ABSTRACT
Intrauterine growth restriction (IUGR) can induce deleterious changes in the modulatory ability of the vascular endothelium, contributing to an increased risk of developing cardiovascular diseases in the long term. However, the mechanisms involved are not fully understood. Emerging evidence has suggested the potential role of endothelial progenitor cells (EPCs) in vascular health and repair. Therefore, we aimed to evaluate the effects of IUGR on vascular reactivity and EPCs derived from the peripheral blood (PB) and bone marrow (BM) in vitro. Pregnant Wistar rats were fed an ad libitum diet (control group) or 50% of the ad libitum diet (restricted group) throughout gestation. We determined vascular reactivity, nitric oxide (NO) concentration, and endothelial nitric oxide synthase (eNOS) protein expression by evaluating the thoracic aorta of adult male offspring from both groups (aged: 19-20 weeks). Moreover, the amount, functional capacity, and senescence of EPCs were assessed in vitro. Our results indicated that IUGR reduced vasodilation via acetylcholine in aorta rings, decreased NO levels, and increased eNOS phosphorylation at Thr495. The amount of EPCs was similar between both groups; however, IUGR decreased the functional capacity of EPCs from the PB and BM. Furthermore, the senescence process was accelerated in BM-derived EPCs from IUGR rats. In summary, our findings demonstrated the deleterious changes in EPCs from IUGR rats, such as reduced EPC function and accelerated senescence in vitro. These findings may contribute towards elucidating the possible mechanisms involved in endothelial dysfunction induced by fetal programming.
Subject(s)
Endothelial Progenitor Cells/pathology , Endothelium, Vascular/pathology , Fetal Growth Retardation/physiopathology , Oxidative Stress , Vasodilation , Animals , Female , Male , Nitric Oxide/metabolism , Pregnancy , Rats , Rats, WistarABSTRACT
It has been demonstrated that intrauterine growth restriction (IUGR) can program increase cardiometabolic risk. There are also evidences of the correlation between IUGR with low-grade inflammation and, thus can contribute to development of several cardiometabolic comorbidities. Therefore, we investigated the influence of IUGR on circulating mitochondrial DNA (mtDNA)/Toll-like receptor 9 (TLR9) and TNF-α expression in adult offspring. Considering that the aerobic training has anti-inflammatory actions, we also investigated whether aerobic training would improve these inflammatory factors. Pregnant Wistar rats received ad libitum or 50% of ad libitum diet throughout gestation. At 8 weeks of age, male offspring from both groups were randomly assigned to control, trained control, restricted and trained restricted. Aerobic training protocol was performed on a treadmill and after that, we evaluated circulating mtDNA, cardiac protein expression of TLR9, plasma and cardiac TNF-α levels, and left ventricle (LV) mass. We found that IUGR promoted an increase in the circulating mtDNA, TLR9 expression and plasma TNF-α levels. Further, our results revealed that aerobic training can restore mtDNA/TLR9 content and plasma levels of TNF-α among restricted rats. The cardiac TNF-α content and LV mass were not influenced either by IUGR or aerobic training. In conclusion, IUGR can program mtDNA/TLR9 content, which may lead to high levels of TNF-α. However, aerobic training was able to normalize these alterations. These findings evidenced that the association of IUGR and aerobic training seems to exert an important interaction effect regarding pro-inflammatory condition and, aerobic training may be used as a strategy to reduce deleterious adaptations in IUGR offspring.
Subject(s)
Cardiomegaly/prevention & control , DNA, Mitochondrial/genetics , Fetal Growth Retardation/physiopathology , Physical Conditioning, Animal/methods , Prenatal Exposure Delayed Effects/physiopathology , Toll-Like Receptor 9/metabolism , Adaptation, Physiological , Animals , Animals, Newborn , Cardiomegaly/etiology , DNA, Mitochondrial/blood , Female , Male , Pregnancy , Rats , Rats, WistarABSTRACT
The recently described 'gasomediator' hydrogen sulfide (H2S) has been involved in pain mechanisms, but its effect on pruritus, a sensory modality that similarly to pain acts as a protective mechanism, is poorly known and controversial. The effects of the slow-releasing (GYY4137) and spontaneous H2S donors (Na2S and Lawesson's reagent, LR) were evaluated in histamine and compound 48/80 (C48/80)-dependent dorsal skin pruritus and inflammation in male BALB/c mice. Animals were intradermally (i.d.) injected with C48/80 (3µg/site) or histamine (1µmol/site) alone or co-injected with Na2S, LR or GYY4137 (within the 0.3-100nmol range). The involvement of endogenous H2S and KATP channel-dependent mechanism were also evaluated. Pruritus was assessed by the number of scratching bouts, whilst skin inflammation was evaluated by the extravascular accumulation of intravenously injected 125I-albumin (plasma extravasation) and myeloperoxidase (MPO) activity (neutrophil recruitment). Histamine or C48/80 significantly evoked itching behavior paralleled by plasma extravasation and increased MPO activity. Na2S and LR significantly ameliorated histamine or C48/80-induced pruritus and inflammation, although these effects were less pronounced or absent with GYY4137. Inhibition of endogenous H2S synthesis increased both Tyrode and C48/80-induced responses in the skin, whereas the blockade of KATP channels by glibenclamide did not. H2S-releasing donors significantly attenuate C48/80-induced mast cell degranulation either in vivo or in vitro. We provide first evidences that H2S donors confer protective effect against histamine-mediated acute pruritus and cutaneous inflammation. These effects can be mediated, at least in part, by stabilizing mast cells, known to contain multiple mediators and to be primary initiators of allergic processes, thus making of H2S donors a potential alternative/complementary therapy for treating inflammatory allergic skin diseases and related pruritus.
Subject(s)
Hydrogen Sulfide/metabolism , Hydrogen Sulfide/pharmacology , Inflammation/drug therapy , Mast Cells/drug effects , Protective Agents/pharmacology , Pruritus/drug therapy , Skin/drug effects , Animals , Glyburide/pharmacology , Histamine/metabolism , Inflammation/metabolism , KATP Channels/metabolism , Male , Mast Cells/metabolism , Mice , Mice, Inbred BALB C , Morpholines/pharmacology , Organothiophosphorus Compounds/pharmacology , Pruritus/metabolism , Skin/metabolismABSTRACT
BACKGROUND AND OBJECTIVE: Protease activated receptor type 1 (PAR1 ) seems to play a role in periodontal repair, while PAR2 is associated with periodontal inflammation. As diabetes is a known risk factor for periodontal disease, the aim of this study was to evaluate the influence of type 2 diabetes on PAR1 and PAR2 mRNA expression in the gingival crevicular fluid of patients with chronic periodontitis before and after non-surgical periodontal treatment. MATERIAL AND METHODS: Gingival crevicular fluid samples and clinical parameters consisting of measuring probing depth, clinical attachment level, bleeding on probing and plaque index were collected from systemically healthy patients and patients with type 2 diabetes and chronic periodontitis, at baseline and after non-surgical periodontal therapy. PAR1 and PAR2 , as well as the presence of the proteases RgpB gingipain and neutrophil proteinase-3 were assessed by quantitative polymerase chain reaction in the gingival crevicular fluid. RESULTS: The periodontal clinical parameters significantly improved after periodontal therapy (p < 0.01). Diabetes led to increased expression of PAR1 in gingival crevicular fluid, and in the presence of chronic periodontitis, it significantly decreased the expression of PAR1 and PAR2 (p < 0.05). Moreover, non-surgical periodontal treatment in diabetics resulted in increased expression of PAR1 and PAR2 (p < 0.05), and decreased expression of RgpB gingipain and proteinase-3 (p < 0.05). CONCLUSION: The present data demonstrated that diabetes was associated with an altered expression of PAR1 and PAR2 in the gingival crevicular fluid cells of subjects with chronic periodontitis. Future studies are necessary to elucidate the effects of PAR1 upregulation in periodontally healthy sites and PAR2 downregulation in chronic periodontitis sites on the increased susceptibility and severity of periodontitis in diabetes.
Subject(s)
Chronic Periodontitis/metabolism , Diabetes Mellitus, Type 2/metabolism , Gingival Crevicular Fluid/chemistry , Receptor, PAR-1/analysis , Receptor, PAR-2/analysis , Adult , Chronic Periodontitis/complications , Chronic Periodontitis/therapy , Dental Plaque Index , Diabetes Mellitus, Type 2/complications , Female , Fibroblasts/chemistry , Humans , Male , Middle Aged , Myeloblastin/analysis , Myeloblastin/genetics , Myeloblastin/metabolism , Periodontal Attachment Loss , Periodontal Pocket , RNA, Messenger/biosynthesis , Receptor, PAR-1/genetics , Receptor, PAR-1/metabolism , Receptor, PAR-2/genetics , Receptor, PAR-2/metabolism , Risk FactorsABSTRACT
AIMS: Hypertension is associated with increased levels of circulating cytokines and recent studies have shown that innate immunity contributes to hypertension. The mechanisms which hypertension stimulates immune response remain unclear, but may involve formation of neo-antigens that activate the immune system. Toll like receptor 4 (TLR4) is an innate immune receptor that binds a wide spectrum of exogenous (lipopolysaccharide) and endogenous ligands. TLR4 signaling leads to activation of nuclear factor kappa B (NFκB) and transcription of genes involved in inflammatory response. We previously demonstrated that TLR4 blockade reduces blood pressure and the augmented vascular contractility in spontaneously hypertensive rats (SHR). Here we hypothesized that inhibition of TLR4 ameliorates the vascular inflammatory process by a NFκB signaling pathway. MAIN METHODS: SHR and Wistar rats were treated with anti-TLR4 antibody (1µg/day) or unspecific IgG for 15days (i.p.). KEY FINDINGS: Anti-TLR4 treatment decreased production of reactive oxygen species and expression of IL-6 cytokine in mesenteric resistance arteries from SHR, when compared with IgG-treated SHR. Anti-TLR4 treatment also abolished the increased vascular reactivity to noradrenaline observed in IgG-treated SHR, as described before, and inhibition of NFκB decreased noradrenaline responses only in IgG-treated SHR. Mesenteric arteries from SHR treated with anti-TLR4 displayed decreased expression of MyD88, but not TRIF, key molecules in TLR4 signaling. Phosphorylation of p38 and NF-κB p65 were decreased in arteries from anti-TLR4-treated SHR versus IgG-treated SHR. SIGNIFICANCE: Together, these results suggest that TLR4 is a key player in hypertension and vascular inflammatory process by a NFκB signaling pathway.
Subject(s)
Antibodies, Monoclonal/pharmacology , Hypertension/prevention & control , Inflammation/prevention & control , Mesenteric Arteries/immunology , Toll-Like Receptor 4/antagonists & inhibitors , Animals , Blood Pressure/drug effects , Blotting, Western , Cells, Cultured , Cytokines/metabolism , Hypertension/immunology , Hypertension/metabolism , Inflammation/immunology , Inflammation/metabolism , Male , Mesenteric Arteries/drug effects , Mesenteric Arteries/metabolism , Phosphorylation/drug effects , Rats , Rats, Inbred SHR , Rats, Wistar , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Toll-Like Receptor 4/immunology , Toll-Like Receptor 4/metabolismABSTRACT
Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-β1 (TGF-β1), and tumor necrosis factor-α (TNF-α) was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO=0.60±0.11, control=1.07±0.11). On the other hand, rhEPO had no significant effect on the expression of TGF-β1 (rhEPO=0.95±0.14, control=1.05±0.16) and TNF-α (rhEPO=0.73±0.20, control=1.01±0.09). These results may help to clarify some of the direct actions of EPO on skeletal muscle.
Subject(s)
Animals , Male , Down-Regulation/drug effects , Erythropoietin/therapeutic use , Gene Expression/drug effects , Muscular Dystrophy, Duchenne/drug therapy , Myostatin/metabolism , Recombinant Proteins/therapeutic use , Disease Models, Animal , Dystrophin/deficiency , Mice, Inbred mdx , Muscle Strength/drug effects , Muscle, Skeletal/metabolism , Muscular Dystrophy, Duchenne/metabolism , Myostatin/genetics , Phenotype , Real-Time Polymerase Chain Reaction , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-ß1 (TGF-ß1), and tumor necrosis factor-α (TNF-α) was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO = 0.60 ± 0.11, control = 1.07 ± 0.11). On the other hand, rhEPO had no significant effect on the expression of TGF-ß1 (rhEPO = 0.95 ± 0.14, control = 1.05 ± 0.16) and TNF-α (rhEPO = 0.73 ± 0.20, control = 1.01 ± 0.09). These results may help to clarify some of the direct actions of EPO on skeletal muscle.
Subject(s)
Down-Regulation/drug effects , Erythropoietin/therapeutic use , Gene Expression/drug effects , Muscular Dystrophy, Duchenne/drug therapy , Myostatin/metabolism , Recombinant Proteins/therapeutic use , Animals , Disease Models, Animal , Dystrophin/deficiency , Male , Mice, Inbred mdx , Muscle Strength/drug effects , Muscle, Skeletal/metabolism , Muscular Dystrophy, Duchenne/metabolism , Myostatin/genetics , Phenotype , Real-Time Polymerase Chain Reaction , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: American tegumentary leishmaniasis (ATL) and sporotrichosis exhibit similar histopathology and low frequencies of microorganism detection. OBJECTIVES: This study seeks to identify microscopic alterations that can distinguish between these diseases. METHODS: Haematoxylin and eosin stained slides of 171 ATL and 97 sporotrichosis samples from active cutaneous lesions were examined for histopathological alterations. The lesions were diagnosed by isolating the agent (which was not visible) in culture. An intuitive diagnosis was assigned to each slide. The strength of the association between the histopathological findings and the diagnosis was estimated by an odds ratio, and each finding was graded according to a regression model. A score was assigned to each sample based on the histopathological findings. A study of the interobserver reliability was performed by calculating kappa coefficients of the histopathological findings and intuitive diagnoses. RESULTS: The markers 'macrophage concentration', 'tuberculoid granuloma' and 'extracellular matrix degeneration' were associated with ATL. 'Suppurative granuloma', 'stellate granuloma', 'different types of giant cells', 'granulomas in granulation tissue' and 'abscess outside the granuloma' were associated with a diagnosis of sporotrichosis. 'Macrophage concentration' and 'suppurative granuloma' had the highest (substantial and almost perfect, respectively) reliability. The regression model score indicated 92.0% accuracy. The intuitive diagnosis had 82.5% diagnostic accuracy and substantial reliability. CONCLUSIONS: Taking into account the clinical and epidemiological context, some histopathological alterations might be useful for the differential diagnosis between ATL and sporotrichosis cutaneous lesions in cases in which the aetiological agent is not visible.
Subject(s)
Dermatomycoses/diagnosis , Leishmaniasis, Cutaneous/diagnosis , Skin Diseases, Parasitic/diagnosis , Sporotrichosis/diagnosis , Brazil , Cross-Sectional Studies , Diagnosis, Differential , Granuloma/pathology , Humans , Logistic Models , Macrophages/pathology , Predictive Value of Tests , Reproducibility of Results , Staining and LabelingABSTRACT
BACKGROUND/AIMS: ß(2)-adrenoceptor (ß(2)-AR) activation induces smooth muscle relaxation and endothelium-derived nitric oxide (NO) release. However, whether endogenous basal ß(2)-AR activity controls vascular redox status and NO bioavailability is unclear. Thus, we aimed to evaluate vascular reactivity in mice lacking functional ß(2)-AR (ß(2)KO), focusing on the role of NO and superoxide anion. METHODS AND RESULTS: Isolated thoracic aortas from ß(2)KO and wild-type mice (WT) were studied. ß(2)KO aortas exhibited an enhanced contractile response to phenylephrine compared to WT. Endothelial removal and L-NAME incubation increased phenylephrine-induced contraction, abolishing the differences between ß(2)KO and WT mice. Basal NO availability was reduced in aortas from ß(2)KO mice. Incubation of ß(2)KO aortas with superoxide dismutase or NADPH inhibitor apocynin restored the enhanced contractile response to phenylephrine to WT levels. ß(2)KO aortas exhibited oxidative stress detected by enhanced dihydroethidium fluorescence, which was normalized by apocynin. Protein expression of eNOS was reduced, while p47(phox) expression was enhanced in ß(2)KO aortas. CONCLUSIONS: The present results demonstrate for the first time that enhanced NADPH-derived superoxide anion production is associated with reduced NO bioavailability in aortas of ß(2)KO mice. This study extends the knowledge of the relevance of the endogenous activity of ß(2)-AR to the maintenance of the vascular physiology.
Subject(s)
Aorta, Thoracic/metabolism , Endothelium, Vascular/physiopathology , NADPH Oxidases/physiology , Receptors, Adrenergic, beta-2/deficiency , Acetophenones/pharmacology , Animals , Aorta, Thoracic/drug effects , Male , Mice , Mice, Knockout , Nitric Oxide/metabolism , Nitric Oxide Synthase Type III/biosynthesis , Oxidative Stress , Phenylephrine/pharmacology , Superoxides/metabolism , Vasoconstriction/drug effectsABSTRACT
Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.
Subject(s)
Humans , Endothelium, Vascular/physiopathology , Hypertension/physiopathology , Obesity/physiopathology , Hypertension/etiology , Insulin Resistance/physiology , Obesity/complications , Risk Factors , Renin-Angiotensin System/physiology , Sympathetic Nervous System/physiopathologyABSTRACT
AIMS: Cytokines interfere with signaling pathways and mediators of vascular contraction. Endothelin-1 (ET-1) plays a major role on vascular dysfunction in conditions characterized by increased circulating levels of adipokines. In the present study we tested the hypothesis that the adipokine chemerin increases vascular contractile responses via activation of ET-1/ET-1 receptors-mediated pathways. MAIN METHODS: Male, 10-12 week-old Wistar rats were used. Endothelium-intact and endothelium-denuded aortic rings were incubated with chemerin (0.5 ng/mL or 5 ng/mL, for 1 or 24h), and isometric contraction was recorded. Protein expression was determined by Western blotting. KEY FINDINGS: Constrictor responses to phenylephrine (PE) and ET-1 were increased in vessels treated for 1h with chemerin. Chemerin incubation for 24h decreased PE contractile response whereas it increased the sensitivity to ET-1. Endothelium removal significantly potentiated chemerin effects on vascular contractile responses to PE and ET-1. Incubation with either an ERK1/2 inhibitor (PD98059) or ETA antagonist (BQ123) abolished chemerin effects on PE- and ET-1-induced vasoconstriction. Phosphorylation of MEK1/2 and ERK1/2 was significantly increased in vessels treated with chemerin for 1 and 24h. Phosphorylation of these proteins was further increased in vessels incubated with ET-1 plus chemerin. ET-1 increased MEK1/2, ERK1/2 and MKP1 protein expression to values observed in vessels treated with chemerin. SIGNIFICANCE: Chemerin increases contractile responses to PE and ET-1 via ERK1/2 activation. Our study contributes to a better understanding of the mechanisms by which the adipose tissue affects vascular function and, consequently, the vascular alterations present in obesity and related diseases.
Subject(s)
Adipokines/administration & dosage , Aorta, Thoracic/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Adipokines/metabolism , Animals , Aorta, Thoracic/metabolism , Blotting, Western , Chemokines , Dose-Response Relationship, Drug , Endothelin-1/administration & dosage , Endothelin-1/metabolism , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Flavonoids/pharmacology , Intercellular Signaling Peptides and Proteins , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/metabolism , Male , Peptides, Cyclic/pharmacology , Phenylephrine/pharmacology , Phosphorylation/drug effects , Rats , Rats, Wistar , Time FactorsABSTRACT
Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.
Subject(s)
Endothelium, Vascular/physiopathology , Hypertension/physiopathology , Obesity/physiopathology , Humans , Hypertension/etiology , Insulin Resistance/physiology , Obesity/complications , Renin-Angiotensin System/physiology , Risk Factors , Sympathetic Nervous System/physiopathologyABSTRACT
AIMS: Inflammation may have an important role in the beginning and in the progress of cardiovascular diseases. Testosterone exerts important effects on vascular function, which is altered in arterial hypertension. Thus, the aim of this study was to evaluate the influence of endogenous testosterone on leukocyte behavior in post-capillary venules of the mesenteric bed of spontaneously hypertensive rats (SHR). MAIN METHODS: 18 week-old intact SHR, castrated SHR and normotensive rats (intact Wistar) were used. Blood pressure was measured by tail plethysmography and serum testosterone levels by ELISA. Leukocyte rolling, adhesion and migration were evaluated in vivo in situ by intravital microscopy. KEY FINDINGS: Castration significantly reduced blood pressure and reversed the increased leukocyte rolling and adhesion observed in SHRs. Leukocyte counts and other hemodynamic parameters did not differ among groups. SHRs displayed increased protein expression of P-selectin and ICAM-1 in mesenteric venules when compared to intact Wistar. Castration of SHRs restored the protein expression of the cell adhesion molecules. SIGNIFICANCE: The findings of the present study demonstrate the critical role of endogenous testosterone mediating the effects of hypertension increasing leukocyte-endothelial cell interaction. Increased expression of cell adhesion molecules contribute to the effects of endogenous testosterone promoting increased leukocyte rolling and adhesion in SHRs.
Subject(s)
Cell Communication , Endothelial Cells/cytology , Hypertension/immunology , Leukocytes/cytology , Rats, Inbred SHR/immunology , Testosterone/immunology , Animals , Cell Adhesion , Endothelial Cells/immunology , Hemodynamics , Hypertension/genetics , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/immunology , Leukocyte Rolling , Leukocytes/immunology , Male , Orchiectomy , P-Selectin/genetics , P-Selectin/immunology , RNA, Messenger/genetics , Rats , Rats, Inbred SHR/genetics , Rats, Wistar , Venules/cytologyABSTRACT
OBJECTIVE: Genetic sonography following first-trimester combined screening appears to increase substantially detection rates for Down syndrome but it relies on the unproved assumption of independence between these tests. In this study we aimed to investigate the relationship between first-trimester nuchal translucency (NT) and a series of second-trimester soft markers and structural defects in unaffected pregnancies. METHODS: NT measurement in the first trimester was followed by second-trimester scan (18 to 23 + 6 weeks) including examination for three categorical markers (intracardiac echogenic foci, hyperechogenic bowel and structural defects) and measurement of nasal bone length, nuchal-fold thickness, femur length, humerus length, renal pelvis diameter and prenasal thickness. All continuous variables were expressed in multiples of the median (MoM) for gestation and correlation coefficients between log-transformed NT and second-trimester variables were calculated. In addition, frequencies of soft markers and structural defects in cases with increased NT were compared to those with normal NT, using MoM cut-offs. RESULTS: In a dataset of 1970 cases, NT was significantly correlated (P < 0.05) with all second-trimester continuous variables, the correlation being strongest for nuchal-fold thickness (r = 0.10). There was a higher frequency of cases with second-trimester nuchal-fold thickness above the 97.5(th) centile (10.7 vs. 2.2%) and hyperechogenic bowel (2.4 vs. 0.1%) in cases with increased NT. CONCLUSIONS: Straightforward reassessment of risk using likelihood ratios derived from the second-trimester genetic sonogram might lead to inaccurate estimates. Multivariate models using continuous second-trimester variables might be preferable in sequential screening strategies.
Subject(s)
Down Syndrome/diagnostic imaging , Nasal Bone/diagnostic imaging , Nuchal Translucency Measurement/methods , Pregnancy Trimester, First , Pregnancy Trimester, Second , Ultrasonography, Prenatal/methods , Adult , Biomarkers/blood , Cohort Studies , Down Syndrome/blood , Female , Gestational Age , Humans , Nasal Bone/embryology , Predictive Value of Tests , Pregnancy , Prospective Studies , Risk AssessmentABSTRACT
AIMS: Metformin is an insulin sensitizing agent with beneficial effects in diabetic patients on glycemic levels and in the cardiovascular system. We examined whether the metabolic changes and the vascular dysfunction in monosodium glutamate-induced obese non-diabetic (MSG) rats might be improved by metformin. MAIN METHODS: 16 week-old MSG rats were treated with metformin for 15 days and compared with age-matched untreated MSG and non-obese non-diabetic rats (control). Blood pressure, insulin sensitivity, vascular reactivity and prostanoid release in the perfused mesenteric arteriolar bed as well as nitric oxide production and reactive oxygen species generation in isolated mesenteric arteries were analyzed. KEY FINDINGS: 18-week-old MSG rats displayed higher Lee index, fat accumulation, dyslipidemia, insulin resistance and hyperinsulinemia. Metformin treatment improved these alterations. The norepinephrine-induced response, increased in the mesenteric arteriolar bed from MSG rats, was corrected by metformin. Indomethacin corrected the enhanced contractile response in MSG rats but did not affect metformin effects. The sensitivity to acetylcholine, reduced in MSG rats, was also corrected by metformin. Indomethacin corrected the reduced sensitivity to acetylcholine in MSG rats but did not affect metformin effects. The sensitivity to sodium nitroprusside was increased in preparations from metformin-treated rats. Metformin treatment restored both the reduced PGI2/TXA2 ratio and the increased reactive oxygen species generation in preparations from MSG rats. SIGNIFICANCE: Metformin improved the vascular function in MSG rats through reduction in reactive oxygen species generation, modulation of membrane hyperpolarization, correction of the unbalanced prostanoids release and increase in the sensitivity of the smooth muscle to nitric oxide.
Subject(s)
Hypoglycemic Agents/administration & dosage , Mesenteric Arteries/metabolism , Metformin/administration & dosage , Nitric Oxide Synthase/metabolism , Obesity/drug therapy , Acetylcholine/pharmacology , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Disease Models, Animal , Dyslipidemias/drug therapy , Epoprostenol/metabolism , Hyperinsulinism/drug therapy , Indomethacin/pharmacology , Insulin/blood , Insulin Resistance , Male , Mesenteric Arteries/drug effects , Nitric Oxide/analysis , Nitric Oxide/metabolism , Nitric Oxide Synthase/analysis , Nitroprusside/pharmacology , Norepinephrine/pharmacology , Obesity/chemically induced , Obesity/physiopathology , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Sodium Glutamate/administration & dosage , Thromboxane A2/metabolismABSTRACT
Tropical soils are particularly vulnerable to fertility losses due to their low capacity to retain organic matter and mineral nutrients. This urges the development of new agricultural practices to manage mineral nutrients and organic matter in a more sustainable way while relying less on fertilizer inputs. Two methods pertaining to ecological engineering and agroecology have been tested with some success: (1) the addition of biochar to the soil, and (2) the maintenance of higher earthworm densities. However, modern crop varieties have been selected to be adapted to agricultural practices and to the soil conditions they lead to and common cultivars might not be adapted to new practices. Using rice as a model plant, we compared the responsiveness to biochar and earthworms of five rice cultivars with contrasted selection histories. These cultivars had contrasted responsivenesses to earthworms, biochar, and the combination of both. The mean relative increase in grain biomass, among all treatments and cultivars, was 94% and 32%, respectively, with and without fertilization. Choosing the best combination of cultivar and treatment led to a more than fourfold increase in this mean benefit (a 437% and a 353% relative increase in grain biomass, respectively, with and without fertilization). Besides, the more rustic cultivar, a local landrace adapted to diverse and difficult conditions, responded the best to earthworms in terms of total biomass, while a modern common cultivar responded the best in term of grain biomass. This suggests that cultivars could be selected to amplify the benefit of biochar- and earthworm-based practices. Overall, selecting new cultivars interacting more closely with soil organisms and soil heterogeneity could increase agriculture sustainability, fostering the positive feedback loop between soils and plants that has evolved in natural ecosystems.
Subject(s)
Adaptation, Physiological/genetics , Oryza/genetics , Oryza/physiology , Soil/chemistry , Tropical Climate , Animals , Biomass , Charcoal , Fertilizers , Oligochaeta/physiologyABSTRACT
The incidence of CRS and CRI has decreased markedly worldwide with the implementation of efficient vaccination programs. We report a congenital rubella case with fetal death occurred at 29th week of gestation. RV was confirmed in placenta. The results of phylogenetic analysis showed that the RVs/SaoPaulo01.- BRA/08.CRI belongs to the genotype 2B of RV.
Subject(s)
Rubella virus/genetics , Rubella virus/isolation & purification , Rubella/congenital , Rubella/virology , Brazil , Cluster Analysis , Fatal Outcome , Female , Genotype , Humans , Molecular Sequence Data , Phylogeny , Pregnancy , RNA, Viral/genetics , Rubella virus/classification , Sequence Analysis, DNA , Young AdultABSTRACT
BACKGROUND AND AIM: given that obesity is an independent risk factor for the development of cardiovascular diseases we decided to investigate the mechanisms involved in microvascular dysfunction using a monosodium glutamate (MSG)-induced model of obesity, which allows us to work on both normotensive and normoglycemic conditions. METHODS AND RESULTS: Male offspring of Wistar rats received MSG from the second to the sixth day after birth. Sixteen-week-old MSG rats displayed higher Lee index, fat accumulation, dyslipidemia and insulin resistance, with no alteration in glycemia and blood pressure. The effect of norepinephrine (NE), which was increased in MSG rats, was potentiated by L-nitro arginine methyl ester (L-NAME) or tetraethylammonium (TEA) and was reversed by indomethacin and NS-398. Sensitivity to acetylcholine (ACh), which was reduced in MSG rats, was further impaired by L-NAME or TEA, and was corrected by indomethacin, NS-398 and tetrahydrobiopterin (BH4). MSG rats displayed increased endothelium-independent relaxation to sodium nitroprusside. A reduced prostacyclin/tromboxane ratio was found in the mesenteric beds of MSG rats. Mesenteric arterioles of MSG rats also displayed reduced nitric oxide (NO) production along with increased reactive oxygen species (ROS) generation; these were corrected by BH4 and either L-NAME or superoxide dismutase, respectively. The protein expression of eNOS and cyclooxygenase (COX)-2 was increased in mesenteric arterioles from MSG rats. CONCLUSION: Obesity/insulin resistance has a detrimental impact on vascular function. Reduced NO bioavailability and increased ROS generation from uncoupled eNOS and imbalanced release of COX products from COX-2 play a critical role in the development of these vascular alterations.
Subject(s)
Animals, Newborn , Microvessels/physiopathology , Nitric Oxide/physiology , Obesity/chemically induced , Prostaglandins/physiology , Sodium Glutamate/administration & dosage , Animals , Arterioles/enzymology , Arterioles/metabolism , Cyclooxygenase 2/analysis , Male , Mesentery/blood supply , Nitric Oxide Synthase Type III/analysis , Obesity/physiopathology , Rats , Rats, Wistar , Reactive Oxygen Species/metabolismABSTRACT
OBJECTIVE AND DESIGN: Knowing that hyperglycemia is a hallmark of vascular dysfunction in diabetes and that neonatal streptozotocin-induced diabetic rats (n-STZ) present reduced inflammatory response, we decided to evaluate the effect of chlorpropamide-lowered blood glucose levels on carrageenan-induced rat paw edema and pleural exudate in n-STZ. MATERIALS: Diabetes was induced by STZ injection (160 mg/kg, ip) in neonates (2-day-old) Wistar rats. TREATMENT: n-STZ diabetic rats were treated with chlorpropamide (200mg/kg, 15d, by gavage) 8 weeks after STZ injection. METHODS: Carrageenan-induced paw edema and pleural exudate volumes were assessed concomitantly with peripheral and exudate leukocyte count. We also evaluated the expression of inducible nitric oxide synthase (iNOS) in lungs of all experimental groups. RESULTS: Chlorpropamide treatment improved glucose tolerance, beta-cell function (assessed by HOMA-beta), corrected paw edema, and pleural exudate volume in n-STZ. Neither leukocyte count nor iNOS expression were affected by diabetes or by chlorpropamide treatment. CONCLUSION: Chlorpropamide treatment by restoring beta-cell function, reducing blood sugar levels, and improving glucose tolerance might be contributing to the correction of the reduced inflammatory response tested as paw edema and pleural exudate in n-STZ diabetic rats.