Withanolides and related steroids

Since the isolation of the first withanolides in the mid-1960s, over 600 new members of this group of compounds have been described, with most from genera of the plant family Solanaceae. The basic structure of withaferin A, a C28 ergostane with a modified side chain forming a δ-lactone between carbons 22 and 26, was considered for many years the basic template for the withanolides. Nowadays, a considerable number of related structures are also considered part of the withanolide class; among them are those containing γ-lactones in the side chain that have come to be at least as common as the δ-lactones. The reduced versions (γ and δ-lactols) are also known. Further structural variations include modified skeletons (including C27 compounds), aromatic rings and additional rings, which may coexist in a single plant species. Seasonal and geographical variations have also been described in the concentration levels and types of withanolides that may occur, especially in the Jaborosa and Salpichroa genera, and biogenetic relationships among those withanolides may be inferred from the structural variations detected. Withania is the parent genus of the withanolides and a special section is devoted to the new structures isolated from species in this genus. Following this, all other new structures are grouped by structural types. Many withanolides have shown a variety of interesting biological activities ranging from antitumor, cytotoxic and potential cancer chemopreventive effects, to feeding deterrence for several insects as well as selective phytotoxicity towards monocotyledoneous and dicotyledoneous species. Trypanocidal, leishmanicidal, antibacterial, and antifungal activities have also been reported. A comprehensive description of the different activities and their significance has been included in this chapter. The final section is devoted to chemotaxonomic implications of withanolide distribution within the Solanaceae. Overall, this chapter covers the advances in the chemistry and biology of withanolides over the last 16 years.Fil: Misico, Rosana Isabel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); ArgentinaFil: Nicotra, V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Orgánica; ArgentinaFil: Oberti, Juan Carlos María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Orgánica; ArgentinaFil: Barboza, Gloria Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; ArgentinaFil: Gil, Roberto Ricardo. University Of Carnegie Mellon; Estados UnidosFil: Burton, Gerardo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); Argentin

Elevated plasma homocysteine levels in patients on isotretinoin therapy for cystic acne

Background The use of Isotretinoin (Iso) for cystic acne (CA) therapy includes marked side-effects such as dyslipidemia, increased liver enzymes, and reduction of biotinidase activity. Moreover, Homocysteine (Hcy), an amino acid, is metabolized in the liver requiring folate, vitamin B6, vitamin B12, and the activity of enzymes, i.e, cystathionine-beta -synthase. Increased blood levels of Hey are associated with premature occlusive vascular disease. Objective The aim of this study was the evaluation of Hey levels and the responsible vitamins for its metabolism in patients with CA on Iso treatment. Methods and Results Twenty-eight patients with CA were submitted to laboratory examinations before (Value 1) and after (Value 2) 45 days on Iso (0.5 mg/kg/24 h) therapy. Blood levels of Hey and vitamin B6 were evaluated by HPLC methods, and folate and vitamin B12 using a commercial Kit. Hey levels (Value 1 = 7.86 +/- 1.6 mu mol/L; Value 2 = 13.65 +/- 3.3 mu mol/L; P< 0.001) were statistically significantly increased in patients on treatment. Vitamins were unaltered, and lipids and liver enzymes increased. Significant correlation between Hey levels, vitamins, and liver enzymes was found. Methionine loading tests performed in nine patient-volunteers showed an abnormal response post-treatment. Conclusions It is suggested that the elevated Hcy levels in patients after 45 days on Iso therapy could be due either to the ‘inhibition’ of cystathionine-<beta>-synthase by the drug and/or their liver dysfunction. Daily vitamin supplementation along with frequent evaluations of Hey blood levels are recommended for the prevention of a premature occlusive vascular disease

In vivo effects of high phenylalanine blood levels on Na+,K+-ATPase, Mg2+-ATPase activities and biogenic amine concentrations in phenylketonuria

Objective: To evaluate the activities of Na+,K+-ATPase and Mg2+-ATPase in erythrocyte membranes from phenylketonuric (PKU) patients and to correlate the enzyme activities with their blood phenylalanine (Phe) levels, biogenic amines as well as with their precursors tyrosine (Tyr) and tryptophan (Try). Design and methods: Twenty three PKU patients were divided into group A (n = 12) on a stricted diet (Phe 1.57 +/- 0.52 mg/dL or 0. 10 +/- 0.03 mM) and group B (n = 11) on a “loose” diet (Phe 24.45 +/- 1.50 mg/dL or 1.72 +/- 0.09 mM). The enzyme activities were measured spectrophotometrically, the amino acids with an automatic amino analyser and the biogenic amines with HPLC methods. Results: In group B, plasma amino acids (Tyr, Try), their biogenic amines [adrenaline (A), noradrenaline (NA), dopamine (DA) and serotonin (5HT)], (Na+,K+)-ATPase and Mg2+-ATPase activities were found remarkably decreased (p < 0.001). Conclusions: High Phe and/or low NA, DA, 5HT plasma levels may indirectly inhibit the erythrocyte membrane Na+,K+-ATPase and Mg2+ -ATPase in PKU patients. The observed enzyme inhibitions could be a very informative peripheral marker as regards the neurotoxic Phe brain effects. (C) 2002 The Canadian Society of Clinical Chemists. All rights reserved

Reduced acetylcholinesterase activity in erythrocyte membranes from patients with phenylketonuria

Objective: a) To evaluate acetylcholinesterase (AChE) activities in erythrocyte membranes from phenylketonuric (PKU) patients and controls and to correlate with their plasma phenylalanine (Phe), tyrosine (Tyr), alanine (Ala) and dopamine (DA) levels. b) To determine the in vitro effects of Phe, Ala and Phe plus Ala on their AChE activities. Design and Methods: AChE activities were determined spectrophotometrically in erythrocyte membranes from PKU children (n = 12) adhering to their diet (group A), from 11 “off diet” (group 13) and from 23 controls. Their plasma amino acids were evaluated with an amino acid analyser and DA with an HPLC method. Ala (1.8 mM) and/or Phe (1.8 mM). were added in the enzyme incubation medium from controls, whereas only Ala was added in that from group B. Results: AChE activity (1.19 +/- 0.05. Delta(OD) over bar /min X mg protein), Tyr (46 +/- 17 mumol/L) and DA (56 +/- 18 mumol/L) were remarkably 9 decreased by about 60% in group B as compared to those of group A (3.01 +/- 0.18 Delta(OD) over bar /min) mg protein, 115 +/-39 mumol/ L, 137 +/- 29 mumol/L, respectively, p <.0.001) and controls (3.13 +/- 0.16 Delta(OD) over bar /min X mg protein, 117 +/- 44 mumol/Ll 142 +/- 22 mumol/L, respectively, p < 0.001). Phe negatively correlated with AChE activity and positively with plasma Tyr and DA. Ala reversed the inhibited AChE by Phe in erythrocyte membranes from healthy children to control values, whereas no reverse effect was observed on the enzyme activity from PKU patients. Conclusions: a). The low levels of DA and its precursor Tyr are due to the high Phe blood levels, as a consequence of the decreased activity of Phe-hydroxylase in the liver of our patients. So, high Phe blood levels. inhibit AChE in PKU patients, probably resulting in higher acetylcholine concentrations. b) Determination of AChE in erythrocyte membranes from PKU could be a useful marker for the neurotoxic effects of Phe. (C) 2002 The Canadian Society of Clinical Chemists. All rights reserved

Morning preprandial plasma ghrelin and catecholamine concentrations in patients with phenylketonuria and normal controls: Evidence for catecholamine-mediated ghrelin regulation

Patients with phenylketonuria (PKU) have a diet-controlled deficiency in the conversion of phenylalanine (Phe) to tyrosine (Tyr), leading to decreased production of noradrenaline, adrenaline, and dopamine. Poor diet control results in high plasma Phe and low plasma Tyr and catecholamine concentrations. Ghrelin, a recently described gastrointestinal hormone that is elevated in the fasting state and low in the fed state, is considered a major appetite-stimulating hormone, possibly involved in the generation of obesity and insulin resistance. We evaluated morning preprandial plasma ghrelin levels in 14 diet-controlled and 15 poorly controlled PKU patients and 20 age- and body mass index (BMI)-matched healthy children ( controls) and correlated its concentrations with those of Phe and catecholamines as well as with their BMI and 24-h nutrient intake. Plasma ghrelin levels were measured by RIA, plasma catecholamine concentrations were determined by HPLC with electrochemical detection, and Phe and Tyr levels were measured in an amino acid analyzer. The ghrelin concentration ( 744 +/- 25 ng/liter) in diet-controlled patients did not differ from that in controls ( 802 +/- 26 ng/liter; P > 0.05). On the contrary, the ghrelin concentration was significantly reduced in poorly controlled patients ( 353 +/- 23 ng/liter; P < 0.0001). Ghrelin correlated negatively with Phe in all three groups, whereas it correlated positively with catecholamine levels and energy intake and negatively with BMI only in diet-controlled patients and controls. We conclude that ghrelin secretion may receive positive direct or indirect input from catecholamines. The absence of a correlation between ghrelin and catecholamines, energy intake, or BMI in PKU patients on an inadequate diet may be due to dysregulation of their neuroendocrine system and might be affected by high Phe levels in the stomach and/or central nervous system

Maternal-neonatal retinol and alpha-tocopherol serum concentrations in Greeks and Albanians

Background: Vitamin A and E are required in physiological processes such as pregnancy and growth. Aim: To evaluate retinol and alpha-tocopherol serum levels in Greek and Albanian mothers and in their newborns. Methods: Data concerned 1125 Greek and 898 Albanian mothers along with their newborns. Immediately after delivery, blood from the umbilical cord and from the mothers was collected into light-protected tubes. Retinol and alpha-tocopherol serum levels were measured with a reversed-phase HPLC method. A 60-d dietetic diary was kept by each woman during the last 2 mo of pregnancy. Results: Retinol (1.3 +/- 0.1 mumol/l) and alpha-tocopherol (32.9 +/- 9.5 mumol/l) levels were estimated to be normal in Greek mothers and in most of their offspring (0.9 +/- 0.1 and 18.5 +/- 3.4 mumol/l, respectively). In contrast, in Albanian mothers, retinol concentration was found to be low (0.6 +/- 0.1 mumol/l), and in 1/3 significantly low (<0.45 mu mol/l). Consequently, the vitamin was evaluated to be very low in their newborns (0.4 +/- 0.1 mu mol/l), and in 1/2 extremely low. However, in 12% of the Albanian cord blood samples, retinol level was determined to be higher as compared with that of their mothers. alpha-Tocopherol was evaluated to be normal in most of the immigrant mothers (20.0 +/- 8.8 mu mol/l) and low (<7.5 mumol/l) in 15% of their newborns. Vitamin A intake was found to be extremely low and vitamin E low (p < 0.05) in the Albanians. Conclusions: (a) The decreased vitamin A and vitamin E intake, and their low blood status in the Albanian mothers and in their newborns, could be due to their low socio-economic and nutritional status. (b) Immigrant Albanians, during their pregnancy, and their newborns should be “followed up”, being at risk of developing symptoms from the very low levels of these lipid-soluble vitamins