of the NPs were confirmed by Fourier-Transform infrared spectroscopy, differential scanning calorimetry and transmission electron microscopy. For in vivo study, selected CA NPs with optimum particle size, polydispersity index, positive and negative zeta potential, were evaluated for their pressure ulcers-healing effect using non-diabetic and diabetic rats. Rate of wound closure, histological examination and histomorphometric assessment were used to evaluate the CA NPs' wound healing potential. Positively and negatively charged CA NPs significantly enhanced wound closure rates, compared to control untreated group. Histological and histomorphometric analysis revealed higher quality and maturation of the formed granulation tissue, less inflammation and higher collagen content with positively charged CA NPs containing higher amount of chitosan. These results suggest that chitosan alginate nanoparticles offer a promising platform for diabetic and non-diabetic wound healing applications.


Assuntos
Quitosana , Diabetes Mellitus Experimental , Nanopartículas , Lesão por Pressão , Alginatos , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Tamanho da Partícula , Lesão por Pressão/tratamento farmacológico , Ratos
20.
Front Immunol ; 12: 616215, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34447366

RESUMO

Tolerogenic vaccinations using beta-cell antigens are attractive for type 1 diabetes prevention, but clinical trials have been disappointing. This is probably due to the late timing of intervention, when multiple auto-antibodies are already present. We therefore devised a strategy to introduce the initiating antigen preproinsulin (PPI) during neonatal life, when autoimmunity is still silent and central tolerance mechanisms, which remain therapeutically unexploited, are more active. This strategy employs an oral administration of PPI-Fc, i.e. PPI fused with an IgG Fc to bind the intestinal neonatal Fc receptor (FcRn) that physiologically delivers maternal antibodies to the offspring during breastfeeding. Neonatal oral PPI-Fc vaccination did not prevent diabetes development in PPI T-cell receptor-transgenic G9C8.NOD mice. However, PPI-Fc was efficiently transferred through the intestinal epithelium in an Fc- and FcRn-dependent manner, was taken up by antigen presenting cells, and reached the spleen and thymus. Although not statistically significant, neonatal oral PPI-Fc vaccination delayed diabetes onset in polyclonal Ins2 -/-.NOD mice that spontaneously develop accelerated diabetes. Thus, this strategy shows promise in terms of systemic and thymic antigen delivery via the intestinal FcRn pathway, but the current PPI-Fc formulation/regimen requires further improvements to achieve diabetes prevention.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Tipo 1/prevenção & controle , Antígenos de Histocompatibilidade Classe I/imunologia , Insulina/farmacologia , Precursores de Proteínas/farmacologia , Receptores Fc/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Timo/imunologia , Administração Oral , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Insulina/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Precursores de Proteínas/genética , Receptores Fc/genética , Proteínas Recombinantes de Fusão/genética
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