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Abstract: Selective oxidation of galacturonic residues of oligo and polyuronic acids by CrVI affords CO2/HCO2H, oxidized uronic acid, and CrIII as final redox products. Kinetic studies show that the redox reaction proceeds through a mechanism combining CrVI →CrIV →CrII and CrVI →CrIV →CrIII pathways. The mechanism is supported by the observation of free radicals, CrO2 2+ and CrV as reaction intermediates. The EPR spectra show that five- and six coordinated oxo-CrV intermediates are formed. Penta-coordinated oxo-CrV species are present at any [H+], whereas hexa-coordinated ones are only observed at pH <1. At low pH CrV predominating species are coordinated by carboxylate groups and Oring (g iso =1.9783/5). At pH 7.5, the predominating ones are those coordinated by alcoholate groups of the ligand (g iso =1.9800). Polygal can reduce CrVI and efficiently trap CrIII. This behaviour represents an interesting model for the study of biomaterials, which possess a high proportion of polygal, in order to remove chromium from polluted waters. [Copyright &y& Elsevier]

Abstract: Thyrotropin (TSH)-releasing hormone (TRH) also known as thyroliberin was the first of a number of peptides exerting several roles as a hormone and as a neuropeptide. Its ubiquitous distribution in the hypothalamus and in the extrahypothalamic regions and its diverse pharmacological and physiological effects are all features of its dual functions. For this reason, TRH has been the subject of much research throughout the past 20 years, work that has examined the structure, function, distribution, and regulation of the tripeptide and it has been extensively reviewed elsewhere [O''Leary R., O''Connor B. Thyrotropin-releasing hormone. J Neurochem. 1995;65:953–963.; Nillni E., Sevarino K. The biology of pro-thyrotropin-releasing hormone-derived peptides. Endocrine Reviews, 1999;20:599–664.]. After a brief overview of its distribution, hypothalamic and extrahypothalamic functions, and receptors involved, this review discusses efforts devoted to support TRH role in cardiovascular regulation with a main focus on hypertension pathophysiology in experimental models and humans. [Copyright &y& Elsevier]

We have recently demonstrated that arterial PTHrP expression and cardiovascular responses to this protein are altered in SHR compared with normotensive animals, Wistar Kyoto (WKY) and Sprague-Dawley (SD) rats. To investigate whether the slightly, but significantly decreased, aortic PTHrP gene expression observed in SHR, compared to that of normotensive animals, may play a causative role in the maintenance of the elevated arterial blood pressure (ABP) of the SHR, we transfected a hepatic lobe with a PTHrP expression vector in a sense and antisense orientation. At 24 and 48 hours, sense pSV2neo-ECE induced a significant five-fold increase in PTHrP mRNA abundance with respect to antisense pSV2neo-ECE and vehicle. This increment in the PTHrP mRNA induced by the sense PTHrP expression vector was totally inhibited by the co-administration of the antisense PTHrP expression vector. At the same time, we observed a significant decrease of mean ABP (MABP) in SHR transfected with the sense pSV2neo-ECE to similar values as those obtained in the normotensive strain. Neither antisense PTHrP expression vector nor vehicle had any significant effect in any strain. Again, the effect of the sense PTHrP expression vector on MABP was blocked by the simultaneous treatment with the antisense PTHrP expression vector. At 48 hours, the hypotensive effect of the sense pSV2neo-ECE in SHR was reverted by the IV bolus injection of a specific competitive PTHrP receptor antagonist such as Nle8,18,Tyr34-bPTH(3–34)amide. We propose that a defect of this potent local vasodilator may contribute to the development and/or maintenance of arterial hypertension in SHR. This defect can be ameliorated by transfecting tissues with protein-exporting capabilities, such as the liver. Finally, our work adds additional data to a cumulative body of evidence suggesting that it might be possible to design an effective gene therapy to treat the common polygenic and multifactorial form of hypertension by increasing the activity of potent and physiological vasodilators. [ABSTRACT FROM AUTHOR]

Objective: Renin-angiotensin-aldosterone system component genes have been associated to essential hypertension. Thus, we studied the association of singe locus or multilocus interactions with young-onset essential hypertension. Setting and Design: This is a case-control study based on a population sample of adolescent at an inner city. Participants: We studied 54 adolescents with hypertension and 121 age-matched normotensives, recruited from a high-school student population of 934 interviewed individuals. Methods: Resting blood pressure was measured on three different days and normalized (Z-score) by sex and age. Genotypes of ACE (I/D) angiotensinogen (T174M and M235T), AT1R (A1166C), and CYP11B2 (C-344T) were determined by PCR/RFLP or ASO. Results: Although genotype frequencies were not different in both groups, we found a significant dominant effect of ACE D and angiotensinogen 235T alleles on normalized systolic arterial blood pressure in males. This effect was confirmed by sib-pair linkage analysis taking normalized blood pressure as a quantitative trait. We independently analyzed multilocus interactions in normotensive and hypertensive adolescents searching for multiple locus deviation from Hardy-Weinberg or linkage equilibrium. We found that from 63 multilocus combinations, 4 deviated significantly from equilibrium in hypertensive adolescents but none in the normotensives. Deviations from equilibrium may indicate that the combination of alleles at different loci affects susceptibility or resistance to the disease. Conclusion: In addition to the angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) gene variants, gene-gene interactions may be important causative factors in a complex disease such as young-onset essential hypertension. [ABSTRACT FROM AUTHOR]

Water pollution by heavy metals represents a serious problem around the world. Among various treatment techniques for water remediation, adsorption is an effective and versatile method due to the low cost, effectiveness and simplicity. Chitosan is a cationic polysaccharide with an excellent adsorption capacity of heavy metal ions. Chitosan has a high molybdate adsorption capacity (265 ± 1 mg g −1 ) at 20 °C and pH 2.7. Participation of hydroxyl groups in the adsorption of molybdate anions was confirmed by FT-IR analysis. SEM images showed that morphological surface changes happen after Mo VI adsorption. Continuous adsorption data were best fitted by Modified Dose- Response model. Scale-up of continuous processes was achieved applying bed depth service time (BDST) model. Application of chitosan in molybdate removal from real groundwater samples suggest that this polysaccharide is a good option to be used for household purposes. [ABSTRACT FROM AUTHOR]

Hypothyroidism exerts deleterious effects on immunity, but the precise role of the hypothalamic–pituitary–thyroid (HPT) axis in immunoregulatory and tolerogenic programs is barely understood. Here, we investigated the mechanisms underlying hypothyroid‐related immunosuppression by examining the regulatory role of components of the HPT axis. We first analyzed lymphocyte activity in mice overexpressing the TRH gene (Tg‐Trh). T cells from Tg‐Trh showed increased proliferation than wild‐type (WT) euthyroid mice in response to polyclonal activation. The release of Th1 pro‐inflammatory cytokines was also increased in Tg‐Trh and TSH levels correlated with T‐cell proliferation. To gain further mechanistic insights into hypothyroidism‐related immunosuppression, we evaluated T‐cell subpopulations in lymphoid tissues of hypothyroid and control mice. No differences were observed in CD3/CD19 or CD4/CD8 ratios between these strains. However, the frequency of regulatory T cells (Tregs) was significantly increased in hypothyroid mice, and not in Tg‐Trh mice. Accordingly, in vitro Tregs differentiation was more pronounced in naïve T cells isolated from hypothyroid mice. Since Tregs overexpress galectin‐1 (Gal‐1) and mice lacking this lectin (Lgals1−/−) show reduced Treg function, we investigated the involvement of this immunoregulatory lectin in the control of Tregs in settings of hypothyroidism. Increased T lymphocyte reactivity and reduced frequency of Tregs were found in hypothyroid Lgals1−/− mice when compared to hypothyroid WT animals. This effect was rescued by the addition of recombinant Gal‐1. Finally, increased expression of Gal‐1 was found in Tregs purified from hypothyroid WT mice compared with their euthyroid counterpart. Thus, a substantial increase in the frequency and activity of Gal‐1‐expressing Tregs underlies immunosuppression associated with hypothyroid conditions, with critical implications in immunopathology, metabolic disorders, and cancer. [ABSTRACT FROM AUTHOR]

Selective oxidation of galacturonic acid residues of apple pectin by CrVI affords CO2/HCO2H, oxidized pectin, and CrIII as final redox products. The reaction shows first-order kinetics in [pectin], [CrVI], and [H+], at fixed ionic strength and temperature. Kinetic studies show that the redox reaction proceeds through a mechanism combining CrVI → CrIV → CrII and CrVI → CrIV → CrIII pathways. The mechanism is supported by the observation of free radicals, CrO22+ (the formation of which implies involvement of CrII and CrIV) and CrV (formed in monoelectronic redox processes) as reaction intermediates. The reduction of CrIV and CrV by pectin was independently studied and found to occur more than 103 times faster than pectin + CrVI reaction, in acid medium. At pH 3–5, apple pectin + CrVI redox reaction is slow, oxo-chromate(V)–pectin species stabilize and remain in solution during several hours. The present results show that these abundant and ubiquitous components of the cell walls of all land plants are able to reduce CrIV–VI or stabilize high-valent chromium depending on pH. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Losartan, a dose of 25 mg/day, has been found to be effective in 50% of patients with portal hypertension without adverse effects. We evaluated the relationship between genetic polymorphisms of the renin-angiotensin system (A1166C angiotensin II type 1 receptor (AT1R), angiotensinogen T174M and M235T, and angiotensin-converting enzyme I/D) and the effects of losartan on portal and systemic hemodynamic in patients with cirrhosis and portal hypertension.METHODS: We performed a longitudinal study that included 23 consecutive patients with cirrhosis and esophageal varices who received 25 mg/day of losartan during 12 wk. Hepatic venous pressure gradient (HVPG) and systemic hemodynamic were measured at baseline and after treatment. Genomic DNA was extracted from peripheral blood leukocytes; genetic polymorphisms of the renin-angiotensin system were investigated by polymerase chain reaction and restriction fragment length polymorphisms.RESULTS: The homozygous patients for AT1R A allele showed higher pulmonary-wedged and free hepatic venous pressure on baseline. After treatment, they showed a higher decrease of HVPG (32.5%± 19.2) in comparison with patients with AC/CC genotype (2.4%±18.9),p<0.01. Ten of 15 patients with AA genotype were responders, while only one of eight with AC/CC genotype (p<0.002); genotype AA showed a positive predictive value of 66.6% and negative predictive value of 87.5%.CONCLUSIONS: These results suggest that there is a relationship between the AT1R A1166C polymorphisms and the therapeutic response to losartan. The genetic testing may be used as a predictive factor of this response.(Am J Gastroenterol 2005;100:636–642) [ABSTRACT FROM AUTHOR]

Thyrotropin-releasing hormone (TRH) hyperactivity has been observed in the left ventricle of spon-taneously hypertensive rats. Its long-term inhibition suppresses the development of hypertrophy, specifically preventing fibrosis. The presence of diverse systemic abnormalities in spontaneously hyper-tensive rat hearts has raised the question of whether specific TRH overexpression might be capable of inducing structural changes in favor of the hypertrophic phenotype in normal rat hearts. We pro-duced TRH overexpression in normal rats by injecting into their left ventricular wall a plasmid driving expression of the preproTRH gene (PCMV-TRH). TRH content and expression of preproTRH, collagen type III, brain natriuretic peptide, ß-myosin heavy chain, Bax-to-Bcl-2 ratio, and caspase-3 were measured. The overexpression ma-neuver was a success, as we found a significant increase in both tripeptide and preproTRH mRNA levels in the PCMV-TRH group compared with the control group. Immunohistochemical staining against TRH showed markedly positive brown signals only in the PCMV-TRH group. TRH overexpression induced a significant in-crease in fibrosis, evident in the increase of collagen type III expres-sion accompanied by a significant increase in extracellular matrix expansion. We found a significant increase in brain natriuretic peptide and ß-myosin heavy chain expression (recognized markers of hyper-trophy). Moreover, TRH overexpression induced a slight but signifi-cant increase in myocyte diameter, indicating the onset of cell hyper-trophy. We confirmed the data "in vitro" using primary cardiac cell cultures (fibroblasts and myocytes). In conclusion, these results show that a specific TRH increase in the left ventricle induced structural changes in the normal heart, thus making the cardiac TRH system a promising therapeutic target. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To explore whether DNA methylation of the mitochondrial transcription factor A (TFAM) promoter is associated with insulin resistance in a sample of adolescents with features of metabolic syndrome. Methods: The data and blood samples were collected from 122 adolescents out of a cross-sectional study of 934 high-school students. The population was divided into two groups: noninsulin resistance (NIR) and insulin resistance (IR). After bisulfite treatment of genomic DNA from peripheral leukocytes, we used methylation-specific polymerase chain reaction (PCR) to assess DNA methylation of three putative methylation target sites (CpG) in the TFAM promoter. Results: The ratio of the promoter methylated DNA/unmethylated DNA was 0.012±0.0009 (1.2% of alleles), and inversely correlated with the biochemical features of insulin resistance (plasma fasting insulin R: −0.26, p <0.004 and homeostasis model assessment (HOMA) index R: −0.27, p <0.002), and obesity (R: −0.27, p <0.002). Multiple regression analysis showed that the log-transformed HOMA index correlated with the status of promoter methylation of TFAM, independently of body mass index (BMI) Z score (β: −0.33±0.094, p =0.00094). Finally, the TFAM promoter methylated DNA/unmethylated DNA ratio was found to be significantly associated with insulin resistance as dichotomous variable (NIR n =45, 0.014±0.002 and IR n =77, 0.011±0.001, respectively, p <0.016). Conclusion: Our findings suggest a potential role of promoter TFAM methylation in the pathogenesis of insulin resistance in adolescents. [Copyright &y& Elsevier]

The neuropeptides arginine vasopressin (AVP) and oxytocin (OT) have been implicated in the genesis of hypertension due to deoxycorticosterone acetate (DOCA)-salt treatment of uninephrectomized rats. In this work, we studied if DOCA treatment of intact rats in doses arousing a salt appetite (a prehypertensive state), modulated mRNA for AVP and OT in the hypothalamus. Male Sprague-Dawley rats were offered both tap water and 3% NaCl in separate bottles and received vehicle or subcutaneous injections of 10 mg DOCA on alternate days for 7 days (4 injections) or 17 days (9 injections). They developed a preference for 3% NaCl solutions 24–48 h after treatment. Brain slices from rats killed on the 8th or 18th day were exposed to [sup 35] S-labeled probes encoding prepro-AVP mRNA or OT mRNA, respectively. Expression of these mRNAs was measured in the magnocellular and parvocellular divisions of the paraventricular nucleus (PVN) and magnocellular cells of the supraoptic nucleus (SON). No changes were obtained in neuropeptide mRNA levels in the parvocellular division of the PVN between control and the two groups of DOCA-treated rats. However, DOCA-treated animals presented an increased number of grains per cell for AVP mRNA in the magnocellular division of the PVN and in magnocellular cells of the SON, as shown by group mean comparisons and frequency histograms. No changes were detected for OT mRNA. In a second series of studies, control or DOCA-treated rats were offered 3% NaCl or water as the only choice. Animals drinking 3% NaCl showed increased AVP and OT mRNA levels, whether they received DOCA or not. However, AVP mRNA levels in both nuclei were higher in DOCA-treated rats drinking 3% NaCl than in controls drinking salt solution. In comparison, control and DOCA-treated rats drinking water showed lower levels of AVP mRNA. OT mRNA levels in the SON remained unchanged in the same groups. The results suggest that in the magnocellular cells of the PVN and SON, increments in AVP mRNA are obtained following increments in salt intake produced by either mineralocorticoid treatment or exclusive salt drinking. In rats offered salt solution and water to drink, DOCA effects on AVP mRNA developed before changes occurred in serum sodium levels. Because combined DOCA + salt treatment induced a higher response in terms of AVP mRNA expression, we suggest that AVP could be a target of the central effects of the mineralocorticoid. [ABSTRACT FROM AUTHOR]