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Understanding the mechanisms underlying vascular regeneration in the heart is crucial for developing novel therapeutic strategies for myocardial ischemia. This study investigates the contribution of bone marrow-derived cells to endothelial cell populations in the heart, and their role in cardiac function and coronary circulation following repetitive ischemia (RI). Chimeric rats were created by transplanting BM cells from GFP female rats into irradiated male recipients. After engraftment chimeras were subjected to RI for 17 days. Vascular growth was assessed from recovery of cardiac function and increases in myocardial blood flow during LAD occlusion. After sorting GFP+ BM cells from heart and bone of Control and RI rats, single-cell RNA sequencing was implemented to determine the fate of BM cells. Our in vivo RI model demonstrated an improvement in cardiac function and myocardial blood flow after 17 days of RI with increased capillary density in the rats subjected to RI compared to Controls. Single-cell RNA sequencing of bone marrow cells isolated from rats' hearts identified distinct endothelial cell (EC) subpopulations. These ECs exhibited heterogeneous gene expression profiles and were enriched for markers of capillary, artery, lymphatic, venous, and immune ECs. Furthermore, BM-derived ECs in the RI group showed an angiogenic profile, characterized by upregulated genes associated with blood vessel development and angiogenesis. This study elucidates the heterogeneity of bone marrow-derived endothelial cells in the heart and their response to repetitive ischemia, laying the groundwork for targeting specific subpopulations for therapeutic angiogenesis in myocardial ischemia.
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Transplante de Medula Óssea , Modelos Animais de Doenças , Células Endoteliais , Ratos Transgênicos , Animais , Masculino , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Neovascularização Fisiológica , Isquemia Miocárdica/patologia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Células da Medula Óssea/metabolismo , Circulação Coronária , Miocárdio/patologia , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , TranscriptomaRESUMO
BACKGROUND AND AIMS: Takotsubo syndrome (TTS) is a conundrum without consensus about the cause. In a murine model of coronary microvascular dysfunction (CMD), abnormalities in myocardial perfusion played a key role in the development of TTS. METHODS AND RESULTS: Vascular Kv1.5 channels connect coronary blood flow to myocardial metabolism and their deletion mimics the phenotype of CMD. To determine if TTS is related to CMD, wild-type (WT), Kv1.5-/-, and TgKv1.5-/- (Kv1.5-/- with smooth muscle-specific expression Kv1.5 channels) mice were studied following transaortic constriction (TAC). Measurements of left ventricular (LV) fractional shortening (FS) in base and apex, and myocardial blood flow (MBF) were completed with standard and contrast echocardiography. Ribonucleic Acid deep sequencing was performed on LV apex and base from WT and Kv1.5-/- (control and TAC). Changes in gene expression were confirmed by real-time-polymerase chain reaction. MBF was increased with chromonar or by smooth muscle expression of Kv1.5 channels in the TgKv1.5-/-. TAC-induced systolic apical ballooning in Kv1.5-/-, shown as negative FS (P < 0.05 vs. base), which was not observed in WT, Kv1.5-/- with chromonar, or TgKv1.5-/-. Following TAC in Kv1.5-/-, MBF was lower in LV apex than in base. Increasing MBF with either chromonar or in TgKv1.5-/- normalized perfusion and function between LV apex and base (P = NS). Some genetic changes during TTS were reversed by chromonar, suggesting these were independent of TAC and more related to TTS. CONCLUSION: Abnormalities in flow regulation between the LV apex and base cause TTS. When perfusion is normalized between the two regions, normal ventricular function is restored.
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Cardiomiopatia de Takotsubo , Animais , Camundongos , Cromonar , Circulação Coronária/fisiologia , Ecocardiografia , Isquemia Miocárdica , MiocárdioRESUMO
BACKGROUND: Family with sequence similarity 19 (chemokine (C-C motif)-like) member A5 (FAM19A5) is a newly identified adipokine. There is a limited number of studies linking FAM19A5 to metabolic disorders. In the current study, we aimed to explore if FAM19A5 is associated with nonalcoholic fatty liver disease (NAFLD). We also sought to determine the possibility of FAM19A5 association with subclinical atherosclerosis in NAFLD patients. METHODS: A total of 69 subjects including 37 NAFLD and 32 control subjects were included in this cross-sectional study. Plasma concentration of FAM19A5 was measured with the ELISA method. Carotid artery intima-media thickness (cIMT) was assessed by the ultrasonography. RESULTS: Plasma concentration of FAM19A5 in patients with NAFLD was significantly lower in NAFLD patients than controls. Moreover, we observed significant negative correlations between plasma level of FAM19A5 and body mass index (BMI), visceral fat, alanine amino transferase (ALT), aspartate amino transferase (AST), liver stiffness (LS), and cIMT. Following stepwise multiple linear regression analysis, ALT and cIMT were the only determinants of FAM19A5 level. CONCLUSIONS: This is the first report to describe association of circulating FAM19A5 levels with NAFLD. Our findings provide further evidence showing relation of FAM19A5 with the risk of atherosclerosis. However, more studies are necessary to unravel the contribution of lower FAM19A5 levels to the NAFLD pathogenesis and the higher risk of atherosclerosis in these patients.
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Aterosclerose/patologia , Biomarcadores/sangue , Espessura Intima-Media Carotídea , Citocinas/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Ultrassonografia/métodos , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/sangue , Aterosclerose/etiologia , Estudos de Casos e Controles , Estudos Transversais , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Onda de Pulso , Fatores de RiscoRESUMO
BACKGROUND: Recent studies showed that atherosclerosis is a lysosomal storage disease (LSD) and Niemann-Pick disease type C1 (NPC1) is the most important protein of the lysosomal membrane that is involved in the removal of FC from lysosomes. Whereas several in vitro and in vivo studies have described the crosstalk between lysosomal cholesterol accumulation and increased inflammation, there is no study addressing the correlation between NPC1 gene expression and an anti-inflammatory cytokine, interleukin 10 (IL-10) serum concentration in atherosclerotic patients. METHODS: IL-10 and 25-hydroxyvitamin D serum concentrations were quantified by enzyme-linked immunosorbent assay (ELISA) in atherosclerotic patients (n = 40) and a control group (n = 40). NPC1 gene expression analysis was performed by quantitative real-time PCR, and correlation between the two parameters was assessed. RESULTS: Mean IL-10 serum concentration and peripheral blood mononuclear cells' (PBMCs) gene expression of NPC1, adjusted for drug consumption, age, and BMI, was not significantly different between the patient and control groups (p = 0.6 and 0.67 respectively). However, NPC1 gene expression showed positive significant correlation with IL-10 serum concentration (p = 0.04, r = 0.29). We also observed lower serum concentration of IL-10 in the subjects with lower 25-hydroxyvitamin D serum concentration (p = 0.034). CONCLUSIONS: Our findings supported the previous observations showing the contribution of lysosomal lipid homeostasis of PBMCs to inflammation and pathogenesis of atherosclerosis.
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Aterosclerose/genética , Proteínas de Transporte/genética , Expressão Gênica , Interleucina-10/sangue , Leucócitos Mononucleares/metabolismo , Glicoproteínas de Membrana/genética , Doença de Niemann-Pick Tipo C/genética , Idoso , Aterosclerose/sangue , Estudos de Casos e Controles , Células Cultivadas , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/sangue , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
Protein tyrosine phosphatase 1B (PTP1B) has been shown to regulate multiple cellular events such as differentiation, cell growth, and proliferation; however, the role of PTP1B in differentiation of embryonic stem (ES) cells into cardiomyocytes remains unexplored. In the present study, we investigated the effects of PTP1B inhibition on differentiation of ES cells into cardiomyocytes. PTP1B mRNA and protein levels were increased during the differentiation of ES cells into cardiomyocytes. Accordingly, a stable ES cell line expressing PTP1B shRNA was established. In vitro, the number and size of spontaneously beating embryoid bodies were significantly decreased in PTP1B-knockdown cells, compared with the control cells. Decreased expression of cardiac-specific markers Nkx2-5, MHC-α, cTnT, and CX43, as assessed by real-time PCR analysis, was further confirmed by immunocytochemistry of the markers. The results also showed that PTP1B inhibition induced apoptosis in both differentiated and undifferentiated ES cells, as presented by increasing the level of cleaved caspase-3, cytochrome C, and cleaved PARP. Further analyses revealed that PTP1B inhibition did not change proliferation and pluripotency of undifferentiated ES cells. Taken together, the data presented here suggest that PTP1B is essential for proper differentiation of ES cells into cardiomyocytes.
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Diferenciação Celular , Regulação Enzimológica da Expressão Gênica , Células-Tronco Embrionárias Murinas/enzimologia , Miócitos Cardíacos/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/biossíntese , Animais , Antígenos de Diferenciação/biossíntese , Linhagem Celular , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Miócitos Cardíacos/citologiaRESUMO
Embryonic stem cells offer multiple advantages over adult stem cells in terms of achieving acceptable number of functional cardiomyocytes to be exploited in cell therapy. However, differentiation efficacy is still a major issue to be solved before moving to regenerative medicine. Although a vast number of chemical compounds have been tested on efficiency of cardiac differentiation, the effect of fish oil components, such as eicosapentaenoic acid (EPA) on developmental bioenergetics, and hence cardiac differentiation, remained unstudied. EPA has been reported to have several cardioprotective effects, but there is no study addressing its role in cardiac differentiation. After mesoderm induction of embryoid bodies (EBs) derived from mouse embryonic stem cells (mESCs) in hanging drops initiated by ascorbic acid, they were treated with various concentrations of EPA. Gene and protein expression and functional properties of cardiomyocytes derived from ESCs were evaluated following treatment with various concentrations of EPA. Exposure to low concentrations of EPA (10 µM) increased percentage of beating colonies and beating area. This treatment also resulted in up to 3 fold increase in expression of NKX2-5, MEF2C, MYH6, TNNT2 and CX43. FACS analysis confirmed gene expression analysis with increased percentage of MYH6 positive cells in EPA-treated group compared to the control group. In contrast, the expression of genes coding for cardiac differentiation, remained constant or even declined with higher concentrations of EPA. In conclusion, we have demonstrated that treatment of mESCs undergoing cardiac differentiation with low concentration, but not high concentration of EPA up-regulate transcription of genes associated with cardiac development.
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Diferenciação Celular/efeitos dos fármacos , Ácido Eicosapentaenoico/farmacologia , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/efeitos dos fármacos , Miócitos Cardíacos/citologia , Animais , Células Cultivadas , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Camundongos , Miócitos Cardíacos/metabolismoRESUMO
Cardiac aging is an intricate and multifaceted process with considerable impact on public health, especially given the global demographic shift towards aged populations. This review discusses structural, cellular and functional changes associated with cardiac aging and heart failure with preserved ejection fraction (HFpEF). Key molecular mediators are considered within the framework of the established hallmarks of aging, with particular attention to promising therapeutic candidates. We further delineate the differential impacts of aging on cardiac structure and function in men and women, addressing hormonal and chromosomal influences. The protective and mitigating effects of exercise in cardiac aging and HFpEF in particular are discussed, as an inspiration for the identification of pathways that mitigate biological aging. We also emphasize how much remains to be learned and the importance of these efforts in enhancing the cardiac health of aging populations worldwide.
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Histone deacetylases (HDACs) are important players in a variety of physiological and pathological conditions. Few studies have addressed HDAC expressions in human adipose tissue in obese individuals, and their association with pro-inflammatory cytokines. Here, we compared 20 non-obese and 20 obese women to investigate possible changes in gene expressions of HDAC2, 4, 5, and 6 in the subcutaneous adipose tissues (SAT) and visceral adipose tissues (VAT) of these individuals. Our findings showed decreased HDAC5 expression in SAT and elevated HDAC4 expression in VAT from the obese group compared with the non-obese group. Our analyses showed negative correlations between HDAC2, 5, and 6 and the obesity indices and positive correlations between HDAC4 and obesity indices. HDAC2 showed a positive correlation with pro-inflammatory cytokines whereas HDAC4, 5, and 6 were negatively correlated with pro-inflammatory cytokines. Our findings provide new evidence that implicates the important roles of HDACs in obesity and obesity-associated inflammation.
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Citocinas , Obesidade , Citocinas/genética , Citocinas/metabolismo , Feminino , Expressão Gênica , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Gordura Subcutânea/metabolismoRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular events. HDL exerts various protective functions on the cardiovascular system including anti-inflammatory activity by suppressing adhesion molecules expression in inflammation-induced endothelial cells. This study was designed to search if the anti-inflammatory capacity of apolipoprotein B-depleted plasma (apoB-depleted plasma) is altered in NAFLD patients. METHODS: A total of 83 subjects including 42 NAFLD and 41 control subjects were included in this cross-sectional study. Anti-inflammatory function of HDL was determined as the ability of apoB-depleted plasma to inhibit tumor necrosis factor-α (TNF-α)-induced expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs). RESULTS: Incubation of inflammation-stimulated HUVECs with the NAFLD patients' apo-B depleted plasma led to higher levels of expression of adhesion molecules compared to the control subjects' plasma samples, reflecting an impaired anti-inflammatory capacity of apoB-depleted plasma in the NAFLD patients. Impaired anti-inflammatory capacity of apoB-depleted plasma was correlated with fatty liver and obesity indices. After adjustment with obesity indices, the association of anti-inflammatory capacity of apoB-depleted plasma with NAFLD remained significant. CONCLUSION: Impaired anti-inflammatory activity of apoB-depleted plasma was independently associated with NAFLD.
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Apolipoproteínas B , Hepatopatia Gordurosa não Alcoólica , Anti-Inflamatórios/sangue , Apolipoproteínas B/sangue , Estudos de Casos e Controles , Estudos Transversais , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , ObesidadeRESUMO
PURPOSE: This study was designed to evaluate the effects of adding Estradiol (E2) supplementation to progesterone (P) on improvement of pregnancy outcomes in poor responder patients who underwent in vitro fertilization (IVF). METHODS: In a prospective randomized clinical trial, 118 poor responder patients, older than 38 years without contraindications of estradiol consumption from Infertility clinic of a university hospital were randomly divided (by computerized software) into two groups. Control group (59 patients) received only P and intervention group (59 patients) received P and E2 (4 mg/d). Supplementation was done with 4 mg E2 in the luteal phase. Fertilization rate, implantation rate, biochemical and clinical pregnancy rates, abortion rate, ongoing pregnancy, multiple pregnancy and ectopic pregnancy rates were documented for those who completed the study protocol in each group (per protocol analysis) and compared between groups. RESULT: Fifty five patients in control group and 53 patients in intervention group successfully completed the study protocol. Treatment outcomes were not significantly different between two groups. CONCLUSION: For poor responder women who underwent IVF, addition of E2 to P supplementation could not significantly improve pregnancy outcomes.
Assuntos
Estradiol/uso terapêutico , Fertilização in vitro , Adulto , Feminino , Humanos , Infertilidade Feminina/tratamento farmacológico , Indução da Ovulação , Gravidez , Resultado da Gravidez , Progesterona/uso terapêuticoRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) patients are at a substantial risk for developing cardiovascular disease (CVD). High-density lipoprotein (HDL) is well known to have protective effects against the development of atherosclerotic CVD. One of the major antiatherogenic effects of HDL is its anti-oxidative function. OBJECTIVES: This study investigated the association of anti-oxidative capacity of HDL with subclinical atherosclerosis in NAFLD and non-NAFLD subjects. METHODS: A total of 143 subjects including 51 NAFLD and 92 control subjects were included in this case-control study. HDL oxidative index (HOI) was determined spectrophotometrically using a cell-free method in the presence of a fluorescent substrate dichlorofluorescein diacetate (DCFDA). Paraoxonase 1 (PON1) activity, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) plasma levels were assessed in both groups. RESULTS: The NAFLD patients with impaired HDL anti-oxidative function (HOI ≥ 1) had higher MDA levels, aspartate amino transferase (AST), liver stiffness (LS), and carotid intima-media thickness (cIMT) values compared to the controls. HDL oxidative index (HOI) was positively correlated with MDA levels and cIMT and negatively correlated with SOD activity. CONCLUSIONS: Higher circulating levels of MDA were associated with the impaired anti-oxidative function of HDL in NAFLD. The impaired anti-oxidative capacity of HDL might be related to NAFLD severity and subclinical atherosclerosis in NAFLD patients.
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The growing evidence has been tried to explain and characterize C1q/TNF- related proteins (CTRPs) family as the potential diagnostic or therapeutic targets of obesity-related metabolic disorders such as insulin resistance, type 2 diabetes (T2D), and cardiovascular disorders. However, the underlying mechanism is still obscure. Unraveling the signaling pathways downstream of CTRP family members is of great interest and could certainly be beneficial for finding new insights into therapeutic strategies for improving metabolic abnormalities. This review focused on the role of CTRP members in the initiation and development of obesity-related metabolic disorders with a focus on T2D and cardiovascular diseases. Here we summarize and discuss the role of CTRPs in the regulation of insulin signaling, inflammatory pathways, and energy metabolism, and other signaling pathways pertinent to the pathogenesis of T2D and cardiovascular diseases. We also review available clinical studies to better elucidate the roles of these potential molecules in the initiation and development of the afore-mentioned disorders.
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Doenças Cardiovasculares/etiologia , Complemento C1q/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Obesidade/complicações , Fator de Necrose Tumoral alfa/metabolismo , Animais , Doenças Cardiovasculares/metabolismo , Complemento C1q/genética , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Resistência à Insulina , RNA Mensageiro , Transdução de Sinais , Fator de Necrose Tumoral alfa/genéticaRESUMO
One of the major issues in cell therapy of myocardial infarction (MI) is early death of engrafted cells in a harsh oxidative stress environment, which limits the potential therapeutic utility of this strategy in the clinical setting. Increasing evidence implicates beneficial effects of omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and ascorbic acid (AA) in cardiovascular diseases, in particular their role in ameliorating fibrosis. In the current study, we aim to assess the cytoprotective role of EPA + DHA and AA in protecting embryonic stem cell (ESC)-derived cardiac lineage cells and amelioration of fibrosis. Herein, we have shown that preincubation of the cells with EPA + DHA + AA prior to H2 O2 treatment attenuated generation of reactive oxygen species (ROS) and enhanced cell viability. Gene expression analysis revealed that preincubation with EPA + DHA + AA followed by H2 O2 treatment, upregulated heme oxygenase-1 (HO-1) along with cardiac markers (GATA4, myosin heavy chain, α isoform [MYH6]), connexin 43 [CX43]) and attenuated oxidative stress-induced upregulation of fibroblast markers (vimentin and collagen type 1 [Col1]). Alterations in gene expression patterns were followed by marked elevation of cardiac troponin (TNNT2) positive cells and reduced numbers of vimentin positive cells. An injection of EPA + DHA + AA-pretreated ESC-derived cardiac lineage cells into the ischemic myocardium of a rat model of MI significantly reduced fibrosis compared to the vehicle group. This study provided evidence that EPA + DHA + AA may be an appropriate preincubation regimen for regenerative purposes. © 2019 BioFactors, 45(3):427-438, 2019.
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Ácido Ascórbico/uso terapêutico , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/efeitos dos fármacos , Ácidos Graxos Ômega-3/uso terapêutico , Animais , Biomarcadores/metabolismo , Western Blotting , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ecocardiografia , Ácido Eicosapentaenoico/uso terapêutico , Heme Oxigenase-1/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Altered production of adipokines is suggested to play a pivotal role in the pathogenesis of polycystic ovarian syndrome (PCOS). C1q/TNF-related proteins (CTRPs) play diverse roles in regulation of metabolism in physiologic and pathologic conditions. In the present study, we assessed serum concentrations of adiponectin, CTRP12, and CTRP13 in individuals with PCOS and those without PCOS. We also evaluated the possible association of these adipokines with metabolic and hormonal variables. A total of 171 premenopausal women (86 with PCOS and 85 without PCOS) enrolled in this study. Serum levels of adiponectin, CTRP12, and CTRP13 were measured. The results showed significantly lower serum concentrations of adiponectin, CTRP12, and CTRP13 in PCOS women compared to non-PCOS women. This difference remained significant after controlling for age, body mass index (BMI), and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). However, we did not observe any significant differences in serum levels of adiponectin, CTRP12, and CTRP13 between the overweight/obese and normal weight subgroups in PCOS and non-PCOS women. Multiple linear regression analysis showed associations of CTRP12 with adiponectin and BMI with CTRP13 in both the PCOS and non-PCOS groups. CTRP12 was significantly associated with BMI and adiponectin in the non-PCOS group, and fasting blood glucose (FBG) and CTRP13 in the PCOS group. Our results indicated that decreased adiponectin, CTRP12, and CTRP13 levels, regardless of obesity, could independently predict PCOS. This finding suggested a novel link between adipokines and PCOS.
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Adipocinas/sangue , Obesidade/sangue , Síndrome do Ovário Policístico/diagnóstico , Adipocinas/metabolismo , Adiponectina/sangue , Adiponectina/metabolismo , Adulto , Glicemia/análise , Índice de Massa Corporal , Estudos de Casos e Controles , Complemento C1q/metabolismo , Feminino , Homeostase , Humanos , Obesidade/metabolismo , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/metabolismo , Pré-Menopausa , PrognósticoRESUMO
The LIM-homeodomain transcription factor ISL1 marks multipotent cardiac progenitors that give rise to cardiac muscle, endothelium, and smooth muscle cells. ISL1+ progenitors can be derived from human pluripotent stem cells, but the inability to efficiently isolate pure populations has limited their characterization. Using a genetic selection strategy, we were able to highly enrich ISL1+ cells derived from human embryonic stem cells. Comparative quantitative proteomic analysis of enriched ISL1+ cells identified ALCAM (CD166) as a surface marker that enabled the isolation of ISL1+ progenitor cells. ALCAM+/ISL1+ progenitors are multipotent and differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells. Transplantation of ALCAM+ progenitors enhances tissue recovery, restores cardiac function, and improves angiogenesis through activation of AKT-MAPK signaling in a rat model of myocardial infarction, based on cardiac MRI and histology. Our study establishes an efficient method for scalable purification of human ISL1+ cardiac precursor cells for therapeutic applications.
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Células-Tronco Embrionárias/citologia , Proteínas com Homeodomínio LIM/metabolismo , Infarto do Miocárdio/terapia , Miócitos Cardíacos/citologia , Células-Tronco/citologia , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/fisiologia , Linhagem da Célula/fisiologia , Células Cultivadas , Células-Tronco Embrionárias/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Humanos , Masculino , Camundongos , Infarto do Miocárdio/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos de Músculo Liso , Proteômica/métodos , Ratos , Ratos Sprague-Dawley , Células-Tronco/metabolismoRESUMO
BACKGROUND: Global epidemic of diabetes is a serious health care concern because of its complications and consequently reduced life expectancy and increased morbidity. However, the bone turnover and thus bone health may be affected or even compromised by diabetes and its complications. The aim of this study was to assess whether bone turnover markers are associated with diabetes micro-vascular complications. METHODS: A total of 204 type 2 diabetes patients (104 patients with diabetic micro-vascular complications (retinopathy and/or nephropathy) as a case group and 100 patients without retinopathy and/or nephropathy) as a control group were recruited in this case-control study. The biochemical and metabolic parameters and bone turnover markers were assessed in all patients. RESULTS: Our findings showed serum levels of osteocalcin (OC) (p = 0.0001) and, carboxy-terminal collagen crosslinks (CTX) (p = 0.006) were higher in diabetic patients with both diabetic retinopathy and nephropathy compared with control group. However, there was no significant difference in serum levels of procollagen I aminoterminal propeptide (P1NP) between diabetic patients with diabetic retinopathy (DR) and/or diabetic nephropathy (DN) compared with control. In diabetes patients with complications, there were significant negative correlation between OC and CTX with estimated-glomerular filtration rate (e-GFR) and also positive correlation between each bone marker (OC and CTX) and PTH levels (p = 0.0001) and BUN (p = 0.0001). In a general linear model, after adjusting for age, sex and BMI, and microvascular complications, there was not any significant association between three bone turnover markers and metabolic markers including fasting glucose, insulin, and lipid profile. Among kidney markers, there were significant positive associations between serum levels of CTX and OC with BUN (p < 0.05) as well as PTH (p < 0.0001). CONCLUSIONS: Our data suggest the possible role of PTH and BUN levels in modulating bone turnover markers in diabetic patients.
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Nonalcoholic fatty liver disease (NAFLD) is considered as one of the most common liver diseases. It is robustly linked to obesity and insulin resistance and is regarded as hepatic manifestation of metabolic syndrome (MetS). Adipokines are involved in the pathophysiology of liver diseases. The aim of this study was to evaluate the plasma concentrations of CTRP1 (complement-C1q TNF-related protein 1) in 22 patients with NAFLD, 22 patients with type 2 diabetes mellitus (T2DM), 22 patients with NAFLD+T2DM and 21 healthy controls, as well as their correlation with the level of metabolic and hepatic parameters. Plasma concentration of CTRP1 was measured with ELISA method. Plasma concentration of CTRP1 in patients with NAFLD, T2DM and NAFLD+T2DM were significantly higher than healthy subjects (p<0.0001). Moreover, we observed significant positive correlations between plasma level of CTRP1 and fasting blood glucose (FBG) (p<0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (p<0.001), body mass index (BMI) (p = 0.001), alanine amino transferase (ALT) (p = 0.002), gamma glutamyl transferase (γ-GT) (p<0.001) and liver stiffness (LS) (p<0.001). Our results indicate the strong association of CTRP1 with insulin resistance in NAFLD. Also, it seems that CTRP1 can be considered as an emerging biomarker for NAFLD, however, more studies are necessary to unravel the role of CTRP1 in NAFLD pathogenesis.
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Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/sangue , Proteínas/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
BACKGROUND: It is well-established that nonalcoholic fatty liver disease (NAFLD) is associated with type 2 diabetes mellitus (T2DM). Complement-C1q TNF-related protein 5 (CTRP5) is a novel adipokine involved in the regulation of lipid and glucose metabolism. We aimed to assess plasma levels of CTRP5 in patients with NAFLD (n = 22), T2DM (n = 22) and NAFLD with T2DM (NAFLD + T2DM) (n = 22) in comparison with healthy subjects (n = 21) and also to study the association between CTRP5 levels and NAFLD and diabetes-related parameters. METHODS: All subjects underwent anthropometric assessment, biochemical evaluation and liver stiffness (LS) measurement. Insulin resistance (IR) was determined by the homeostasis model assessment (HOMA). Plasma CTRP5 levels were measured by enzyme-linked immunosorbent assay. RESULTS: We found significantly lower plasma levels of CTRP5 in patients with NAFLD + T2DM, NAFLD and T2DM (122.52 ± 1.92, 124.7 ± 1.82 and 118.31 ± 1.99 ng/ml, respectively) in comparison with controls (164.96 ± 2.95 ng/ml). In the whole study population, there was a significant negative correlations between CTRP5 and body mass index (r = -0.337; p = 0.002), fasting blood glucose (FBG) (r = -0.488; p < 0.001), triglyceride (TG) (r = -0.245; p = 0.031), HOMA-IR (r = -0.492; p < 0.001), insulin(r = -0.338; p = 0.002), LS (r = -0.544; p < 0.001), alanine aminotransferase (ALT) (r = -0.251; p = 0.027), waist-to-hip ratio (WHR) (r = -0.352; p = 0.002) and waist circumference (WC) (r = -0.357; p = 0.001). After adjustment for BMI, decrease in circulating levels of CTRP5 remained as a significant risk factor for NAFLD, T2DM and NAFLD + T2DM. The receiver operating characteristic (ROC) curves of circulating CTRP5 in predicting NAFLD and T2DM demonstrated an area under the curve (AUC) of 0.763 in T2DM, and 0.659 in NAFLD + T2DM. CONCLUSIONS: It appears that the decreased levels of CTRP5 contribute to the increased risk of T2DM and NAFLD.