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

RESUMO

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


Assuntos
Dendrobium , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Hipoglicemiantes/farmacologia , Camundongos , Estresse Oxidativo , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia
2.
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
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.
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
5.
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
6.
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
7.
Life Sci ; 311(Pt A): 121145, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36336129

RESUMO

AIM: We compared the efficacy of n3-polyunsaturated fatty acids (n3-PUFAs) and metformin in halting the progression of non-alcoholic fatty liver disease (NAFLD) developed in the milieu of insulin deficiency. MAIN METHODS: NAFLD was induced by a chronic high-fat diet (HFD) in male Sprague Dawley rats, rendered diabetic by a low dose streptozotocin (STZ). Diabetic rats were treated with n3-PUFAs (300 mg/kg/d) or metformin (150 mg/kg/d) for 8 weeks. Improvements in the NAFLD score and hepatic insulin resistance (IR) were addressed and correlated to changes in the hepatic expression of Forkhead box protein O1 (FOXO-1), microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B) and gamma-aminobutyric acid receptor-associated protein-like 1 (GABARAPL1) genes. Hepatic peroxisome proliferator-activated receptor alpha (PPAR-α), and B-cell lymphoma 2 (Bcl-2) protein expression was also assessed. KEY FINDINGS: Driven by insulin deficiency and HFD, the FOXO-1 gene along with its downstream targets, MAP1LC3B and GABARAPL1, were highly expressed in the liver tissue of the HFD/STZ group. Meanwhile, hepatic expression of PPAR-α and Bcl-2 was markedly decreased. These abnormalities coincided with a marked increase in the hepatic IR and NAFLD activity. Comparable to metformin, n3-PUFAs were able to rearrange hepatic PPAR-α and FOXO-1 expression in HFD/STZ rats, resulting in improved diabetic/steatotic liver phenotype. SIGNIFICANCE: Along with the enhancement of PPAR-α expression, inhibition of FoxO1/GABARAPL1/MAP1LC3B transcription is suggested as a core mechanism for the protective effects of n3-PUFAs on hepatic IR and NAFLD. Under conditions of insulin deficiency, n3-PUFAs retain their potential as a safe and promising approach for the control of NAFLD.


Assuntos
Diabetes Mellitus Experimental , Ácidos Graxos Ômega-3 , Resistência à Insulina , Metformina , Hepatopatia Gordurosa não Alcoólica , Animais , Masculino , Ratos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Metformina/uso terapêutico , Proteínas do Tecido Nervoso/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR alfa/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley
8.
PLoS One ; 17(11): e0265854, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36395179

RESUMO

BACKGROUND: Diabetes mellitus is a chronic metabolic disorder which induces endothelial dysfunction and platelet activation. Eicosanoids produced from arachidonic acid regulate cellular and vascular functions. Sigma-1 receptors (S1R) are expressed in platelets and endothelial cells and S1R expression is protective in diabetes. OBJECTIVES: Our aim was to examine the influence of sub-chronic, in vivo administered S1R ligands PRE-084, (S)-L1 (a new compound) and NE-100 on the ex vivo arachidonic acid metabolism of platelets and aorta in streptozotocin-induced diabetic rats. METHODS: The serum level of the S1R ligands was detected by LC-MS/MS before the ex vivo analysis. Sigma-1 receptor and cyclooxygenase gene expression in platelets were determined by RT-qPCR. The eicosanoid synthesis was examined with a radiolabelled arachidonic acid substrate and ELISA. RESULTS: One month after the onset of STZ-induced diabetes, in vehicle-treated, diabetic rat platelet TxB2 and aortic 6-k-PGF1α production dropped. Sub-chronic in vivo treatment of STZ-induced diabetes in rats for one week with PRE-084 enhanced vasoconstrictor and platelet aggregator and reduced vasodilator and anti-aggregator cyclooxygenase product formation. (S)-L1 reduced the synthesis of vasodilator and anti-aggregator cyclooxygenase metabolites and promoted the recovery of physiological platelet function in diabetic rats. The S1R antagonist NE-100 produced no significant changes in platelet arachidonic acid metabolism. (S)-L1 decreased the synthesis of vasoconstrictor and platelet aggregator cyclooxygenase metabolites, whereas NE-100 increased the quantity of aortic vasodilator and anti-aggregator cyclooxygenase products and promoted the recovery of diabetic endothelial dysfunction in the aorta. The novel S1R ligand, (S)-L1 had similar effects on eicosanoid synthesis in platelets as the agonist PRE-084 and in aortas as the antagonist NE-100. CONCLUSIONS: S1R ligands regulate cellular functions and local blood circulation by influencing arachidonic acid metabolism. In diabetes mellitus, the cell-specific effects of S1R ligands have a compensatory role and aid in restoring physiological balance between the platelet and vessel.


Assuntos
Diabetes Mellitus Experimental , Animais , Ratos , Estreptozocina , Ácido Araquidônico/farmacologia , Diabetes Mellitus Experimental/metabolismo , Ligantes , Células Endoteliais/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Ácidos Araquidônicos/metabolismo , Aorta/metabolismo , Eicosanoides , Ciclo-Oxigenase 2 , Vasodilatadores , Vasoconstritores
9.
Circ Res ; 131(12): 1018-1033, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36345826

RESUMO

BACKGROUND: L-type CaV1.2 channels undergo cooperative gating to regulate cell function, although mechanisms are unclear. This study tests the hypothesis that phosphorylation of the CaV1.2 pore-forming subunit α1C at S1928 mediates vascular CaV1.2 cooperativity during diabetic hyperglycemia. METHODS: A multiscale approach including patch-clamp electrophysiology, super-resolution nanoscopy, proximity ligation assay, calcium imaging' pressure myography, and Laser Speckle imaging was implemented to examine CaV1.2 cooperativity, α1C clustering, myogenic tone, and blood flow in human and mouse arterial myocytes/vessels. RESULTS: CaV1.2 activity and cooperative gating increase in arterial myocytes from patients with type 2 diabetes and type 1 diabetic mice, and in wild-type mouse arterial myocytes after elevating extracellular glucose. These changes were prevented in wild-type cells pre-exposed to a PKA inhibitor or cells from knock-in S1928A but not S1700A mice. In addition, α1C clustering at the surface membrane of wild-type, but not wild-type cells pre-exposed to PKA or P2Y11 inhibitors and S1928A arterial myocytes, was elevated upon hyperglycemia and diabetes. CaV1.2 spatial and gating remodeling correlated with enhanced arterial myocyte Ca2+ influx and contractility and in vivo reduction in arterial diameter and blood flow upon hyperglycemia and diabetes in wild-type but not S1928A cells/mice. CONCLUSIONS: These results suggest that PKA-dependent S1928 phosphorylation promotes the spatial reorganization of vascular α1C into "superclusters" upon hyperglycemia and diabetes. This triggers CaV1.2 activity and cooperativity, directly impacting vascular reactivity. The results may lay the foundation for developing therapeutics to correct CaV1.2 and arterial function during diabetic hyperglycemia.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hiperglicemia , Humanos , Camundongos , Animais , Músculo Liso Vascular/metabolismo , Fosforilação , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hiperglicemia/metabolismo
10.
Life Sci ; 311(Pt A): 121142, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36367498

RESUMO

AIMS: Our previous studies showed that the nonsteroidal anti-inflammatory drug-activated gene-1, or growth differentiation factor-15 (NAG-1/GDF15) inhibits obesity and diabetes in mice. The current study aimed to examine the role and molecular mechanisms of NAG-1/GDF15 in diabetic nephropathy (DN), which is largely unknown. MAIN METHODS: Both male and female wild-type (Wt) C57BL/6 mice and mice overexpressing human NAG-1/GDF15 (transgenic, Tg) were used, which were induced by high-fat diet (HFD)/streptozotocin (STZ) to establish the mouse model of DN. Transcriptome study was performed to identify the underlying molecular mechanisms of NAG-1/GDF15 against DN. In addition, human renal tubular epithelial cells (HK-2) were cultured with high glucose (HG) to establish a DN cellular model and were treated with NAG-1/GDF15 plasmid or the recombinant NAG-1/GDF15 protein for mechanism studies. KEY FINDINGS: Overexpression of NAG-1/GDF15 in Tg mice significantly alleviated HFD/STZ-induced typical symptoms of DN, improved lipid homeostasis, glucose intolerance, and insulin sensitivity. Histopathology of renal tissues revealed that NAG-1/GDF15 mice had significantly reduced renal injury, glycogen deposition, and renal fibrosis. Transcriptome study uncovered inflammation, cell adhesion, and the inflammation-related signaling pathways as major pathways suppressed in the NAG-1/GDF15 mice. Further studies demonstrated that NAG-1/GDF15 overexpression inhibited renal and systematic inflammation, inhibited the AGE/RAGE axis and its associated downstream inflammatory molecules and adhesion molecules, and inhibited the upregulation of TLR4/MyD88/NF-κB signaling pathway in mice. These results were further confirmed in HG-induced HK-2 cells. SIGNIFICANCE: NAG-1/GDF15 plays an important role in the inhibition of the development and progression of DN via targeting AGE/RAGE-mediated inflammation pathways.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Feminino , Humanos , Masculino , Camundongos , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Fator 15 de Diferenciação de Crescimento/genética , Inflamação/patologia , Camundongos Endogâmicos C57BL , Transdução de Sinais , Estreptozocina/farmacologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/metabolismo
11.
J Diabetes Res ; 2022: 1861940, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36387940

RESUMO

Background: GLP-1 receptor agonists (GLP-1RA) are common clinical agents that are clinically protective against diabetic complications, such as diabetic retinopathy (DR). Previous studies have shown that the RhoA/ROCK pathway plays an important role in the development of DR. However, the specific mechanism of action between GLP-1RA and DR remains unclear. The aim of this study was thus to investigate the main mechanism involved in the protective effect of GLP-1RA on DR. Methods: Type 2 diabetic mice were fed a high-sugar, high-fat diet. Changes in the retinal structure were observed via HE staining and transmission electron microscopy. The expression of retinal GLP-1R, blood-retinal barrier- (BRB-) related proteins, inflammatory factors, and related pathway proteins were studied via Western blot or immunohistochemistry/immunofluorescence analysis. Results: GLP-1RA treatment reduced the blood glucose and lipid levels as well as the body weight of the diabetic mice while also improving retinal thickness, morphology, and vascular ultrastructure. Moreover, restored GLP-1R expression, increased Occludin and ZO-1 levels, and decreased albumin expression led to reduced retinal leakage and improved the BRB by inhibiting the RhoA/ROCK pathway. Conclusions: We found that the protective effect of GLP-1RA on the retina may be realized through the GLP-1R-ROCK-p-MLC signaling pathway.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Camundongos , Animais , Barreira Hematorretiniana/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/prevenção & controle , Retinopatia Diabética/etiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Transdução de Sinais , Fatores de Transcrição
12.
Mol Med ; 28(1): 129, 2022 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-36316651

RESUMO

Curcumin is a polyphenolic compound derived from turmeric that has potential beneficial properties for cardiovascular and renal diseases and is relatively safe and inexpensive. However, the application of curcumin is rather problematic due to its chemical instability and low bioavailability. The experimental results showed improved chemical stability and potent pharmacokinetics of one of its analogs - (2E,6E)-2,6-bis[(2-trifluoromethyl)benzylidene]cyclohexanone (C66). There are several advantages of C66, like its synthetic accessibility, structural simplicity, improved chemical stability (in vitro and in vivo), presence of two reactive electrophilic centers, and good electron-accepting capacity. Considering these characteristics, we reviewed the literature on the application of C66 in resolving diabetes-associated cardiovascular and renal complications in animal models. We also summarized the mechanisms by which C66 is preventing the release of pro-oxidative and pro-inflammatory molecules in the priming and in activation stage of cardiomyopathy, renal fibrosis, and diabetic nephropathy. The cardiovascular protective effect of C66 against diabetes-induced oxidative damage is Nrf2 mediated but mainly dependent on JNK2. In general, C66 causes inhibition of JNK2, which reduces cardiac inflammation, fibrosis, oxidative stress, and apoptosis in the settings of diabetic cardiomyopathy. C66 exerts a powerful antifibrotic effect by reducing inflammation-related factors (MCP-1, NF-κB, TNF-α, IL-1ß, COX-2, and CAV-1) and inducing the expression of anti-inflammatory factors (HO-1 and NEDD4), as well as targeting TGF-ß/SMADs, MAPK/ERK, and PPAR-γ pathways in animal models of diabetic nephropathy. Based on the available evidence, C66 is becoming a promising drug candidate for improving cardiovascular and renal health.


Assuntos
Curcumina , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Curcumina/farmacologia , Curcumina/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/patologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Rim/metabolismo , Fibrose , Estresse Oxidativo , Inflamação/metabolismo
13.
Int J Immunopathol Pharmacol ; 36: 3946320221137435, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36319192

RESUMO

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a worldwide health problem with high prevalence and morbidity associated with obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and dyslipidemia. Nano-formulation of luteolin with Zn oxide in the form of Lut/ZnO NPs may improve the anti-diabetic property of each alone and ameliorate the insulin resistance thus management of NAFLD. This study aimed to measure the efficiency of Lut/ZnO NPs against insulin resistance coupled with NAFLD and T2DM. METHODS: A diabetic rat model with NAFLD was induced by a high-fat diet and streptozotocin (30 mg/kg I.P). Serum diabetogenic markers levels, lipid profile, and activity of liver enzymes were measured beside liver oxidative stress markers. Moreover, the hepatic expressions of PI3K/AKT/FoxO1/SERBP1c as well as heme oxygenase-1 were measured beside the histopathological examination. RESULTS: Lut/ZnO NPs treatment effectively reduced hyperglycemia, hyperinsulinemia, and ameliorated insulin resistance. Additionally, Lut/ZnO NPs improved the hepatic functions, the antioxidant system, and reduced the oxidative stress markers. Furthermore, the lipid load in the liver, as well as the circulating TG and TC, was minified via the suppression of lipogenesis and gluconeogenesis. Moreover, Lut/ZnO NPs activated the PI3K/AKT signaling pathway, hence inactivating FoxO1, therefore enhancing the hepatic cells' insulin sensitivity. CONCLUSION: Lut/ZnO NPs have a hepatoprotective effect and may relieve the progression of NAFLD by alleviating insulin resistance, ameliorating the antioxidant status, and regulating the insulin signal pathway.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Nanopartículas , Hepatopatia Gordurosa não Alcoólica , Óxido de Zinco , Ratos , Animais , Óxido de Zinco/metabolismo , Óxido de Zinco/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Luteolina , Diabetes Mellitus Tipo 2/metabolismo , Antioxidantes/farmacologia , Diabetes Mellitus Experimental/metabolismo , Insulina/metabolismo , Fígado , Lipídeos , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/farmacologia
14.
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
15.
Injury ; 53(12): 3920-3929, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36357245

RESUMO

Mesenchymal stem cells (MSCs) play a key role in wound healing, and the advantages of pretreated MSCs in wound healing have previously been reported. In the present study, we investigated the impact of LPS pretreated human adipose-derived MSCs on skin wound healing in diabetic rats. We found that some improvements occurred through improving angiogenesis. Then, we scrutinized the impact of lipopolysaccharide (LPS) treatment on human adipose-derived MSCs in a high-glucose (HG) medium, as an in vitro diabetic model. In vivo findings revealed significant improvements in epithelialization and angiogenesis of diabetic wounds which received LPS pre-MSCs. Particularly, LPS pre-MSCs-treated diabetic wounds reached considerably higher percentages of wound closure. Also, the granulation tissue of these wounds had higher pronounced epithelialization and more vascularization compared with PBS-treated and MSCs-treated diabetic ones by CD31, VEGF, CD90, collagen 1, and collagen 3 immunostaining. Western-blots analyses indicated that LPS pre-MSCs led to the upregulation of vascular endothelial growth factor (VEGF) and DNMT1. In addition, significantly higher cell viability (proliferation/colonie), and elevated VEGF and DNMT1 protein expression were observed when MSCs were treated with LPS (10 ng/ml, 6 h) in HG culture media. Based on these findings, it is suggested that LPS pre-MSCs could promote wound repair and skin regeneration, in some major processes, via the improvement of cellular behaviors of MSCs in the diabetic microenvironment. The beneficial advantages of LPS treated with mesenchymal stem cells on wound healing may lead to establishing a novel approach as an alternative therapeutic procedure to cure chronic wounds in diabetic conditions.


Assuntos
Diabetes Mellitus Experimental , Células-Tronco Mesenquimais , Ratos , Humanos , Animais , Lipopolissacarídeos/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Experimental/metabolismo , Cicatrização , Colágeno/metabolismo
16.
Int J Mol Sci ; 23(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36362050

RESUMO

Diabetic kidney disease (DKD) frequently leads to end-stage renal disease and other life-threatening illnesses. The dysregulation of glomerular cell types, including mesangial cells, endothelial cells, and podocytes, appears to play a vital role in the development of DKD. Myeloid-derived suppressor cells (MDSCs) exhibit immunoregulatory and anti-inflammatory properties through the depletion of L-arginine that is required by T cells, through generation of oxidative stress, interference with T-cell recruitment and viability, proliferation of regulatory T cells, and through the promotion of pro-tumorigenic functions. Under hyperglycemic conditions, mouse mesangial cells reportedly produce higher levels of fibronectin and pro-inflammatory cytokines. Moreover, the number of MDSCs is noticeably decreased, weakening inhibitory immune activities, and creating an inflammatory environment. In diabetic mice, immunotherapy with MDSCs that were induced by a combination of granulocyte-macrophage colony-stimulating factor, interleukin (IL)-1ß, and IL-6, reduced kidney to body weight ratio, fibronectin expression, and fibronectin accumulation in renal glomeruli, thus ameliorating DKD. In conclusion, MDSCs exhibit anti-inflammatory activities that help improve renal fibrosis in diabetic mice. The therapeutic targeting of the proliferative or immunomodulatory pathways of MDSCs may represent an alternative immunotherapeutic strategy for DKD.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Células Supressoras Mieloides , Animais , Camundongos , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/imunologia , Nefropatias Diabéticas/metabolismo , Células Endoteliais/metabolismo , Fibronectinas/metabolismo , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia
17.
Int J Mol Sci ; 23(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36430204

RESUMO

FLIM (Fluorescence Lifetime Imaging Microscopy) is a powerful tool that could be used in the future to diagnose islet cell recovery after therapy. The identification of appropriate FLIM parameters is required to determine islet quality and islet cell metabolism throughout the organ under various conditions of insulin deficiency. The aim of the work was to identify key FLIM parameters, changes of which are characteristic of pancreatic pathologies. The τm, τ1, τ2, α1, α2 and α1/α2 of free and bound forms of NAD(P)H of the islet cells of animals (rats and pigs) and of humans with and without pathologies were measured and analyzed. The data were confirmed by IHC and histological studies. We identified three FLIM parameters in islet cells from animals with streptozotocin (STZ)-induced diabetes mellitus (DM) and from humans with chronic pancreatitis + type 2 diabetes (T2D), which differ in the same way: τm and α2 take lower values compared to the nonpathological islet cells, while α1/α2 takes higher values. In islet cells from patients with adenocarcinoma (PDAC) and chronic pancreatitis, these parameters had reverse tendency relative to the norm or did not differ. Thus, minimally invasive and non-contrast FLIM methods may, in the future, be used to diagnose pathological islet cells.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Pancreatite Crônica , Humanos , Ratos , Suínos , Animais , Ilhotas Pancreáticas/metabolismo , Insulina/metabolismo , Diabetes Mellitus Experimental/metabolismo , NAD
18.
Int J Mol Sci ; 23(22)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36430714

RESUMO

Diabetes is a long-term metabolic disorder characterized by persistently elevated blood sugar levels. Chronic hyperglycemia enhances glucose-protein interactions, leading to the formation of advanced glycation end products (AGEs), which form irreversible cross-links with a wide variety of macromolecules, and accumulate rapidly in the body tissues. Thus, the objective of this study was to assess the therapeutic properties of C-phycocyanin (C-PC) obtained from Plectonema species against oxidative stress, glycation, and type 2 diabetes mellitus (T2DM) in a streptozotocin (STZ)-induced diabetic Wistar rat. Forty-five days of C-PC administration decreased levels of triglycerides (TGs), blood glucose, glycosylated hemoglobin, (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), liver and kidney function indices, and raised body weight in diabetic rats. C-PC suppressed biochemical glycation markers, as well as serum carboxymethyllysine (CML) and fluorescent AGEs. Additionally, C-PC maintained the redox state by lowering lipid peroxidation and protein-bound carbonyl content (CC), enhancing the activity of high-density lipoprotein cholesterol (HDL-C) and renal antioxidant enzymes, and preserving retinal and renal histopathological characteristics. Thus, we infer that C-PC possesses antidiabetic and antiglycation effects in diabetic rats. C-PC may also act as an antidiabetic and antiglycation agent in vivo that may reduce the risk of secondary diabetic complications.


Assuntos
Produtos Biológicos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hiperglicemia , Ratos , Animais , Diabetes Mellitus Experimental/metabolismo , Estreptozocina , Ficocianina/farmacologia , Ficocianina/uso terapêutico , Produtos Biológicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ratos Wistar , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hiperglicemia/tratamento farmacológico , HDL-Colesterol
19.
Sci Rep ; 12(1): 20278, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36434087

RESUMO

Despite increasing knowledge about the factors involved in the progression of diabetic complications, diabetic kidney disease (DKD) continues to be a major health burden. Current therapies only slow but do not prevent the progression of DKD. Thus, there is an urgent need to develop novel therapy to halt the progression of DKD and improve disease prognosis. In our preclinical study where we administered a histone deacetylase (HDAC) inhibitor, valproic acid, to streptozotocin-induced diabetic mice, albuminuria and glomerulosclerosis were attenuated. Furthermore, we discovered that valproic acid attenuated diabetes-induced upregulation of complement C5a receptors, with a concomitant reduction in markers of cellular senescence and senescence-associated secretory phenotype. Interestingly, further examination of mice lacking the C5a receptor 1 (C5aR1) gene revealed that cellular senescence was attenuated in diabetes. Similar results were observed in diabetic mice treated with a C5aR1 inhibitor, PMX53. RNA-sequencing analyses showed that PMX53 significantly regulated genes associated with cell cycle pathways leading to cellular senescence. Collectively, these results for the first time demonstrated that complement C5a mediates cellular senescence in diabetic kidney disease. Cellular senescence has been implicated in the pathogenesis of diabetic kidney disease, thus therapies to inhibit cellular senescence such as complement inhibitors present as a novel therapeutic option to treat diabetic kidney disease.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Camundongos , Animais , Nefropatias Diabéticas/patologia , Ácido Valproico/farmacologia , Receptor da Anafilatoxina C5a/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Senescência Celular , Complemento C5a , Inibidores de Histona Desacetilases
20.
Cells ; 11(21)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36359733

RESUMO

Liver fibrosis can develop on the background of hyperglycemia in diabetes mellitus. However, xenobiotic-related factors may accelerate diabetes-associated liver fibrosis. In this study, we aimed to assess the antfibrotic effect of ADSC and HGF therapy and to establish the cellular and molecular mechanisms through in vitro and in vivo experiments. In vitro, TGF-ß1-activated hepatic stellate cells (HSCs) were cocultured with ADSCs or HGF, and the expression of several fibrosis markers was investigated. The antifibrotic effect of the ADSCs, HGF, and ADSCs supplemented with HGF was further assessed in vivo on diabetic mice with liver fibrosis experimentally induced. In vitro results showed the inhibition of HSC proliferation and decrease in fibrogenesis markers. Coadministration of ADSCs and HGF on diabetic mice with liver fibrosis enhanced antifibrotic effects confirmed by the downregulation of Col I, α-SMA, TGF-ß1, and Smad2, while Smad7 was upregulated. Moreover, stem cell therapy supplemented with HGF considerably attenuated inflammation and microvesicular steatosis, decreased collagen deposits, and alleviated liver fibrosis. In conclusion, the HGF-based ADSC therapy might be of interest for the treatment of liver fibrosis in diabetic patients, consecutive aggression exerts by different environmental factors.


Assuntos
Diabetes Mellitus Experimental , Células Estreladas do Fígado , Cirrose Hepática , Animais , Camundongos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Experimental/metabolismo , Células Estreladas do Fígado/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Fator de Crescimento de Hepatócito/farmacologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/terapia , Cirrose Hepática/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Células-Tronco/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células-Tronco Mesenquimais
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