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1.
Anal Chim Acta ; 1316: 342852, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-38969409

RESUMO

BACKGROUND: With the advent of personalized medical approaches, precise and tailored treatments are expected to become widely accepted for the prevention and treatment of diabetes. Paper-based colorimetric sensors that function in combination with smartphones have been rapidly developed in recent years because it does not require additional equipment and is inexpensive and easy to perform. In this study, we developed a portable, low-cost, and wearable sweat-glucose detection device for in situ detection. RESULTS: The sensor adopted an integrated biomimetic nanoenzyme of glucose oxidase (GOx) encapsulated in copper 1, 4-benzenedicarboxylate (CuBDC) (GOx@CuBDC) through a biomimetic mineralization process. CuBDC exhibited a peroxide-like effect, cascade catalytic effect with the encapsulated GOx, and increased the enzyme stability. GOx@CuBDC and 3,3,5,5-tetramethylbenzidine were combined to form a hybrid membrane that achieved single-step paper-based glucose detection. SIGNIFICANCE AND NOVELTY: This GOx@CuBDC-based colorimetric glucose sensor was used to quantitatively analyze the sweat-glucose concentration with smartphone readings. The sensor exhibited a good linear relationship over the concentration range of 40-900 µM and a limit of detection of 20.7 µM (S/N = 3). Moreover, the sensor performed well in situ monitoring and in evaluating variations based on the consumption of foods with different glycemic indices. Therefore, the fabricated wearable sweat-glucose sensors exhibited optimal practical application performance.


Assuntos
Técnicas Biossensoriais , Colorimetria , Cobre , Glucose Oxidase , Glucose , Smartphone , Suor , Glucose Oxidase/química , Glucose Oxidase/metabolismo , Cobre/química , Suor/química , Humanos , Glucose/análise , Dispositivos Eletrônicos Vestíveis , Limite de Detecção , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo
2.
Anal Chim Acta ; 1316: 342882, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-38969418

RESUMO

BACKGROUND: Transition metal phosphides with properties similar to platinum metal have received increasing attention for the non-enzymatic detection of glucose. However, the requirement of highly corrosive reagent during sample pretreatment would impose a potential risk to the human body, limiting their practical applications. RESULTS: In this study, we report a self-powered microfluidic device for the non-enzymatic detection of glucose using nickel phosphide (Ni2P) hybrid as the catalyst. The Ni2P hybrid is synthesized by pyrolysis of metal-organic framework (MOF)-based precursor and in-situ phosphating process, showing two linear detection ranges (1 µM-1 mM, 1 mM-6 mM) toward glucose with the detection limit of 0.32 µM. The good performance of Ni2P hybrid for glucose is attributed to the synergistic effect of Ni2P active sites and N-doped porous carbon matrix. The microchip is integrated with a NaOH-loaded paper pad and a capillary-based micropump, enabling the automatic NaOH redissolution and delivery of sample solution into the detection chamber. Under the optimized condition, the Ni2P hybrid-based microchip realized the detection of glucose in a user-friendly way. Besides, the feasibility of using this microchip for glucose detection in real serum samples has also been validated. SIGNIFICANCE: This article presents a facile fabrication method utilizing a MOF template to synthesize a Ni2P hybrid catalyst. By leveraging the synergy between the Ni2P active sites and the N-doped carbon matrix, an exceptional electrochemical detection performance for glucose has been achieved. Additionally, a self-powered chip device has been developed for convenient glucose detection based on the pre-established high pH environment on the chip.


Assuntos
Técnicas Eletroquímicas , Eletrodos , Níquel , Níquel/química , Técnicas Eletroquímicas/instrumentação , Humanos , Glucose/análise , Fosfinas/química , Estruturas Metalorgânicas/química , Limite de Detecção , Dispositivos Lab-On-A-Chip , Glicemia/análise , Catálise
3.
Int Ophthalmol ; 44(1): 316, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38969958

RESUMO

BACKGROUND: Diabetic cataract (DC) is a common complication of diabetes and its etiology and progression are multi-factorial. In this study, the roles of specific protein 1 (SP1) and fibroblast growth factor 7 (FGF7) in DC development were explored. METHODS: DC cell model was established by treating SRA01/04 cells with high glucose (HG). MTT assay was conducted to evaluate cell viability. Transwell assay and wound-healing assay were performed to assess cell migration and invasion. Western blot assay and qRT-PCR assay were conducted to measure the expression of N-cadherin, E-cadherin, Collagen I, Fibronectin, SP1 and FGF7 expression. CHIP assay and dual-luciferase reporter assay were conducted to analyze the combination between FGF7 and SP1. RESULTS: FGF7 was upregulated in DC patients and HG-induced SRA01/04 cells. HG treatment promoted SRA01/04 cell viability, migration, invasion and epithelial-mesenchymal transition (EMT), while FGF7 knockdown abated the effects. Transcription factor SP1 activated the transcription level of FGF7 and SP1 overexpression aggravated HG-induced SRA01/04 cell injury. SP1 silencing repressed HG-induced SRA01/04 cell viability, migration, invasion and EMT, but these effects were ameliorated by upregulating FGF7. Additionally, SP1 knockdown inhibited the PI3K/AKT pathway by regulating the transcription level of FGF7. CONCLUSION: Transcription factor SP1 activated the transcription level of FGF7 and the PI3K/AKT pathway to regulate HG-induced SRA01/04 cell viability, migration, invasion and EMT.


Assuntos
Movimento Celular , Sobrevivência Celular , Células Epiteliais , Transição Epitelial-Mesenquimal , Fator 7 de Crescimento de Fibroblastos , Glucose , Cristalino , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Fator de Transcrição Sp1 , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genética , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Glucose/farmacologia , Células Epiteliais/metabolismo , Fator 7 de Crescimento de Fibroblastos/metabolismo , Fator 7 de Crescimento de Fibroblastos/genética , Fator 7 de Crescimento de Fibroblastos/farmacologia , Cristalino/metabolismo , Cristalino/citologia , Catarata/metabolismo , Células Cultivadas , Regulação da Expressão Gênica
4.
Cell Metab ; 36(7): 1619-1633.e5, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38959864

RESUMO

Population-level variation and mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized. We defined prototypical insulin secretion responses to three macronutrients in islets from 140 cadaveric donors, including those with type 2 diabetes. The majority of donors' islets exhibited the highest insulin response to glucose, moderate response to amino acid, and minimal response to fatty acid. However, 9% of donors' islets had amino acid responses, and 8% had fatty acid responses that were larger than their glucose-stimulated insulin responses. We leveraged this heterogeneity and used multi-omics to identify molecular correlates of nutrient responsiveness, as well as proteins and mRNAs altered in type 2 diabetes. We also examined nutrient-stimulated insulin release from stem cell-derived islets and observed responsiveness to fat but not carbohydrate or protein-potentially a hallmark of immaturity. Understanding the diversity of insulin responses to carbohydrate, protein, and fat lays the groundwork for personalized nutrition.


Assuntos
Diabetes Mellitus Tipo 2 , Secreção de Insulina , Insulina , Ilhotas Pancreáticas , Proteômica , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Feminino , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Pessoa de Meia-Idade , Nutrientes/metabolismo , Adulto , Glucose/metabolismo , Idoso , Ácidos Graxos/metabolismo
5.
Adipocyte ; 13(1): 2374062, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38953241

RESUMO

Obesity is associated with a low-grade chronic inflammatory process characterized by higher circulating TNFα levels, thus contributing to insulin resistance. This study evaluated the effect of silybin, the main bioactive component of silymarin, which has anti-inflammatory properties, on TNFα levels and its impact on glucose uptake in the adipocyte cell line 3T3-L1 challenged with two different inflammatory stimuli, TNFα or lipopolysaccharide (LPS). Silybin's pre-treatment effect was evaluated in adipocytes pre-incubated with silybin (30 or 80 µM) before challenging with the inflammatory stimuli (TNFα or LPS). For the post-treatment effect, the adipocytes were first challenged with the inflammatory stimuli and then post-treated with silybin. After treatments, TNFα production, glucose uptake, and GLUT4 protein expression were determined. Both inflammatory stimuli increased TNFα secretion, diminished GLUT4 expression, and significantly decreased glucose uptake. Silybin 30 µM only reduced TNFα secretion after the LPS challenge. Silybin 80 µM as post-treatment or pre-treatment decreased TNFα levels, improving glucose uptake. However, glucose uptake enhancement induced by silybin did not depend on GLUT4 protein expression. These results show that silybin importantly reduced TNFα levels and upregulates glucose uptake, independently of GLUT4 protein expression.


Assuntos
Células 3T3-L1 , Adipócitos , Glucose , Lipopolissacarídeos , Silibina , Fator de Necrose Tumoral alfa , Animais , Silibina/farmacologia , Camundongos , Fator de Necrose Tumoral alfa/metabolismo , Glucose/metabolismo , Adipócitos/metabolismo , Adipócitos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Silimarina/farmacologia
6.
Nat Commun ; 15(1): 5571, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956041

RESUMO

Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.


Assuntos
Ácidos Docosa-Hexaenoicos , Inibidores de Hidroximetilglutaril-CoA Redutases , Mitocôndrias , Cromossomo X , Animais , Feminino , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Humanos , Cromossomo X/genética , Ácidos Docosa-Hexaenoicos/farmacologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Dosagem de Genes , Camundongos Endogâmicos C57BL , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Glucose/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo
7.
Sci Rep ; 14(1): 15177, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956174

RESUMO

Human activities associated with large-scale farms and the monocultures expose honey bees to one type of food. Moreover, there is an ongoing decline of plant species producing pollen and nectar in Europe. A poorly balanced diet affects a number of processes occurring in a bee's body. The fat body and hemolymph are the tissues that participate in all of them. Therefore, the aim of our study was to determine the effect of hazel, pine, rapeseed, buckwheat, phacelia and goldenrod pollen on the morphological parameters of fat body trophocytes, the diameters of cell nuclei in oenocytes and the concentrations of compounds involved in energy metabolism (glucose, glycogen, triglycerides and protein). In the cage tests, the bees were fed from the first day of life with sugar candy (control group) or candy with a 10% addition of one of the 6 pollen types. Hemolymph and fat body from various locations were collected from 1-, 7- and 14-day-old workers. Pollen produced by plant species such as hazel and pine increased glucose concentrations in the bee tissues, especially in the hemolymph. It can therefore be concluded that they are valuable sources of energy (in the form of simple carbohydrates) which are quickly used by bees. Pollen from plants blooming in the summer and autumn increased the concentrations of proteins, glycogen and triglycerides in the fat body, especially that from the third tergite. The accumulation of these compounds was associated with an increased the length and width of trophocytes as well as with enhanced metabolic activity, which was evidenced in the increasing diameter of oenocyte cell nuclei. It seems a balanced multi-pollen diet is more valuable for bees, but it is important to understand the effects of the particular pollen types in the context of a mono-diet. In the future, this will make it possible to produce mixtures that can ensure homeostasis in the apian body.


Assuntos
Metabolismo Energético , Corpo Adiposo , Hemolinfa , Pólen , Abelhas/metabolismo , Abelhas/fisiologia , Animais , Pólen/metabolismo , Hemolinfa/metabolismo , Corpo Adiposo/metabolismo , Glicogênio/metabolismo , Glucose/metabolismo
8.
Mol Biol Rep ; 51(1): 788, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38970704

RESUMO

Despite many efforts, a comprehensive understanding and clarification of the intricate connections within cancer cell metabolism remain elusive. This might pertain to intracellular dynamics and the complex interplay between cancer cells, and cells with the tumor stroma. Almost a century ago, Otto Warburg found that cancer cells exhibit a glycolytic phenotype, which continues to be a subject of thorough investigation. Past and ongoing investigations have demonstrated intricate mechanisms by which tumors modulate their functionality by utilizing extracellular glucose as a substrate, thereby sustaining the essential proliferation of cancer cells. This concept of "aerobic glycolysis," where cancer cells (even in the presence of enough oxygen) metabolize glucose to produce lactate plays a critical role in cancer progression and is regulated by various signaling pathways. Recent research has revealed that the canonical wingless-related integrated site (WNT) pathway promotes aerobic glycolysis, directly and indirectly, thereby influencing cancer development and progression. The present review seeks to gather knowledge about how the WNT/ß-catenin pathway influences aerobic glycolysis, referring to relevant studies in different types of cancer. Furthermore, we propose the concept of impeding the glycolytic phenotype of tumors by employing specific inhibitors that target WNT/ß-catenin signaling.


Assuntos
Glicólise , Neoplasias , Via de Sinalização Wnt , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/genética , beta Catenina/metabolismo , Efeito Warburg em Oncologia , Animais , Glucose/metabolismo
9.
J Clin Invest ; 134(12)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38950317

RESUMO

Glucose plays a key role in shaping pancreatic ß cell function. Thus, deciphering the mechanisms by which this nutrient stimulates ß cells holds therapeutic promise for combating ß cell failure in type 2 diabetes (T2D). ß Cells respond to hyperglycemia in part by rewiring their mRNA metabolism, yet the mechanisms governing these changes remain poorly understood. Here, we identify a requirement for the RNA-binding protein PCBP2 in maintaining ß cell function basally and during sustained hyperglycemic challenge. PCBP2 was induced in primary mouse islets incubated with elevated glucose and was required to adapt insulin secretion. Transcriptomic analysis of primary Pcbp2-deficient ß cells revealed impacts on basal and glucose-regulated mRNAs encoding core components of the insulin secretory pathway. Accordingly, Pcbp2-deficient ß cells exhibited defects in calcium flux, insulin granule ultrastructure and exocytosis, and the amplification pathway of insulin secretion. Further, PCBP2 was induced by glucose in primary human islets, was downregulated in islets from T2D donors, and impacted genes commonly altered in islets from donors with T2D and linked to single-nucleotide polymorphisms associated with T2D. Thus, these findings establish a paradigm for PCBP2 in governing basal and glucose-adaptive gene programs critical for shaping the functional state of ß cells.


Assuntos
Diabetes Mellitus Tipo 2 , Glucose , Células Secretoras de Insulina , Insulina , Proteínas de Ligação a RNA , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Animais , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Camundongos , Humanos , Glucose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Insulina/metabolismo , Secreção de Insulina , Camundongos Knockout , Masculino , Adaptação Fisiológica
10.
Yale J Biol Med ; 97(2): 153-164, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38947101

RESUMO

The blood-brain barrier (BBB) prevents the use of many drugs for the treatment of neurological disorders. Recently, nitrogen-doped carbon dots (NCDs) have emerged as promising nanocarriers to cross BBB. The primary focus of our study was to evaluate the effectiveness of NCDs for the symptomatic treatment of Alzheimer's disease (AD). In this study, we developed and characterized NCDs bound to rutin, a flavonoid with known benefits for AD. Despite its benefits, the transportation of rutin via NCDs for AD therapy has not been explored previously. We characterized the particles using FTIR and UV-visible spectroscopy followed by atomic force microscopy. Once the design was optimized and validated, we performed in vivo testing via a hemolytic assay to optimize the dosage. Preliminary in vitro testing was performed in AlCl3-induced rat models of AD whereby a single dose of 10 mg/kg NCDs-rutin was administered intraperitoneally. Interestingly, this single dose of 10 mg/kg NCDs-rutin produced the same behavioral effects as 50 mg/kg rutin administered intraperitoneally for 1 month. Similarly, histological and biomarker profiles (SOD2 and TLR4) also presented significant protective effects of NCDs-rutin against neuronal loss, inflammation, and oxidative stress. Hence, NCDs-rutin are a promising approach for the treatment of neurological diseases.


Assuntos
Doença de Alzheimer , Carbono , Glucose , Nitrogênio , Rutina , Rutina/farmacologia , Rutina/química , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Carbono/química , Carbono/farmacologia , Nitrogênio/química , Ratos , Glucose/metabolismo , Masculino , Pontos Quânticos/química , Modelos Animais de Doenças , Estresse Oxidativo/efeitos dos fármacos , Humanos
11.
Mikrochim Acta ; 191(8): 451, 2024 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-38970693

RESUMO

Ti3C2Tx MXene/CuxO composites were prepared by acid etching combined with electrochemical technique. The abundant active sites on the surface of MXene greatly increase the loading of CuxO nanoparticles, and the synergistic effect between the different components of the composite can accelerate the oxidation reaction of glucose. The results indicate that at the working potential of 0.55 V (vs. Ag/AgCl), the glucose sensor based on Ti3C2Tx MXene/CuxO composite presents large linear concentration ranges from 1 µM to 4.655 mM (sensitivity of 361 µA mM-1 cm-2) and from 5.155 mM to 16.155 mM (sensitivity of 133 µA mM-1 cm-2). The limit of detection is 0.065 µM. In addition, the sensor effectively avoids the oxidative interference of common interfering species such as ascorbic acid, dopamine and uric acid. The sensor has good reproducibility, stability and acceptable recoveries for the detection of glucose in human sweat sample (97.5-103.3%) with RSD values less than 4%. Based on these excellent properties it has great potential for the detection of glucose in real samples.


Assuntos
Cobre , Técnicas Eletroquímicas , Glucose , Limite de Detecção , Titânio , Cobre/química , Humanos , Titânio/química , Glucose/análise , Glucose/química , Técnicas Eletroquímicas/métodos , Técnicas Eletroquímicas/instrumentação , Suor/química , Eletrodos , Oxirredução , Reprodutibilidade dos Testes , Técnicas Biossensoriais/métodos , Nanocompostos/química
13.
Front Cell Infect Microbiol ; 14: 1414188, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38979511

RESUMO

In Escherichia coli, the disaccharide trehalose can be metabolized as a carbon source or be accumulated as an osmoprotectant under osmotic stress. In hypertonic environments, E. coli accumulates trehalose in the cell by synthesis from glucose mediated by the cytosolic enzymes OtsA and OtsB. Trehalose in the periplasm can be hydrolyzed into glucose by the periplasmic trehalase TreA. We have previously shown that a treA mutant of extraintestinal E. coli strain BEN2908 displayed increased resistance to osmotic stress by 0.6 M urea, and reduced production of type 1 fimbriae, reduced invasion of avian fibroblasts, and decreased bladder colonization in a murine model of urinary tract infection. Since loss of TreA likely results in higher periplasmic trehalose concentrations, we wondered if deletion of otsA and otsB genes, which would lead to decreased internal trehalose concentrations, would reduce resistance to stress by 0.6 M urea and promote type 1 fimbriae production. The BEN2908ΔotsBA mutant was sensitive to osmotic stress by urea, but displayed an even more pronounced reduction in production of type 1 fimbriae, with the consequent reduction in adhesion/invasion of avian fibroblasts and reduced bladder colonization in the murine urinary tract. The BEN2908ΔtreAotsBA mutant also showed a reduction in production of type 1 fimbriae, but in contrast to the ΔotsBA mutant, resisted better than the wild type in the presence of urea. We hypothesize that, in BEN2908, resistance to stress by urea would depend on the levels of periplasmic trehalose, but type 1 fimbriae production would be influenced by the levels of cytosolic trehalose.


Assuntos
Fímbrias Bacterianas , Osmorregulação , Trealose , Bexiga Urinária , Infecções Urinárias , Animais , Trealose/metabolismo , Camundongos , Bexiga Urinária/microbiologia , Fímbrias Bacterianas/metabolismo , Fímbrias Bacterianas/genética , Infecções Urinárias/microbiologia , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Escherichia coli/metabolismo , Escherichia coli/genética , Modelos Animais de Doenças , Feminino , Pressão Osmótica , Escherichia coli Extraintestinal Patogênica/metabolismo , Escherichia coli Extraintestinal Patogênica/genética , Ureia/metabolismo , Trealase/metabolismo , Trealase/genética , Deleção de Genes , Glucose/metabolismo
14.
Int J Nanomedicine ; 19: 6643-6658, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38979532

RESUMO

Purpose: Nanovesicles (NVs) derived from bone mesenchymal stem cells (BMSCs) as drug delivery systems are considered an effective therapeutic strategy for diabetes. However, its mechanism of action remains unclear. Here, we evaluated the efficacy and molecular mechanism of BMSC-derived NVs carrying the curcumin analog H8 (H8-BMSCs-NVs) on hepatic glucose and lipid metabolism in type 2 diabetes (T2D). Subjects and Methods: Mouse BMSCs were isolated by collagenase digestion and H8-BMSCs-NVs were prepared by microvesicle extrusion. The effects of H8-BMSCs-NVs on hepatic glucose and lipid metabolism were observed in a T2D mouse model and a HepG2 cell insulin resistance model. To evaluate changes in potential signaling pathways, the PI3K/AKT/AMPK signaling pathway and expression levels of G6P and PEPCK were assessed by Western blotting. Results: H8-BMSCs-NVs effectively improved lipid accumulation in liver tissues and restored liver dysfunction in T2D mice. Meanwhile, H8-BMSCs-NVs effectively inhibited intracellular lipid accumulation in the insulin resistance models of HepG2 cells. Mechanistic studies showed that H8-BMSCs-NVs activated the PI3K/AKT/AMPK signaling pathway and decreased the expression levels of G6P and PEPCK. Conclusion: These findings demonstrate that H8-BMSCs-NVs improved hepatic glucose and lipid metabolism in T2D mice by activating the PI3K/AKT/AMPK signaling pathway, which provides novel evidence suggesting the potential of H8-BMSCs-NVs in the clinically treatment of T2D patients.


Assuntos
Diabetes Mellitus Tipo 2 , Glucose , Metabolismo dos Lipídeos , Fígado , Células-Tronco Mesenquimais , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células Hep G2 , Glucose/metabolismo , Camundongos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Curcumina/farmacologia , Curcumina/química , Curcumina/administração & dosagem , Resistência à Insulina , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Diabetes Mellitus Experimental/metabolismo
15.
Front Endocrinol (Lausanne) ; 15: 1422869, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38948514

RESUMO

Objectives: Obesity impairs bone marrow (BM) glucose metabolism. Adult BM constitutes mostly of adipocytes that respond to changes in energy metabolism by modulating their morphology and number. Here we evaluated whether diet or exercise intervention could improve the high-fat diet (HFD) associated impairment in BM glucose uptake (BMGU) and whether this associates with the morphology of BM adipocytes (BMAds) in rats. Methods: Eight-week-old male Sprague-Dawley rats were fed ad libitum either HFD or chow diet for 24 weeks. Additionally after 12 weeks, HFD-fed rats switched either to chow diet, voluntary intermittent running exercise, or both for another 12 weeks. BMAd morphology was assessed by perilipin-1 immunofluorescence staining in formalin-fixed paraffin-embedded tibial sections. Insulin-stimulated sternal and humeral BMGU were measured using [18F]FDG-PET/CT. Tibial microarchitecture and mineral density were measured with microCT. Results: HFD rats had significantly higher whole-body fat percentage compared to the chow group (17% vs 13%, respectively; p = 0.004) and larger median size of BMAds in the proximal tibia (815 µm2 vs 592 µm2, respectively; p = 0.03) but not in the distal tibia. Switch to chow diet combined with running exercise normalized whole-body fat percentage (p < 0.001) but not the BMAd size. At 32 weeks of age, there was no significant difference in insulin-stimulated BMGU between the study groups. However, BMGU was significantly higher in sternum compared to humerus (p < 0.001) and higher in 8-week-old compared to 32-week-old rats (p < 0.001). BMAd size in proximal tibia correlated positively with whole-body fat percentage (r = 0.48, p = 0.005) and negatively with humeral BMGU (r = -0.63, p = 0.02). HFD significantly reduced trabecular number (p < 0.001) compared to the chow group. Switch to chow diet reversed this as the trabecular number was significantly higher (p = 0.008) than in the HFD group. Conclusion: In this study we showed that insulin-stimulated BMGU is age- and site-dependent. BMGU was not affected by the study interventions. HFD increased whole-body fat percentage and the size of BMAds in proximal tibia. Switching from HFD to a chow diet and running exercise improved glucose homeostasis and normalized the HFD-induced increase in body fat but not the hypertrophy of BMAds.


Assuntos
Adiposidade , Medula Óssea , Dieta Hiperlipídica , Glucose , Obesidade , Condicionamento Físico Animal , Ratos Sprague-Dawley , Animais , Masculino , Ratos , Dieta Hiperlipídica/efeitos adversos , Medula Óssea/metabolismo , Glucose/metabolismo , Obesidade/metabolismo , Adipócitos/metabolismo
16.
Front Endocrinol (Lausanne) ; 15: 1395028, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38989001

RESUMO

Introduction: Biphasic insulin secretion is an intrinsic characteristic of the pancreatic islet and has clinical relevance due to the loss of first-phase in patients with Type 2 diabetes. As it has long been shown that first-phase insulin secretion only occurs in response to rapid changes in glucose, we tested the hypothesis that islet response to an increase in glucose is a combination of metabolism plus an osmotic effect where hypertonicity is driving first-phase insulin secretion. Methods: Experiments were performed using perifusion analysis of rat, mouse, and human islets. Insulin secretion rate (ISR) and other parameters associated with its regulation were measured in response to combinations of D-glucose and membrane-impermeable carbohydrates (L-glucose or mannitol) designed to dissect the effect of hypertonicity from that of glucose metabolism. Results: Remarkably, the appearance of first-phase responses was wholly dependent on changes in tonicity: no first-phase in NAD(P)H, cytosolic calcium, cAMP secretion rate (cAMP SR), or ISR was observed when increased D-glucose concentration was counterbalanced by decreases in membrane-impermeable carbohydrates. When D-glucose was greater than 8 mM, rapid increases in L-glucose without any change in D-glucose resulted in first-phase responses in all measured parameters that were kinetically similar to D-glucose. First-phase ISR was completely abolished by H89 (a non-specific inhibitor of protein kinases) without affecting first-phase calcium response. Defining first-phase ISR as the difference between glucose-stimulated ISR with and without a change in hypertonicity, the peak of first-phase ISR occurred after second-phase ISR had reached steady state, consistent with the well-established glucose-dependency of mechanisms that potentiate glucose-stimulated ISR. Discussion: The data collected in this study suggests a new model of glucose-stimulated biphasic ISR where first-phase ISR derives from (and after) a transitory amplification of second-phase ISR and driven by hypertonicity-induced rise in H89-inhibitable kinases likely driven by first-phase responses in cAMP, calcium, or a combination of both.


Assuntos
Glucose , Secreção de Insulina , Insulina , Animais , Secreção de Insulina/efeitos dos fármacos , Glucose/metabolismo , Ratos , Humanos , Insulina/metabolismo , Camundongos , Masculino , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , AMP Cíclico/metabolismo , Cálcio/metabolismo
17.
Biol Direct ; 19(1): 54, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38978074

RESUMO

OBJECTIVE: Retinal vascular endothelial cell (RVECs) injury is a major cause of morbidity and mortality among the patients with diabetes. RVECs dysfunction is the predominant pathological manifestation of vascular complication in diabetic retinopathy. N6-methyladenosine (m6A) serves as the most prevalent modification in eukaryotic mRNAs. However, the role of m6A RNA modification in RVECs dysfunction is still unclear. METHODS: RT-qPCR analysis and western blot were conducted to detect the change of m6A RNA modification in diabetic retinopathy. CCK-8 assay, transwell experiment, wound healing assay, tube formation experiment, m6A-IP-qPCR were performed to determine the role of YTHDC1 in RVECs. Retinal trypsin digestion test and H&E staining were used to evaluate histopathological changes. RESULTS: The levels of m6A RNA methylation were significantly up-regulated in HG-induced RVECs, which were caused by increased expression of YTHDC1. YTHDC1 regulated the viability, proliferation, migration and tube formation ability in vitro. YTHDC1 overexpression impaired RVECs function by repressing CDK6 expression, which was mediated by YTHDC1-dependent mRNA decay. Moreover, it showed sh-YTHDC1 inhibited CDK6 nuclear export. Sh-YTHDC1 promotes the mRNA degradation of CDK6 in the nucleus but does not affect the cytoplasmic CDK6 mRNA. In vivo experiments showed that overexpression of CDK6 reversed the protective effect of sh-YTHDC1 on STZ-induced retinal tissue damage. CONCLUSION: YTHDC1-mediated m6A methylation regulates diabetes-induced RVECs dysfunction. YTHDC1-CDK6 signaling axis could be therapeutically targeted for treating DR.


Assuntos
Adenosina , Quinase 6 Dependente de Ciclina , Retinopatia Diabética , Células Endoteliais , Glucose , Células Endoteliais/metabolismo , Animais , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Retinopatia Diabética/metabolismo , Retinopatia Diabética/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Glucose/metabolismo , Glucose/farmacologia , Humanos , Retina/metabolismo , Masculino , Fatores de Processamento de RNA/metabolismo , Fatores de Processamento de RNA/genética , Proliferação de Células , Proteínas do Tecido Nervoso
18.
J Cell Biol ; 223(9)2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-38980288

RESUMO

Autophagy is essential for maintaining glucose homeostasis. However, the mechanism by which cells sense and respond to glucose starvation to induce autophagy remains incomplete. Here, we show that calcium serves as a fundamental triggering signal that connects environmental sensing to the formation of the autophagy initiation complex during glucose starvation. Mechanistically, glucose starvation instigates the release of vacuolar calcium into the cytoplasm, thus triggering the activation of Rck2 kinase. In turn, Rck2-mediated Atg11 phosphorylation enhances Atg11 interactions with Bmh1/2 bound to the Snf1-Sip1-Snf4 complex, leading to recruitment of vacuolar membrane-localized Snf1 to the PAS and subsequent Atg1 activation, thereby initiating autophagy. We also identified Glc7, a protein phosphatase-1, as a critical regulator of the association between Bmh1/2 and the Snf1 complex. We thus propose that calcium-triggered Atg11-Bmh1/2-Snf1 complex assembly initiates autophagy by controlling Snf1-mediated Atg1 activation in response to glucose starvation.


Assuntos
Autofagia , Cálcio , Glucose , Proteínas Serina-Treonina Quinases , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Glucose/metabolismo , Cálcio/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/genética , Fosforilação , Vacúolos/metabolismo , Vacúolos/genética
19.
Sci Rep ; 14(1): 15841, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982178

RESUMO

Intense psychosocial stress during early life has a detrimental effect on health-disease balance in later life. Simultaneously, despite its sensitivity to stress, the developing microbiome contributes to long-term health. Following stress exposure, HPA-axis activation regulates the "fight or flight" response with the release of glucose and cortisol. Here, we investigated the interaction between the oral microbiome and the stress response. We used a cohort of 115 adults, mean age 24, who either experienced institutionalisation and adoption (n = 40) or were non-adopted controls (n = 75). Glucose and cortisol measurements were taken from participants following an extended socially evaluated cold pressor test (seCPT) at multiple time points. The cohort´s oral microbiome was profiled via 16S-V4 sequencing on microbial DNA from saliva and buccal samples. Using mixed-effect linear regressions, we identified 12 genera that exhibited an interaction with host's cortisol-glucose response to stress, strongly influencing intensity and clearance of cortisol and glucose following stress exposure. Particularly, the identified taxa influenced the glucose and cortisol release profiles and kinetics following seCPT exposure. In conclusion, our study provided evidence for the oral microbiome modifying the effect of stress on the HPA-axis and human metabolism, as shown in glucose-cortisol time series data.


Assuntos
Hidrocortisona , Sistema Hipotálamo-Hipofisário , Microbiota , Sistema Hipófise-Suprarrenal , Saliva , Estresse Psicológico , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Estresse Psicológico/microbiologia , Estresse Psicológico/metabolismo , Hidrocortisona/metabolismo , Hidrocortisona/análise , Masculino , Feminino , Adulto , Sistema Hipófise-Suprarrenal/metabolismo , Saliva/microbiologia , Saliva/metabolismo , Adulto Jovem , Boca/microbiologia , Glucose/metabolismo
20.
Vascul Pharmacol ; 155: 107324, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38985581

RESUMO

Doxorubicin (DOX) is a highly effective chemotherapeutic agent whose clinical use is hindered by the onset of cardiotoxic effects, resulting in reduced ejection fraction within the first year from treatment initiation. Recently it has been demonstrated that DOX accumulates within mitochondria, leading to disruption of metabolic processes and energetic imbalance. We previously described that phosphoinositide 3-kinase γ (PI3Kγ) contributes to DOX-induced cardiotoxicity, causing autophagy inhibition and accumulation of damaged mitochondria. Here we intend to describe the maladaptive metabolic rewiring occurring in DOX-treated hearts and the contribution of PI3Kγ signalling to this process. Metabolomic analysis of DOX-treated WT hearts revealed an accumulation of TCA cycle metabolites due to a cycle slowdown, with reduced levels of pyruvate, unchanged abundance of lactate and increased Acetyl-CoA production. Moreover, the activity of glycolytic enzymes was upregulated, and fatty acid oxidation downregulated, after DOX, indicative of increased glucose oxidation. In agreement, oxygen consumption was increased in after pyruvate supplementation, with the formation of cytotoxic ROS rather than energy production. These metabolic changes were fully prevented in KD hearts. Interestingly, they failed to increase glucose oxidation in response to DOX even with autophagy inhibition, indicating that PI3Kγ likely controls the fuel preference after DOX through an autophagy-independent mechanism. In vitro experiments showed that inhibition of PI3Kγ inhibits pyruvate dehydrogenase (PDH), the key enzyme of Randle cycle regulating the switch from fatty acids to glucose usage, while decreasing DOX-induced mobilization of GLUT-4-carrying vesicles to the plasma membrane and limiting the ensuing glucose uptake. These results demonstrate that PI3Kγ promotes a maladaptive metabolic rewiring in DOX-treated hearts, through a two-pronged mechanism controlling PDH activation and GLUT-4-mediated glucose uptake.


Assuntos
Cardiotoxicidade , Doxorrubicina , Metabolismo Energético , Ácidos Graxos , Glucose , Oxirredução , Animais , Doxorrubicina/toxicidade , Glucose/metabolismo , Ácidos Graxos/metabolismo , Metabolismo Energético/efeitos dos fármacos , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Glicólise/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Masculino , Transdução de Sinais/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Ciclo do Ácido Cítrico/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/prevenção & controle , Cardiopatias/fisiopatologia , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/patologia , Mitocôndrias Cardíacas/enzimologia , Camundongos Knockout , Modelos Animais de Doenças , Espécies Reativas de Oxigênio/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Antibióticos Antineoplásicos/toxicidade , Antibióticos Antineoplásicos/efeitos adversos
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