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1.
Int J Mol Sci ; 23(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36362021

RESUMO

Diabetes mellitus (DM) is a chronic progressive metabolic disorder associated with several gastrointestinal complications, affecting up to 75% of patients. Knowing that Angiotensin II (AngII) also regulates intestinal contraction, we decided to evaluate changes in ileum and colon histomorphometry and AngII reactivity in a rat model of DM. Streptozotocin (STZ, 55 mg/kg) was administered to induce DM to 24 adult male Wistar rats. Diabetic rats displayed all the characteristic signs of type 1 DM (T1DM) and fecal excretion increased about 4-fold over 14 days, while the excretion of controls remained unaltered. Compared to controls, diabetic ileum and colon presented an increase in both macroscopic (length, perimeter and weight) and microscopic (muscular wall thickness) parameters. Functionally, AngII-induced smooth muscle contraction was lower in diabetic rats, except in the distal colon. These differences in the contractile response to AngII may result from an imbalance between AngII type 1 (antagonized by candesartan, 10 nM) and type 2 receptors activation (antagonized by PD123319, 100 nM). Taken together, these results indicate that an early and refined STZ-induced T1DM rat model already shows structural remodelling of the gut wall and decreased contractile response to AngII, findings that may help to explain diabetic dysmotility.


Assuntos
Angiotensina II , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Animais , Masculino , Ratos , Angiotensina II/farmacologia , Angiotensina II/fisiologia , Colo/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/complicações , Íleo/metabolismo , Ratos Wistar , Estreptozocina/farmacologia
2.
Molecules ; 27(21)2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36364022

RESUMO

Herb-drug interactions are vital in effectively managing type-2-diabetes complications. Puerarin is a natural isoflavonoid in the Pueraria genus, and its pharmacological activities, including antidiabetic activity, are well established. The similar modes of action of puerarin and metformin in diabetic models suggest their positive pharmacodynamic interactions. This study investigated this in streptozotocin/nicotinamide-induced type-2 diabetic rats. Puerarin at doses of 80 mg/kg, 120 mg/kg and 160 mg/kg improved the activity of metformin in reversing hyperglycaemia, dysregulated lipid profiles, dysfunction of the liver, kidney, and pancreas, and inflammation. The treatment with either puerarin (high dose, 160 mg/kg intraperitoneally) or metformin (100 mg/kg intraperitoneally) did not bring the dysregulated biomarkers to normal levels in 4 weeks. By contrast, the combination of puerarin (160 mg/kg) and metformin (100 mg/kg) did. This study is the first to report scientific evidence for the positive pharmacodynamic interactions between puerarin and metformin.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Isoflavonas , Metformina , Ratos , Animais , Metformina/farmacologia , Metformina/uso terapêutico , Diabetes Mellitus Experimental/induzido quimicamente , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações
3.
Pharm Biol ; 60(1): 2229-2236, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36367996

RESUMO

CONTEXT: Ginsenoside Rb1 (Rb1) is a biologically active component of ginseng [Panax ginseng C.A. Meyer (Araliaceae)]. OBJECTIVE: This study determined the underlying mechanisms of Rb1 treatment that acted on diabetes-injured lungs in diabetic rats. MATERIALS AND METHODS: Streptozotocin (STZ)-induced diabetic rat model was used. Male Sprague-Dawley (SD) rats were divided into four groups (n = 10): control, Rb1 (20 mg/kg), insulin (15 U/kg to attain the euglycaemic state) and diabetic (untreated). After treatment for six weeks, oxidative stress assay; histological and ultrastructure analyses; TNF-α, TGF-ß, IL-1 and IL-6 protein expression analyses; and the detection of apoptosis were performed. RESULTS: There was decreased activity of SOD (3.53-fold), CAT (2.55-fold) and GSH (1.63-fold) and increased levels of NO (4.47-fold) and MDA (3.86-fold) in the diabetic group from control. Rb1 treatment increased SOD (2.4-fold), CAT (1.9-fold) and GSH (1.29-fold) and decreased the levels of NO (1.76-fold) and MDA (1.51-fold) as compared with diabetic rats. The expression of IL-6 (5.13-fold), IL-1α (2.35-fold), TNF-α (2.35-fold) and TGF-ß (2.39-fold) was increased in diabetic rats from control. IL-6 (2.43-fold), IL-1α (2.27-fold), TNF-α (1.68-fold) and TGF-ß (2.3-fold) were decreased in the Rb1 treatment group. Diabetes increased the apoptosis rate (2.23-fold vs. control), and Rb1 treatment decreased the apoptosis rate (1.73-fold vs. the diabetic rats). Rb1 and insulin ameliorated lung tissue injury. DISCUSSION AND CONCLUSIONS: These findings indicate that Rb1 could be useful for mitigating oxidative damage and inflammatory infiltration in the diabetic lung.


Assuntos
Diabetes Mellitus Experimental , Ginsenosídeos , Panax , Ratos , Masculino , Animais , Estreptozocina , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/induzido quimicamente , Fator de Necrose Tumoral alfa , Interleucina-6 , Ratos Sprague-Dawley , Ginsenosídeos/farmacologia , Estresse Oxidativo , Inflamação/tratamento farmacológico , Panax/química , Pulmão , Insulina , Fator de Crescimento Transformador beta , Superóxido Dismutase
4.
Curr Protoc ; 2(11): e580, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36326552

RESUMO

This article describes a protocol for chemically inducing type I diabetes mellitus in beagle dogs using a mixture of alloxan (ALX) and streptozotocin (STZ). ALX and STZ are both cytotoxic, diabetogenic agents that cause necrosis of pancreatic ß-cells and therefore halt the production of insulin. Although both compounds are widely used in experimental animal models of diabetes, standard protocols employing a single high dose of either agent are also implicated in adjacent organ damage. In contrast, combined administration of ALX and STZ allows for the use of lower doses, a method that effectively destroys ß-cells and circumvents unwanted adverse effects. The procedures described in this protocol produce persistent, insulin-dependent hyperglycemia in beagle dogs using combined doses of ALX and STZ lower than those previously described for a single intravenous administration. This model can be used to test experimental compounds indicated for the treatment of diabetes. © 2022 Wiley Periodicals LLC. Basic Protocol: Induction of type I diabetes mellitus in beagle dogs using alloxan and streptozotocin.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Cães , Animais , Aloxano/farmacologia , Estreptozocina/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/tratamento farmacológico , Insulina
5.
Am J Physiol Endocrinol Metab ; 323(6): E480-E491, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36223521

RESUMO

Several aspects of diabetes pathophysiology and complications result from hyperglycemia-induced alterations in the structure and function of plasma proteins. Furthermore, insulin has a significant influence on protein metabolism by affecting both the synthesis and degradation of proteins in various tissues. To understand the role of progressive hyperglycemia on plasma proteins, in this study, we measured the turnover rates of high-density lipoprotein (HDL)-associated proteins in control (chow diet), prediabetic [a high-fat diet (HFD) for 8 wk] or diabetic [HFD for 8 wk with low-dose streptozotocin (HFD + STZ) in weeks 5-8 of HFD] C57BL/6J mice using heavy water (2H2O)-based metabolic labeling approach. Compared with control mice, HFD and HFD + STZ mice showed elevations of fasting plasma glucose levels in the prediabetic and diabetic range, respectively. Furthermore, the HFD and HFD + STZ mice showed increased hepatic triglyceride (TG) levels, total plasma cholesterol, and plasma TGs. The kinetics of 40 proteins were quantified using the proteome dynamics method, which revealed an increase in the fractional synthesis rate (FSR) of HDL-associated proteins in the prediabetic mice compared with control mice, and a decrease in FSR in the diabetic mice. The pathway analysis revealed that proteins with altered turnover rates were involved in acute-phase response, lipid metabolism, and coagulation. In conclusion, prediabetes and diabetes have distinct effects on the turnover rates of HDL proteins. These findings suggest that an early dysregulation of the HDL proteome dynamics can provide mechanistic insights into the changes in protein levels in these conditions.NEW & NOTEWORTHY This study is the first to examine the role of gradual hyperglycemia during diabetes disease progression on HDL-associated protein dynamics in the prediabetes and diabetic mice. Our results show that the fractional synthesis rate of HDL-associated proteins increased in the prediabetic mice whereas it decreased in the diabetic mice compared with control mice. These kinetic changes can help to elucidate the mechanism of altered protein levels and HDL dysfunction during diabetes disease progression.


Assuntos
Diabetes Mellitus Experimental , Hiperglicemia , Estado Pré-Diabético , Camundongos , Animais , Estado Pré-Diabético/complicações , Lipoproteínas HDL , Diabetes Mellitus Experimental/induzido quimicamente , Glicemia/metabolismo , Proteoma , Camundongos Endogâmicos C57BL , Estreptozocina , Dieta Hiperlipídica , Hiperglicemia/metabolismo , Progressão da Doença
6.
Bioorg Chem ; 129: 106203, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36265352

RESUMO

Farnesoid X receptor (FXR) ligands have been actively pursued to treat metabolic disorders, liver and bile diseases, among others. Starting from a widely occurring natural product, oleanolic acid (OA), we discovered potent and selective FXR modulator from the 12ß-oxygenated OA alkyl esters, with the assistance of molecular modeling. The representative compound 7b modulated some FXR downstream genes involved in glucose and lipid metabolism in cells, and significantly improved hyperglycemia in KKay fat mice fed with high fat diet, through the reduction of mRNA expression of gluconeogenesis genes PEPCK and G6Pase. This study provides a new series of selective FXR modulator, as well as the in vitro and in vivo evidence for their potential to improve hyperglycemia in diabetic mice through FXR antagonism.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hiperglicemia , Hipoglicemiantes , Ácido Oleanólico , Receptores Citoplasmáticos e Nucleares , Animais , Camundongos , Ácidos e Sais Biliares/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Ésteres/química , Ésteres/farmacologia , Ésteres/uso terapêutico , Hiperglicemia/tratamento farmacológico , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gluconeogênese/efeitos dos fármacos
7.
Nutrients ; 14(19)2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36235791

RESUMO

Diabetes mellitus (DM) impairs the wound healing process, seriously threatening the health of the diabetic population. To date, few effective approaches have been developed for the treatment of diabetic wounds. Krill oil (KO) contains bioactive components that have potent anti-inflammatory and anti-oxidative activities. As prolonged inflammation is a crucial contributor to DM-impaired wound healing, we speculated that the local application of KO would accelerate diabetic wound healing. Therefore, KO was applied to artificially created wounds of type 2 diabetic mice induced by streptozotocin and high-fat diet. The diabetic mice had a delayed wound healing process compared with the non-diabetic control mice, with excessive inflammation, impaired collagen deposition, and depressed neovascularization in the wound area. These effects were dramatically reversed by KO. In vitro, KO blocked the TNF-α-induced macrophage inflammation, fibroblast dysfunction, and endothelial angiogenic impairment. The present study in mice suggests that KO local application could be a viable approach in the management of diabetic wounds.


Assuntos
Anti-Inflamatórios , Diabetes Mellitus Experimental , Euphausiacea , Cicatrização , Animais , Anti-Inflamatórios/farmacologia , Colágeno/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Euphausiacea/química , Inflamação/tratamento farmacológico , Camundongos , Pele , Estreptozocina/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo , Cicatrização/efeitos dos fármacos
8.
Braz J Biol ; 84: e261518, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36228225

RESUMO

Plants have profound therapeutic benefits, more economical treatments, fewer side effects, and a relatively cheap cost, making them a source of drugs for protective, preventative, curative, or conducive purposes and creating novel phytomedicines. Plant derived medicines are relatively safe compared to synthetic medicines. Many plants have proved to successfully aid in the treatment of diabetes including Filago hurdwarica (Wall. ex DC.) Wagenitz. The current investigations were therefore designed to assess the phytochemical, antioxidant, antidiabetic, and antihyperlipidemic activities of F. hurdwarica. The phytochemical investigations and antioxidant activities of different extracts were carried out using standard chemical tests, DPPH, and H2O2 scavenging assays. F. hurdwarica plant extract in Hydromethanolic solution were prepared by Soxhletation method and stored in refrigerator at 4°C for two days before use. Swiss Albino mice were made diabetic by a single dose of alloxan (150 mg/kg). Hydromethanolic plant extract and fractions of F. hurdwarica were screened for antidiabetic activity and given to the alloxan-induced diabetic mice at a concentration of 150-250 mg/kg of body weight in different groups of 6 diabetic mice each orally once a day for 15 days. Glibenclamide is also given to another group to as a standard drug to support the result at a dose of 10 mg/kg of body weight orally once a day for 15 days. Blood glucose levels and body weights of mice were measured on 0, 4, 7, 11 and 15th days. The study found that the extract was safe up to the dose level of 2000 mg/kg and the dose response effect of chloroform extract (150-250 mg/kg) of F. hurdwarica showed expressive antihyperglycemic effects and also improved other altered biochemical parameters associated with diabetes. The FTIR and XRD spectra demonstrated the occurrence of phenols, alcohols, alkenes, alkyl halides, ketones, and aromatic compounds and confirmed the amorphous nature of the extract. GC-MS spectral analysis showed the tentative presence of 31 phytochemical constituents in the chloroform extract of F. hurdwarica with different retention time. To conclude, the chloroform extract (250 mg/kg) of F. hurdwarica revealed considerable antioxidant, antihyperglycemic, and antihyperlipidemic potential and is safe for treating diabetes and related complications.


Assuntos
Asteraceae , Diabetes Mellitus Experimental , Alcenos/uso terapêutico , Aloxano/uso terapêutico , Animais , Antioxidantes/farmacologia , Glicemia , Peso Corporal , Clorofórmio/uso terapêutico , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Glibureto/uso terapêutico , Peróxido de Hidrogênio/uso terapêutico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Cetonas/uso terapêutico , Camundongos , Fenóis/análise , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
9.
Front Endocrinol (Lausanne) ; 13: 1011383, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36313766

RESUMO

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes mellitus that is characterized by aberrant myocardial structure and function and is the primary cause of heart failure and death in diabetic patients. Endothelial dysfunction plays an essential role in diabetes and is associated with an increased risk of cardiovascular events, but its role in DCM is unclear. Previously, we showed that S-nitroso-L-cysteine(CSNO), an endogenous S-nitrosothiol derived from eNOS, inhibited the activity of protein tyrosine phosphatase 1B (PTP1B), a critical negative modulator of insulin signaling. In this study, we reported that CSNO treatment induced cellular insulin-dependent and insulin-independent glucose uptake. In addition, CSNO activated insulin signaling pathway and promoted GLUT4 membrane translocation. CSNO protected cardiomyocytes against high glucose-induced injury by ameliorating excessive autophagy activation, mitochondrial impairment and oxidative stress. Furthermore, nebulized CSNO improved cardiac function and myocardial fibrosis in diabetic mice. These results suggested a potential site for endothelial modulation of insulin sensitivity and energy metabolism in the development of DCM. Data from these studies will not only help us understand the mechanisms of DCM, but also provide new therapeutic options for treatment.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , S-Nitrosotióis , Camundongos , Animais , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/induzido quimicamente , S-Nitrosotióis/efeitos adversos , S-Nitrosotióis/metabolismo , Insulina/efeitos adversos
10.
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
11.
Adv Sci (Weinh) ; 9(31): e2202590, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36180407

RESUMO

Diabetes manifests as chronic inflammation and leads to the development diabetic cardiomyopathy (DCM). Targeting key proteins in inflammatory signaling may provide new therapy for DCM. In this study, the authors explore the pharmacological effects and mechanisms of Schisandrin B (Sch B), a natural compound with anti-inflammatory activity against DCM. It is shown that Sch B prevents high-level glucose (HG)-induced hypertrophic and fibrotic responses in cultured cardiomyocytes. RNA sequencing and inflammatory qPCR microarray show that Sch B mainly affects myeloid differentiation primary response 88 (MyD88)-dependent inflammatory gene expression in HG-challenged cardiomyocytes. Further studies indicate that Sch B directly binds to and inhibits MyD88 activation, but does not alter MyD88-independent Toll-like receptor signaling in vivo and in vitro. Inhibiting or silencing MyD88 is associated with reduced levels of HG-induced inflammatory cytokines and myocardial injuries in vitro. Treatment of type 1 and type 2 diabetic mice with Sch B protects heart function, reduces myocardial injuries, and decreases secretion of inflammatory cytokines. Cardiomyocyte-specific MyD88 knockout also protects mice against cardiac inflammation and injury in type 1 diabetic mice. In conclusion, these studies show that cardiomyocyte MyD88 plays an apathogenetic role in DCM and Sch B specifically targets MyD88 to reduce inflammatory DCM.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Animais , Camundongos , Citocinas/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/complicações , Cardiomiopatias Diabéticas/prevenção & controle , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/uso terapêutico
12.
Neurochem Int ; 160: 105417, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36067928

RESUMO

BACKGROUND: The incidence of cognitive dysfunction in diabetes is increasing yearly, which severely affects the quality of life of patients and places a heavy burden on families and society. It has been demonstrated that impaired clearance of cerebral amyloid ß-protein (Aß) is a central event in the initiation and progression of Aß deposition and cognitive impairment in diabetic patients. However, until now, the molecular mechanism by which diabetes mellitus induces impaired clearance of Aß has remained unclear. OBJECTIVE: To investigate the role and mechanism of lipoprotein receptor-related protein 1 (LRP1) in Aß clearance impairment and cognitive function damage caused by diabetes. METHODS: SPF male C57BL/6 mice were bred, and streptozotocin (STZ) (60 mg/kg/d) was intraperitoneally injected for 5 days to establish a diabetes model. The novel object recognition test and fear conditioning test were used to assess the cognitive function of mice in each group. Western blotting, qRT-PCR, ELISAs, and immunofluorescence staining were used to detect the expression levels of Aß and Aß clearance-related proteins in mouse brains. HBMECs were cultured in vitro to establish the blood-brain barrier model. The clearance rate of Aß and the expression levels of LRP1 were measured under different glucose concentration culture conditions. HBMECs were transfected with lentivirus to overexpress or knock down the LRP1, and then, the changes in Aß clearance were detected again. We injected adeno-associated virus AAV9-SP-A-LRP1 shRNA into the tail vein of DM mice to selectively knock down LRP1 gene expression in cerebral vascular endothelial cells. Then, the cognitive function and the expression levels of Aß and Aß clearance-related proteins in the brains of normal, DM and LRP1 knockdown mice were detected. RESULTS: Compared with the controls, diabetic mice showed impaired cognitive performance, increased deposition of Aß in the brain and decreased expression of LRP1 in the brain microvasculature. In vitro experiments showed that high glucose can downregulate the expression of LRP1 in HBMECs and damage the Aß clearance across the blood-brain barrier (BBB). The reduction in the clearance rate of Aß induced by high glucose was reversed by LRP1 overexpression but further substantially decreased when LRP1 was knocked down. CONCLUSION: Hyperglycemia can impair Aß efflux in the brain by downregulating the expression of LRP1 in the brain microvasculature, eventually resulting in cognitive impairment.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Diabetes Mellitus Experimental , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais/metabolismo , Glucose/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/metabolismo , Qualidade de Vida , RNA Interferente Pequeno , Receptores de LDL/genética , Receptores de LDL/metabolismo , Estreptozocina/toxicidade , Proteínas Supressoras de Tumor/metabolismo
13.
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
14.
Molecules ; 27(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36080407

RESUMO

The absence of a treatment efficient in the control of type 2 diabetes mellitus requires more functional products to assist treatment. Luteolin (LU) and diosmin (DIO) have been known as bioactive molecules with potential for the treatment of diabetes. This work aimed to establish the role that a combination of LU and DIO in selenium nanoparticles (SeNPs) played in streptozotocin (STZ)- induced diabetes mice. Green synthesis of Se NPs was performed by mixing luteolin and diosmin with the solution of Na2SeO3 under continuous stirring conditions resulting in the flavonoids conjugated with SeNPs. The existence of flavonoids on the surface of SeNPs was confirmed by UV-Vis spectra, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) images, and DLS graphs via Zetasizer. The average diameter of GA/LU/DIO-SeNPs was 47.84 nm with a PDI of -0.208, a zeta potential value of -17.6, a Se content of 21.5% with an encapsulation efficiency of flavonoids of 86.1%, and can be stabilized by gum Arabic for approximately 175 days without any aggregation and precipitation observed at this time. Furthermore, The C57BL/6 mice were treated with STZ induced-diabetes and were exposed to LU/DIO, SeNPs, and GA/LU/DIO-SeNPs for six weeks. The treatment by nanospheres (GA/LU/DIO-SeNPs) in the mice with diabetes for a period of 6 weeks restored their blood glucose, lipid profile, glycogen, glycosylated hemoglobin, and insulin levels. At the same time, there were significant changes in body weight, food intake, and water intake compared with the STZ- untreated induced diabetic mice. Moreover, the GA/LU/DIO-SeNPs showed good antioxidant activity examined by catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) in liver and kidney and can prevent the damage in the liver evaluated by aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) activities. The nanospheres exhibited a significant anti-diabetic activity with a synergistic effect between the selenium and flavonoids. This investigation provides novel SeNPs nanospheres prepared by a high-efficiency strategy for incorporating luteolin and diosmin to improve the efficiency in type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Diosmina , Nanopartículas , Selênio , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Luteolina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Selênio/química , Estreptozocina
15.
Eur J Pharmacol ; 933: 175289, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36122758

RESUMO

Diabetic nephropathy (DN) is a renal complication of diabetic hyperglycemia. The Signal transducer and activator of transcription 3 (Stat3) is a center molecule of the chronic inflammation causing DN progression. Therefore, the study investigated the possible inhibitory effects of Rutin (Ru) and Selenium (Se), formulated as nanoparticles (SeNPs), on Stat3 pathway in streptozotocin (STZ)-induced DN in Sprague-Dawley rats. Ru (100 mg/kg/orally) and SeNPs (equivalent to 5 mg of Se/kg/orally) were given as treatment for eight weeks. An assessment of fasting blood glucose, renal function biomarkers, GSH, and MDA was carried out spectrophotometrically. ELISA assessment of renal IL-6, NF-κB, TNF-α, Jak-2, and p-Stat3 was performed. Sirt-1, Nrf-2, and HO-1 were assessed immunohistochemically. DN group receiving Ru + SeNPs showed a decrease in fasting blood glucose, serum creatinine, and urea (163.8 ± 22.8, 0.54 ± 0.1, and 53.6 ± 25.7 mg/dl, respectively), compared to the DN group (443.8 ± 42.72, 1.58 ± 0.4, and 281.8 ± 47.35 mg/dl, respectively). In addition, it exhibited elevation in the levels of Sirt-1, Nrf-2 and HO-1 compared to the DN group. Finally, Ru + SeNPs exhibited a significant reduction in IL-6, NF-κB, TNF-α, Jak-2, and p-Stat3 (42.8 ± 10.3, 1.2 ± 0.1, 53.4 ± 3.87, 0.8 ± 0.06 and 1.1 ± 0.2 U/g tissue, respectively) when compared to the DN group (155.3 ± 13.97, 2.8 ± 0.3, 105.5 ± 32.84, 2.03 ± 0.2 and 2.56 ± 0.15 U/g tissue, respectively). Therefore, combining Ru with SeNPs has a potential renoprotective effect against DN by upregulating Nrf-2/HO-1 and downregulating Jak-2/Stat3 Pathways.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Nanopartículas , Selênio , Sirtuínas , Animais , Biomarcadores , Glicemia/análise , Creatinina , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Rutina/farmacologia , Rutina/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Selênio/farmacologia , Selênio/uso terapêutico , Transdução de Sinais , Sirtuínas/metabolismo , Estreptozocina/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo
16.
Molecules ; 27(18)2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36144807

RESUMO

BACKGROUND: Type-one diabetes (T1D), a chronic autoimmune disease with marked inflammatory responses, is associated with infertility complications and implications. Based on the anti-diabetic, antioxidant, and anti-hyperlipidemic potential of Portulaca oleracea (PO), this study aimed to evaluate the protective effect of this plant extract on streptozotocin-induced type-I-diabetes-associated reproductive system dysfunction and inflammation. METHODS: Male rats were randomly divided into four experimental groups: control, diabetic, and treatment/s (PO extract at 100 or 300 mg/kg/daily). Then food and water consumption, body, testis and epididymis weights, histopathological evaluation, seminiferous tubules diameter, sperm count and motility, glucose levels, sex hormones, and inflammatory and oxidative stress markers were evaluated. RESULTS: Our results showed that streptozotocin-induced diabetes significantly increased food and water consumption; increased glucose, MDA, TGF-ß1, and TNF-α levels; and decreased the seminiferous tubules diameter, sperm count and motility, levels of LH, testosterone, total thiol, VEGF, and SOD activity. Interestingly, PO extract (phytochemically characterized by using liquid chromatography-mass spectrometry to detect bioactive molecules) significantly ameliorated these parameters and histopathological indexes' damage in rats. CONCLUSION: Even if more preclinical assessments are needed to better characterize the mechanism/s of action, the results of this study will pave the way for the rational use of PO on diabetic-associated clinical complications and implications.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Portulaca , Animais , Antioxidantes/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Glucose/metabolismo , Inflamação/metabolismo , Masculino , Estresse Oxidativo , Extratos Vegetais/metabolismo , Portulaca/química , Ratos , Estreptozocina/farmacologia , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/metabolismo , Testículo , Testosterona/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Zhen Ci Yan Jiu ; 47(9): 785-92, 2022 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-36153453

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Tianshu" (ST25) on nitrergic neurons in jejunum and distal colon in type 2 diabetic rats, so as to explore its mechanism of regulating different intestinal segments. METHODS: Twenty-four SD rats were randomly divided into control, model and EA groups (n=8 in each group). The diabetes model was established by intraperitoneal injection of streptozotocin (35 mg/kg) and high-sugar and high-fat diet for 2 weeks. EA (2 Hz/15 Hz, 2 mA) was applied to bilateral ST25 for 20 min, once a day, 6 days a week for 4 weeks. The intestinal motility was evaluated by observing the first red stool excretion time and the distal colon bead excretion time. HE staining was used to observe the histological changes of jejunum and distal colon. The positive expression and protein expression of intestinal total neuronal marker protein gene product 9.5(PGP9.5) and neuronal nitric oxide synthase (nNOS) in jejunum and distal colon were detected by immunofluorescence staining and Western blot, respectively. RESULTS: After modeling, the blood glucose was significantly increased (P<0.01), the first red stool excretion time and the distal colon bead excretion time were shortened (P<0.01), the expression levels of PGP9.5 and nNOS in jejunum and distal colon were decreased (P<0.01) in the model group relevant to the control group. After treatment, compared with the model group, the blood glucose was decreased (P<0.01), the first red stool excretion time and the distal colon bead excretion time were prolonged (P<0.01, P<0.05), and the expression levels of PGP9.5 and nNOS in jejunum and distal colon were increased (P<0.05, P<0.01) in the EA group. HE staining showed disordered structure in intestinal mucosa of the jejunum and distal colon, and reduction of the number of goblet cells in the model group, which was relatively milder in the EA group. CONCLUSION: EA can effectively improve the intestinal mucosal damage and restore intestinal motor function in type 2 diabetic rats, which may be related to its function in regulating the number of nitrergic neurons in the intestinal nervous system.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Eletroacupuntura , Neurônios Nitrérgicos , Pontos de Acupuntura , Animais , Glicemia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/terapia , Óxido Nítrico Sintase Tipo I/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina
18.
Eur J Pharmacol ; 933: 175265, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36108734

RESUMO

Hydrogen sulfide (H2S) has been reported to have beneficial effects in different pathological conditions. OBJECTIVES: the effects of chronic treatment of diabetic rats with GYY4137 (slow releasing H2S donor) or NaHS (fast releasing H2S donor) on the reactivity of the mesenteric bed to vasoactive agonists and the changes in its downstream effectors, ERK1/2 and p38 MAP Kinase have been investigated. In addition, the levels of nitric oxide (NO) and H2S in all groups were measured. METHODS: diabetes was induced by a single intraperitoneal (ip) injection of streptozotocin (STZ; 55 mg/kg). Sprague Dawley (SD; n = 10-12/group) rats were randomly divided into six groups: control, STZ-induced diabetic rats, GYY4137-treated control, NaHS-treated control, GYY4137-treated diabetic, and NaHS-treated diabetic. After 28 days of treatment, rats were sacrificed and mesenteric beds were isolated for functional or biochemical studies. The vascular reactivity of the perfused mesenteric bed to norepinephrine, carbachol and sodium nitroprusside were determined by measurement of changes in perfusion pressure. Western blotting was performed to measure the protein expression of ERK1/2, p38, eNOS, and H2S biosynthesizing enzymes cystathionine-ß-synthase and cystathionine-γ-lyase. NO and H2S levels were measured in all groups in isolated mesenteric tissues or plasma. RESULTS: diabetes resulted in a significant increase in vasoconstrictor responses to norepinephrine (e.g., 129.6 ± 6.77 mmHg in diabetic vs 89.3 ± 8.48 mmHg in control at 10-7 dose), and carbachol-induced vasodilation was significantly reduced in diabetic mesenteric bed (e.g., 68.9 ± 4.8 mmHg in diabetic vs 90.6 ± 2.2 mmHg in control at 10-7 dose). Chronic treatment of the diabetic rats with GYY4137 resulted in a significant improvement in the response to norepinephrine (e.g., 86.66 ± 8.04 mmHg in GYY4137-treated diabetic vs 129.6 ± 6.77 mmHg in untreated diabetic at 10-7 dose) or carbachol (e.g., 84.90 ± 2.48 mmHg in GYY4137-treated diabetic vs 68.9 ± 4.8 mmHg in untreated diabetic at 10-7 dose). The biochemical studies showed a marked reduction of the protein expression of ERK and p38 and a significant upregulation of the expression of eNOS and H2S synthesizing enzymes after chronic treatment with GYY4137. Plasma levels of NO and H2S were significantly elevated after treatment with GYY4137. However, H2S production in the mesenteric bed showed a marginal elevation in diabetic tissues compared to controls. CONCLUSION: the results indicate that GYY4137 may be a novel therapeutic tool to prevent diabetes-associated vascular dysfunction.


Assuntos
Diabetes Mellitus Experimental , Sulfeto de Hidrogênio , Animais , Carbacol , Cistationina/uso terapêutico , Cistationina gama-Liase , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Sulfeto de Hidrogênio/metabolismo , Morfolinas , Óxido Nítrico/metabolismo , Nitroprussiato , Norepinefrina , Compostos Organotiofosforados , Ratos , Ratos Sprague-Dawley , Estreptozocina , Sulfetos , Vasoconstritores/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno
19.
Physiol Res ; 71(5): 631-641, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36047725

RESUMO

Diabetes is closely connected with skeletal muscle dysfunction. Ellagic acid (EA) possesses a variety of bio-effects and is applied to the improvement of diabetes. The purpose of this study was to explore the potential improvement effect and mechanisms of EA in streptozotocin (STZ)-induced diabetic muscle atrophy. The model of diabetic mice was established by intra-peritoneal STZ to evaluate treatment effect of EA (100 mg/kg/d for 8 weeks) on muscle atrophy. Our data exhibited that EA enhanced fiber size and weight of gastrocnemius, and promoted grip strength to relieve STZ-induced muscle lesions. In serum, the levels of Creatine kinase (CK), lactate dehydrogenase (LDH), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL) were inhibited, while high-density lipoprotein cholesterol (HDL) level was enhanced by EA treatment in diabetic mice. In gastrocnemius, EA decreased Atrogin-1 and MuRF-1 expressions to relieve STZ-induced muscle atrophy. Moreover, EA increased NRF-1 and PGC-1alpha expressions to alleviate mitochondrial disorder. Meanwhile, EA suppressed CHOP and GRP-87 levels to relieve ER stress. Lastly, EA inhibited BAX expressions and enhanced Bcl-2 expressions to mitigate apoptosis. In conclusion, EA is preventing the event of STZ-induced gastrocnemia by amelioration of mitochondrial dysfunction, ER stress and apoptosis, and could be used in the protection and therapeutic of muscle atrophy in diabetes.


Assuntos
Diabetes Mellitus Experimental , Ácido Elágico , Camundongos , Animais , Estreptozocina/metabolismo , Estreptozocina/farmacologia , Ácido Elágico/farmacologia , Ácido Elágico/uso terapêutico , Ácido Elágico/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/prevenção & controle , Atrofia Muscular/metabolismo , Músculo Esquelético/metabolismo , Colesterol/metabolismo
20.
Int J Biol Macromol ; 221: 1415-1427, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36096255

RESUMO

To overcome the low bioavailability of lipophilic free thymoquinone (TQ), this study aims to evaluate a novel oral formula of TQ-loaded chitosan nanoparticles (TQ-CsNPs) for the effective treatment of diabetes. The XRD, FTIR, FESEM, HRTEM, and dynamic light scattering were all conducted on the prepared formula. The release pattern of TQ, cytotoxicity against MRC-5 cell line (human lung fibroblast cells), and antidiabetic activity on streptozotocin/nicotinamide (STZ/NA) rat model of diabetes were investigated. The results confirmed the formation of TQ-CsNPs with an entrapment efficiency of 75.7 ± 6.52 %, a mean Zetasizer distribution of 84.25 nm, and an average particle size of about 50 nm. After 24 h, the percentage of free TQ-cumulative release was approximately 35.8 %, whereas TQ-CsNPs showed a sustained release pattern of 78.5 %. The investigated formula was not toxic to normal lung cells, and more efficient in ameliorating the altered glycemia, dyslipidemia, inflammation, and oxidative stress induced by STZ/NA than free TQ, blank CsNPs, and metformin-HCl (as a reference drug). Additionally, TQ-CsNPs restored the normal pancreatic islets' configuration and morphometry, suggesting a potent insulinotropic action. In conclusion, the antidiabetic efficacy of TQ was improved by engaging TQ with CsNPs as an excellent nanoplatform to enhance the oral bioavailability of TQ.


Assuntos
Quitosana , Diabetes Mellitus Experimental , Nanopartículas , Animais , Ratos , Humanos , Estreptozocina , Niacinamida/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Benzoquinonas/farmacologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico
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