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Clinical Science - published by Portland Press - Editor: The American Association for Clinical Chemistry
The Journal publishes papers in the field of translational science and medicine, defined as the whole range of biochemical, physiological, immunological and other approaches that may have relevance to disease in humans, particularly those which explore integrative biology of systems and pathways and the translation of molecular mechanisms to clinical applications.
The RAS (renin-angiotensin system) is one of the earliest and most extensively studied hormonal systems. The RAS is an atypical hormonal system in several ways. The major bioactive peptide of the system, AngII (angiotensin II), is neither synthesized in nor targets one specific organ. New research has identified additional peptides with important physiological and pathological roles. More peptides also mean newer enzymatic cascades that generate these peptides and more receptors that mediate their function. In addition, completely different roles of components that constitute the RAS have been uncovered, such as that for prorenin via the prorenin receptor. Complexity of the RAS is enhanced further by the presence of sub-systems in tissues, which act in an autocrine/paracrine manner independent of the endocrine system. The RAS seems relevant at the cellular level, wherein individual cells have a complete system, termed the intracellular RAS. Thus, from cells to tissues to the entire organism, the RAS exhibits continuity while maintaining independent control at different levels. The intracellular RAS is a relatively new concept for the RAS. The present review provides a synopsis of the literature on this system in different tissues.
BNP (B-type natriuretic peptide) has been reported to be elevated in preclinical states of vascular damage. To elucidate the relationship between plasma BNP and endothelial function, we have investigated the relationship between BNP and endothelial function in a cohort of subjects comprising healthy subjects as well as at-risk subjects with cardiovascular risk factors. To also clarify the relative contribution of different biological pathways to the individual variation in endothelial function, we have examined the relationship between a panel of multiple biomarkers and endothelial function. A total of 70 subjects were studied (mean age, 58.1±4.6 years; 27% had a history of hypertension and 18% had a history of hypercholesterolaemia). Endothelium-dependent vasodilatation was evaluated by the invasive ACH (acetylcholine)-induced forearm vasodilatation technique. A panel of biomarkers of biological pathways was measured: BNP, haemostatic factors PAI-1 (plasminogen-activator inhibitor 1) and tPA (tissue plasminogen activator), inflammatory markers, including cytokines [hs-CRP (high sensitive C-reactive protein), IL (interleukin)-6, IL-8, IL-18, TNFα (tumour necrosis factor α) and MPO (myeloperoxidase] and soluble adhesion molecules [E-selectin and sCD40 (soluble CD40)]. The median BNP level in the study population was 26.9 pg/ml. Multivariate regression analyses show that age, the total cholesterol/HDL (high-density lipoprotein) ratio, glucose and BNP were independent predictors of endothelial function, and BNP remained an independent predictor (P=0.009) in a binary logistic regression analysis using FBF (forearm blood flow) as a dichotomous variable based on the median value. None of the other plasma biomarkers was independently related to ACH-mediated vasodilatation. In a strategy using several biomarkers to relate to endothelial function, plasma BNP was found to be an independent predictor of endothelial function as assessed by endothelium-dependent vasodilatation in response to ACH.
Blockade of the MR (mineralocorticoid receptor) in CKD (chronic kidney disease) reduces LVMI [LV (left ventricular) mass index] and proteinuria. The MR can be activated by aldosterone, cortisol and DOC (deoxycorticosterone). The aim of the present study was to explore the influence of mineralocorticoids on LVMI and proteinuria in patients with CKD. A total of 70 patients with CKD and 30 patients with EH (essential hypertension) were recruited. Patients underwent clinical phenotyping; biochemical assessment and 24 h urinary collection for THAldo (tetrahydroaldosterone), THDOC (tetrahydrodeoxycorticosterone), cortisol metabolites (measured using GC-MS), and urinary electrolytes and protein [QP (proteinuira quantification)]. LVMI was measured using CMRI (cardiac magnetic resonance imaging). Factors that correlated significantly with LVMI and proteinuria were entered into linear regression models. In patients with CKD, significant predictors of LVMI were male gender, SBP (systolic blood pressure), QP, and THAldo and THDOC excretion. Significant independent predictors on multivariate analysis were THDOC excretion, SBP and male gender. In EH, no association was seen between THAldo or THDOC and LVMI; plasma aldosterone concentration was the only significant independent predictor. Significant univariate determinants of proteinuria in patients with CKD were THAldo, THDOC, USod (urinary sodium) and SBP. Only THAldo excretion and SBP were significant multivariate determinants. Using CMRI to determine LVMI we have demonstrated that THDOC is a novel independent predictor of LVMI in patients with CKD, differing from patients with EH. Twenty-four hour THAldo excretion is an independent determinant of proteinuria in patients with CKD. These findings emphasize the importance of MR activation in the pathogenesis of the adverse clinical phenotype in CKD.
Regular exercise can reduce the risk of CVD (cardiovascular disease). Although moderate-intensity exercise can attenuate postprandial TAG (triacylglycerol), high-intensity intermittent exercise might be a more effective method to improve health. We compared the effects of high-intensity intermittent exercise and 30 min of brisk walking on postprandial TAG, soluble adhesion molecules and markers of oxidative stress. Nine men each completed three 2-day trials. On day 1, subjects rested (control), walked briskly for 30 min (walking) or performed 5×30 s maximal sprints (high-intensity). On day 2, subjects consumed a high-fat meal for breakfast and 3 h later for lunch. Blood samples were taken at various times and analysed for TAG, glucose, insulin, ICAM-1 (intracellular adhesion molecule-1), VCAM-1 (vascular adhesion molecule-1), TBARS (thiobarbituric acid- reactive substances), protein carbonyls and β-hydroxybutyrate. On day 2 of the high-intensity trial, there was a lower (P<0.05) incremental TAG AUC (area under the curve; 6.42±2.24 mmol/l per 7 h) compared with the control trial (9.68±4.77 mmol/l per 7 h) with no differences during day 2 of the walking trial (8.98±2.84 mmol/l per 7 h). A trend (P=0.056) for a reduced total TAG AUC was also seen during the high-intensity trial (14.13±2.83 mmol/l per 7 h) compared with control (17.18±3.92 mmol/l per 7 h), walking showed no difference (16.33±3.51 mmol/l per 7 h). On day 2 of the high-intensity trial plasma TBARS and protein carbonyls were also reduced (P<0.05) when compared with the control and walking trials. In conclusion, high-intensity intermittent exercise attenuates postprandial TAG and markers of oxidative stress after the consumption of a high-fat meal.
COX-2 (cyclo-oxygenase-2) and PGE2 (prostaglandin E2) play a key role in sustaining CRC (colorectal cancer) cell growth and survival. Indeed, the use of agents targeting the COX-2/PGE2 axis has been associated with a reduction in the development of CRC in both humans and murine models of colon carcinogenesis. In the present study, we investigated whether 2-methoxy-5-amino-N-hydroxybenzamide (herein termed 2-14), a derivative of mesalamine that inhibits CRC cell growth both in vitro and in vivo, negatively regulates COX-2/PGE2 expression in CRC cells and assessed whether the 2-14-mediated anti-neoplastic effect is strictly dependent on the inhibition of this pathway. Our results show that 2-14 blocks the growth and enhances the death of HT-115, a CRC cell line overexpressing COX-2, and that these effects associate with inhibition of COX-2 but not COX-1. 2-14 also down-regulates TNFα (tumour necrosis factor α)-induced COX-2 in HT-29 cells as well as COX-2/PGE2 expression in ex vivo cultures of human CRC explants. Similarly, 2-14 reduces COX-2, but not COX-1, in tumoural areas developing in a mouse model of CAC (colitis-associated colon cancer). Finally, we show that 2-14 exhibits in vitro and in vivo anti-mitogenic effects in DLD-1, a COX-deficient CRC cell line. Taken together, these results suggest that 2-14 inhibits CRC cell growth through COX-2-dependent and -independent mechanisms.
NEFA (non-esterified 'free' fatty acid)-mediated lipotoxicity plays a critical role in the pathogenesis of NASH (non-alcoholic steatohepatitis). In the light of the growing need for new therapeutic options for NASH, we investigated the action of A2aR (adenosine A2a receptor) stimulation against lipotoxicity. The effects of the A2aR agonist CGS21680 [2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxyamidoadenosine] were evaluated 'in vitro' in liver cells exposed to SA (stearic acid) and 'in vivo' in rats with NASH induced by 8 weeks of feeding with an MCD diet (methionine/choline-deficient diet). In cultured hepatocytes, SA promoted apoptosis by inducing MKK4 (mitogen-activated protein kinase kinase 4)/SEK1 (stress-activated protein kinase/extracellular-signal-regulated kinase kinase-1) and JNK-1/2 (c-Jun N-terminal kinase-1/2) activation. CGS21680 addition prevented JNK-1/2 activation and reduced apoptosis without interfering with lipid accumulation. CGS21680 action required PI3K (phosphoinositide 3-kinase)/Akt-mediated block of MKK4/SEK1. Consistently, PI3K inhibition with wortmannin abolished the cytoprotective action of CGS21680 and reverted MKK4 inhibition. SA lipotoxicity was also prevented by transfecting HTC cells with a specific MKK4/SEK1 siRNA (small interfering RNA). In rats receiving the MCD diet, the development of NASH was associated with MKK4/SEK1 and JNK-1/2 activation. CGS21680 (0.5 mg/kg of body weight, intraperitoneal) administration to MCD-fed rats prevented JNK-1/2 activation by acting on MKK4/SEK1. CGS21680 also effectively reduced NASH-associated ALT (alanine aminotransferase) release, hepatocyte apoptosis, liver inflammation and fibrosis without affecting hepatic steatosis. Taken together, these results demonstrate that, by inhibiting JNK-1/2, A2aR stimulation reduces lipotoxicity and ameliorates NASH, giving a rationale to investigate A2aR agonists as possible new therapeutic agents in preventing fatty liver progression to NASH.
Background. Local and systemic angiotensin II (Ang II) levels are regulated by Angiotensin Converting Enzyme 2 (ACE2), which is reduced in diabetic tissues. In this study, we examine the effect of ACE2 deficiency on the early cardiac and vascular changes associated with experimental diabetes.
Methods. Streptozotocin diabetes was induced in male C57bl6 mice and Ace2 knockout (KO) mice, and markers of RAS activity, cardiac function and injury were assessed after 10 weeks. In a second protocol, diabetes was induced in male apolipoprotein (apo) E KO mice and apoE/ACE2 double KO mice, and plaque accumulation and markers of atherogenesis assessed after 20 weeks.
Results. The induction of diabetes in wild type mice led to reduced ACE2 expression and activity in the heart, elevated circulating Ang II levels and reduced cardiac Ang1-7 levels This was associated structurally with thinning of the left ventricular wall and mild ventricular dilatation, and histologically with increased cardiomyocyte apoptosis on TUNEL staining and compensatory hypertrophy denoted by an increased cardiomyocyte cross-sectional area. By contrast Ace2 KO mice failed to increase circulating Ang II concentration, experienced a paradoxical fall in cardiac Ang II levels and no change in Ang 1-7 following the onset of diabetes. At the same time the major phenotypic differences between ACE2 deficient and ACE2 replete mice with respect to blood pressure and cardiac hypertrophy were eliminated following the induction of diabetes. Consistent with findings in the heart, the accelerated atherosclerosis that was observed in diabetic apoE KO mice was not seen in diabetic apoE/ Ace2 KO mice, which experienced no further increase in plaque accumulation or expression in key adhesion molecules beyond that seen in apo E/ Ace2 KO mice.
Conclusions. These data point to the potential role of ACE2 deficiency in regulating the tissue and circulating levels of Ang II and their sequelae in the context of diabetes, as well as the preservation or augmentation of ACE2 expression or activity as a potential therapeutic target for the prevention of cardiovascular disease in diabetes.
Aims/hypothesis: Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) has recently been shown to ameliorate the natural history of diabetes mellitus (DM). It has not been determined yet whether systemic TRAIL delivery would prevent the metabolic abnormalities due to a high fat diet (HFD).
Methods: For this purpose 27 male mice C57bl6 aged 8 weeks were randomly allocated to standard diet, HFD or HFD + TRAIL for 12 weeks. TRAIL was delivered weekly by intra-peritoneal injection. Body composition was evaluated; indirect calorimetry studies, glucose tolerance test (GTT) and insulin tolerance tests (ITT) were performed. Pro-inflammatory cytokines together with adipose tissue gene expression and apoptosis were measured.
Results: TRAIL treatment reduced significantly the increased adiposity associated with a HFD. Moreover, it reduced significantly hyperglycaemia and hyperisulinemia during a GTT and it improved significantly the peripheral response to insulin. TRAIL reversed the changes in substrate utilization induced by HFD and ameliorated skeletal muscle free fatty acids oxidation rate. This was associated with a significant reduction of pro-inflammatory cytokines together with a modulation of adipose tissue gene expression and apoptosis.
Conclusions: This data sheds light on the possible anti-adipogenic and anti-inflammatory effects of TRAIL and opens new therapeutic possibilities against obesity, systemic inflammation and type 2 DM.
The risk stratification in patients presenting with acute dyspnea remains a challenge.
We therefore conducted a prospective, observational cohort study enrolling 292 patients presenting to the emergency department with acute dyspnea. A proteomic approach for antibody-free targeted protein quantitation based on high-end mass spectrometry was used to measure latent transforming growth factor binding protein 2 (LTBP2) levels. Final diagnosis and death during follow-up were adjudicated blinded to LTBP2 levels.
Acute heart failure (AHF) was the final diagnosis in 54% of patients. In both AHF (p<0.001) and non-AHF (p=0.015) patients, LTBP2 levels at presentation were significantly higher in non-survivors compared to survivors with differences on median levels being 2.2-fold and 1.5-fold respectively. When assessing the cause of death, LTBP2 levels were significantly higher in patients dying from pulmonary causes (p=0.0005). Overall, LTBP2 powerfully predicted early pulmonary death (AUC: 0.95; 95%CI 0.91-0.98). In ROC curve analyses for the prediction of 1-year mortality LTBP2 achieved an AUC of 0.77 (95%CI 0.71-0.84); comparable to the predictive potential of NT-proBNP (0.77; 95%CI 0.72-0.82). Importantly, the predictive potential of LTBP2 persisted in patients with AHF as the cause of dypnea (AUC 0.78) and was independent of renal dysfunction (AUC 0.77). In a multivariate Cox regression analysis LTBP2 was the strongest independent predictor of death (HR 3.76; 95%CI 2.13-6.64, p< 0.0001).
In conclusion, plasma levels of LTBP2 present a novel and powerful predictor of all-cause mortality, and particularly pulmonary death. Cause-specific prediction of death would enable targeted prevention e.g. with pre-emptive antibiotic therapy.
Estrogen protects cardiovascular health partially via an upregulation of nitric oxide (NO·) production. Its synthetic analog diethylstilbestrol (DES), used as a potent androgen deprivation therapy for patients with prostate cancer, is however associated with high incidence of thromboembolic events. Exposure of bovine aortic endothelial cells to pharmacologically relevant dosage (12.5 µmol/L, 24 hr) of DES resulted in a marked reduction in endothelial NO· bioavailability determined by electron spin resonance (ESR), while 17β-estradiol instead increased NO· levels as expected. Intriguingly, endothelial superoxide (O2·-) production was upregulated by DES in vitro and in vivo, which was however attenuated by estrogen receptor antagonist ICI 182780, xanthine oxidase (XO) inhibitor oxypurinol, or NADPH oxidase (NOX) inhibitor NSC23766. These agents also restored NO· production. DES alone in a cell free system did not produce any ESR-sound O2·- signal. Of note, eNOS mRNA and protein remained unchanged in response to DES. These data suggest that receptor dependent-activation of XO or NOX, and subsequent production of O2·-, mediate DES-induced NO· deficiency. This could represent a previously unrecognized mechanism that is responsible for cardiovascular complications of DES administration. Importantly, DES-induced suppression of LNCaP cell invasion was not affected by XO or NOX inhibitor. Therefore, combinatorial therapy of DES and XO/NOX inhibitor may prove to be an innovative and useful therapeutic option in eliminating cardiovascular complications of DES while preserving its anti-cancer effects, benefiting patients with advanced cancer who do not respond well to any other treatments but DES.
Objective. Red wine polyphenols may preserve endothelial function during aging. Endothelial cell senescence enhances age-related endothelial dysfunction. We investigated whether red wine extract (RWE) prevents oxidative stress-induced senescence in human umbilical vein endothelial cells (HUVECs).
Methods and Results. Senescence was induced by exposing HUVECs to tert-butylhydroperoxide (tBHP), and quantified by senescence-associated β-galactosidase staining. RWE (0-50 μg/mL) concentration-dependently decreased senescence by maximally 33±7.1%. RWE prevented the senescence-associated increase in p21 protein expression, inhibited tBHP-induced DNA damage of endothelial cells, and induced relaxation of porcine coronary arteries. Inhibition of SIRT1 by sirtinol partially reversed the effect of RWE on tBHP-induced senescence, whereas both the nitric oxide (NO) synthase inhibitor L-NMMA and the cyclo-oxygenase (COX) inhibitor indomethacin fully inhibited it. Furthermore, incubation of HUVECs with RWE increased eNOS and COX-2 mRNA levels as well as phosphorylation of eNOS at Ser1177.
Conclusions. RWE protects endothelial cells from tBHP-induced senescence. NO and COX-2, in addition to activation of SIRT1, play a critical role in the inhibition of senescence induction in human endothelial cells by RWE.
Expression of chemokine (C-C motif) ligand 2 (CCL2, or monocyte chemoattractant protein-1) regulates inflammatory cell infiltration in the liver and adipose tissue, favoring steatosis. However, its role in the pathogenesis of steatohepatitis is still uncertain. In this study we investigated the development of nonalcoholic steatohepatitis induced by a diet deficient in methionine and choline (MCD) in mice lacking the CCL2 gene on two different genetic backgrounds, Balb/C and C57/Bl6J. Wild type and CCL2 knock-out mice were administered a lipid-enriched MCD diet or a control diet for 8 weeks. In Balb/C mice administered the MCD diet, lack of CCL2 was associated with lower ALT levels and reduced infiltration of inflammatory cells, together with lower generation of generation of oxidative stress-related products. Sirius red staining demonstrated pericellular fibrosis in zone 3, and image analysis showed a significantly lower matrix accumulation in CCL2-deficient mice. This was associated with reduced hepatic expression of TGF-beta, type I procollagen, TIMP-1 and alpha-smooth muscle actin. In contrast, in mice on a C57Bl/6 background, neither ALT levels nor inflammation or fibrosis were significantly different comparing wild type and CCL2-deficient animals on a MCD diet. In agreement, genes related to fibrogenesis were expressed to comparable levels in the two groups of animals. Comparison of the expression of several genes involved in inflammation and repair demonstrated that IL-4 and the M2 marker, MGL-1 were differentially expressed in Balb/C and C57Bl/6 mice. No significant differences in the degree of steatosis were observed in all groups of mice administered the MCD diet.
We conclude that in experimental murine steatohepatitis, the effects of CCL2 deficiency are markedly dependent on the genetic background.
Epidemiologic studies revealed an association between intrauterine growth restriction and an increased risk to develop cardiovascular diseases, like atherosclerosis or hypertension, in later life. Whether or not intrauterine growth restriction contributes to the development of atherosclerotic lesions, however, is unclear. We tested the hypothesis that intrauterine growth restriction aggravates experimentally induced vascular remodeling. Intrauterine growth restriction was induced in rats by maternal protein restriction during pregnancy (8% protein diet). To detect possible differences in the development of vascular injury, a model of carotid artery ligation to induce vascular remodeling was applied in 8 week old intrauterine growth restricted and control rat offspring. Histologic and immunohistochemical analyses were performed in the ligated and non-ligated carotid arteries 8 weeks after ligation. Intrauterine growth restriction alone neither caused overt histologic changes, nor significant dedifferentiation of vascular smooth muscle cells. After carotid artery ligation, however, neointima formation, media thickness and media-to-lumen ratio were significantly increased in rats after intrauterine growth restriction compared to controls. Moreover, dedifferentiation of vascular smooth muscle cells and collagen deposition in the media were more prominent in ligated carotids from rats after intrauterine growth restriction compared to ligated carotids from control rats. We conclude that intrauterine growth restriction aggravates atherosclerotic vascular remodeling induced by a second injury later in life.
Sympathetic activities are elevated in the central sympathetic nervous systems of hypertensive animals but it is not known if sympathetic innervation is also elevated in the heart. Sympathetic hyperresponsiveness in hypertension may result from oxidative stress. The aim of this study was to investigate sympathetic hyperinnervation in deoxycorticosterone acetate (DOCA)-salt hypertensive rats with established hypertension. Four weeks after the start of DOCA–salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 8 weeks: vehicle, N-acetylcysteine and triple therapy (hydralazine, hydrochlorothiazide, and reserpine). DOCA-salt was associated with increased oxidant release. DOCA-salt produced concentric left ventricular hypertrophy and cardiomyocyte hypertrophy. Sympathetic hyperinnervation was observed in DOCA-salt rats, assessed by myocardial norepinephrine levels, immunofluorescent analysis of tyrosine hydroxylase, growth associated factor 43 and neurofilament and Western blotting and real-time quantitative RT-PCR of nerve growth factor. Arrhythmic scores during programmed stimulation in DOCA-salt rats were significantly higher than those in the control rats. Triple therapy, despite being effective on blood pressure, offered neither attenuated cardiomyocyte hypertrophy nor antiarrhythmia. The effects of DOCA-salt treatment on nerve growth factor expression, sympathetic hyperinnervation and arrhythmias were attenuated by N-acetylcysteine. Furthermore, the effects of N-acetylcysteine on nerve growth factor were abolished by administering L-buthionine sulfoximine, an inhibitor of γ-glutamylcysteine synthetase. In conclusion, DOCA-salt treatment contributes to up-regulation of nerve growth factor proteins probably through a free radicals-dependent pathway in a blood pressure-independent manner. DOCA-salt rats treated with N-acetylcysteine attenuate sympathetic hyperinnervation and thus show a beneficial effect on arrhythmogenic response to programmed electrical stimulation.
We examined the relationship between the calcium /calmodulin-dependent protein kinase II (CaMKII) pathway and endothelial dysfunction in aortas from Goto-Kakizaki type 2 diabetic rats. The acetylcholine-induced relaxation and NO production were each attenuated in diabetic aortas (vs. those from age-matched control rats). Acetylcholine -stimulated Ser1177-endothelial NO synthase (eNOS) phosphorylation was significantly decreased in diabetic aortas (vs. their controls). Acetylcholine markedly increased the CaMKII phosphorylation level within endothelial cells only in control aortas (as assessed by immunohistochemistry and western blotting). Acetylcholine -stimulated Thr286-CaMKII phosphorylation within endothelial cells was significantly decreased in diabetic aortas (vs. their controls). The acetylcholine -induced relaxations, NO production, eNOS phosphorylation, and CaMKII phosphorylation were inhibited by KN93 and/or by lavendustin C (inhibitors of CaMKII) in control aortas, but not in diabetic ones. Preincubation of aortic strips with a protein phosphatase-1 inhibitor, PPI2, or with a protein phosphatase-2A inhibitor, cantharidic acid (CA), corrected the above abnormalities in diabetic aortas. The expression of protein phosphatase (PP)2A type A subunit was increased in diabetic aortas. The acetylcholine-stimulated Thr320-phosphorylation level of PP1a was lower in diabetic aortas than in their controls, but the total PP1a protein level was not different. These results suggest that the aortic relaxation responses, NO production, and eNOS activity mediated by CaMKII phosphorylation are decreased in this type 2 diabetic model, and that these impairments of CaMKII signaling may be, at least in part, due to enhancements of PP1a activity and PP2A expression.
Dendritic cells play an important role in the immune system. They invade peripheral tissues to detect harmful antigens, inducing a local immune response. Studies suggest that dendritic cell precursors (DCPs) might be reduced in acute myocardial infarction (AMI). The reason for their reduction is unknown yet. Circulating myeloid (mDCPs), plasmacytoid (pDCPs), total (tDCPs) DCPs and serum levels of Tumor necrosis factor-a (TNF-a), Interleukin (IL)-2, -4, -5, -6, -10, and -12 were analyzed by flow cytometry in blood of patients with Non-ST-Segment Elevation Myocardial Infarction (NSTEMI) (n=44) and ST-Segment Elevation Myocardial Infarction (STEMI) (n=34) compared to controls with excluded coronary artery disease (CAD) (n=45). Post-mortem myocardial specimens of patients with AMI (n=12) and healthy myocardium of accident victims (n=10) were immunostained for myeloid DCs T cells, and macrophages. Compared to controls, in patients with AMI a significant decrease in circulating mDCPs, pDCPs, and tDCPs was observed (each p<0.0001). The extent of the decrease was higher in STEMI than NSTEMI patients. Serum levels were significantly higher in patients with AMI compared to controls for IL-6, -10, -12, and TNF-a (each p<0.03). Immunostaining revealed significantly higher numbers of DCs, T cells, and macrophages (each p<0.002) in infarcted than control myocardium. We show that circulating DCPs are significantly reduced in AMI, with a pronounced reduction in STEMI patients. This was accompanied by a significant increase of inflammatory serum cytokines in patients with AMI. Immunohistochemical analysis unraveled that the reduction of circulating DCPs might be due to recruitment into the infarcted myocardium.
A reduction in endothelial progenitor cells (EPCs) number could explain the development and progression of atherosclerosis in metabolic syndrome (MetS). Although much research in recent years has focused on Mediterranean dietary pattern and MetS; the effect of this diet with/without moderate-to-high intensity endurance training on EPCs levels and cardiorespiratory fitness (CrF) remains unclear. In the present study, the objective was to assess the effect of a Mediterranean diet hypocaloric model with and without moderate-to-high intensity endurance training on EPCs number and CrF of MetS patients. Thus, Forty-five MetS (50-66y) were randomized to a 12-w intervention with hypocaloric Mediterranean diet (MeD) or to the same diet plus moderate-to-high intensity endurance training (MeDE). Training included two weekly supervised sessions (80% MaxHR; leg and arm pedaling) and one at-home session (65-75% MaxHR; walking controlled by heart rate monitors). Changes on: a) EPCs number (CD34+KDR+); b) CrF variables; and c) MetS components and ischemic reactive hyperaemia (IRH), were determined at the end of the study. Forty subjects completed all 12 weeks of the study, 20 in each group. MeDE led to a greater increase in EPCs numbers and CrF than did MeD intervention (P≤0.001). Additionally, a positive correlation was observed between the increases of EPCs and fitness in MeDE group (r=0.72; r2=0.52; P≤0.001). Body weight loss, insulin sensitivity, triglycerides, and blood pressure showed greater decrease in MeDE than MeD. Furthermore, IRH was only improved after MeDE intervention. In conclusion, compliance with moderate-to-high intensity endurance training enhances the positive effects of a model of Mediterranean diet on the regenerative capacity of endothelium and on fitness of MetS patients.
This study aims to evaluate if cord blood stem cells (CBSCs) can be new source of dendritic cells (DCs) which can generate more potent antigen-specific immune responses and anti-tumor effects. The CBSCs and peripheral blood mononuclear cells (PBMCs) were collected, cultured and differentiated into DCs. Surface markers, secreting cytokines, antigen presentation activity, antigen-specific cell-mediated immunity and cytotoxic killing effects induced by these two origins of DCs were evaluated and compared. The CBSCs expanded for ~17-fold by ex vivo culture. The expressions of surface markers in CBSC-derived DCs were higher than those in PBMC-derived DCs treated with LPS. The CBSC-derived DCs mainly secreted IL-6, IL-10, and TNF-a, while PBMC-derived DCs mainly secreted IL-5 and IFN-γ. The CBSC-derived DCs had better antigen presentation abilities when stimulated with LPS or TNF-a, induced higher numbers of IFN-g-secreting, antigen-specific CD8+ T lymphocytes by ELLIspot assay, and stimulated stronger antigen-specific CTL activities (p<0.01, one-way ANOVA). The CBSC-derived DCs showed quicker and stronger ERK and Akt phosphorylation, and weaker p38 phosphorylation than PBMC-derived DCs when stimulated with LPS. The CBSC-derived DCs have abilities of inducing stronger antigen-specific immunity and more potent anti-tumor effects. The CBSCs can be a good source of DCs in the strategy of DC-based cancer vaccine and immunotherapy.
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