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1.
J Ethnopharmacol ; 301: 115791, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36240976

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang-zhenzhu-tiaozhi formula (FTZ) is a patented preparation of traditional Chinese medicine that has been used to treat hyperglycemia and hyperlipidemia in the clinic for almost 10 years. Our previous study had demonstrated that FTZ can protect islet ß cell injury in vitro. However, the efficacy of FTZ on ß cell regeneration in vivo and the involved anti-diabetic mechanism remains unknown. AIM OF THE STUDY: We aim to investigate the effects of FTZ as a good remedy for islet protection and ß cell regeneration, and to reveal the underlying mechanism. MATERIALS AND METHODS: C57BL/6 mice were fed with high-fat diet for 3 weeks and then intraperitoneally injected with streptozotocin (90 mg/kg/d × 1 d) to establish type 2 diabetes (T2D) models. Mice in each group were divided into three batches that sacrificed after 3, 7 and 28 days of FTZ administration. Body weight, blood glucose, and oral glucose tolerance test were measured at indicated time points. Fasting insulin was determined by enzyme-linked immunosorbent assay (ELISA) kit. Neonatal ß cell was assessed by insulin & PCNA double immunofluorescence staining, and the underlying mechanisms related to ß cell regeneration were further performed by hematoxylin-eosin staining, insulin & glucagon double immunofluorescence staining and Western blot. RESULTS: FTZ and metformin can significantly help with the symptoms of DM, such as alleviating weight loss, reducing blood glucose, improving the level of insulin in vivo, and relieving insulin resistance, suggesting FTZ and metformin treatment maintained the normal morphological function of islet. Notably, ß cell regeneration, which is indicated by insulin and PCNA double-positive cells, was promoted by FTZ, whereas few neonatal ß cells were observed in metformin group. Hematoxylin-eosin staining, and its quantification results showed that FTZ effectively prevented the invasion of inflammatory cells into the islets in diabetic mice. Most ß cells in the islets of diabetic model mice were devoid, and the islets were almost all α cells, while the diabetic mice administered FTZ could still maintain about half of the ß cells in the islet. Furthermore, FTZ upregulated the expression of critical transcription factors during ß cell development and maturation (such as PDX-1, MAFA and NGN3) in diabetic mice. CONCLUSIONS: FTZ can alleviate diabetes symptoms and promote ß cell regeneration in diabetic mice. Moreover, FTZ promotes ß cell regeneration by preserving islet (resisting inflammatory cells invading islets), maintaining the number of ß cells in islets, and increasing the expression of PDX-1, MAFA and NGN3.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Metformina , Camundongos , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Camundongos Endogâmicos C57BL , Insulina , Regeneração , Metformina/farmacologia
2.
J Steroid Biochem Mol Biol ; 225: 106197, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36183994

RESUMO

Activated dendritic cells (DCs) undergo significant metabolic reprogramming, which is characterized by an increase in aerobic glycolysis and a concurrent progressive loss of oxidative phosphorylation. The modulation of metabolic reprogramming is believed to be closely related to the function of DCs. Vitamin D has been reported to inhibit the maturation of DCs. DC dysfunction has been reported in diabetic patients, and hyperglycemia is associated with impaired glycolytic metabolism in immune cells. Therefore, vitamin D and diabetes may affect intracellular metabolism, thereby regulating the activity of DCs. We investigated the effect of in vitro treatment of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on metabolic reprogramming and maturation of bone marrow-derived dendritic cells (BMDCs) from diabetic mouse. Six-week-old male C57BLKS/J-m+/m+ mice (CON) and C57BLKS/J-db/db mice (db/db) were fed with a 10% kcal fat diet for seven weeks. BMDCs were generated by culturing bone marrow cells from the mice with rmGM-CSF (20 ng/mL) in the absence or presence of 10 nM 1,25(OH)2D3. The maturation of BMDCs was induced via lipopolysaccharide (LPS, 50 ng/mL) stimulation for 24 h. LPS stimulation induced iNOS protein expression and decreased the mitochondrial respiration, while increased lactate production and the expression of glycolytic pathway-related genes (Glut1 and Pfkfb3) in BMDCs from both CON and db/db groups. In LPS-stimulated mature BMDCs, 1,25(OH)2D3 treatment decreased the expression of surface markers related to immunostimulatory functions (MHC class II, CD80, CD86, and CD40) and production of IL-12p70 in both CON and db/db groups. While the mRNA level of the gene related to glucose uptake (Glut1) was increased in both groups, lactate production was decreased by 1,25(OH)2D3 treatment. mTORC1 activity was suppressed following 1,25(OH)2D3 treatment. Collectively, our findings confirmed that metabolic reprogramming occurred in BMDCs following LPS stimulation. In vitro 1,25(OH)2D3 treatment induced tolerogenic phenotypes by reducing the expression of surface markers, as well as cytokine production. However, no significant difference was observed regarding the effects of 1,25(OH)2D3 treatment on metabolic conversion and maturation of BMDCs between the control and diabetic mice. Additionally, the decreased aerobic glycolysis induced by the 1,25(OH)2D3 treatment appeared to be associated with the diminished maturation of BMDCs, and mTORC1 appears to play a key role in the 1,25(OH)2D3-mediated regulation of glycolysis.


Assuntos
Células Dendríticas , Diabetes Mellitus Experimental , Camundongos , Masculino , Animais , Lipopolissacarídeos/farmacologia , Calcitriol/farmacologia , Calcitriol/metabolismo , Medula Óssea/metabolismo , Diabetes Mellitus Experimental/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Células da Medula Óssea , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Lactatos/metabolismo , Lactatos/farmacologia , Diferenciação Celular
3.
Food Chem ; 403: 134334, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36182856

RESUMO

In our previous study, two crude polysaccharides from red kidney bean and small black soybean (RK, SB) have shown the alleviative effect on type 2 diabetic mice. Meanwhile, hepatic dysfunction usually accompanied with type 2 diabetes mellitus (T2DM), and closely related to glucose and lipid homeostasis. Therefore, this time we further investigated the protective effect on hepatic dysfunction of RK and SB. Results found that both crude polysaccharides had the protective effects. In addition, investigation on purified polysaccharides identified that the polysaccharide was the biofunctional component basis in crude RK and SB. Subsequently, further research investigated the regulating mechanism of two pure polysaccharides (RKPH and SBPH) on hepatic metabolism and lipid metabolism. The results showed the improved different metabolites of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) by RKPH and SBPH to affect glycerophospholipid metabolism pathway might be involved in the improvement of the glucose, lipids homeostasis and liver function in T2DM.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Phaseolus , Camundongos , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Soja/metabolismo , Phaseolus/metabolismo , Fígado/metabolismo , Polissacarídeos/farmacologia , Metabolismo dos Lipídeos , Glucose/metabolismo
4.
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
5.
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
6.
J Ethnopharmacol ; 300: 115750, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36162547

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Different Physalis plants have been widely employed in traditional medicine for management of diabetes mellitus. Previous studies with respect to the in vivo antidiabetic activity of Physalis plants illustrated that they improved glucose and lipid metabolism in streptozotocin (STZ) -induced diabetic rats yet the mechanism of action of bioactive constituents of the different organs of Physalis plants on diabetes remains obscure. AIM OF STUDY: Our objective is to study the effects of the different organs of ground cherry (P. pruinosa) on diabetes in rat models and elucidate their mechanism of actions through serum pharmacochemistry combined to network pharmacology analyses and in-vivo testing. MATERIALS AND METHODS: Characterization of the constituents in the drug-dosed serum samples relative to the blank serum after treatment with different extracts was performed by UPLC -MS/MS technique. The absorbed metabolites where then subjected to network pharmacology analysis to construct an interaction network linking "compound-target-pathway". In vivo verification was implemented to determine a hypothesized mechanism of action on a STZ and high fat diet induced type II diabetes mellitus (T2DM) model based on functional and enrichment analyses of the Kyoto Encyclopedia of Genes and Genome and Gene Ontology. RESULTS: Identification of a total of 73 compounds (22 prototypes and 51 metabolites) derived from P. pruinosa extracts was achieved through comparison of the serum samples collected from diabetic control group and extracts treated groups. The identified compounds were found to belong to different classes according to their structural type including withanolides, physalins and flavonoids. The absorbed compounds in the analyzed serum samples were considered as the potential bioactive components. The component-target network was found to have 23 nodes with 17 target genes including MAPK8, CYP1A1 and CYP1B1. Quercetin and withaferin A were found to possess the highest combined score in the C-T network. Integrated serum pharmacochemistry and network pharmacology analyses revealed the enrichment of leaves extract with the active constituents, which can be utilized in T2DM treatment. In the top KEGG pathways, lipid and atherosclerosis metabolic pathways in addition to T2DM pathways were found to be highly prioritized. The diabetic rats, which received leaves extract exhibited a substantial increment in GLUT2, INSR, IRS-1, PI3K-p85 and AKT-ser473 proteins by 105%, 142%, 109%, 81% and 73%, respectively relative to the untreated diabetic group. The immunoblotting performed for MAPK and ERK1/2 part of the inflammatory pathway studied in STZ induced diabetic rats revealed that leaves, calyces and stems extracts resulted in a substantial diminish in p38-MAPK, ERK 1/2, NF-κB, and TNF-α. Histopathological examination revealed that the hepatic histoarchitecture was substantially improved in the leaves, stems, and clayces-treated rats in comparison with untreated diabetic rats. Further, pancreatic injuries, which induced by STZ were dramatically altered by the treatment with P. pruinosa leaves, calyces and stems extracts. ß-cells in diabetic rats received leaves extract disclosed moderate insulin immunostaining with a notable increase in the mean insulin area%. CONCLUSIONS: The study in hand offers a comprehensive study to clarify the bioactive metabolites of the different organs of P. pruinosa. The basic pharmacological effects and underlying mechanism of actions in the management of STZ and high fat diet induced T2DM were specifically covered in this paper.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Physalis , Vitanolídeos , Animais , Citocromo P-450 CYP1A1 , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Hipoglicemiantes/análise , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina , NF-kappa B , Farmacologia em Rede , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/uso terapêutico , Ratos , Estreptozocina , Espectrometria de Massas em Tandem , Fator de Necrose Tumoral alfa
7.
Food Chem ; 404(Pt A): 134598, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36444040

RESUMO

Crude polysaccharides extracted from red kidney bean (RK) display significant antidiabetic activity in type 2 diabetic mice, but the underlying mechanism and the core functional component has not been elucidated. In this study, the antidiabetic effect and mechanism of RK are investigated by serum metabolomics and high-throughput sequencing. In addition, the key component was identified by evaluating the improvement on glucose and lipid homeostasis in type 2 diabetic rats. Our data indicated that RK relieved the symptoms of hyperglycemia, hyperlipidemia in STZ-induced diabetic rats. RK not only improved the metabolic disturbance by regulating the biosynthesis of unsaturated fatty acids, but also modified gut microbiota composition by selectively enriching in key genera of Bacteroides, Phascolarctobacterium, Succinivibrio, Blautia. We further found the purified polysaccharides (RKP) were identified as the core biofunctional component in RK. Our present studies provide evidence that RKP are potential effective dietary supplement for type 2 diabetic individuals.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Hiperglicemia , Hiperlipidemias , Phaseolus , Ratos , Camundongos , Animais , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/genética , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Polissacarídeos , Hipoglicemiantes , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Lipídeos
8.
Food Chem ; 404(Pt B): 134735, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36444094

RESUMO

Foxtail millet and its components have hypoglycemic effects on mice, but the role of starch and protein in millet in these effects is unclear. The present study investigated the impact of heat-treated foxtail millet starch and protein on type 2 diabetic mice and the underlying mechanisms, including the influence of gut microbiota and serum metabolic profile. In diabetic mice, the consumption of heat-treated foxtail millet starch and protein reduced, respectively, fasting blood glucose 18.52% and 26.33% and insulin levels 12.22% and 15.96%. In addition, heat-treated foxtail millet starch and protein altered the gut microbiota composition, enriched the abundance of probiotics and short-chain fatty acids producing bacteria, reduced harmful bacteria, and increased fecal short-chain fatty acids concentration. Heat-treated foxtail millet protein had greater effects on gut microbiota composition, whereas heat-treated foxtail millet starch had greater effects on metabolic function. The hypoglycemic potential of heat-treated foxtail millet starch and protein was associated with the modulation of both gut microbiota and serum metabolic profile.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Setaria (Planta) , Camundongos , Animais , Setaria (Planta)/genética , Amido , Temperatura Alta , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes , Diabetes Mellitus Tipo 2/tratamento farmacológico
9.
J Nutr Biochem ; 111: 109161, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36184012

RESUMO

The ketogenic diet (KD) might improve cardiac function in diabetic cardiomyopathy, but the mechanisms remain unclear. This study investigated the effects of KD on myocardial fatty acid (FA), glucose, and ketone metabolism in diabetic cardiomyopathy. Echocardiograms, biochemistry, and micro-positron emission tomography were performed to evaluate cardiac function and glucose uptake in control rats and streptozotocin-induced diabetes mellitus (DM) rats with normal diet (ND) or KD for 6 weeks. Histopathology, adenosine triphosphate measurement, and Western blot were performed in the ventricular myocytes to analyze fibrosis, FA, ketone body, and glucose utilization. The ND-fed DM rats exhibited impaired left ventricular systolic function and increased chamber dilatation, whereas control and KD-fed DM rats did not. The KD reduced myocardial fibrosis and apoptosis in the DM rats. Myocardial glucose uptake in the micro-positron emission tomography was similar between ND-fed DM rats and KD-fed DM rats and was substantially lower than the control rats. Compared with the control rats,  ND-fed DM rats had increased phosphorylation of acetyl CoA carboxylase and higher expressions of CD-36, carnitine palmitoyltransferase-1ß, tumor necrosis factor-α, interleukin-1ß, interleukin6, PERK, and e-IF2α as well as more myocardial fibrosis and apoptosis (assessed by Bcl-2, BAX, and caspase-3 expression); these increases were attenuated in the KD-fed DM rats. Moreover, ND-fed DM rats had significantly lower myocardial adenosine triphosphate, BHB, and OXCT1 levels than the control and KD-fed DM rats. The KD may improve the condition of diabetic cardiomyopathy by suppressing FA metabolism, increasing ketone utilization, and decreasing endoplasmic reticulum stress and inflammation.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Dieta Cetogênica , Ratos , Animais , Estreptozocina/efeitos adversos , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos , Glucose/metabolismo , Corpos Cetônicos/efeitos adversos , Corpos Cetônicos/metabolismo , Fibrose , Trifosfato de Adenosina/metabolismo
10.
Med Gas Res ; 13(2): 72-77, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36204786

RESUMO

Diabetic peripheral neuropathy (DPN) is a complex disorder caused by long-standing diabetes. Oxidative stress was considered the critical creed in this DPN pathophysiology. Hydrogen has antioxidative effects on diabetes mellitus and related complications. However, there is still no concern on the beneficial effects of hydrogen in DPN. This paper aimed to evaluate the effects of exogenous hydrogen to reduce the severity of DPN in streptozotocin-induced diabetic rats. Compared with hydrogen-rich saline treatment, hydrogen inhalation significantly reduced blood glucose levels in diabetic rats in the 4th and 8th weeks. With regard to nerve function, hydrogen administration significantly attenuated the decrease in the velocity of motor nerve conduction in diabetic animals. In addition, hydrogen significantly attenuated oxidative stress by reducing the level of malondialdehyde, reactive oxygen species, and 8-hydroxy-2-deoxyguanosine and meaningfully enhanced the antioxidant capability by partially restoring the activities of superoxide dismutase. Further studies showed that hydrogen significantly upregulated the expression of nuclear factor erythroid-2-related factor 2 and downstream proteins such as catalase and hemeoxygenase-1 in the nerves of diabetic animals. Our paper showed that hydrogen exerts significant protective effects in DPN by downregulating oxidative stress via the pathway of nuclear factor erythroid-2-related factor 2, which suggests its potential value in clinical applications.


Assuntos
Diabetes Mellitus Experimental , Neuropatias Diabéticas , Fármacos Neuroprotetores , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Glicemia , Catalase/metabolismo , Catalase/farmacologia , Catalase/uso terapêutico , Desoxiguanosina/metabolismo , Desoxiguanosina/farmacologia , Desoxiguanosina/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Hidrogênio , Malondialdeído , NAD/metabolismo , NAD/farmacologia , NAD/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Ratos , Espécies Reativas de Oxigênio , Estreptozocina , Superóxido Dismutase/metabolismo , Superóxido Dismutase/farmacologia , Superóxido Dismutase/uso terapêutico
11.
J Ethnopharmacol ; 301: 115862, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36283638

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C. A. Meyer (Ginseng) has traditionally been used to treat diabetes. Polysaccharide is the main active component of ginseng, and has been proved to have hypoglycaemic and hypolipidaemic effects, but its mechanism remains unclear. AIM OF THE STUDY: This study aimed to evaluate the effect and the potential mechanism of rhamnogalacturonan-I enriched pectin (GPS-1) from steamed ginseng on lipid metabolism in type 2 diabetes mellitus (T2DM) rats. MATERIALS AND METHODS: GPS-1 was prepared by water extraction, ion-exchange and gel chromatography. High-glucose/high-fat diet combined with streptozotocin was used to establish T2DM rat models, and lipid levels in serum and liver were tested. 16S rRNA sequencing and gas chromatography-mass spectrometry were used to detect the changes of gut microbiota and metabolites. The protein and mRNA levels of lipid synthesis-related genes were detected by Western blot and quantitative real-time polymerase chain reaction. RESULTS: The polyphagia, polydipsia, weight loss, hyperglycaemia, hyperlipidaemia and hepatic lipid accumulation in T2DM rats were alleviated after GPS-1 intervention. GPS-1 modulated the gut microbiota composition of T2DM rats, increased the levels of short-chain fatty acids, and promoted the secretion of glucagon-like peptide-1 and peptide tyrosine tyrosine. Further, GPS-1 activated AMP-activated protein kinases, phosphorylated acetyl-CoA carboxylase, reduced the expression of sterol regulatory element-binding protein-1c and fatty acid synthases in T2DM rats. CONCLUSIONS: The regulation effects of GPS-1 on lipid metabolism in T2DM rats are related to the regulation of gut microbiota and activation of AMP-activated protein kinase pathway.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Panax , Ratos , Animais , Metabolismo dos Lipídeos , Panax/química , Proteínas Quinases Ativadas por AMP/metabolismo , Ramnogalacturonanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , RNA Ribossômico 16S , Pectinas/farmacologia , Pectinas/metabolismo , Ácidos Graxos Voláteis , Tirosina/metabolismo
12.
J Ethnopharmacol ; 302(Pt A): 115899, 2023 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-36336219

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Hypericum perforatum L., commonly known as St. John's Wort (SJW), represents one of the best-known and most thoroughly researched medicinal plant species. The ethnobotanical usage and bioactivities related to H. perforatum include treatment of skin diseases, wounds and burns, gastrointestinal problems, urogenital diseases and psychiatric disorders, particularly depression. In the last decade, many studies focused on the bioactive constituents responsible for the antihyperglycemic and antidiabetic activity of SJW extracts. However, the mechanism by which H. perforatum extract exhibits these properties is still unclear. Hence, the current study was designed to gain insight into the underlying biochemical and molecular mechanisms by which wildly growing H. perforatum exerts its antihyperglycemic and antidiabetic activities. MATERIAL AND METHODS: Plant material of H. perforatum was harvested from a natural population in the Republic of North Macedonia during full flowering season. Methanol (80% v/v) was used to extract bioactive components from HH powder. The dissolved HH dry extract (in 0.3% CMC) was given daily as a single treatment (200 mg/kg bw) during 14 days both in healthy and streptozotocin-induced diabetic rats. As a positive control, we applied glibenclamide. The activity of key enzymes involved in carbohydrate methabolisam in the liver were assessed, along with substrate concentration, as well as AMPK mRNA levels, PKCε concentration, plasma insulin level and pancreatic PARP activity. RESULTS: Compared to diabetic rats, treatment of diabetic rats with HH extract resulted with decreased activity of hepatic enzymes glucose-6-phospatase and fructose-1,6-bisphosphatase, increased liver glycogen and glucose-6-phosphate content, which resulted with reduced blood glucose concentration up to normoglycaemia. Non-significant changes were observed in the activity of hexokinase, glycogen phosphorylase and glucose-6-phospahte dehydrogenase. HH-treatment also caused an increase in plasma insulin concentration and increase in pancreatic PARP activity. Finally, HH treatment of diabetic rats showed significant increase in AMPK expression and decrease of PKCε concentration. CONCLUSION: We present in vivo evidence that HH- extract exert insulinotropic effects and regulate endogenous glucose production mostly by suppressing liver gluconeogenesis. The HH-treatment did not effected glycogenolysys and glycolysis. Finally, we confirm the antihyperglycemic and antidiabetic effect of HH-extract and the mechanism of this effect involves amelioration of AMPK and PKCε changes in the liver.


Assuntos
Diabetes Mellitus Experimental , Hypericum , Ratos , Animais , Hypericum/química , Proteínas Quinases Ativadas por AMP , Diabetes Mellitus Experimental/tratamento farmacológico , Gluconeogênese , Proteína Quinase C-épsilon , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Óleos Vegetais/uso terapêutico , Insulina , Glucose
13.
Front Endocrinol (Lausanne) ; 13: 984452, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36465609

RESUMO

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease, and its early pathogenesis is critical. Shear stress caused by glomerular hyperfiltration contributes to the initiation of kidney injury in diabetes. The primary cilium of renal tubular epithelial cells (RTECs) is an important mechanical force sensor of shear stress and regulates energy metabolism homeostasis in RTECs to ensure energy supply for reabsorption functions, but little is known about the alterations in the renal cilium number and length during the progression of DKD. Here, we demonstrate that aberrant ciliogenesis and dramatic increase in the cilium length, the number of ciliated cells, and the length of cilia are positively correlated with the DKD class in the kidney biopsies of DKD patients by super-resolution imaging and appropriate statical analysis methods. This finding was further confirmed in STZ-induced or db/db diabetic mice. These results suggest that the number and length of renal cilia may be clinically relevant indicators and that cilia will be attractive therapeutic targets for DKD.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Falência Renal Crônica , Animais , Camundongos , Nefropatias Diabéticas/etiologia , Cílios , Diabetes Mellitus Experimental/complicações , Rim
14.
Front Endocrinol (Lausanne) ; 13: 1040040, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36465619

RESUMO

Prior investigation shows an increase in the activity of both hypothalamus-pituitary-adrenal (HPA) axis and the renin-angiotensin system (RAS) in diabetic patients. Moreover, activation of angiotensin-II type 1 receptor (AT1) has been associated with adrenal steroidogenesis. This study investigates the role of RAS on the overproduction of corticosterone in diabetic mice. Diabetes was induced by intravenous injection of alloxan into fasted Swiss-webster mice. Captopril (angiotensin-converting enzyme inhibitor), Olmesartan (AT1 receptor antagonist), CGP42112A (AT2 receptor agonist) or PD123319 (AT2 receptor antagonist) were administered daily for 14 consecutive days, starting 7 days post-alloxan. Plasma corticosterone was evaluated by ELISA, while adrenal gland expressions of AT1 receptor, AT2 receptor, adrenocorticotropic hormone receptor MC2R, pro-steroidogenic enzymes steroidogenic acute regulatory protein (StAR), and 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) were assessed using immunohistochemistry or western blot. Diabetic mice showed adrenal gland overexpression of AT1 receptor, MC2R, StAR, and 11ßHSD1 without altering AT2 receptor levels, all of which were sensitive to Captopril or Olmesartan treatment. In addition, PD123319 blocked the ability of Olmesartan to reduce plasma corticosterone levels in diabetic mice. Furthermore, CGP42112A significantly decreased circulating corticosterone levels in diabetic mice, without altering the overexpression of MC2R and StAR in the adrenal glands. Our findings revealed that inhibition of both angiotensin synthesis and AT1 receptor activity reduced the high production of corticosterone in diabetic mice via the reduction of MC2R signaling expression in the adrenal gland. Furthermore, the protective effect of Olmesartan on the overproduction of corticosterone by adrenals in diabetic mice depends on both AT1 receptor blockade and AT2 receptor activation.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Camundongos , Animais , Sistema Renina-Angiotensina , Glucocorticoides , Corticosterona , Captopril/farmacologia , Aloxano
15.
Front Endocrinol (Lausanne) ; 13: 914872, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36465647

RESUMO

Purpose: Exercise therapy and key regulators of bone quality exert anti-hyperglycemic effects on type 2 diabetes mellitus (T2DM) mice. A number of programs have been reported to have an effect on bone disease in T2DM. Major unanswered questions concern the potential correlation of exercise with the improvement of bone quality in T2DM mice and how the nonlinear optical properties of bone are correlated with changes to its crystal structure. Methods: Subjects were randomly divided into six groups: 1) control (C) group, which was fed a normal diet (n = 8); 2) T2DM quiet group, which was given a high-fat diet and quiet (n = 8); 3) T2DM plus swimming (T2DM+S) group, which received T2DM and swim training (n = 8); 4) T2DM plus resistance exercise (T2DM+RE) group, which was given T2DM and resistance exercise (n = 8); 5) T2DM plus aerobic exercise (T2DM+AE) group, with T2DM and medium-intensity treadmill exercise (n = 8); and 6) T2DM plus high-intensity interval training (T2DM+HIIT), with T2DM and high-intensity variable-speed intervention (n = 8). The levels of runt-related transcription factor 2 (RUNX2), osterix (OSX), and alkaline phosphatase (ALP), as well as the bone microstructure and morphometry, were measured at the end of the 8-week exercise intervention. Results: Compared with the C group, the bone microstructure indexes [bone mineral density (BMD), bone volume/tissue volume (BV/TV), cortical thickness (Ct.Th), and connectivity density (Conn.D)], the bone biomechanical properties (maximum load, fracture load, yield stress, and elastic modulus), and the osteogenic differentiation factors (RUNX2, OSX, and BMP2) of the T2DM group were significantly decreased (all p < 0.05). Compared with the T2DM group, there were obvious improvements in the osteogenic differentiation factor (OSX) and Th.N, while the separation of trabecular bone (Tb.Sp) decreased in the T2DM+AE and T2DM+HIIT groups (all p < 0.05). In addition, the bone microstructure indicators BV/TV, tissue mineral density (TMD), Conn.D, and degree of anisotropy (DA) also increased in the T2DM+HIIT group, but the yield stress and Ct.Th deteriorated compared with the T2DM group (all p < 0.05). Compared with the T2DM+S and T2DM+RE groups, the BV/TV, trabecular number (Tb.N), Tb.Sp, and Conn.D in the T2DM+AE and T2DM+HIIT groups were significantly improved, but no significant changes in the above indicators were found between the T2DM+S and T2DM+RE groups (all p < 0.05). In addition, the BMD and the expression of ALP in the T2DM+AE group were significantly higher than those in the T2DM+HIIT group (all p < 0.05). Conclusion: There was a significant deterioration in femur bone mass, trabecular bone microarchitecture, cortical bone geometry, and bone mechanical strength in diabetic mice. However, such deterioration was obviously attenuated in diabetic mice given aerobic and high-intensity interval training, which would be induced mainly by suppressing the development of T2DM. Regular physical exercise may be an effective strategy for the prevention of not only the development of diabetes but also the deterioration of bone properties in patients with chronic T2DM.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Osteoporose , Camundongos , Animais , Humanos , Subunidade alfa 1 de Fator de Ligação ao Core , Diabetes Mellitus Tipo 2/terapia , Osteogênese , Fêmur , Osteoporose/etiologia , Osteoporose/terapia , Terapia por Exercício , Fosfatase Alcalina
16.
Eur Rev Med Pharmacol Sci ; 26(22): 8534-8538, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36459034

RESUMO

INTRODUCTION: The limitations imposed by the blood-brain barrier (BBB) on the sufficient accumulation of antiepileptic drugs (AEDs) in the epileptogenic focus is considered the major cause of the high percentage of morbidity and mortality cases among epilepsy patients. This study aimed at examining the potential effect of insulin on the anticonvulsant action of phenytoin (PHT) in the mouse maximal electroshock-induced seizure model. SUBJECTS AND METHODS: PHT was administered orally in single doses either alone or in combination with insulin given as single intraperitoneal injections. To assess the anticonvulsant activity of PHT, the ED50 values were calculated. The current strength (CS50) threshold for insulin was also estimated. The animals were sacrificed, and the brains were removed to measure their PHT concentrations in the brain. RESULTS: It has been demonstrated that insulin (in all used doses) has no effect on the CS50 but can cause a significant increase in concentrations of PHT in the brain and potentiate the antiepileptic efficiency of this drug in electroshock-induced models of epilepsy in mice. CONCLUSIONS: The combination of insulin with PHT may be of great importance for developing new treatment possibilities following further investigations with other animal models of epilepsy and preclinical studies. Further research is also needed to explore the concentrations of PHT in the brain and the anticonvulsant activity of this drug against maximal electroshock seizures in diabetic mice.


Assuntos
Diabetes Mellitus Experimental , Insulina , Animais , Camundongos , Fenitoína/farmacologia , Eletrochoque , Anticonvulsivantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Convulsões/tratamento farmacológico , Convulsões/etiologia , Modelos Animais de Doenças
17.
BMC Cardiovasc Disord ; 22(1): 518, 2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36460963

RESUMO

BACKGROUND: The diabetic heart exhibits a high sensitivity to ischaemia/reperfusion (I/R) injury. Diabetes mellitus (DM) can affect the efficacy of cardioprotective interventions and reduce the therapeutic potential of existing treatment options. This study aimed to investigate the feasibility of shifting from monotherapy to combination therapy in diabetic myocardial I/R injury. METHODS: 6-8 week rats were randomized into 10 groups: sham, I/R, ischaemia postconditioning (I-Post), nicorandil (Nic), combination therapy (I-Post + Nic), DM sham, DM I/R, DM I-Post, DM Nic and DM I-Post + Nic. The extent of myocardial injury was clarified by measuring CK-MB and NO levels in plasma, ROS content in myocardial tissues, and TTC/Evans Blue staining to assess the area of myocardial infarction. Pathological staining of cardiac tissue sections were performed to clarify the structural changes in myocardial histopathology. Finally, Western blotting was performed to detect the phosphorylation levels of some key proteins in the PI3K/Akt signalling pathway in myocardial tissues. RESULTS: We confirms that myocardial injury in diabetic I/R rats remained at a high level after treatment with I-Post or nicorandil alone. I-Post combined with nicorandil showed better therapeutic effects in diabetic I/R rats, and the combined treatment further reduced the area of myocardial injury in diabetic I/R rats compared with I-Post or nicorandil treatment alone (P < 0.001), as well as the levels of the myocardial injury markers CK-MB and ROS (P < 0.001); it also significantly increased plasma NO levels. Pathological staining also showed that diabetic rats benefited significantly from the combination therapy. Further mechanistic studies confirmed this finding. The protein phosphorylation levels of PI3K/Akt signalling pathway in the heart tissue of diabetic I/R rats were significantly higher after the combination treatment than after one treatment alone (all P < 0.05). CONCLUSION: I-Post combined with nicorandil treatment maintains effective cardioprotection against diabetic myocardial I/R injury by activating the PI3K/Akt signalling pathway.


Assuntos
Diabetes Mellitus Experimental , Traumatismos Cardíacos , Pós-Condicionamento Isquêmico , Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Ratos , Animais , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Nicorandil/farmacologia , Diabetes Mellitus Experimental/complicações , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Espécies Reativas de Oxigênio , Infarto do Miocárdio/prevenção & controle , Creatina Quinase Forma MB
18.
Mol Med ; 28(1): 144, 2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36463128

RESUMO

BACKGROUND: The T helper 17 (Th17)/T regulatory (Treg) cell imbalance is involved in the course of obesity and type 2 diabetes mellitus (T2DM). In the current study, the exact role of glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide on regulating the Th17/Treg balance and the underlying molecular mechanisms are investigated in obese diabetic mice model. METHODS: Metabolic parameters were monitored in db/db mice treated with/without exenatide during 8-week study period. The frequencies of Th17 and Treg cells from peripheral blood and pancreas in db/db mice were assessed. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box O1 (FoxO1) pathway in Th17 and Treg cells from the spleens of male C57BL/6J mice was detected by western blotting. In addition, the expression of glucagon-like peptide-1 receptor (GLP-1R) in peripheral blood mononuclear cells (PBMCs) of male C57BL/6J mice was analyzed. RESULTS: Exenatide treatment improved ß-cell function and insulitis in addition to glucose, insulin sensitivity and weight. Increased Th17 and decreased Treg cells in peripheral blood were present as diabetes progressed while exenatide corrected this imbalance. Progressive IL-17 + T cell infiltration of pancreatic islets was alleviated by exenatide intervention. In vitro study showed no significant difference in the level of GLP-1R expression in PBMCs between control and palmitate (PA) groups. In addition, PA could promote Th17 but suppress Treg differentiation along with down-regulating the phosphorylation of PI3K/Akt/FoxO1, which was reversed by exenatide intervention. FoxO1 inhibitor AS1842856 could abrogate all these effects of exenatide against lipid stress. CONCLUSIONS: Exenatide could restore systemic Th17/Treg balance via regulating FoxO1 pathway with the progression of diabetes in db/db mice. The protection of pancreatic ß-cell function may be partially mediated by inhibiting Th17 cell infiltration into pancreatic islets, and the resultant alleviation of islet inflammation.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Masculino , Camundongos , Animais , Fosfatidilinositol 3-Quinase , Exenatida/farmacologia , Proteínas Proto-Oncogênicas c-akt , Fosfatidilinositol 3-Quinases , Linfócitos T Reguladores , Receptor do Peptídeo Semelhante ao Glucagon 1 , Diabetes Mellitus Tipo 2/tratamento farmacológico , Leucócitos Mononucleares , Camundongos Endogâmicos C57BL , Proteína Forkhead Box O1
19.
Turk J Med Sci ; 52(4): 1362-1370, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36326417

RESUMO

BACKGROUND: Dapagliflozin (DAPA), sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an insulin-independent antidiabetic drug used to control hyperglycaemia by promoting glucose excretion from the kidney. Its adverse effects include orthostatic hypotension, dehydration and urinary tract and genital infections caused by glycosuria. DAPA is subjected to constant additional monitoring, as drugrelated adverse reactions are frequently updated in line with the results of case studies, clinical trials and in vivo studies. Some antidiabetic drugs have shown potential harmful effects on the male reproductive system; however, the effects of DAPA have not been sufficiently studied in this capacity. Aiming to fill this gap in the literature, the present work investigates the toxic effects of DAPA on the male reproductive system. METHODS: Diabetes was induced using streptozotocin (STZ) in adult male Sprague-Dawley (SD) rats. DAPA (10 mg/kg) was administered by gavage to the diabetic rats over 28 days, after which the animals were sacrificed. The biochemical, morphological and histological examinations were performed on testicle, sperm and plasma samples. RESULTS: As a result of this study, we observed reproductive system damage in the form of induction of apoptosis in the seminiferous tubules, changes in testis and sperm parameters and oxidative damage, alongside the development of diabetes in test animals. With the exception of sperm morphological damage, the changes observed in diabetic animals treated with DAPA were similar to those of the control group. Improvements were observed in histological, hormonal and proliferative parameters in the DAPA group compared to the DC group. DISCUSSION: Even if DAPA is found to have antioxidant effects, it may raise abnormal sperm counts through a mechanism completely independent of these effects and thus may not have a significant toxic effect on the male reproductive system.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Masculino , Ratos , Animais , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Ratos Sprague-Dawley , Sêmen , Hipoglicemiantes/toxicidade , Hipoglicemiantes/uso terapêutico , Glucose/uso terapêutico , Genitália , Diabetes Mellitus Tipo 2/tratamento farmacológico
20.
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
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