Curcumin dietary supplementation ameliorates disease phenotype in an animal model of Huntington's disease.

Huntington's disease (HD) has traditionally been described as a disorder purely of the brain; however, evidence indicates that peripheral abnormalities are also commonly seen. Among others, severe unintended body weight loss represents a prevalent and often debilitating feature of HD pathology, with no therapies available. It correlates with disease progression and significantly affects the quality of life of HD patients. Curcumin, a naturally occurring polyphenol with multiple therapeutic properties, has been validated to exert important beneficial effects under health conditions as well as in different pathological settings, including neurodegenerative and gastrointestinal (GI) disorders. Here, we investigated the potential therapeutic action that curcumin-supplemented diet may exert on central and peripheral dysfunctions in R6/2 mice, a well-characterized HD animal model which recapitulates some features of human pathology. Maintenance of normal motor function, protection from neuropathology and from GI dysfunction and preservation of GI emptying and conserved intestinal contractility, proved the beneficial role of life-long dietary curcumin in HD and corroborated the potential of the compound to be exploited to alleviate very debilitating symptoms associated with the disease.

High cysteine levels in renal transplant recipients: relationship with hyperhomocysteinemia and 5,10-MTHFR polymorphism.

BACKGROUND: Long-term survival of renal transplant recipients seems to be influenced by the occurrence of thromboembolic complications and cardiovascular disease. Preliminary data available in the literature found high levels of cysteine (Cy) as a risk factor for deep venous thrombosis independently of high homocysteine (tHcy) levels, but no data are available about Cy levels in renal transplant recipients. METHODS: To investigate Cy, tHcy, and plasminogen activator inhibitor-1 (PAI-1) levels and the prevalence of 5,10-methylenetetrahydrofolate reductase (MTHFR) in renal transplantation, we studied 70 stable renal transplant recipients and 66 age- and sex-matched normal subjects as controls. RESULTS: Cy, tHcy, and PAI-1 levels were significantly higher in renal transplant recipients with respect to controls (Cy: 254 micromol/L [117-466] vs. 198 micromol/L [99-331], P<0.001; tHcy: 17.0 micromol/L [4.0-68] vs. 8.1 micromol/L [2.0-24.0], P<0.00001; PAI-1: 16.8 IU/ml [5.1-45.5] vs. 7.9 IU/ml [4.0-18.0], P<0.00001). High Cy levels were detected in 35.8% of patients. Hyperhomocysteinemia, both in the fasting state and postmethionine loading test, was diagnosed in 90% of cases. The odds ratios for Cy and tHcy levels within the fourth quartile with respect to the other quartiles were markedly increased in renal transplant recipients even after adjustment for prevalent cardiovascular risk factors, glomerular filtration rate, tHcy and, Cy, respectively (Cy: 29.0 micromol/L [95% CI 7.0-111]; tHcy: 29.9 micromol/L [95% CI 7.5-118.1]). Fasting tHcy levels correlated well with PAI-1 (r=0.65; P<0.0001) but not with Cy levels (r=0.10; P=0.4). The prevalence of the MTHFR 677TT genotype in renal transplant recipients was not significantly higher in patients than in controls (mutant allele frequency: 0.48 in patients and 0.47 in controls) and was associated with significantly higher fasting and postmethionine tHcy levels both in controls and patients. After 2 months of vitamin supplementation, tHcy (Pre: 17.0 micromol/L [4.0-68]; Post: 7.5 micromol/L [2.3-21.9]; P<0.0001) and PAI-1 levels (Pre: 16.8 IU/ml [5.1-45.5]; Post: 10 IU/ml [2.0-25]; P<0.001) were significantly decreased, whereas Cy levels showed a small decrease that did not reach statistical significance (Pre: 254 micromol/L [117-466]; Post: 209 micromol/L [168-300]; P=0.3). Patients with the MTHFR 677TT genotype had the major percentage of decrease of tHcy levels with respect to the other genotypes. CONCLUSION: In conclusion, this study demonstrates the presence of elevated Cy plasma levels in renal transplant recipients. Vitamin supplementation reduces tHcy but not Cy levels, and the amount of decrease seems to be influenced by the MTHFR genotype.

Hyperhomocysteinemia in renal transplant patients: an independent factor of cardiovascular disease.

Hyperhomocysteinemia (Hcy) is an independent factor of cardiovascular disease, which is the main cause of morbidity and mortality both in uremic and kidney transplant patients. The aim of the study was to determine Hcy, plasminogen activator inhibitor (PAI-1) and lipoprotein (a) (Lp(a)) serum levels in 70 patients with a well functioning renal transplant. We also verified whether these levels were modified by a multivitamin therapy. The genetic polymorphism of the methylenetetrahydrofolate reductase (MTHFR) enzyme which plays a main role in Hcy metabolism, was studied as well. We found Hcy, PAI-1 and Lp(a) levels significantly elevated with respect to healthy control subjects. The thermolabile form of the MTHFR enzyme was linked to higher Hcy levels. After a short time on therapy with B6, B12 and folic acid vitamins, Hcy and PAI-1 decreased to normal levels. The authors conclude that high Hcy levels could be a relevant covariate for cardiovascular disease in transplant patients and they suggest that vitamin supplementation be recommended as a part of therapy.

Synthesis and anti-HIV activity of alpha-thiophenoxy-hydroxyethylamide derivatives.

A series of new anti-HIV derivatives containing a novel alpha-thiophenoxyhydroxyethylamide core have been synthesized, using S-phenylbenzenethiosulfonate as the thiosulfenylating reagent. Some of the new synthesized compounds (1a, 1c, 1g, 1i, 1j and 1l) inhibited HIV replication in cell culture assays (syncytia formation) with effective concentrations (EC(50)) ranging from 0.1-1 microM. Incorporation of thiophenoxy substitution within various pseudomimetic peptide backbones provided a series of highly potent HIV inhibitors.

Developmental maturation of baboon placental trophoblast: expression of messenger ribonucleic acid and protein levels of cytosolic and secretory phospholipases A2.

Although the human placenta at term exhibits high levels of phospholipase A2 (PLA2) enzyme activity, our understanding of the ontogenesis, regulation, and specific roles of placental phospholipases A2 remains relatively incomplete. Using the baboon as the experimental model, the present study determined whether the levels of the messenger ribonucleic acid (mRNA) for the cytosolic (cPLA2) and/or type IIa, nonpancreatic secretory (sPLA2) enzymes are developmentally regulated and modulated by glucocorticoid treatment. Total RNA was extracted from whole villous placenta obtained on days 60 (early; n = 3), 100 (mid; n = 3), and 165 (late; n = 4) of gestation (term = day 184) from untreated baboons and on day 100 (n = 4) after maternal administration on days 60-99 of betamethasone (3 mg/day). The complementary DNA to cPLA2 recognized a single 2.9-kb mRNA transcript in both baboon and human placenta. Mean (+/-SE) levels of cPLA2 mRNA, expressed, in arbitrary units as a ratio to that of beta-actin, were similar at early (0.19 +/- 0.05) and midgestation (0.34 +/- 0.17) and increased (P < 0.005) 10-fold (2.53 +/- 0.53) by late gestation. Levels of cPLA2 protein were also greater (P < 0.05) on day 165 (2.6 +/- 0.3 arbitrary units) than on day 60 (0.6 +/- 0.2). Like that in the human, the baboon placenta contained very high levels of a single 0.9-kb mRNA transcript for sPLA2. In contrast to that of cPLA2, normalized levels of sPLA2 mRNA were similar at all three time points and were associated with high levels of sPLA2 protein throughout gestation. Treatment with betamethasone increased (P < 0.02) cPLA2 mRNA levels on day 100 by over 4-fold, but had no effect on sPLA2 mRNA levels. Additional studies indicated that the mRNAs for sPLA2 and cPLA2 were detected in an enriched fraction of nontrophoblast cells isolated by collagenase dispersion and Percoll density centrifugation. The mRNA for cPLA2 was also expressed in cytotrophoblast and syncytiotrophoblast cell fractions. Collectively, these findings indicate that the baboon placenta expresses mRNA and protein for both the cytosolic and secretory PLA2 enzymes, and that expression of cPLA2 is developmentally regulated and modulated by glucocorticoids. We previously demonstrated an estrogen-dependent developmental increase in placental expression of specific components of the progesterone steroidogenic pathway during the second half of baboon pregnancy. The current findings indicate that the developmental increase in placental function also includes expression of at least one specific PLA2 enzyme controlling arachidonic acid mobilization and eicosanoid synthesis.

Hypothalamic corticotropin-releasing hormone expression in the baboon fetus at mid- and late gestation.

We have proposed that estrogen, via regulation of the placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) enzyme(s) catalyzing the oxidation of cortisol to its inactive metabolite cortisone, regulates the baboon fetal pituitary-adrenocortical axis and the onset of de novo production of cortisol by the fetus near term. In support of this hypothesis we have demonstrated that the increase in expression of the mRNA for the ACTH precursor proopiomelanocortin (POMC) in the fetal pituitary and in the specific activity of steroidogenic enzymes in the fetal adrenal normally observed at term were enhanced at midgestation by maternal estrogen administration. However, it is not known whether activation of the fetal pituitary reflects a concomitant increase in corticotropin-releasing hormone (CRH) mRNA expression and/or peptide production by the fetal hypothalamus. Therefore, an aim of the present study was to determine whether the increase in POMC mRNA in fetal baboons delivered at term, and at midgestation to mothers treated with estradiol, reflected an increase in hypothalamic CRH. Fetal hypothalami were obtained on Day 100 (n = 6) and Day 165 of gestation (term = Day 184) from untreated baboons (n = 5) and on Day 100 from baboons (n = 4) whose mother had been treated daily with 1.0 mg estradiol on Days 70 to 100. Hypothalamic CRH peptide concentrations were determined by RIA, and CRH mRNA expression was quantified by in situ hybridization in sections of the fetal hypothalamus through the paraventricular nucleus (PVN) using a 48-base synthetic oligodeoxynucleotide probe 3' end-labeled with [35S]dATP. The mean (+/- SE) maternal serum estradiol concentration in baboons treated with estradiol at midgestation (2.4 +/- 0.4 ng/ml) was greater (p < 0.05) than that in untreated baboons on Day 100 (1.0 +/- 0.2), but similar to that in late gestation (2.0 +/- 0.2). The mean steady-state concentration of CRH in the baboon fetal hypothalamus at midgestation (15.8 +/- 6.0 ng/g tissue) was not altered in fetuses whose mothers had been treated with estradiol (17.6 +/- 0.9 ng/g). Hypothalamic CRH concentrations in fetal baboons of late gestation (20.7 ng/g; n = 2) were also similar to mean CRH values measured at midgestation but, owing to the marked increase in weight of the fetal hypothalamus with advancing pregnancy, the content of hypothalamic CRH in late gestation (28.8 ng/structure) exceeded (p < 0.01) that at midgestation. Mean levels of CRH mRNA at midgestation when expressed per cell (17.4 +/- 1.3 grains per cell) or per unit area of PVN (375 +/- 20 grains per area) were similar to respective values in late gestation (18.3 +/- 1.1 grains per cell; 350 +/- 55 grains per area; n = 3 per group). These findings support the suggestion that the increase in fetal pituitary POMC mRNA expression and ACTH peptide previously reported to occur normally between midgestation and term are not associated with a concomitant increase in hypothalamic CRH peptide or CRH mRNA concentrations. Moreover, it would appear that by midgestation, hypothalamic CRH is available in adequate concentrations to "drive" the fetal pituitary and that it is the levels of maternal cortisol arriving within the fetal circulation, as dictated by estrogen-regulated placental 11 beta-HSD-oxidase activity, that establish the extent to which the fetal pituitary responds to CRH.