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1.
J Sci Food Agric ; 102(1): 53-61, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34031881

RESUMO

BACKGROUND: Corn silk is a very important by-product of corn production with medicinal value. Corn silk polysaccharide (CSP) is the main active ingredient. In the present study, ultrasound and spheroidization by anti-solvent were applied to improve the biological activity of CSP. RESULTS: The results showed that ultrasonic degradation improved the α-glucosidase inhibitory activity of CSP by changing its physicochemical characteristics. As the anti-solvent ratio increased, the particle size of the nanoparticles (NPs) from the spheroidization of ultrasonic-degraded corn silk polysaccharide (UCSP) gradually increased, and NP-1 exhibited the highest inhibitory effect of α-glucosidase. Isothermal titration calorimetry (ITC) results indicated that the enhanced activity might be due to more α-glucosidase binding sites with NP-1 compared with no spheroidization. Western blotting results showed that NP-1 could improve the 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) uptake in the L6 cells by regulating the phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway and the translocation of glucose transporter 4 (GLUT4). NP-1 also exhibited excellent stability in different environments. CONCLUSION: The study revealed that ultrasonic treatment and spheroidization processing showed potential applications for improving the biological activity of polysaccharides. © 2021 Society of Chemical Industry.


Assuntos
Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polissacarídeos/química , Polissacarídeos/farmacologia , Zea mays/química , Animais , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Ultrassom , alfa-Glucosidases/química
2.
Nat Commun ; 12(1): 7256, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34907199

RESUMO

Several members of the FGF family have been identified as potential regulators of glucose homeostasis. We previously reported that a low threshold of FGF-induced FGF receptor 1c (FGFR1c) dimerization and activity is sufficient to evoke a glucose lowering activity. We therefore reasoned that ligand identity may not matter, and that besides paracrine FGF1 and endocrine FGF21, other cognate paracrine FGFs of FGFR1c might possess such activity. Indeed, via a side-by-side testing of multiple cognate FGFs of FGFR1c in diabetic mice we identified the paracrine FGF4 as a potent anti-hyperglycemic FGF. Importantly, we found that like FGF1, the paracrine FGF4 is also more efficacious than endocrine FGF21 in lowering blood glucose. We show that paracrine FGF4 and FGF1 exert their superior glycemic control by targeting skeletal muscle, which expresses copious FGFR1c but lacks ß-klotho (KLB), an obligatory FGF21 co-receptor. Mechanistically, both FGF4 and FGF1 upregulate GLUT4 cell surface abundance in skeletal muscle in an AMPKα-dependent but insulin-independent manner. Chronic treatment with rFGF4 improves insulin resistance and suppresses adipose macrophage infiltration and inflammation. Notably, unlike FGF1 (a pan-FGFR ligand), FGF4, which has more restricted FGFR1c binding specificity, has no apparent effect on food intake. The potent anti-hyperglycemic and anti-inflammatory properties of FGF4 testify to its promising potential for use in the treatment of T2D and related metabolic disorders.


Assuntos
Fator 4 de Crescimento de Fibroblastos/farmacologia , Hipoglicemiantes/farmacologia , Músculo Esquelético/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Fator 4 de Crescimento de Fibroblastos/administração & dosagem , Fator 4 de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/farmacologia , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/metabolismo , Inflamação , Resistência à Insulina , Ligantes , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Comunicação Parácrina , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Int J Mol Sci ; 22(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34639094

RESUMO

Insulin stimulates glucose uptake in adipose tissue and skeletal muscle by inducing plasma membrane translocation of the glucose transporter GLUT4. Although the small GTPase Rac1 is a key regulator downstream of phosphoinositide 3-kinase (PI3K) and the protein kinase Akt2 in skeletal muscle, it remains unclear whether Rac1 also regulates glucose uptake in white adipocytes. Herein, we investigated the physiological role of Rac1 in white adipocytes by employing adipocyte-specific rac1 knockout (adipo-rac1-KO) mice. Subcutaneous and epididymal white adipose tissues (WATs) in adipo-rac1-KO mice showed significant reductions in size and weight. Actually, white adipocytes lacking Rac1 were smaller than controls. Insulin-stimulated glucose uptake and GLUT4 translocation were abrogated in rac1-KO white adipocytes. On the other hand, GLUT4 translocation was augmented by constitutively activated PI3K or Akt2 in control, but not in rac1-KO, white adipocytes. Similarly, to skeletal muscle, the involvement of another small GTPase RalA downstream of Rac1 was demonstrated. In addition, mRNA levels of various lipogenic enzymes were down-regulated in rac1-KO white adipocytes. Collectively, these results suggest that Rac1 is implicated in insulin-dependent glucose uptake and lipogenesis in white adipocytes, and reduced insulin responsiveness due to the deficiency of Rac1 may be a likely explanation for atrophy of WATs.


Assuntos
Tecido Adiposo Branco/patologia , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , Insulina/farmacologia , Neuropeptídeos/fisiologia , Proteínas rac1 de Ligação ao GTP/fisiologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Atrofia , Feminino , Transportador de Glucose Tipo 4/genética , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Edulcorantes/farmacologia
4.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638553

RESUMO

Low-grade chronic inflammation plays a pivotal role in the pathogenesis of insulin resistance (IR), and skeletal muscle has a central role in this condition. NLRP3 inflammasome activation pathways promote low-grade chronic inflammation in several tissues. However, a direct link between IR and NLRP3 inflammasome activation in skeletal muscle has not been reported. Here, we evaluated the NLRP3 inflammasome components and their role in GLUT4 translocation impairment in skeletal muscle during IR. Male C57BL/6J mice were fed with a normal control diet (NCD) or high-fat diet (HFD) for 8 weeks. The protein levels of NLRP3, ASC, caspase-1, gasdermin-D (GSDMD), and interleukin (IL)-1ß were measured in both homogenized and isolated fibers from the flexor digitorum brevis (FDB) or soleus muscle. GLUT4 translocation was determined through GLUT4myc-eGFP electroporation of the FBD muscle. Our results, obtained using immunofluorescence, showed that adult skeletal muscle expresses the inflammasome components. In the FDB and soleus muscles, homogenates from HFD-fed mice, we found increased protein levels of NLRP3 and ASC, higher activation of caspase-1, and elevated IL-1ß in its mature form, compared to NCD-fed mice. Moreover, GSDMD, a protein that mediates IL-1ß secretion, was found to be increased in HFD-fed-mice muscles. Interestingly, MCC950, a specific pharmacological NLRP3 inflammasome inhibitor, promoted GLUT4 translocation in fibers isolated from the FDB muscle of NCD- and HFD-fed mice. In conclusion, we found increased NLRP3 inflammasome components in adult skeletal muscle of obese insulin-resistant animals, which might contribute to the low-grade chronic metabolic inflammation of skeletal muscle and IR development.


Assuntos
Transportador de Glucose Tipo 4/metabolismo , Inflamassomos/metabolismo , Resistência à Insulina/fisiologia , Interleucina-1beta/metabolismo , Músculo Esquelético/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Caspase 1/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Furanos/farmacologia , Indenos/farmacologia , Inflamassomos/química , Interleucina-1beta/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Obesidade/induzido quimicamente , Obesidade/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Sulfonamidas/farmacologia
6.
BMC Cancer ; 21(1): 1026, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34525987

RESUMO

BACKGROUND: Current treatment methods for patients with triple-negative breast cancer (TNBC) are very limited, and the prognosis of TNBC is relatively poor. It has been reported that glucose transporter 1 (GLUT1) is overexpressed in breast cancer cells; however, its association with the prognosis is mostly unclear. Moreover, retinoblastoma gene 1 (RB1) might be used as a biomarker for the sensitivity of breast cancer cells to GLUT1 inhibitors, which brought us to the hypothesis that there might be a close correlation between the expression of GLUT1-4 and the expression of RB1. METHODS: In this study, we systematically analyzed the co-expression of GLUT1-4 and the influence of GLUT1-4 gene expression on the prognosis of breast cancer using data mining methods. We also explored possible relationships between GLUT1-4 and RB1 expression in breast cancer tissues. We used public databases such as ONCOMINE, GEPIA, LinkedOmics, and COEXPEDIA. RESULTS: According to the results, the mRNA expression of SLC2A1 was significantly higher in breast cancer, while the expression levels of SLC2A2-4 were downregulated. The results also indicate that GLUT1 expression does not have significant influence on the overall survival of patients with breast cancer. The mRNA expression of SLC2A1 and RB1 is significantly correlated, which means that tissues with high RB1 mRNA expression might have relatively higher mRNA expression of SLC2A1; however, further study analyzing their roles in the expression regulation pathways with human samples is needed to verify the hypothesis. CONCLUSIONS: The mRNA expression of SLC2A1 was significantly higher in breast cancer. The overall survival of breast cancer patients wasn't significantly correlated with GLUT1-4 expression. The mRNA expression of SLC2A1 and RB1 is significantly correlated according to the analysis conducted in LinkedOmics. It provides reference for future possible individualized treatment of TNBC using GLUT1 inhibitors, especially in patients with higher mRNA expression of RB1. Further study analyzing the roles of these two genes in the regulation pathways is needed.


Assuntos
Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Proteínas de Ligação a Retinoblastoma/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Ubiquitina-Proteína Ligases/metabolismo , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Regulação para Baixo , Feminino , Genes do Retinoblastoma , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 3/genética , Transportador de Glucose Tipo 4/genética , Humanos , Prognóstico , RNA Mensageiro/metabolismo , Proteínas de Ligação a Retinoblastoma/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Ubiquitina-Proteína Ligases/genética , Regulação para Cima
7.
Sci Rep ; 11(1): 16983, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417511

RESUMO

Obesity (Ob) poses a significant risk factor for the onset of metabolic syndrome with associated complications, wherein the Mesenchymal Stem Cell (MSC) therapy shows pre-clinical success. Here, we explore the therapeutic applications of human Placental MSCs (P-MSCs) to address Ob-associated Insulin Resistance (IR) and its complications. In the present study, we show that intramuscular injection of P-MSCs homed more towards the visceral site, restored HOMA-IR and glucose homeostasis in the WNIN/GR-Ob (Ob-T2D) rats. P-MSC therapy was effective in re-establishing the dysregulated cytokines. We report that the P-MSCs activates PI3K-Akt signaling and regulates the Glut4-dependant glucose uptake and its utilization in WNIN/GR-Ob (Ob-T2D) rats compared to its control. Our data reinstates P-MSC treatment's potent application to alleviate IR and restores peripheral blood glucose clearance evidenced in stromal vascular fraction (SVF) derived from white adipose tissue (WAT) of the WNIN/GR-Ob rats. Gaining insights, we show the activation of the PI3K-Akt pathway by P-MSCs both in vivo and in vitro (palmitate primed 3T3-L1 cells) to restore the insulin sensitivity dysregulated adipocytes. Our findings suggest a potent application of P-MSCs in  pre-clinical/Ob-T2D management.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Experimental/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Modelos Biológicos , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Células Cultivadas , Citocinas/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Diabetes Mellitus Tipo 2/terapia , Feminino , Transportador de Glucose Tipo 4/metabolismo , Homeostase , Humanos , Insulina/metabolismo , Macrófagos/metabolismo , Obesidade/complicações , Fosfatidilinositol 3-Quinases/metabolismo , Placenta/citologia , Gravidez , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais
8.
Sci Rep ; 11(1): 17273, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446814

RESUMO

Recent focus has been given on the effects of high-intensity infrasound (HII) exposure, and whether it induces changes in pancreatic morphology and glucose metabolism is still unknown. As such, we have studied the impact of HII exposure on glucose tolerance, insulin sensitivity, pancreatic islet morphology, muscle GLUT4 and plasma insulin and corticosterone levels. Normal and glucose intolerant wild-type Wistar rats were randomly divided in two groups: one group not exposed to HII and the other continuously exposed to HII. Animals were sacrificed at three timepoints of exposure (1, 6 or 12 weeks). An intraperitoneal glucose tolerance test was performed, blood samples were collected and the pancreas and the quadriceps femoris muscle were excised. Circulating insulin and corticosterone levels were determined and pancreatic and muscular tissue were routinely processed for histochemistry and immunohistochemistry with an anti-GLUT4 antibody. Animals exposed to HII had higher corticosterone levels than animals not exposed. No differences were found on insulin concerning HII exposure or glucose intolerance. Glucose intolerant animals had pancreatic islet fibrosis and no differences were found in GLUT4 ratio concerning HII exposure. In conclusion, we found that continuous exposure to HII increases stress hormone levels without inducing glucose intolerance in rats.


Assuntos
Glicemia/metabolismo , Intolerância à Glucose/metabolismo , Glucose/metabolismo , Resistência à Insulina , Som , Animais , Corticosterona/sangue , Transportador de Glucose Tipo 4/metabolismo , Imuno-Histoquímica/métodos , Insulina/sangue , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Músculo Esquelético/metabolismo , Ratos Wistar
9.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299331

RESUMO

BACKGROUND: Due to its prominence in the regulation of metabolism and inflammation, adipose tissue is a major target to investigate alterations in insulin action. This hormone activates PI3K/AKT pathway which is essential for glucose homeostasis, cell differentiation, and proliferation in insulin-sensitive tissues, like adipose tissue. The aim of this work was to evaluate the impact of chronic and intermittent high glucose on the expression of biomolecules of insulin signaling pathway during the differentiation and maturation of human visceral preadipocytes. METHODS: Human visceral preadipocytes (HPA-V) cells were treated with high glucose (30 mM)during the proliferation and/or differentiation and/or maturation stage. The level of mRNA (by Real-Time PCR) and protein (by Elisa tests) expression of IRS1, PI3K, PTEN, AKT2, and GLUT4 was examined after each culture stage. Furthermore, we investigated whether miR-29a-3p, miR-143-3p, miR-152-3p, miR-186-5p, miR-370-3p, and miR-374b-5p may affect the expression of biomolecules of the insulin signaling pathway. RESULTS: Both chronic and intermittent hyperglycemia affects insulin signaling in visceral pre/adipocytes by upregulation of analyzed PI3K/AKT pathway molecules. Both mRNA and protein expression level is more dependent on stage-specific events than the length of the period of high glucose exposure. What is more, miRs expression changes seem to be involved in PI3K/AKT expression regulation in response to hyperglycemic stimulation.


Assuntos
Hiperglicemia/metabolismo , Gordura Intra-Abdominal/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Hiperglicemia/patologia , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Gordura Intra-Abdominal/citologia , Gordura Intra-Abdominal/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais
10.
Chem Biol Interact ; 346: 109595, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34302803

RESUMO

Glycyrrhizic acid (GA), a major constituent of the root of licorice (Glycyrrhiza glabra), and has various biological activities, including anti-obesity property. However, the molecular mechanism of anti-adipogenic effect of GA is still unclear. In this study, we investigated the anti-adipogenic effects of GA in mouse adipocytic 3T3-L1 cells and elucidated its underlying molecular mechanism. GA decreased the intracellular triglyceride level. The expression levels of the adipogenic and lipogenic genes were lowered by treatment with GA in a concertation-dependent manner. In contrast, GA did not affect the lipolytic gene expression and the released glycerol level. GA suppressed the early stage of adipogenesis when it was added for 0-3 h after initiation of adipogenesis. Moreover, GA reduced the mRNA levels of CCAAT/enhancer binding protein (C/EBP) ß and C/EBPδ, both of which activate the early stage of adipogenesis. Furthermore, GA decreased phosphorylation of extracellular signal-regulated kinase [ERK: p44/42 mitogen-activated protein kinase (MAPK)] in the early stage of adipogenesis. In addition, a MAPK kinase (MEK) inhibitor, PD98059 reduced the C/EBPß and C/EBPδ gene expression. These results indicate that GA suppressed the early stage of adipogenesis through repressing the MEK/ERK-mediated C/EBPß and C/EBPδ expression in 3T3-L1 cells. Thus, GA has an anti-adipogenic ability and a possible agent for treatment of obesity.


Assuntos
Adipogenia/efeitos dos fármacos , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Diferenciação Celular/efeitos dos fármacos , Ácido Glicirrízico/farmacologia , Células 3T3-L1 , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína delta de Ligação ao Facilitador CCAAT/genética , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavonoides/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Lipólise/efeitos dos fármacos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Triglicerídeos/metabolismo
11.
Molecules ; 26(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299455

RESUMO

An unprecedented novel flavanone davidone F (1) with a seven-membered ring side chain, and a novel flavanonol davidone G (2), along with 11 known flavonoids, were isolated from the ethyl acetate fraction of Sophora davidii (Franch.) Skeels. Their planar structures were established by UV, IR, HRESIMS, 1D and 2D NMR data. The relative configurations of 1 and 2 were determined by calculation of NMR chemical shift values, the absolute configuration of 1 and 2 were assigned by comparing their experimental and calculated electronic circular dichroism (ECD) spectra. Moreover, compounds 1-13 were screened for the translocation activity of glucose transporter 4 (GLUT-4), and the fluorescence intensity was increased to the range of 1.56 and 2.79 folds. Compounds 1 and 2 showed moderate GLUT-4 translocation activity with 1.64 and 1.79 folds enhancement, respectively, at a concentration of 20 µg/mL.


Assuntos
Flavonoides/química , Flavonoides/isolamento & purificação , Sophora/metabolismo , China , Dicroísmo Circular/métodos , Flavanonas/química , Flavanonas/isolamento & purificação , Transportador de Glucose Tipo 4/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Raízes de Plantas/química , Sophora/química
12.
Molecules ; 26(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299508

RESUMO

Although the hypoglycemic potential of brewer's yeast extract has been reported, there is limited information pertaining to the hypoglycemic ingredients of Saccharomyces pastorianus extract and their mechanisms of action available. This study aimed to investigate the in vivo and in vitro hypoglycemic effect of S. pastorianus extract and to elucidate its molecular mechanisms. S. pastorianus extract was mainly composed of proteins followed by carbohydrates. In diabetic rats, oral administration of S. pastorianus extract significantly reduced the levels of plasma glucose and enhanced the activity of hepatic glucose-6-phosphatase dehydrogenase. Treatment with S. pastorianus extract increased the localization of type 4 glucose transporter (GLUT4), PTP, and insulin receptor at 3T3-L1 cell membranes and raised the levels of P38 MAPK, PI3K, and AKT in the cytosol. In agreement with these results, pretreatment of 3T3-L1 cells with inhibitors of PTP, PI3K, Akt/PKB, and p38 MAPK inhibited glucose uptake induced by application of S. pastorianus extract. Most importantly, a 54 kDa protein with hypoglycemic activity was identified and suggested as the major ingredient contributing to the hypoglycemic activity of S. pastorianus extract. In summary, these results clearly confirm the hypoglycemic activity of S. pastorianus extract and provide critical insights into the underlying molecular mechanisms.


Assuntos
Hipoglicemiantes/farmacologia , Saccharomyces/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Metabolismo dos Carboidratos/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Camundongos , Proteínas de Transporte de Monossacarídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Molecules ; 26(14)2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34299620

RESUMO

Type 2 diabetes mellitus (T2DM) is linked to insulin resistance and a loss of insulin sensitivity, leading to millions of deaths worldwide each year. T2DM is caused by reduced uptake of glucose facilitated by glucose transporter 4 (GLUT4) in muscle and adipose tissue due to decreased intracellular translocation of GLUT4-containing vesicles to the plasma membrane. To treat T2DM, novel medications are required. Through a fluorescence microscopy-based high-content screen, we tested more than 600 plant extracts for their potential to induce GLUT4 translocation in the absence of insulin. The primary screen in CHO-K1 cells resulted in 30 positive hits, which were further investigated in HeLa and 3T3-L1 cells. In addition, full plasma membrane insertion was examined by immunostaining of the first extracellular loop of GLUT4. The application of appropriate inhibitors identified PI3 kinase as the most important signal transduction target relevant for GLUT4 translocation. Finally, from the most effective hits in vitro, four extracts effectively reduced blood glucose levels in chicken embryos (in ovo), indicating their applicability as antidiabetic pharmaceuticals or nutraceuticals.


Assuntos
Glicemia/efeitos dos fármacos , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Extratos Vegetais/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Células CHO , Linhagem Celular , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cricetulus , Diabetes Mellitus Tipo 2 , Transportador de Glucose Tipo 4/metabolismo , Células HeLa , Humanos , Resistência à Insulina/fisiologia , Camundongos , Transporte Proteico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
14.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199897

RESUMO

Transthyretin (TTR), a 55 kDa evolutionarily conserved protein, presents altered levels in several conditions, including malnutrition, inflammation, diabetes, and Alzheimer's Disease. It has been shown that TTR is involved in several functions, such as insulin release from pancreatic ß-cells, recovery of blood glucose and glucagon levels of the islets of Langerhans, food intake, and body weight. Here, the role of TTR in hepatic glucose metabolism was explored by studying the levels of glucose in mice with different TTR genetic backgrounds, namely with two copies of the TTR gene, TTR+/+; with only one copy, TTR+/-; and without TTR, TTR-/-. Results showed that TTR haploinsufficiency (TTR+/-) leads to higher glucose in both plasma and in primary hepatocyte culture media and lower expression of the influx glucose transporters, GLUT1, GLUT3, and GLUT4. Further, we showed that TTR haploinsufficiency decreases pyruvate kinase M type (PKM) levels in mice livers, by qRT-PCR, but it does not affect the hepatic production of the studied metabolites, as determined by 1H NMR. Finally, we demonstrated that TTR increases mitochondrial density in HepG2 cells and that TTR insufficiency triggers a higher degree of oxidative phosphorylation in the liver. Altogether, these results indicate that TTR contributes to the homeostasis of glucose by regulating the levels of glucose transporters and PKM enzyme and by protecting against mitochondrial oxidative stress.


Assuntos
Transportador de Glucose Tipo 3/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , Fígado/metabolismo , Dinâmica Mitocondrial , Pré-Albumina/fisiologia , Piruvato Quinase/metabolismo , Animais , Feminino , Transportador de Glucose Tipo 3/genética , Transportador de Glucose Tipo 4/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Piruvato Quinase/genética
15.
Arch Biochem Biophys ; 709: 108985, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34252390

RESUMO

The protein deacetylase sirtuin 1 (SIRT1) and adenosine monophosphate-dependent protein kinase (AMPK) play important roles in the development of insulin resistance. In glomerular podocytes, crosstalk between these two enzymes may be altered under hyperglycemic conditions. SIRT1 protein levels and activity and AMPK phosphorylation decrease under hyperglycemic conditions, with concomitant inhibition of the effect of insulin on glucose uptake into these cells. Nitric oxide (NO)-dependent regulatory signaling pathways have been shown to be downregulated under diabetic conditions. The present study examined the involvement of the NO synthase (NOS)/NO pathway in the regulation of SIRT1-AMPK signaling and glucose uptake in podocytes. We examined the effects of NOS/NO pathway alterations on SIRT1/AMPK signaling and glucose uptake using pharmacological tools and a small-interfering transfection approach. We also examined the ability of the NOS/NO pathway to protect podocytes against high glucose-induced alterations of SIRT1/AMPK signaling and insulin-dependent glucose uptake. Inhibition of the NOS/NO pathway reduced SIRT1 protein levels and activity, leading to a decrease in AMPK phosphorylation and blockade of the effect of insulin on glucose uptake. Treatment with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) prevented high glucose-induced decreases in SIRT1 and AMPK activity and increased GLUT4 protein expression, thereby improving glucose uptake in podocytes. These findings suggest that inhibition of the NOS/NO pathway may result in alterations of the effects of insulin on glucose uptake in podocytes. In turn, the enhancement of NOS/NO pathway activity may prevent these deleterious effects of high glucose concentrations, thus bidirectionally stimulating the SIRT1-AMPK reciprocal activation loop.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Glucose/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico/metabolismo , Podócitos/metabolismo , Sirtuína 1/metabolismo , Animais , Regulação para Baixo/fisiologia , Inibidores Enzimáticos/farmacologia , Técnicas de Silenciamento de Genes , Transportador de Glucose Tipo 4/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Ratos , S-Nitroso-N-Acetilpenicilamina/farmacologia , Transdução de Sinais , Sirtuína 1/genética
16.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281282

RESUMO

Urinary acrolein adduct levels have been reported to be increased in both habitual smokers and type-2 diabetic patients. The impairment of glucose transport in skeletal muscles is a major factor responsible for glucose uptake reduction in type-2 diabetic patients. The effect of acrolein on glucose metabolism in skeletal muscle remains unclear. Here, we investigated whether acrolein affects muscular glucose metabolism in vitro and glucose tolerance in vivo. Exposure of mice to acrolein (2.5 and 5 mg/kg/day) for 4 weeks substantially increased fasting blood glucose and impaired glucose tolerance. The glucose transporter-4 (GLUT4) protein expression was significantly decreased in soleus muscles of acrolein-treated mice. The glucose uptake was significantly decreased in differentiated C2C12 myotubes treated with a non-cytotoxic dose of acrolein (1 µM) for 24 and 72 h. Acrolein (0.5-2 µM) also significantly decreased the GLUT4 expression in myotubes. Acrolein suppressed the phosphorylation of glucose metabolic signals IRS1, Akt, mTOR, p70S6K, and GSK3α/ß. Over-expression of constitutive activation of Akt reversed the inhibitory effects of acrolein on GLUT4 protein expression and glucose uptake in myotubes. These results suggest that acrolein at doses relevant to human exposure dysregulates glucose metabolism in skeletal muscle cells and impairs glucose tolerance in mice.


Assuntos
Acroleína/toxicidade , Transportador de Glucose Tipo 4/antagonistas & inibidores , Glucose/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Acroleína/administração & dosagem , Animais , Transporte Biológico Ativo/efeitos dos fármacos , Glicemia/metabolismo , Linhagem Celular , Intolerância à Glucose/induzido quimicamente , Intolerância à Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Humanos , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206320

RESUMO

Type 2 diabetes (T2D) is a chronic metabolic disease, which could affect the daily life of patients and increase their risk of developing other diseases. Synthetic anti-diabetic drugs usually show severe side effects. In the last few decades, plant-derived drugs have been intensively studied, particularly because of a rapid development of the instruments used in analytical chemistry. We tested the efficacy of Gundelia tournefortii L. (GT) in increasing the translocation of glucose transporter-4 (GLUT4) to the myocyte plasma membrane (PM), as a main strategy to manage T2D. In this study, GT methanol extract was sub-fractionated into 10 samples using flash chromatography. The toxicity of the fractions on L6 muscle cells, stably expressing GLUTmyc, was evaluated using the MTT assay. The efficacy with which GLUT4 was attached to the L6 PM was evaluated at non-toxic concentrations. Fraction 6 was the most effective, as it stimulated GLUT4 translocation in the absence and presence of insulin, 3.5 and 5.2 times (at 250 µg/mL), respectively. Fraction 1 and 3 showed no significant effects on GLUT4 translocation, while other fractions increased GLUT4 translocation up to 2.0 times. Gas chromatography-mass spectrometry of silylated fractions revealed 98 distinct compounds. Among those compounds, 25 were considered anti-diabetic and glucose disposal agents. These findings suggest that GT methanol sub-fractions exert an anti-diabetic effect by modulating GLUT4 translocation in L6 muscle cells, and indicate the potential of GT extracts as novel therapeutic agents for T2D.


Assuntos
Asteraceae/química , Diabetes Mellitus Tipo 2/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Hipoglicemiantes , Células Musculares/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Transportador de Glucose Tipo 4/genética , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Transporte Proteico/efeitos dos fármacos , Ratos
18.
Int J Mol Sci ; 22(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205666

RESUMO

Bisphenol A (BPA) is a synthetic phenol extensively used in the manufacture of polycarbonate plastics and epoxy resins and a component of liquid and food storages. Among health disorders potentially attributed to BPA, the effects on metabolism have been especially studied. BPA represents a hazard in prenatal life because of its presence in tissues and fluids during pregnancy. Our recent study in rats fed with BPA showed a placental increase in glucose type 1 transporter (GLUT-1), suggesting a higher uptake of glucose. However, the role of BPA on GLUT transporters in pregnant women with metabolic dysfunction has not yet been investigated. In this study, placental tissue from 26 overweight (OW) women and 32 age-matched normal weight (NW) pregnant women were examined for expression of GLUT1 and GLUT4. Placental explants from OW and NW mothers were exposed to BPA 1 nM and 1 µM and tested for GLUTs expression. The data showed a different response of placental explants to BPA in GLUT1 expression with an increase in NW mothers and a decrease in OW ones. GLUT4 expression was lower in the explants from OW than NW mothers, while no difference was showed between OW and NW in placental biopsies for any of the transporters.


Assuntos
Compostos Benzidrílicos/toxicidade , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Sobrepeso/complicações , Fenóis/toxicidade , Placenta/efeitos dos fármacos , Complicações na Gravidez/induzido quimicamente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Sobrepeso/metabolismo , Placenta/metabolismo , Gravidez , Complicações na Gravidez/metabolismo
19.
Cell Death Dis ; 12(7): 669, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34218261

RESUMO

Malignant transformation of gastrointestinal stromal tumors (GISTs) is correlated with poor prognosis; however, the underlying biological mechanism is not well understood. In the present study, low-risk (LR) GISTs, GISTs categorized as high-risk based on tumor size (HBS), and on mitotic rate (HBM) were collected for RNA sequencing. Candidate hub lncRNAs were selected by Oncomine analysis. Expression of a selected hub lncRNA, DNM3OS, and its correlation with patients' prognosis were analyzed using FISH staining, followed with the determination of function and underlying mechanism. Our results revealed a series of key pathways and hub lncRNAs involved in the malignant transformation of GISTs. Oncomine analysis revealed a tight association between clinical signatures and DNM3OS and suggested that DNM3OS is a hub lncRNA that is involved in the Hippo signaling pathway. In addition, DNM3OS was upregulated in HBS, HBM, and HBS/M GIST and correlated with worse prognosis in patients with GISTs. In addition, DNM3OS promoted GIST cell proliferation and mitosis by regulating the expression of GLUT4 and CD36. Collectively, these results improve our understanding of the malignant transformation of GISTs and unveil a series of hub lncRNAs in GISTs.


Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Perfilação da Expressão Gênica , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Transcriptoma , Antígenos CD36/genética , Antígenos CD36/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Bases de Dados Genéticas , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Mitose , Mapas de Interação de Proteínas , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais
20.
Biomolecules ; 11(5)2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065777

RESUMO

In the presence of stress, the hypothalamic-pituitary-adrenal (HPA) axis activity can be enhanced to promote the secretion of a large amount of glucocorticoids (GCs), which play an important role in the anabolism and catabolism of skeletal muscle. When the endogenous and exogenous glucocorticoids are deficient or excessive, the body will produce stress-related resistance and change the protein metabolism. In this study, we investigated the effect of GC receptor GRα on protein breakdown and synthesis in porcine skeletal muscle cells (PSCs). Overexpression of GRα was shown to increase the expression of protein degradation-related genes, while knockdown of GRα decreased the expression of these genes. Additionally, we found a relationship between GRα and solute carrier family 2 member 4 (SLC2A4), SLC2A4 expression level increases when stress occurs, suggesting that increasing SLC2A4 expression can partially alleviate stress-induced damage, and we found that there is a combination between them via luciferase reporter assays, which still needs to be confirmed in further studies.


Assuntos
Transportador de Glucose Tipo 4/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Músculo Esquelético/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Células Cultivadas , Regulação da Expressão Gênica , Sistema Hipotálamo-Hipofisário/patologia , Biossíntese de Proteínas , Proteólise , Estresse Fisiológico , Suínos
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