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1.
Food Chem ; 399: 133974, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35998493

RESUMO

In this research, two sequential Dendrobium officinale water extracts (WDOE and WDOP1) were shown to significantly ameliorate type 2 diabetic mellitus (T2DM) in a mouse model. WDOP1 was identified as a glucomannan with a backbone of 1,4-linked Manp and 1,4-linked Glcp and an average molecular weight of 731 kDa. We also found that both WDOE and WDOP1 could significantly alleviate glucose intolerance, insulin resistance, oxidative stress injury, serum lipid metabolism disturbances, and histopathological damage in T2DM mice. In addition, we demonstrated that WDOE and WDOP1 reversed gut dysbiosis by reshaping the microbiota spectrum in T2DM mice. It should be emphasized that both Dendrobium officinale extracts afforded beneficial effects in T2DM mice comparable to metformin, despite differences in examined dosages. In conclusion, we demonstrated that Dendrobium officinale derivatives have potential as T2DM management nutraceuticals.


Assuntos
Dendrobium , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Hipoglicemiantes/farmacologia , Camundongos , Estresse Oxidativo , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia
2.
Braz. j. biol ; 83: e247071, 2023. tab
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1285609

RESUMO

Abstract The present study was conducted to evaluate the chemical composition, antioxidant activity and hypoglycemic effects of whole kumquat (Ku) powder in diabetic rats fed a high-fat-high-cholesterol (HFHC) diet. The antioxidant activities were evaluated using stable 1,1-diphenyl 2-picrylhydrazyl (DPPH) free radical scavenging method, 2,2´-azinobis (3-ethyl benzo thiazoline-6-sulphonic acid) radical cation (ABTS) and Ferric reducing antioxidant power (FRAP). Total phenolic content was (51.85 mg GAE/g) and total flavonoid content was (0.24 mg Cateachin Equivalent, CE/g). DPPH and ABTS values were 3.32 and 3.98 mg Trolox equivalent (TE)/g where FRAP value was 3.00 mM Fe2+/kg dry material. A total of 90 albino rats were used in the present study. Rats group were as follows: normal diet; normal treated (2, 4, and 6% Ku.), diabetic rats (non-treated), diabetic + HFHC diet (non-treated), HFHC (non-treated), Diabetic (treated), HFHC (treated) and Diabetic + HFHC (treated). The diets were followed for 8 weeks. Blood samples were collected at the end of the experiment. Serum glucose was recorded and thyroid hormones (T4, Thyroxine and T3, Triiodothyronine) were conducted. Diet supplemented with Kumquat at different concentrations have a hypoglycemic effect and improve the thyroid hormones of both diabetic rats and HFHC diabetic rats.


Resumo O presente estudo foi conduzido para avaliar a composição química, a atividade antioxidante e os efeitos hipoglicêmicos do pó de kumquat (Ku) em ratos diabéticos alimentados com uma dieta rica em gordura e colesterol (HFHC). As atividades antioxidantes foram avaliadas usando o método de eliminação de radicais livres de 1,1-difenil 2-picrilhidrazil (DPPH), 2,2'-azinobis (ácido 3-etilbenzotiazolina-6-sulfônico) radical cátion (ABTS) e antioxidante redutor férrico potência (FRAP). O conteúdo fenólico total foi (51,85 mg GAE / g) e o conteúdo total de flavonoides foi (0,24 mg Cateachin Equivalent, CE / g). Os valores de DPPH e ABTS foram 3,32 e 3,98 mg equivalente de Trolox (TE) / g, em que o valor de FRAP foi de 3,00 mM Fe2 + / kg de material seco. Um total de 90 ratos albinos foi usado ​​no presente estudo. O grupo dos ratos foi o seguinte: dieta normal: tratados normais (2, 4 e 6% Ku.), ratos diabéticos (não tratados), diabéticos + dieta HFHC (não tratados), HFHC (não tratados), diabéticos (tratados), HFHC (tratados) e diabéticos + HFHC (tratados). As dietas foram seguidas por 8 semanas. Amostras de sangue foram coletadas ao final do experimento. A glicose sérica foi registrada e os hormônios tireoidianos (T4, Tiroxina e T3, Triiodotironina) foram conduzidos. A dieta suplementada com kumquat em diferentes concentrações tem um efeito hipoglicêmico e melhora os hormônios tireoidianos tanto de ratos diabéticos quanto de ratos diabéticos com HFHC.


Assuntos
Animais , Ratos , Rutaceae , Diabetes Mellitus Experimental/tratamento farmacológico , Pós , Hormônios Tireóideos , Glicemia , Frutas
3.
Front Cell Infect Microbiol ; 12: 958497, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118019

RESUMO

Dermatophytosis is one of the most prevalent fungal infections and a major public health problem worldwide. Recent years have seen a change in the epidemiological patterns of infecting fungi, corresponding to an alarming rise in the prevalence of drug-recalcitrant dermatophyte infections. In patients with diabetes mellitus, dermatophytosis is more severe and recurrent. The potency of promising new antifungal drugs in the pipeline must be expanded to include dermatophytosis. To facilitate this effort, we established a clinically pertinent mouse model of dermatophyte infections, in which diabetic mice were infected with Trichophyton mentagrophytes on abraded skin. The diabetic mouse model was optimized as a simple and robust system for simulating dermatophytoses in diabetic patients. The outcome of infection was measured using clinical and mycological parameters. Infected mice with fungal lesions were treated with oral and topical formulations of terbinafine or topical administration of the FDA-approved and repurposed pan-antifungal drug alexidine dihydrochloride (AXD). In this model, AXD was found to be highly effective, with outcomes comparable to those of the standard of care drug terbinafine.


Assuntos
Diabetes Mellitus Experimental , Tinha , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Biguanidas , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Terbinafina/uso terapêutico , Tinha/tratamento farmacológico
4.
Oxid Med Cell Longev ; 2022: 2297268, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120597

RESUMO

Objective: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) commonly coexist and act synergistically to drive adverse clinical outcomes. This study is aimed at investigating the effects of exercise intervention and oral hypoglycaemic drug of metformin (MET) alone or combined on hepatic lipid accumulation. To investigate if oxidative stress and endoplasmic reticulum stress (ERS) are involved in lipotoxicity-induced hepatocyte apoptosis in diabetic mice and whether exercise and/or MET alleviated oxidative stress or ERS-apoptosis by AMPK-Nrf2-HO-1 signaling pathway. Methods: Forty db/db mice with diabetes (random blood glucose ≥ 250 mg/dL) were randomly allocated into four groups: control (CON), exercise training alone (EX), metformin treatment alone (MET), and exercise combined with metformin (EM) groups. Hematoxylin-eosin and oil red O staining were carried out to observe hepatic lipid accumulation. Immunohistochemical and TUNEL methods were used to detect the protein expression of the binding immunoglobulin protein (BiP) and superoxide dismutase-1 (SOD1) and the apoptosis level of hepatocytes. ERS-related gene expression and the AMPK-Nrf2-HO-1 signaling pathway were tested by western blotting. Results: Our data showed that db/db mice exhibited increased liver lipid accumulation, which induced oxidative and ER stress of the PERK-eIF2α-ATF4 pathway, and hepatocyte apoptosis. MET combined with exercise training significantly alleviated hepatic lipid accumulation by suppressing BiP expression, the central regulator of ER homeostasis, and its downstream PERK-eIF2α-ATF4 pathway, as well as upregulated the AMPK-Nrf2-HO-1 signaling pathway. Moreover, the combination of exercise and MET displayed protective effects on hepatocyte apoptosis by downregulating Bax expression and TUNEL-positive staining, restoring the balance of cleaved-caspase-3 and caspase-3, and improving the antioxidant defense system to prevent oxidative damage in db/db mice. Conclusion: Compared to MET or exercise intervention alone, the combined exercise and metformin exhibited significant effect on ameliorating hepatic steatosis, inhibiting oxidative and ER stress-induced hepatocyte apoptosis via improving the capacity of the antioxidant defense system and suppression of the PERK-eIF2α-ATF4 pathway. Furthermore, upregulation of AMPK-Nrf2-HO-1 signaling pathway might be a key crosstalk between MET and exercise, which may have additive effects on alleviating hepatic lipid accumulation.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Metformina , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose , Glicemia , Caspase 3/metabolismo , Diabetes Mellitus Experimental/metabolismo , Estresse do Retículo Endoplasmático , Amarelo de Eosina-(YS)/farmacologia , Hematoxilina/farmacologia , Hepatócitos/metabolismo , Hipoglicemiantes/farmacologia , Lipídeos , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Transdução de Sinais , Superóxido Dismutase-1/metabolismo , Proteína X Associada a bcl-2/metabolismo
5.
Biomed Pharmacother ; 153: 113411, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076481

RESUMO

Myocardial disorders are the most common cause of renal failure and mortality in diabetic patients, but the molecular mechanism of this process is not yet clear. The reduction of nuclear Erythroid2-related factor-2 (Nrf-2) and positive regulators of Nrf-2 proteins, such as DJ-1 and microRNA-126 (miR-126), after hypoxia and the promotion of reactive oxygen species, might be an intervention indicator in renal failure after myocardial ischemia-reperfusion. Therefore, this study evaluates the renoprotective effect of exercise training and Crataegus persica extract (CE) on myocardial ischemia-reperfusion-induced kidney injury in diabetic rats. Fifty rats were divided into five groups: healthy sedentary control (Con), sedentary diabetic (D), interval trained diabetic (TD), diabetic plus Crataegus persica extract treatment (CD), and interval trained diabetic plus Crataegus persica extract treatment (TCD) groups. The rats in the exercise groups were subjected to moderate-intensity interval training five days per week for ten weeks. The rats in CD and TCD groups received 300 mg/kg of Crataegus persica through gavage for ten weeks. Then, the subjects underwent 30 min of myocardial ischemia and subsequently reperfusion for 24 h. At the end of the experiment, insulin sensitivity, oxidative stress, renal function, histopathology of the kidney, Nrf-2, miR-126, and DJ-1 gene expression levels were evaluated. The results show that the treatments decreased elevated levels of renal oxidative stress, glomerular filtration rate, insulin sensitivity, and pathological score in diabetic rats. Also, the expression of Nrf-2 and miR-126, unlike DJ-1, decreased in diabetic rats due to interval training. Due to the results, diabetes aggravates acute myocardial ischemia-reperfusion-induced kidney injury, while moderate-intensity interval training and Crataegus persica treatment simultaneously ameliorate myocardial ischemia-reperfusion-induced renal injury via miR-126/Nrf-2 pathway and improve insulin sensitivity and renal function in type 1 diabetic rats.


Assuntos
Crataegus , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Resistência à Insulina , MicroRNAs , Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Insuficiência Renal , Traumatismo por Reperfusão , Animais , Diabetes Mellitus Experimental/patologia , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Extratos Vegetais/efeitos adversos , Ratos , Traumatismo por Reperfusão/metabolismo
6.
Iran J Med Sci ; 47(5): 484-493, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36117578

RESUMO

Background: Brown algae have gained worldwide attention due to their significant biological activities, such as antidiabetic properties. In the present study, the antidiabetic properties of six brown algae from the Persian Gulf were investigated. Methods: An experimental study was conducted from 2017 to 2019 to examine the inhibitory effects of six brown algae against the α-glucosidase activity. Methanol (MeOH) and 80% MeOH extracts of Colpomenia sinuosa, Sargassum acinaciforme, Iyengaria stellata, Sirophysalis trinodis, and two accessions of Polycladia myrica were analyzed. The effect of 80% MeOH extracts of Sirophysalis trinodis on blood glucose levels in streptozotocin-induced diabetic rats was evaluated. Chemical constituents of brown algae were analyzed using thin-layer chromatography and liquid chromatography-mass spectrometry techniques. Data were analyzed using SPSS software, and P<0.05 was considered statistically significant. Results: The 80% MeOH extracts of Iyengaria stellata (IC50=0.33±0.15 µg/mL) and Colpomenia sinuosa (IC50=3.50±0.75 µg/mL) as well as the MeOH extracts of Colpomenia sinuosa (IC50=3.31±0.44 µg/mL) exhibited stronger inhibitory effect on α-glucosidase than the acarbose (IC50=160.15±27.52 µg/mL, P<0.001). The 80% MeOH extracts of Sirophysalis trinodis reduced postprandial blood glucose levels in diabetic rats compared to the control group (P=0.037). Fucoxanthin was characterized as the major antidiabetic agent in most of the algal extracts. Conclusion: Sirophysalis trinodis is recommended as a novel source for isolation and identification of potential antidiabetic compounds due to its high in vivo and in vitro antidiabetic effects.


Assuntos
Diabetes Mellitus Experimental , Feófitas , Acarbose , Animais , Glicemia/análise , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/análise , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Oceano Índico , Metanol , Feófitas/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Estreptozocina/análise , alfa-Glucosidases
7.
J Mater Sci Mater Med ; 33(9): 62, 2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36057883

RESUMO

The purpose of this study is to investigate the role of Silibinin (SIL)-modified Hydroxyapatite coating on osseointegration in diabetes in vivo and in vitro and explore the mechanism of osteogenic differentiation of MC3T3-E1. RT-qPCR, Immunofluorescence, and Western blot were used to measure the expression level of oxidative Stress Indicators and osteogenic markers proteins. Moreover, CCK-8 assay was conducted to detect cell viability in hyperglycemia. Alizarin red staining and alkaline phosphatase staining were used to examine osteogenic function and calcium deposits. The diabetic rat model receive titanium rod implantation was set up successfully and Von-Gieson staining was used to examine femoral bone tissue around titanium rod. Our results showed that intracellular oxidative stress in hyperglycemia was overexpressed, while FoxO1, SIRT1, GPX1, and SOD2 were downregulated. SIL suppressed oxidative stress to promote osteogenic differentiation. Additionally, it was confirmed that SIL promoted osteogenic differentiation of MC3T3-E1 and obviously restored the osseointegration ability of diabetic rats. Further study indicated that SIL exerted its beneficial function through activation SIRT1/SOD2 signaling pathway to restore osteoblast function, and improved the osseointegration and stability of titanium rods in vivo. Our research suggested that the SIL-modulated oxidative Stress inhibition is responsible for the activation of the process of osteogenic differentiation through activation SIRT1/SOD2 signaling pathway in hyperglycemia, providing a novel insight into improving prosthetic osseointegration in diabetic patients. Hyperglycemia impaired the activity and function of MC3T3-E1 and inhibits bone formation by up-regulating intracellular ROS levels through inhibition of SIRT1/SOD2 signaling pathway. Local administrator SIL can improve the activity and function of osteoblasts and enhance osseointegration by reducing intracellular ROS through activation of SIRT1/SOD2 signaling pathway in DM rat models.


Assuntos
Diabetes Mellitus Experimental , Hiperglicemia , Animais , Diferenciação Celular , Durapatita , Osseointegração , Osteoblastos , Osteogênese , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Silibina , Sirtuína 1/metabolismo , Superóxido Dismutase/metabolismo , Titânio/farmacologia
8.
FASEB J ; 36(10): e22531, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36063130

RESUMO

Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus and will lead to visual impairment. We aim to explore the effects and mechanisms of wnt inhibitory factor 1 (WIF1) in the progression of DR. To establish DR in vitro and in vivo, human retinal pigment epithelium (RPE) cell line ARPE-19 was treated with high-glucose (HG) and diabetic mice models were induced by streptozotocin (STZ), respectively. Different dose of recombinant WIF1 protein was used to treat DR. qRT-PCR and western blotting results demonstrated that WIF1 was downregulated, while VEGFA was upregulated in HG-induced ARPE-19 cells. WIF1 overexpression promoted cell migration. The ARPE-19 cells culture medium treated with WIF1 inhibited retinal endothelial cell tube formation and downregulated VEGFA expression. Moreover, WIF1 decreased the levels of ROS and MDA, while increasing the activity of SOD and GPX. WIF1 increased the ΔΨm in the mitochondria and downregulated the expression of mitochondrial autophagy-related proteins including Parkin, Pink1, LC3-II/LC3-I ratio, cleaved caspase 3, and cyt-c, which ameliorated mitochondrial dysfunction. The in vivo studies further demonstrated the consistent effects of WIF1 in STZ-induced mice. Taken together, WIF1 ameliorated mitochondrial dysfunction in DR by downregulating the AMPK/mTOR pathway.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/metabolismo , Humanos , Camundongos , Mitocôndrias/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Serina-Treonina Quinases TOR/metabolismo
9.
Pharm Biol ; 60(1): 1690-1700, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36073930

RESUMO

CONTEXT: Kirenol possesses anti-inflammatory, antifibrotic and anti-arthritic effects. However, its reno-protective effects against diabetic nephropathy (DN) have not been evaluated. OBJECTIVE: This study explores the reno-protective effects of kirenol against DN and clarifies the potential mechanisms. MATERIALS AND METHODS: The mesangial cells were treated with 20 µM kirenol and 10 ng/mL human recombinant TGF-ß1 or 30 mM glucose for 24 h. Then the cells were harvested to assay the expression of the target genes or proteins. Thirty C57BL/6J male mice were given high-fat diet with streptozotocin injection to induce diabetes and then were randomized into three groups (n = 10): vehicle administration (DM group), 2 mg/kg kirenol (DM + kirenol group) and 200 mg/kg metformin (Met group) for 3 months, orally. A healthy group (Con, n = 10) was included as the control. RESULTS: Compared to the DM group, kirenol treatment decreased the phosphorylation of Smad2/3 and NF-κB (0.64- and 0.43-fold) as well as the accumulation of FN and Col IV (0.58- and 0.35-fold); moreover, the expression of IκBα was restored to normal level by kirenol treatment both in vivo and in vitro. After kirenol treatment, IL-6 expression was decreased 0.35- and 0.57-fold, and TNF-α expression was decreased 0.34- and 0.46-fold, in vitro and in vivo, respectively. Furthermore, kirenol alleviated the glomerular basement membrane thickness and foot process fusion. DISCUSSION AND CONCLUSIONS: Kirenol could alleviate DN by downregulating the TGF-ß/Smads and the NF-κB signal pathway. Our study provides a potential mechanism for the treatment of DN with kirenol.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Diterpenos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
10.
Pharm Biol ; 60(1): 1732-1738, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36086879

RESUMO

CONTEXT: Salidroside (SAL), one of the major glycosides isolated from the roots of Rhodiola rosea L. (Crassulaceae), has anti-inflammatory, antioxidant, and antidiabetic properties. OBJECTIVE: Our study assessed whether SAL exerts a protective effect on streptozotocin (STZ)-induced diabetic nephropathy (DN) in rats via the Akt/GSK-3ß signalling pathway. MATERIALS AND METHODS: Adult male Wistar rats were divided into three groups (n = 8): normal control, DN + vehicle, and DN + SAL. SAL (50 mg/kg/day, oral) was administered for 8 weeks. Biochemical and histopathologic examinations were performed to evaluate the therapeutic effects of SAL on oxidative stress, inflammation, renal function, and apoptosis. RESULTS: SAL induced rats demonstrated ameliorated levels of FBG (20.53 ± 0.72 mmol/L vs. 26.02 ± 1.44 mmol/L), urine albumin excretion (27.00 ± 1.46 mmol/L vs. 41.00 ± 1.59 mmol/L), blood urea nitrogen (14.42 ± 0.70 mmol/L vs. 17.77 ± 0.72 mmol/L), and serum creatinine (112.80 ± 6.98 mmol/L vs. 159.00 ± 3.81 mmol/L) compared to normal control rats, along with the alleviation of renal pathologic changes by improving the irregular shape of glomeruli tissues. Biochemical analysis showed that SAL-treated animals displayed suppressed levels of serum inflammatory cytokines and kidney oxidative stress markers and attenuated apoptotic characteristics. Moreover, it increased the phosphorylation levels of Akt and GSK-3ß in kidneys. DISCUSSION AND CONCLUSION: The present study validated the involvement of the Akt/GSK-3ß signalling pathway in renal improvement. These findings can form the basis to investigate the protective effect of SAL in DN in clinical trials.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Glucosídeos , Glicogênio Sintase Quinase 3 beta/metabolismo , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Masculino , Estresse Oxidativo , Fenóis , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Estreptozocina/farmacologia
11.
Front Endocrinol (Lausanne) ; 13: 938680, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093092

RESUMO

Obesity plays a major role in type II diabetes (T2DM) progression because it applies metabolic and oxidative stress resulting in dysfunctional beta-cells and activation of intra-islet pancreatic stellate cells (PaSCs) which cause islet fibrosis. Administration of antioxidant N-acetyl-L-cysteine (NAC) in vivo improves metabolic outcomes in diet-induced obese diabetic mice, and in vitro inhibits PaSCs activation. However, the effects of NAC on diabetic islets in vivo are unknown. This study examined if dosage and length of NAC treatment in HFD-induced diabetic mice effect metabolic outcomes associated with maintaining healthy beta-cells and quiescent PaSCs, in vivo. Male C57BL/6N mice were fed normal chow (ND) or high-fat (HFD) diet up to 30 weeks. NAC was administered in drinking water to HFD mice in preventative treatment (HFDpNAC) for 23 weeks or intervention treatment for 10 (HFDiNAC) or 18 (HFDiNAC+) weeks, respectively. HFDpNAC and HFDiNAC+, but not HFDiNAC, mice showed significantly improved glucose tolerance and insulin sensitivity. Hyperinsulinemia led by beta-cell overcompensation in HFD mice was significantly rescued in NAC treated mice. A reduction of beta-cell nuclear Pdx-1 localization in HFD mice was significantly improved in NAC treated islets along with significantly reduced beta-cell oxidative stress. HFD-induced intra-islet PaSCs activation, labeled by αSMA, was significantly diminished in NAC treated mice along with lesser intra-islet collagen deposition. This study determined that efficiency of NAC treatment is beneficial at maintaining healthy beta-cells and quiescent intra-islet PaSCs in HFD-induced obese T2DM mouse model. These findings highlight an adjuvant therapeutic potential in NAC for controlling T2DM progression in humans.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Acetilcisteína/metabolismo , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/etiologia , Estresse Oxidativo , Células Estreladas do Pâncreas/metabolismo
12.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 57(9): 938-945, 2022 Sep 09.
Artigo em Chinês | MEDLINE | ID: mdl-36097941

RESUMO

Objective: To study the effect of gastrodin on oxidative stress and bone tissue around implants in type 2 diabetes mellitus rats (T2DM), so as to provide therapeutic basis for the problems of poor osseointegration and long repair period of implants in type 2 diabetic patients, to provide the basis for the development of new therapeutic drugs. Methods: Forty SD rats aged 5 weeks were divided into control group (n=10) and model group (n=30). The model group was fed with high glycolipid diet for 4 weeks and injected with 35 mg/kg streptozocin. The T2DM were divided into diabetic group (n=10) and gastrodin group (n=10). Pure screw titanium implants were placed in the metaphysis of both tibia. Rats in gastrodin group were given gastrodin 13.6 mg/kg everyday, while the control group and diabetic group were given the same dose of saline solution. Blood glucose was measured every two weeks after operation in all rats. After 4 and 8 weeks, the contents of serum malondialdehyde (MDA) and superoxide dismutase (SOD) were measured to analyze the oxidative stress level in rats. The expression of anti-apoptosis protein [B cell lymphoma/lewkmia-2 (bcl-2)]and apoptosis protein [bcl-2-associated X protein (bax)] was analyzed by immunohistochemistry. HE staining and micro-CT scanning were used to analyze the osseointegration around the implants. Results: The blood glucose of gastrodin [(12.98±2.53), (13.64±1.96), (14.58±3.40) and (12.84±2.82) mmol/L] were significantly lower than that of diabetic group [(20.97±2.27), (17.94±3.76), (23.66±2.90) and (21.22±2.67) mmol/L] at corresponding time point (P<0.017). Four and 8 weeks following surgery, the MDA concentration in gastrodin group [(5.21±1.60) and (3.47±1.17) nmol/ml] was significantly lower than that in diabetic group [(11.42±5.11) and (7.31±1.37) nmol/ml] at the corresponding time points (P<0.017), while SOD activity in gastrodin group [(42.89±6.00) and (53.12±9.73) U/ml] was significantly higher than those in diabetic group [(27.09±6.11) and (32.08±2.97) U/ml] at the corresponding time points (P<0.017). Immunohistochemistry showed that the bcl-2 expression in gastrodin group was significantly higher than that in diabetic group at 4 and 8 weeks following surgery (P<0.017), while the bax expression in gastrodin group was significantly lower than that in diabetic group (P<0.017). Four weeks after surgery, the bone volume/tissue volume (BV/TV), connection density (Conn.D), trabecular number (Tb.N), trabecular thickness (Tb.Th) in gastrodin group were significantly higher than those in diabetic group (P<0.017). There was no significant difference in trabecular separation/spacing (Tb.sp) between gastrodin group and diabetic group (P<0.017). Eight weeks after surgery, the BV/TV, Tb.N in gastrodin group were significantly higher than those in the diabetic group (P<0.017). There was no significant difference in Conn.D between gastrodin group and diabetic group (P<0.017). There was no significant difference in Tb.Th and Tb.sp in three groups (P<0.017). The trabecular structure in gastrodin group was better than that in diabetic group by HE staining. Conclusions: Gastrodin can decrease blood glucose, improve oxidative stress, protect bone tissue from apoptosis and promote bone formation around implants in T2DM.


Assuntos
Implantes Dentários , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , Álcoois Benzílicos , Glicemia , Glucosídeos , Proteínas Proto-Oncogênicas c-bcl-2 , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase , Tíbia , Proteína X Associada a bcl-2
13.
Front Immunol ; 13: 976511, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059533

RESUMO

Human Mesenchymal Stromal Cells (hMSCs) are a promising source for cell-based therapies. Yet, transition to phase III and IV clinical trials is remarkably slow. To mitigate donor variabilities and to obtain robust and valid clinical data, we aimed first to develop a manufacturing concept balancing large-scale production of pooled hMSCs in a minimal expansion period, and second to test them for key manufacture and efficacy indicators in the clinically highly relevant indication wound healing. Our novel clinical-scale manufacturing concept is comprised of six single donor hMSCs master cell banks that are pooled to a working cell bank from which an extrapolated number of 70,000 clinical doses of 1x106 hMSCs/cm2 wound size can be manufactured within only three passages. The pooled hMSC batches showed high stability of key manufacture indicators such as morphology, immune phenotype, proliferation, scratch wound healing, chemotactic migration and angiogenic support. Repeated topical hMSCs administration significantly accelerated the wound healing in a diabetic rat model by delivering a defined growth factor cargo (specifically BDNF, EGF, G-CSF, HGF, IL-1α, IL-6, LIF, osteopontin, VEGF-A, FGF-2, TGF-ß, PGE-2 and IDO after priming) at the specific stages of wound repair, namely inflammation, proliferation and remodeling. Specifically, the hMSCs mediated epidermal and dermal maturation and collagen formation, improved vascularization, and promoted cell infiltration. Kinetic analyses revealed transient presence of hMSCs until day (d)4, and the dynamic recruitment of macrophages infiltrating from the wound edges (d3) and basis (d9), eventually progressing to the apical wound on d11. In the wounds, the hMSCs mediated M2-like macrophage polarization starting at d4, peaking at d9 and then decreasing to d11. Our study establishes a standardized, scalable and pooled hMSC therapeutic, delivering a defined cargo of trophic factors, which is efficacious in diabetic wound healing by improving vascularization and dynamic recruitment of M2-like macrophages. This decision-making study now enables the validation of pooled hMSCs as treatment for impaired wound healing in large randomized clinical trials.


Assuntos
Diabetes Mellitus Experimental , Células-Tronco Mesenquimais , Animais , Medula Óssea , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/terapia , Humanos , Macrófagos , Células-Tronco Mesenquimais/metabolismo , Neovascularização Patológica/metabolismo , Ratos , Cicatrização
14.
Sci Data ; 9(1): 558, 2022 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-36088402

RESUMO

Mouse models for streptozotocin (STZ) induced diabetes probably represent the most widely used systems for preclinical diabetes research, owing to the compound's toxic effect on pancreatic ß-cells. However, a comprehensive view of pancreatic ß-cell mass distribution subject to STZ administration is lacking. Previous assessments have largely relied on the extrapolation of stereological sections, which provide limited 3D-spatial and quantitative information. This data descriptor presents multiple ex vivo tomographic optical image datasets of the full ß-cell mass distribution in mice subject to single high and multiple low doses of STZ administration, and in glycaemia recovered mice. The data further include information about structural features, such as individual islet ß-cell volumes, spatial coordinates, and shape as well as signal intensities for both insulin and GLUT2. Together, they provide the most comprehensive anatomical record of the effects of STZ administration on the islet of Langerhans in mice. As such, this data descriptor may serve as reference material to facilitate the planning, use and (re)interpretation of this widely used disease model.


Assuntos
Diabetes Mellitus Experimental , Ilhotas Pancreáticas , Animais , Glicemia/análise , Insulina/análise , Camundongos , Estreptozocina/análise
15.
Int J Mol Sci ; 23(17)2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36077003

RESUMO

New quinazoline-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds VI-6-a, V, IV-4, VI-4-c, IV-6, VI-2-a, IV-1, and IV-2 were more potent than the reference glibenclamide. They induced significant reduction in the blood glucose levels of diabetic rats: 78.2, 73.9, 71.4, 67.3, 62, 60.7, 58.4, and 55.9%, respectively, while the reference glibenclamide had 55.4%. Compounds IV-1, VI-2-a, IV-2, V, and IV-6 showed more prolonged antidiabetic activity than glibenclamide. Moreover, molecular docking and pharmacokinetic studies were performed to examine binding modes of the prepared compounds against peroxisome proliferator-activated receptor gamma (PPARγ). The highest active compounds exhibited good binding affinity with high free energy of binding against PPARγ. In silico absorption, distribution, metabolism, elimination and toxicity (ADMET) studies were performed to investigate pharmacokinetics and safety of the synthesized compounds. They showed considerable human intestinal absorption with low toxicity profile.


Assuntos
Diabetes Mellitus Experimental , PPAR gama , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Glibureto/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Simulação de Acoplamento Molecular , PPAR gama/metabolismo , Quinazolinas/efeitos adversos , Ratos , Compostos de Sulfonilureia/efeitos adversos , Receptores de Sulfonilureias/agonistas
16.
Int J Mol Sci ; 23(17)2022 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-36077157

RESUMO

Sexual dysfunction is a common problem for men with diabetes. Epigallocatechin gallate (EGCG) is known to ameliorate erectile function in aging rats. However, there has not yet been a report to evaluate its effects on diabetic male rat sexual behavior in the literature. In this study, we investigated the effects of EGCG on male sexual behavior in diabetic rats. Diabetic rats were induced by a single intraperitoneal injection of 65 mg/kg of streptozotocin. After streptozotocin injection for one week, animals were then orally treated with 40 mg/kg of EGCG or vehicle. Copulatory behavior and fasting blood glucose levels were recorded before treatment, as well as 7 and 14 days after treatment. Serum LH, testosterone, and PDE5a levels were measured by EIA assay after the last behavioral test. Data showed that diabetic rats who had diminished sexual functions demonstrated significantly increased latencies in mount, intromission, and ejaculation, as well as significant decreases in frequencies of intromission and ejaculation, compared to non-diabetic controls, indicating sexual function recovery. Lower blood glucose levels were also found in diabetic rats after EGCG treatment. Additionally, the lower LH and higher PDE5a levels in diabetic rats than controls were also noted. The findings declared that EGCG had a protective effect on male sexual behavior in diabetic rats.


Assuntos
Catequina , Diabetes Mellitus Experimental , Animais , Glicemia , Catequina/análogos & derivados , Catequina/farmacologia , Catequina/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Humanos , Masculino , Ratos , Estreptozocina
17.
Int J Mol Sci ; 23(17)2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36077238

RESUMO

Patients with diabetes mellitus tend to develop ischemia-related complications and have compromised endothelial progenitor cell (EPC) function. Melatonin protects against ischemic injury, possibly via EPC modulation. We investigated whether melatonin pretreatment could restore EPC function impairment and improve circulation recovery in a diabetic critical limb ischemia mouse model. Under 25 mM high-glucose medium in vitro, EPC proliferation, nitric oxide production, tube formation, and endothelial nitric oxide synthase (eNOS) phosphorylation were significantly suppressed. Hyperglycemia promoted EPC senescence and apoptosis as well as increased reactive oxygen species (ROS) production. Melatonin treatment reversed the harmful effects of hyperglycemia on EPC through adenosine monophosphate-activated protein kinase-related mechanisms to increase eNOS phosphorylation and heme oxygenase-1 expression. In an in-vivo study, after a 4-week surgical induction of hindlimb ischemia, mice with streptozotocin (STZ)-induced diabetes showed significant reductions in new vessel formation, tissue reperfusion, and EPC mobilization in ischemic hindlimbs compared to non-diabetic mice. Mice with STZ-induced diabetes that received melatonin treatment (10 mg/kg/day, intraperitoneal) had significantly improved blood perfusion ratios of ischemic to non-ischemic limb, EPC mobilization, and densities of capillaries. In addition, a murine bone marrow transplantation model to support these findings demonstrated that melatonin stimulated bone marrow-originated EPCs to differentiate into vascular endothelial cells in femoral ligation-induced ischemic muscles. In summary, this study suggests that melatonin treatment augments EPC function along with neovascularization in response to ischemia in diabetic mice. We illustrated the protective effects of melatonin on EPC H2O2 production, senescence, and migration through melatonin receptors and modulating eNOS, AMPK, and HO-1 activities at the cellular level. Thus, melatonin might be used to treat the impairment of EPC mobilization and circulation recuperation in response to ischemic injury caused by chronic hyperglycemia. Additional studies are needed to elucidate the applicability of the results in humans.


Assuntos
Diabetes Mellitus Experimental , Células Progenitoras Endoteliais , Hiperglicemia , Melatonina , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Células Progenitoras Endoteliais/metabolismo , Membro Posterior/irrigação sanguínea , Humanos , Peróxido de Hidrogênio/metabolismo , Hiperglicemia/metabolismo , Isquemia/metabolismo , Melatonina/metabolismo , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica , Estreptozocina/farmacologia
18.
Int J Mol Sci ; 23(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36077579

RESUMO

Background: Diabetic retinopathy (DR) is a neurovascular disease, characterized by a deficiency of brain-derived neurotrophic factor (BDNF), a regulator of autophagy. Beta-hydroxybutyrate (BHB), previously reported as a protective agent in DR, has been associated with BDNF promotion. Here, we investigated whether systemic BHB affects the retinal levels of BDNF and local autophagy in diabetic mice with retinopathy; Methods: C57BL/6J mice were administered with intraperitoneal (i.p.) streptozotocin (STZ) (75 mg/kg) injection to develop diabetes. After 2 weeks, they received i.p. injections of BHB (25-50-100 mg/kg) twice a week for 10 weeks. Retinal samples were collected in order to perform immunofluorescence, Western blotting, and ELISA analysis; Results: BHB 50 mg/kg and 100 mg/kg significantly improved retinal BDNF levels (p < 0.01) in diabetic mice. This improvement was negatively associated with autophagosome-lysosome formations (marked by LC3B and ATG14) and to higher levels of connexin 43 (p < 0.01), a marker of cell integrity. Moreover, BHB administration significantly reduced M1 microglial activation and autophagy (p < 0.01); Conclusions: The systemic administration of BHB in mice with DR improves the retinal levels of BDNF, with the consequent reduction of the abnormal microglial autophagy. This leads to retinal cell safety through connexin 43 restoration.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Ácido 3-Hidroxibutírico/farmacologia , Animais , Autofagia , Fator Neurotrófico Derivado do Encéfalo , Conexina 43 , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Retinopatia Diabética/complicações , Retinopatia Diabética/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Retina
19.
Cells ; 11(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36078059

RESUMO

INTRODUCTION: Diabetes mellitus results in high rates of cardiovascular disease, such as microcirculation disorder of the lower limbs, with angiogenesis impairment being the main factor. The endothelium functions as a barrier between blood and the vessel wall. Vascular endothelial cell dysfunction caused by hyperglycemia is the main factor leading to angiogenesis impairment. Hydrogen sulfide (H2S) and miR-126-3p are known for their pro-angiogenesis effects; however, little is known about how H2S regulates miR-126-3p to promote angiogenesis under high-glucose conditions. OBJECTIVES: The main objective of this research was to explore how H2S regulates the miR-126-3p levels under high-glucose conditions. METHODS: We evaluated the pro-angiogenesis effects of H2S in the diabetic hindlimb of an ischemia mice model and in vivo Matrigel plugs. Two microRNA datasets were used to screen microRNAs regulated by both diabetes and H2S. The mRNA and protein levels were detected through real-time PCR and Western blot, respectively. Immunofluorescent staining was also used to assess the capillary density and to evaluate the protein levels in vascular endothelial cells. Human umbilical vein endothelial cells (HUVECs) were used in in vitro experiments. A scratch wound-healing assay was applied to detect the migration ability of endothelial cells. Methylated DNA immunoprecipitation combined with real-time PCR was chosen to identify the DNA methylation level in the HUVECs. RESULTS: Exogenous H2S improved angiogenesis in diabetic mice. miR-126-3p was regulated by both diabetes and H2S. Exogenous H2S up-regulated the miR-126-3p level and recovered the migration rate of endothelial cells via down-regulating the DNMT1 protein level, which was increased by high glucose. Furthermore, DNMT1 upregulation in the HUVECs increased the methylation levels of the gene sequences upstream of miR-126-3p and then inhibited the transcription of primary-miR-126, thus decreasing the miR-126-3p level. CSE overexpression in the HUVECs rescued the miR-126-3p level, by decreasing the methylation level to improve migration. CONCLUSION: H2S increases the miR-126-3p level through down-regulating the methylation level, by decreasing the DNMT1 protein level induced by high glucose, thus improving the angiogenesis originally impaired by high glucose.


Assuntos
Diabetes Mellitus Experimental , Sulfeto de Hidrogênio , MicroRNAs , Indutores da Angiogênese/metabolismo , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Camundongos , MicroRNAs/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo
20.
Drug Deliv ; 29(1): 2831-2845, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36050870

RESUMO

The lipophilicity of a peptide drug can be considerably increased by hydrophobic ion pairing with amphiphilic counterions for successful incorporation into lipid-based formulations. Herein, to enhance the oral absorption of insulin (INS), a self-microemulsifying drug delivery system (SMEDDS) formulation was developed. Prior to optimization, INS was complexed with sodium n-octadecyl sulfate (SOS) to increase the loading into the SMEDDS. The INS-SOS complex was characterized via scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and its dissociation behavior. The SMEDDS was optimized using a D-optimal mixture design with three independent variables including Capmul MCM (X1, 9.31%), Labrasol (X2, 49.77%), and Tetraglycol (X3, 40.92%) and three response variables including droplet size (Y1, 115.2 nm), INS stability (Y2, 46.75%), and INS leakage (Y3, 17.67%). The desirability function was 0.766, indicating excellent agreement between the predicted and experimental values. The stability of INS-SOS against gastrointestinal enzymes was noticeably improved in the SMEDDS, and the majority of INS remained in oil droplets during release. Following oral administration in diabetic rats, the optimized SMEDDS resulted in pharmacological availabilities of 3.23% (50 IU/kg) and 2.13% (100 IU/kg). Thus, the optimized SMEDDS is a good candidate for the practical development of oral delivery of peptide drugs such as INS.


Assuntos
Diabetes Mellitus Experimental , Insulina , Administração Oral , Animais , Disponibilidade Biológica , Diabetes Mellitus Experimental/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Ratos , Solubilidade
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