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1.
Stem Cell Res Ther ; 13(1): 438, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056427

RESUMO

BACKGROUND: The therapeutic potential of mesenchymal stem cells (MSCs)-derived conditioned media (CM) can be increased after preconditioning with various chemical agents. The aim of this study is comparative evaluation of effects of N-CM and DFS-CM which are collected from normal (N) and deferoxamine (DFS) preconditioned umbilical cord-derived MSCs on rat diabetic nephropathy (DN) model. METHODS: After incubation of the MSCs in serum-free medium with/without 150 µM DFS for 48 h, the contents of N-CM and DFS-CM were analyzed by enzyme-linked immunosorbent assay. Diabetes (D) was induced by single dose of 55 mg/kg streptozotocin. Therapeutic effects of CMs were evaluated by biochemical, physical, histopathological and immunohistochemical analysis. RESULTS: The concentrations of vascular endothelial growth factor alpha, nerve growth factor and glial-derived neurotrophic factor in DFS-CM increased, while one of brain-derived neurotrophic factor decreased in comparison with N-CM. The creatinine clearance rate increased significantly in both treatment groups, while the improvement in albumin/creatinine ratio and renal mass index values were only significant for D + DFS-CM group. Light and electron microscopic deteriorations and loss of podocytes-specific nephrin and Wilms tumor-1 (WT-1) expressions were significantly restored in both treatment groups. Tubular beclin-1 expression was significantly increased for DN group, but it decreased in both treatment groups. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cell death increased in the tubules of D group, while it was only significantly decreased for D + DFS-CM group. CONCLUSIONS: DFS-CM can be more effective in the treatment of DN by reducing podocyte damage and tubular apoptotic cell death and regulating autophagic activity with its more concentrated secretome content than N-CM.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Células-Tronco Mesenquimais , Animais , Creatinina/metabolismo , Meios de Cultivo Condicionados/metabolismo , Meios de Cultivo Condicionados/farmacologia , Desferroxamina , Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Ratos , Cordão Umbilical/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Sci Rep ; 12(1): 14840, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36050326

RESUMO

Understanding the interactions between diet, obesity, and diabetes is important to tease out mechanisms in painful pathology. Western diet is rich in fats, producing high amounts of circulating bioactive metabolites. However, no research has assessed how a high-fat diet (HFD) alone may sensitize an individual to non-painful stimuli in the absence of obesity or diabetic pathology. To investigate this, we tested the ability of a HFD to stimulate diet-induced hyperalgesic priming, or diet sensitization in male and female mice. Our results revealed that 8 weeks of HFD did not alter baseline pain sensitivity, but both male and female HFD-fed animals exhibited robust mechanical allodynia when exposed to a subthreshold dose of intraplantar Prostaglandin E2 (PGE2) compared to mice on chow diet. Furthermore, calcium imaging in isolated primary sensory neurons of both sexes revealed HFD induced an increased percentage of capsaicin-responsive neurons compared to their chow counterparts. Immunohistochemistry (IHC) showed a HFD-induced upregulation of ATF3, a neuronal marker of injury, in lumbar dorsal root ganglia (DRG). This suggests that a HFD induces allodynia in the absence of a pre-existing condition or injury via dietary components. With this new understanding of how a HFD can contribute to the onset of pain, we can understand the dissociation behind the comorbidities associated with obesity and diabetes to develop pharmacological interventions to treat them more efficiently.


Assuntos
Diabetes Mellitus , Dieta Hiperlipídica , Animais , Diabetes Mellitus/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Dor/metabolismo
3.
Front Endocrinol (Lausanne) ; 13: 983723, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120471

RESUMO

Atherosclerosis (AS) is a chronic inflammatory disease and leading cause of cardiovascular diseases. The progression of AS is a multi-step process leading to high morbidity and mortality. Hyperglycemia, dyslipidemia, advanced glycation end products (AGEs), inflammation and insulin resistance which strictly involved in diabetes are closely related to the pathogenesis of AS. A growing number of studies have linked AGEs to AS. As one of the risk factors of cardiac metabolic diseases, dysfunction of VSMCs plays an important role in AS pathogenesis. AGEs are increased in diabetes, participate in the occurrence and progression of AS through multiple molecular mechanisms of vascular cell injury. As the main functional cells of vascular, vascular smooth muscle cells (VSMCs) play different roles in each stage of atherosclerotic lesions. The interaction between AGEs and receptor for AGEs (RAGE) accelerates AS by affecting the proliferation and migration of VSMCs. In addition, increasing researches have reported that AGEs promote osteogenic transformation and macrophage-like transformation of VSMCs, and affect the progression of AS through other aspects such as autophagy and cell cycle. In this review, we summarize the effect of AGEs on VSMCs in atherosclerotic plaque development and progression. We also discuss the AGEs that link AS and diabetes mellitus, including oxidative stress, inflammation, RAGE ligands, small noncoding RNAs.


Assuntos
Aterosclerose , Diabetes Mellitus , Aterosclerose/metabolismo , Diabetes Mellitus/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Inflamação/metabolismo , Ligantes , Músculo Liso Vascular/metabolismo
4.
Front Immunol ; 13: 942768, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119084

RESUMO

Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness among working-age people. Inflammation is recognized as a critical driver of the DR process. However, the main retina-specific cell type producing pro-inflammatory cytokines and its mechanism underlying DR are still unclear. Here, we used single-cell sequencing to identify microglia with metabolic pathway alterations that were the main source of IL-1ß in STZ-induced DR mice. To profile the full extent of local metabolic shifts in activated microglia and to reveal the metabolic microenvironment contributing to immune mechanisms, we performed integrated metabolomics, lipidomics, and RNA profiling analyses in microglia cell line samples representative of the DR microenvironment. The results showed that activated microglia with IL-1ß increase exhibited a metabolic bias favoring glycolysis, purine metabolism, and triacylglycerol synthesis, but less Tricarboxylic acid (TCA). In addition, some of these especially glycolysis was necessary to facilitate their pro-inflammation. These findings suggest that activated microglia with intracellular metabolic reprogramming in retina may contribute to pro-inflammation in the early DR.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Animais , Citocinas/metabolismo , Diabetes Mellitus/metabolismo , Humanos , Inflamação/metabolismo , Camundongos , Microglia/metabolismo , Purinas/metabolismo , RNA/metabolismo , Retina/metabolismo , Ácidos Tricarboxílicos/metabolismo , Triglicerídeos/metabolismo
5.
Stem Cell Res Ther ; 13(1): 455, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064604

RESUMO

BACKGROUND: While rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5+ mesenchymal stem cells (MSCs) might provide a new adjunctive DFU treatment, based on their remarkable skin wound homing and engraftment potential, their ability to adaptively respond to inflammatory signals, and their wound healing-promoting efficacy in mouse wound models and human chronic venous ulcers. METHODS: The angiogenic potential of ABCB5+ MSCs was characterized with respect to angiogenic factor expression at the mRNA and protein level, in vitro endothelial trans-differentiation and tube formation potential, and perfusion-restoring capacity in a mouse hindlimb ischemia model. Finally, the efficacy and safety of ABCB5+ MSCs for topical adjunctive treatment of chronic, standard therapy-refractory, neuropathic plantar DFUs were assessed in an open-label single-arm clinical trial. RESULTS: Hypoxic incubation of ABCB5+ MSCs led to posttranslational stabilization of the hypoxia-inducible transcription factor 1α (HIF-1α) and upregulation of HIF-1α mRNA levels. HIF-1α pathway activation was accompanied by upregulation of vascular endothelial growth factor (VEGF) transcription and increase in VEGF protein secretion. Upon culture in growth factor-supplemented medium, ABCB5+ MSCs expressed the endothelial-lineage marker CD31, and after seeding on gel matrix, ABCB5+ MSCs demonstrated formation of capillary-like structures comparable with human umbilical vein endothelial cells. Intramuscularly injected ABCB5+ MSCs to mice with surgically induced hindlimb ischemia accelerated perfusion recovery as measured by laser Doppler blood perfusion imaging and enhanced capillary proliferation and vascularization in the ischemic muscles. Adjunctive topical application of ABCB5+ MSCs onto therapy-refractory DFUs elicited median wound surface area reductions from baseline of 59% (full analysis set, n = 23), 64% (per-protocol set, n = 20) and 67% (subgroup of responders, n = 17) at week 12, while no treatment-related adverse events were observed. CONCLUSIONS: The present observations identify GMP-manufactured ABCB5+ dermal MSCs as a potential, safe candidate for adjunctive therapy of otherwise incurable DFUs and justify the conduct of a larger, randomized controlled trial to validate the clinical efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03267784, Registered 30 August 2017, https://clinicaltrials.gov/ct2/show/NCT03267784.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Pé Diabético , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Neovascularização Fisiológica , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Derme/citologia , Derme/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Pé Diabético/genética , Pé Diabético/metabolismo , Pé Diabético/patologia , Pé Diabético/terapia , Humanos , Isquemia/metabolismo , Isquemia/terapia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica/fisiologia , RNA Mensageiro/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/genética , Cicatrização/fisiologia
6.
Mediators Inflamm ; 2022: 8373389, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36081650

RESUMO

Diabetes is well recognized to increase the risk of heart failure, which is associated with higher mortality and morbidity. It is important for the development of novel therapeutic methods targeting heart failure in diabetic patients. Ferroptosis, an iron-dependent regulated cell death, has been implicated in the progression of diabetes-induced heart failure (DIHF). This study was designed to investigate the contribution of Nr2f2 to the activation of ferroptosis and mitochondrial dysfunction in DIHF. We established a diabetic model by a high-fat feeding diet combined with an intraperitoneal injection of streptozotocin. After 16 weeks, Nr2f2 expression was increased in heart tissue of DIHF mice. In vivo, DIHF mice overexpressing Nr2f2 (AAV9-cTNT-Nr2f2) exhibited severe heart failure and enhanced cardiac ferroptosis compared with DIHF control mice (AAV9-cTNT-ctrl), accompanied by mitochondrial dysfunction and aggravated oxidative stress reaction. In vitro, Nr2f2 knockdown ameliorated ferroptosis and mitochondrial dysfunction by negatively regulating PGC-1α, a crucial metabolic regulator. PGC-1α knockdown counteracted the protective effect of Nr2f2 knockdown. These data suggest that Nr2f2 promotes heart failure and ferroptosis in DIHF by modulating the PGC-1α signaling. Our study provides a new idea for the treatment of diabetes-induced heart failure.


Assuntos
Fator II de Transcrição COUP , Diabetes Mellitus , Ferroptose , Insuficiência Cardíaca , Animais , Fator II de Transcrição COUP/genética , Fator II de Transcrição COUP/metabolismo , Diabetes Mellitus/metabolismo , Insuficiência Cardíaca/metabolismo , Camundongos , Mitocôndrias/metabolismo , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais
7.
Front Immunol ; 13: 998947, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091076

RESUMO

Hepatic glucose production (HGP) is fine-regulated via glycogenolysis or gluconeogenesis to maintain physiological concentration of blood glucose during fasting-feeding cycle. Aberrant HGP leads to hyperglycemia in obesity-associated diabetes. Adipose tissue cooperates with the liver to regulate glycolipid metabolism. During these processes, adipose tissue macrophages (ATMs) change their profiles with various physio-pathological settings, producing diverse effects on HGP. Here, we briefly review the distinct phenotypes of ATMs under different nutrition states including feeding, fasting or overnutrition, and detail their effects on HGP. We discuss several pathways by which ATMs regulate hepatic gluconeogenesis or glycogenolysis, leading to favorable or unfavorable metabolic consequences. Furthermore, we summarize emerging therapeutic targets to correct metabolic disorders in morbid obesity or diabetes based on ATM-HGP axis. This review puts forward the importance and flexibility of ATMs in regulating HGP, proposing ATM-based HGP modulation as a potential therapeutic approach for obesity-associated metabolic dysfunction.


Assuntos
Diabetes Mellitus , Glucose , Tecido Adiposo/metabolismo , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Humanos , Fígado/metabolismo , Macrófagos/metabolismo , Obesidade/metabolismo
8.
Front Endocrinol (Lausanne) ; 13: 889729, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35992101

RESUMO

Diabetic nephropathy (DN) causes serious renal tubule and interstitial damage, but effective prevention and treatment measures are lacking. Abnormal mitophagy may be involved in the progression of DN, but its upstream and downstream regulatory mechanisms remain unclear. Melatonin, a pineal hormone associated with circadian rhythms, is involved in regulating mitochondrial homeostasis. Here, we demonstrated abnormal mitophagy in the kidneys of DN mice or high glucose (HG)-treated HK-2 cells, which was accompanied by increased oxidative stress and inflammation. At the same time, the melatonin treatment alleviated kidney damage. After mitochondrial isolation, we found that melatonin promoted AMPK phosphorylation and accelerated the translocation of PINK1 and Parkin to the mitochondria, thereby activating mitophagy, reducing oxidative stress, and inhibiting inflammation. Interestingly, the renal protective effect of melatonin can be partially blocked by downregulation of PINK1 and inhibition of AMPK. Our studies demonstrated for the first time that melatonin plays a protective role in DN through the AMPK-PINK1-mitophagy pathway.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Melatonina , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Inflamação/metabolismo , Rim/metabolismo , Melatonina/metabolismo , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Mitofagia
9.
Cells ; 11(16)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36010558

RESUMO

Mitochondrial dysfunction is implicated in the pathogenesis of diabetic kidney disease (DKD). Compared to the vast body of evidence from preclinical in vitro and in vivo studies, evidence from human studies is limited. In a comprehensive search of the published literature, findings from studies that reported evidence of mitochondrial dysfunction in individuals with DKD were examined. Three electronic databases (PubMed, Embase, and Scopus) were searched in March 2022. A total of 1339 articles were identified, and 22 articles met the inclusion criteria. Compared to non-diabetic controls (NDC) and/or individuals with diabetes but without kidney disease (DC), individuals with DKD (age ~55 years; diabetes duration ~15 years) had evidence of mitochondrial dysfunction. Individuals with DKD had evidence of disrupted mitochondrial dynamics (11 of 11 articles), uncoupling (2 of 2 articles), oxidative damage (8 of 8 articles), decreased mitochondrial respiratory capacity (1 of 1 article), decreased mtDNA content (5 of 6 articles), and decreased antioxidant capacity (3 of 4 articles) compared to ND and/or DC. Neither diabetes nor glycemic control explained these findings, but rather presence and severity of DKD may better reflect degree of mitochondrial dysfunction in this population. Future clinical studies should include individuals closer to diagnosis of diabetes to ascertain whether mitochondrial dysfunction is implicated in the development of, or is a consequence of, DKD.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Antioxidantes/metabolismo , Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/patologia , Humanos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Estresse Oxidativo
10.
Cells ; 11(16)2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-36010643

RESUMO

Mitochondrial dysfunction is a major pathophysiological event leading to the onset of diabetic complications. This study investigated the temporal effects of hyperglycemia on mitochondrial metabolism in corneal epithelial cells. To accomplish this, human telomerase-immortalized corneal epithelial cells were cultured in a defined growth medium containing 6 mM glucose. To simulate hyperglycemia, cells were cultured in a medium containing 25 mM D-glucose, and control cells were cultured in mannitol. Using metabolic flux analysis, there was a hyperosmolar-mediated increase in mitochondrial respiration after 24 h. By day 5, there was a decrease in spare respiratory capacity in cells subject to high glucose that remained suppressed throughout the 14-day period. Although respiration remained high through day 9, glycolysis was decreased. Mitochondrial respiration was decreased by day 14. This was accompanied by the restoration of glycolysis to normoglycemic levels. These changes paralleled a decrease in mitochondrial polarization and cell cycle arrest. Together, these data show that chronic but not acute hyperglycemic stress leads to mitochondrial dysfunction. Moreover, the hyperglycemia-induced loss of spare respiratory capacity reduces the ability of corneal epithelial cells to respond to subsequent stress. Compromised mitochondrial function represents a previously unexplored mechanism that likely contributes to corneal complications in diabetes.


Assuntos
Diabetes Mellitus , Hiperglicemia , Córnea/metabolismo , Diabetes Mellitus/metabolismo , Células Epiteliais/metabolismo , Glucose/metabolismo , Humanos , Hiperglicemia/metabolismo , Mitocôndrias/metabolismo
11.
Cells ; 11(16)2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-36010644

RESUMO

Chronic wounds resulting from diabetes are a major health concern in both industrialized and developing countries, representing one of the leading causes of disability and death. This study aimed to investigate the effect of adipose mesenchymal stem cell-derived exosomes (ADSC-exos) on diabetic wounds and the mechanism underlying this effect. The results showed that ADSC-exos could improve oxidative stress and secretion of inflammatory cytokines in diabetic wounds, thereby increasing periwound vascularization and accelerating wound healing. At the cellular level, ADSC-exos reduced reactive oxygen species (ROS) generation in human umbilical vein endothelial cells (HUVECs) and improved mitochondrial function in a high-glucose environment. Moreover, the Western blot analysis showed that the high-glucose environment decreased Sirtuin 3 (SIRT3) expression, while exosome treatment increased SIRT3 expression. The activity of superoxide dismutase 2 (SOD2) was enhanced, and the level of inflammatory cytokines was decreased. Further, SIRT3 interference experiments indicated that the effects of ADSC-exos on oxidative stress and angiogenesis were partly dependent on SIRT3. After SIRT3 was inhibited, ROS production increased, while mitochondrial membrane potential and SOD2 activity decreased. These findings confirmed that ADSC-exos could improve the level of high-glucose-induced oxidative stress, promote angiogenesis, and reduce mitochondrial functional impairment and the inflammatory response by regulating SIRT3/SOD2, thus promoting diabetic wound healing.


Assuntos
Diabetes Mellitus , Exossomos , Células-Tronco Mesenquimais , Sirtuína 3 , Citocinas/metabolismo , Diabetes Mellitus/metabolismo , Exossomos/metabolismo , Glucose/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Células-Tronco Mesenquimais/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/metabolismo , Superóxido Dismutase , Cicatrização
12.
Obesity (Silver Spring) ; 30(9): 1831-1841, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35912825

RESUMO

OBJECTIVE: This study aimed to validate xenon-enhanced computed tomography (XECT) for the detection of brown adipose tissue (BAT) and to use XECT to assess differences in BAT distribution and perfusion between lean, obese, and diabetic nonhuman primates (NHPs). METHODS: Whole-body XECT imaging was performed in anesthetized rhesus and vervet monkeys during adrenergic stimulation of BAT thermogenesis. In XECT images, BAT was identified as fat tissue that, during xenon inhalation, underwent significant radiodensity enhancement compared with subcutaneous fat. To measure BAT blood flow, BAT radiodensity enhancement was measured over time on the six computed tomography scans acquired during xenon inhalation. Postmortem immunohistochemical staining was used to confirm imaging findings. RESULTS: XECT was able to correctly identify all BAT depots that were confirmed at necropsy, enabling construction of the first comprehensive anatomical map of BAT in NHPs. A significant decrease in BAT perfusion was found in diabetic animals compared with obese animals and healthy animals, as well as absence of axillary BAT and significant reduction of supraclavicular BAT in diabetic animals compared with obese and lean animals. CONCLUSIONS: The use of XECT in NHP models of obesity and diabetes allows the analysis of the impact of metabolic status on BAT mass and perfusion.


Assuntos
Tecido Adiposo Marrom , Diabetes Mellitus , Tecido Adiposo Marrom/metabolismo , Animais , Chlorocebus aethiops , Diabetes Mellitus/diagnóstico por imagem , Diabetes Mellitus/metabolismo , Obesidade/diagnóstico por imagem , Obesidade/metabolismo , Perfusão , Primatas , Tomografia Computadorizada por Raios X/métodos , Xenônio/metabolismo
13.
Biochem Biophys Res Commun ; 624: 40-46, 2022 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-35932578

RESUMO

Diabetic nephropathy (DN) is one of the most important complications of diabetes mellitus (DM) and has become the second cause of end-stage renal disease (ESRD). This study intends to investigate the molecular mechanism of increased mitochondrial fission in podocytes under the effect of high glucose (HG), and to preliminarily study the role of mitochondrial fission factor (MFF)-mediated mitochondrial fission in podocyte injury of DN. In vitro studies, we found that HG induced increased mitochondrial fission and podocyte damage. At the same time MFF mRNA and protein levels was increased, suggesting that MFF was transcriptional upregulated under HG conditions. Consistent with this, in vivo studies found that mitochondrial fission was also significantly increased in podocytes of diabetic nephropathy mice, and MFF expression was up-regulated. Therefore, our study proves that mitochondrial fission increases in podocytes under DM both in vitro and in vivo, and the up-regulation of MFF expression may be one of the reasons for the increase of mitochondrial fission. After inhibiting the expression of MFF, the survival rate of podocytes was significantly decreased under HG conditions, suggesting that MFF may play a protective role in podocyte injury in DN.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Podócitos , Animais , Apoptose , Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/metabolismo , Camundongos , Dinâmica Mitocondrial , Podócitos/metabolismo , Regulação para Cima
14.
Front Immunol ; 13: 918223, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35990622

RESUMO

Diabetes is a systemic disease in which patients with diabetes may develop peripheral neuropathy of the lower extremities and peripheral vascular disease due to long-term continuous exposure to high glucose. Delayed wound healing in diabetes is one of the major complications of diabetes. Slow wound healing in diabetic patients is associated with high glucose toxicity. When the condition deteriorates, the patient needs to be amputated, which seriously affects the quality of life and even endangers the life of the patient. In general, the delayed healing of diabetes wound is due to the lack of chemokines, abnormal inflammatory response, lack of angiogenesis and epithelial formation, and fibroblast dysfunction. The incidence of several chronic debilitating conditions is increasing in patients with diabetes, such as chronic renal insufficiency, heart failure, and hepatic insufficiency. Fibrosis is an inappropriate deposition of extracellular matrix (ECM) proteins. It is common in diabetic patients causing organ dysfunction. The fibrotic mechanism of diabetic fibroblasts may involve direct activation of permanent fibroblasts. It may also involve the degeneration of fibers after hyperglycemia stimulates immune cells, vascular cells, or organ-specific parenchymal cells. Numerous studies confirm that fibroblasts play an essential role in treating diabetes and its complications. The primary function of fibroblasts in wound healing is to construct and reshape the ECM. Nowadays, with the widespread use of single-cell RNA sequencing (scRNA-seq), an increasing number of studies have found that fibroblasts have become the critical immune sentinel cells, which can detect not only the activation and regulation of immune response but also the molecular pattern related to the injury. By exploring the heterogeneity and functional changes of fibroblasts in diabetes, the manuscript discusses that fibroblasts may be used as immunomodulatory factors in refractory diabetic wound healing, providing new ideas for the treatment of refractory diabetic wound healing.


Assuntos
Diabetes Mellitus , Pé Diabético , Diabetes Mellitus/metabolismo , Fibroblastos/metabolismo , Glucose/metabolismo , Humanos , Imunidade , Qualidade de Vida , Cicatrização/fisiologia
15.
Dev Cell ; 57(16): 1922-1936.e9, 2022 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-35998583

RESUMO

Sequence variants in cis-acting enhancers are important for polygenic disease, but their role in Mendelian disease is poorly understood. Redundancy between enhancers that regulate the same gene is thought to mitigate the pathogenic impact of enhancer mutations. Recent findings, however, have shown that loss-of-function mutations in a single enhancer near PTF1A cause pancreas agenesis and neonatal diabetes. Using mouse and human genetic models, we show that this enhancer activates an entire PTF1A enhancer cluster in early pancreatic multipotent progenitors. This leading role, therefore, precludes functional redundancy. We further demonstrate that transient expression of PTF1A in multipotent progenitors sets in motion an epigenetic cascade that is required for duct and endocrine differentiation. These findings shed insights into the genome regulatory mechanisms that drive pancreas differentiation. Furthermore, they reveal an enhancer that acts as a regulatory master key and is thus vulnerable to pathogenic loss-of-function mutations.


Assuntos
Diabetes Mellitus , Fatores de Transcrição , Animais , Diferenciação Celular/genética , Diabetes Mellitus/metabolismo , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Recém-Nascido , Camundongos , Mutação/genética , Pâncreas/metabolismo , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/metabolismo
16.
Diabetes Metab J ; 46(4): 533-542, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35929171

RESUMO

Pancreatic beta cell homeostasis is crucial for the synthesis and secretion of insulin; disruption of homeostasis causes diabetes, and is a treatment target. Adaptation to endoplasmic reticulum (ER) stress through the unfolded protein response (UPR) and adequate regulation of autophagy, which are closely linked, play essential roles in this homeostasis. In diabetes, the UPR and autophagy are dysregulated, which leads to beta cell failure and death. Various studies have explored methods to preserve pancreatic beta cell function and mass by relieving ER stress and regulating autophagic activity. To promote clinical translation of these research results to potential therapeutics for diabetes, we summarize the current knowledge on ER stress and autophagy in human insulin-secreting cells.


Assuntos
Diabetes Mellitus , Células Secretoras de Insulina , Autofagia , Diabetes Mellitus/metabolismo , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Humanos , Células Secretoras de Insulina/metabolismo
17.
Int J Mol Sci ; 23(16)2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-36012215

RESUMO

The underlying pathological mechanisms of diabetes are complicated and varied in diabetic patients, which may lead to the current medications often failing to maintain glycemic control in the long term. Thus, the discovery of diverse new compounds for developing medicines to treat diabetes and its complications are urgently needed. Polyphenols are metabolites of plants and have been employed in the prevention and treatment of a variety of diseases. Caffeic acid phenethyl ester (CAPE) is a category of compounds structurally similar to polyphenols. In this study, we aimed to investigate the antidiabetic activity and potential molecular mechanisms of a novel synthetic CAPE derivative N-octyl caffeamide (36M) using high-fat (HF) diet induced obese mouse models. Our results demonstrate that 36M prevented the progression of diabetes in the HF diet fed obese mice via increasing phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and inhibiting expression of protein tyrosine phosphatase 1B (PTP1B). We also found that 36M could prevent hepatic lipid storage in the HF diet fed mice via inhibition of fatty acid synthase and lipid droplet proteins, including perilipins and Fsp27. In conclusion, 36M is a potential candidate compound that can be developed as AMPK inhibitor and PTP1B inhibitor for treating diabetes and hepatic steatosis.


Assuntos
Diabetes Mellitus , Fígado Gorduroso , Proteínas Quinases Ativadas por AMP/metabolismo , Amidas/metabolismo , Amidas/farmacologia , Animais , Ácidos Cafeicos , Diabetes Mellitus/metabolismo , Dieta Hiperlipídica , Fígado Gorduroso/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Polifenóis/metabolismo , Polifenóis/farmacologia , Polifenóis/uso terapêutico
18.
Int J Mol Sci ; 23(16)2022 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-36012692

RESUMO

Resistance training increases insulin secretion and beta cell function in healthy mice. Here, we explored the effects of resistance training on beta cell glucose sensing and survival by using in vitro and in vivo diabetic models. A pancreatic beta cell line (INS-1E), incubated with serum from trained mice, displayed increased insulin secretion, which could be linked with increased expression of glucose transporter 2 (GLUT2) and glucokinase (GCK). When cells were exposed to pro-inflammatory cytokines (in vitro type 1 diabetes), trained serum preserved both insulin secretion and GCK expression, reduced expression of proteins related to apoptotic pathways, and also protected cells from cytokine-induced apoptosis. Using 8-week-old C57BL/6 mice, turned diabetic by multiple low doses of streptozotocin, we observed that resistance training increased muscle mass and fat deposition, reduced fasting and fed glycemia, and improved glucose tolerance. These findings may be explained by the increased fasting and fed insulinemia, along with increased beta cell mass and beta cell number per islet, observed in diabetic-trained mice compared to diabetic sedentary mice. In conclusion, we believe that resistance training stimulates the release of humoral factors which can turn beta cells more resistant to harmful conditions and improve their response to a glucose stimulus.


Assuntos
Diabetes Mellitus , Células Secretoras de Insulina , Condicionamento Físico Animal , Treinamento de Força , Animais , Glicemia/metabolismo , Diabetes Mellitus/metabolismo , Glucoquinase/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
19.
Cells ; 11(15)2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35954275

RESUMO

Macrophage differentiation and polarization are essential players in the success of the wound-healing process. Acute simple wounds progress from inflammation to proliferation/regeneration and, finally, to remodeling. In injured skin, macrophages either reside in the epithelium or are recruited from monocytes. Their main role is supported by their plasticity, which allows them to adopt different phenotypic states, such as the M1-inflammatory state, in which they produce TNF and NO, and the M2-reparative state, in which they resolve inflammation and exhibit a reparative function. Reparative macrophages are an essential source of growth factors such as TGF-ß and VEGF and are not found in nonhealing wounds. This review discusses the differences between macrophage phenotypes in vitro and in vivo, how macrophages originate, and how they cross-communicate with other cellular components in a wound. This review also highlights the dysregulation of macrophages that occurs in nonhealing versus overhealing wounds and fibrosis. Then, the therapeutic manipulation of macrophages is presented as an attractive strategy for promoting healing through the secretion of growth factors for angiogenesis, keratinocyte migration, and collagen production. Finally, Hoxa3 overexpression is discussed as an example of the therapeutic repolarization of macrophages to the normal maturation state and phenotype with better healing outcomes.


Assuntos
Diabetes Mellitus , Cicatrização , Diabetes Mellitus/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/metabolismo , Fenótipo
20.
Int J Mol Sci ; 23(15)2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-35955647

RESUMO

Proper regulation of energy metabolism in the brain is crucial for maintaining brain activity in physiological and different pathophysiological conditions. Ischemic stroke has a complex pathophysiology which includes perturbations in the brain energy metabolism processes which can contribute to worsening of brain injury and stroke outcome. Smoking and diabetes are common risk factors and comorbid conditions for ischemic stroke which have also been associated with disruptions in brain energy metabolism. Simultaneous presence of these conditions may further alter energy metabolism in the brain leading to a poor clinical prognosis after an ischemic stroke event. In this review, we discuss the possible effects of smoking and/or diabetes on brain glucose utilization and mitochondrial energy metabolism which, when present concurrently, may exacerbate energy metabolism in the ischemic brain. More research is needed to investigate brain glucose utilization and mitochondrial oxidative metabolism in ischemic stroke in the presence of smoking and/or diabetes, which would provide further insights on the pathophysiology of these comorbid conditions and facilitate the development of therapeutic interventions.


Assuntos
Isquemia Encefálica , Diabetes Mellitus , AVC Isquêmico , Acidente Vascular Cerebral , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Diabetes Mellitus/metabolismo , Metabolismo Energético , Glucose/metabolismo , Humanos , Fumar/efeitos adversos , Acidente Vascular Cerebral/complicações
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