CiteULike: Group: Boydian_Society - library [312 articles]

Were inefficient mitochondrial haplogroups selected during radiations of modern humans? - a test using modular kinetic analysis of coupling in mitochondria from cybrid cell lines.

Taku Amo — 2007-03-25T01:43:04-00:00

Biochem J (13 March 2007)

We introduce a general test of the bioenergetic importance of mitochondrial DNA variants: modular kinetic analysis of oxidative phosphorylation in mitochondria from cybrid cells with constant nuclear DNA but different mitochondrial DNA. We apply this test to the hypothesis [Ruiz-Pesini, Mishmar, Brandon, Procaccio and Wallace (2004) Science 303, 223-226] that particular mitochondrial DNA haplogroups (specific combinations of polymorphisms) that cause lowered coupling efficiency, leading to generation of less ATP and more heat, were positively selected during radiations of modern humans into colder climates. Contrary to the predictions of this hypothesis, mitochondria from Arctic haplogroups had similar or even greater coupling efficiency than mitochondria from tropical haplogroups.

Calorie Restriction Increases Muscle Mitochondrial Biogenesis in Healthy Humans.

Anthony E Civitarese — 2007-03-25T01:58:02-00:00

PLoS Med, Vol. 4, No. 3. (6 March 2007)

BACKGROUND: Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood. METHODS AND FINDINGS: The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 +/- 1.0 y), overweight (body mass index, 27.8 +/- 0.7 kg/m(2)) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, -135 +/- 42 kcal/d, p = 0.002 and CREX, -117 +/- 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05). In parallel, mitochondrial DNA content increased by 35% +/- 5% in the CR group (p = 0.005) and 21% +/- 4% in the CREX group (p < 0.004), with no change in the control group (2% +/- 2%). However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid) cycle (citrate synthase), beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase), and electron transport chain (cytochrome C oxidase II) was unchanged. DNA damage was reduced from baseline in the CR (-0.56 +/- 0.11 arbitrary units, p = 0.003) and CREX (-0.45 +/- 0.12 arbitrary units, p = 0.011), but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling) induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR. CONCLUSIONS: The observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults.

Mitochondrial dysfunction in atherosclerosis.

NR Madamanchi — 2007-03-25T02:02:39-00:00

Circ Res, Vol. 100, No. 4. (2 March 2007), pp. 460-473.

Increased production of reactive oxygen species in mitochondria, accumulation of mitochondrial DNA damage, and progressive respiratory chain dysfunction are associated with atherosclerosis or cardiomyopathy in human investigations and animal models of oxidative stress. Moreover, major precursors of atherosclerosis-hypercholesterolemia, hyperglycemia, hypertriglyceridemia, and even the process of aging-all induce mitochondrial dysfunction. Chronic overproduction of mitochondrial reactive oxygen species leads to destruction of pancreatic beta-cells, increased oxidation of low-density lipoprotein and dysfunction of endothelial cells-factors that promote atherosclerosis. An additional mechanism by which impaired mitochondrial integrity predisposes to clinical manifestations of vascular diseases relates to vascular cell growth. Mitochondrial function is required for normal vascular cell growth and function. Mitochondrial dysfunction can result in apoptosis, favoring plaque rupture. Subclinical episodes of plaque rupture accelerate the progression of hemodynamically significant atherosclerotic lesions. Flow-limiting plaque rupture can result in myocardial infarction, stroke, and ischemic/reperfusion damage. Much of what is known on reactive oxygen species generation and modulation comes from studies in cultured cells and animal models. In this review, we have focused on linking this large body of literature to the clinical syndromes that predispose humans to atherosclerosis and its complications.

Introduction of an single nucleodite polymorphism-based "Major Y-chromosome haplogroup typing kit" suitable for predicting the geographical origin of male lineages.

M Brión — 2006-02-20T04:54:56-00:00

Electrophoresis, Vol. 26, No. 23. (December 2005), pp. 4411-4420.

The European Consortium "High-throughput analysis of single nucleotide polymorphisms for the forensic identification of persons--SNPforID", has performed a selection of candidate Y-chromosome single nucleotide polymorphisms (SNPs) for making inferences on the geographic origin of an unknown sample. From more than 200 SNPs compiled in the phylogenetic tree published by the Y-Chromosome Consortium, and looking at the population studies previously published, a package of 29 SNPs has been selected for the identification of major population haplogroups. A "Major Y-chromosome haplogroup typing kit" has been developed, which allows the multiplex amplification of all 29 SNPs in a single reaction. Allele genotyping was performed with a single base extension reaction (minisequencing) detected by CE. The validation of the multiplex was performed in a total of 1126 unrelated males distributed among 12 worldwide populations. The approach takes advantage of the specific geographic distribution of the Y-chromosome haplogroups and demonstrates the utility of binary polymorphisms to infer the origin of a male lineage.

The Interleukin-6 inflammation pathway from cholesterol to aging - Role of statins, bisphosphonates and plant polyphenols in aging and age-related diseases

Sota Omoigui — 2007-03-24T18:36:44-00:00

Immunity & Ageing, Vol. 4 (20 March 2007), 1.

The study of tasters and non-tasters of phenyl-thio-carbamide (PTC) and its relation to blood groups.

RS Bhatkar — 2007-03-05T18:51:05-00:00

Indian J Physiol Pharmacol, Vol. 33, No. 3. (p 1989), pp. 168-170.

The ability to taste phenyl-thio-Carbamide (PTC) is one of the gene marker systems which provides one of the means to reconstruct relationships of ethnic groups of man. In 433 Maharashtrian subjects the ability to taste PTC was studied by Harris and Kalmus method. At the same time, blood groups of these subjects were determined by slide agglutination method. It was found that 63.74% of local population was taster and 36.26% non-taster. The percentage of non-tasters was higher in males, than in females. No significant relation was found between the ability to taste PTC and the blood groups. The results were compared with those observed by other workers and it was found that the percentage of non-tasters in local population in the present study was similar to that found in Indian elsewhere.

Relation of PTC responses and secretor status to blood groups.

S Bhatia — 2007-03-05T18:48:55-00:00

Indian J Physiol Pharmacol, Vol. 23, No. 4. (c 1979), pp. 269-276.

Blood groups (ABO, Rh-including sub-types M-N, Duffy), secretor status and ability to taste Phenylthiocarbamide (PTC) were investigated in 102 medical students of Delhi University, and the distribution was found similar to that observed in the north Indians. Both faster and secretors had highest percentage in AB, O and in rr, while the lowest values were obtained in B and R1r.

Lewis blood group phenotype as an independent risk factor for coronary heart disease (the NHLBI Family Heart Study).

RC Ellison — 2007-03-05T13:48:58-00:00

Am J Cardiol, Vol. 83, No. 3. (1 February 1999), pp. 345-348.

In the Copenhagen Male Study, men with Lewis blood group phenotype Le(a-b-) were found to have increased risk for coronary heart disease (CHD); such a relation has not been confirmed in men, and has not been evaluated in women. In the NHLBI Family Heart Study, we determined the Lewis blood type of 1,620 white subjects (790 male and 830 female subjects). The Lewis(a-b-) phenotype was found in 142 subjects (8.8%), 6.3% of subjects from randomly chosen families and 9.7% of subjects from families found to be at high risk for CHD. A history of CHD was present in 39.1% of men with Le(a-b-) versus 27.2% of men with other Lewis types; for women, the corresponding numbers were 12.3% versus 9.4%, respectively. In multivariate analysis, adjusting for age, sex, and risk group, the odds ratio for CHD was 2.0 (95% confidence interval = 1.2 to 3.1) for Le(a-b-) versus other Lewis groups. Mean values for body mass index, blood pressure, total cholesterol, low-density lipoprotein and high-density lipoprotein cholesterol, glucose, insulin, homocysteine, and fibrinogen were not significantly different between Le(a-b-) subjects and others, but triglycerides (p = 0.002) were higher in the Le(a-b-) subjects. However, inclusion of all risk factors in multivariate analysis did not diminish the increased risk for CHD associated with the Le(a-b-) phenotype. We conclude that the Le(a-b-) phenotype is associated with an increased risk for CHD; its effect does not appear to act predominantly through conventional cardiovascular risk factors. At present, mechanisms of effect are unknown.

Genetic markers in coronary heart disease.

NS Kassem — 2007-03-05T13:46:26-00:00

J Egypt Public Health Assoc, Vol. 69, No. 5-6. (1994), pp. 359-378.

Coronary heart disease (CHD) was found to aggregate in families. So the present study aimed at studying certain genetic markers (lipoproteins, ABO blood groups and dermatoglyphics), in a group of 60 patients with CHD and a control group to detect any significant association between such genetics markers in this disorder. This can throw light on its genetics. The study revealed significant and marked association of CHD with low alpha-lipoprotein, high pre-beta and beta-lipoproteins. No significant association wa detected with ABO phenotypes. Definite significant association was also detected between CHD and certain dermatoglyphics phenotypes including FTP, T-D count and palm patterns. These significant associations of CHD and these genetic markers "which are genetically determined" denoted strongly genetic etiology or at least genetic predisposition of CHD. Detection of such genetic markers may help in determination of risky individuals in population and families of CHD patients. This can help in prevention by proper genetic counseling.

The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer

Weihua Zhou — 2007-02-22T17:11:13-00:00

Nutrition & Metabolism, Vol. 4, No. 1. (2007)

BACKGROUND:Malignant brain cancer persists as a major disease of morbidity and mortality in adults and is the second leading cause of cancer death in children. Many current therapies for malignant brain tumors fail to provide long-term management because they ineffectively target tumor cells while negatively impacting the health and vitality of normal brain cells. In contrast to brain tumor cells, which lack metabolic flexibility and are largely dependent on glucose for growth and survival, normal brain cells can metabolize both glucose and ketone bodies for energy. This study evaluated the efficacy of KetoCal(R), a new nutritionally balanced high fat/low carbohydrate ketogenic diet for children with epilepsy, on the growth and vascularity of a malignant mouse astrocytoma (CT-2A) and a human malignant glioma (U87-MG). METHODS:Adult mice were implanted orthotopically with the malignant brain tumors and KetoCal(R) was administered to the mice in either unrestricted amounts or in restricted amounts to reduce total caloric intake according to the manufacturers recommendation for children with refractory epilepsy. The effects KetoCal(R) on tumor growth, vascularity, and mouse survival were compared with that of an unrestricted high carbohydrate standard diet.RESULTS:KetoCal(R) administered in restricted amounts significantly decreased the intracerebral growth of the CT-2A and U87-MG tumors by about 65% and 35%, respectively, and significantly enhanced health and survival relative to that of the control groups receiving the standard low fat/high carbohydrate diet. The restricted KetoCal(R) diet reduced plasma glucose levels while elevating plasma ketone body (beta-hydroxybutyrate) levels. Tumor microvessel density was less in the calorically restricted KetoCal(R) groups than in the calorically unrestricted control groups. Moreover, gene expression for the mitochondrial enzymes, beta-hydroxybutyrate dehydrogenase and succinyl-CoA: 3-ketoacid CoA transferase, was lower in the tumors than in the contralateral normal brain suggesting that these brain tumors have reduced ability to metabolize ketone bodies for energy. CONCLUSIONS:The results indicate that KetoCal(R) has anti-tumor and anti-angiogenic effects in experimental mouse and human brain tumors when administered in restricted amounts. The therapeutic effect of KetoCal(R) for brain cancer management was due largely to the reduction of total caloric content, which reduced circulating glucose required for rapid tumor growth. A dependency on glucose for energy together with defects in ketone body metabolism largely account for why the brain tumors grow minimally on either a ketogenic-restricted diet or on a standard-restricted diet. Genes for ketone body metabolism should be useful for screening brain tumors that could be targeted with calorically restricted high fat/low carbohydrate ketogenic diets. This preclinical study indicates that restricted KetoCal(R) is a safe and effective diet therapy and should be considered as an alternative therapeutic option for malignant brain cancer.

A mitochondria-k(+) channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth.

S Bonnet — 2007-01-22T13:17:37-00:00

Cancer Cell, Vol. 11, No. 1. (January 2007), pp. 37-51.

The unique metabolic profile of cancer (aerobic glycolysis) might confer apoptosis resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential (DeltaPsim) and low expression of the K(+) channel Kv1.5, both contributing to apoptosis resistance. Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases DeltaPsim, increases mitochondrial H(2)O(2), and activates Kv channels in all cancer, but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a promising selective anticancer agent.

Lewis and Secretor gene effects on Lewis antigen and postnatal development of Lewis blood type.

S Ameno — 2006-11-24T21:41:32-00:00

Biol Neonate, Vol. 79, No. 2. (February 2001), pp. 91-96.

Lewis (Le) and Secretor (Se) gene effects on postnatal change in Lewis antigens are described based on the quantitative analysis of Lewis antigens in blood. Genuine Lewis blood types were determined by Le and Se genotyping in DNA samples obtained from umbilical cord blood and infant blood. Lewis(a) (Le(a)) and Lewis(b) (Le(b)) antigen levels were measured by a time-resolved fluoroimmunoassay. We found that Lewis phenotypes in infants over 9 months of age agreed with the genuine types. In cord blood, the dosage effect of the Se gene on antigen levels was observed, but the Le gene effect was not observed. Both Se and Le gene effects were observed in newborn babies' blood 3-6 days after birth.

Agrarian diet and diseases of affluence – Do evolutionary novel dietary lectins cause leptin resistance?

Tommy Jönsson — 2006-06-06T16:27:07-00:00

BMC Endocrine Disorders, Vol. 5 (10 December 2005), 10.

Norovirus binds to blood group A-like antigens in oyster gastrointestinal cells

Tian — 2006-11-09T07:13:02-00:00

Letters in Applied Microbiology, Vol. 43, No. 6. (December 2006), pp. 645-651.

Expression of the histo-blood group B gene predominates in AB-genotype cells

Twu — 2006-10-26T10:45:32-00:00

Transfusion, Vol. 46, No. 11. (November 2006), pp. 1988-1996.

Deficiency of coenzyme Q in gingiva of patients with periodontal disease.

R Nakamura — 2006-11-06T18:28:45-00:00

Int J Vitam Nutr Res, Vol. 43, No. 1. (1973), pp. 84-92.

Coenzyme Q10: blood levels and metabolic demand.

GP Littarru — 2006-11-06T18:27:28-00:00

Int J Tissue React, Vol. 12, No. 3. (1990), pp. 145-148.

Blood levels of CoQ10 were found to be lower in patients affected by hyperthyroidism and in athletes during a severe training period. In patients who had received a kidney transplant decreasing CoQ10 levels were found, during the first 30 min after transplant, in the blood leaving the newly transplanted organ. No decrease was detectable in patients who had received the kidney from a sibling. It may reasonably be hypothesized that the ischaemia/reperfusion damage is responsible for a certain degree of impoverishment of CoQ10, leading to a CoQ10 uptake from perfusing blood. A comparable trend was also evident in liver transplants. Low CoQ10 plasma levels may therefore reflect increased metabolic needs from various tissues, on the basis of increased overall metabolic rate and/or peroxidative damage.

Metabolic implications of coenzyme Q10 in red blood cells and plasma lipoproteins.

GP Littarru — 2006-11-06T18:26:40-00:00

Mol Aspects Med, Vol. 15 Suppl (1994)

Plasma coenzyme Q10 (CoQ10) is currently assayed in our laboratory for its well-known diagnostic meaning; in fact plasma CoQ10 levels are inversely related to metabolic demand. Definite levels of CoQ10 are also found in white and red blood cell components, as well as in platelets. Plasma and erythrocyte CoQ10 has a well assessed antioxidant role, which was demonstrated through a series of experiments. Erythrocytes previously enriched with exogenous CoQ10 were found more resistant to a hemolysis induced by a free radical initiator. Several enzymatic activities of erythrocyte ghosts were also protected by different side chain CoQ homologues, both when reduced and, although at a lesser extent, in the oxidized state. CoQ was not effective in preventing metal-catalyzed oxidation of erythrocyte membrane enzymes, and this effect is likely to be due to lack of interaction of CoQ with the metal target. Moreover CoQ was able to protect isolated enzymes and erythrocyte membrane bound enzymes from the inactivating effect of free radicals generated by water sonolysis or radiolysis. As far as plasma lipoproteins are concerned it is well known that LDL isolated from healthy volunteers supplemented with CoQ10 are more resistant to peroxidation induced by an azoinitiator. We started to systematically investigate CoQ10 and vitamin E levels in isolated human LDL and HDL. Both CoQ10 and vitamin E concentrations, referred to protein, were found higher in LDL than in HDL. Susceptibility to exogenously applied peroxidation did not correlate with the endogeneous content of the two antioxidants, possibly on the basis of different lipid content of these lipoproteins.

Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson's disease.

M Ebadi — 2006-11-06T18:24:56-00:00

Biol Signals Recept, Vol. 10, No. 3-4. (g 2001), pp. 224-253.

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease affecting approximately1% of the population older than 50 years. There is a worldwide increase in disease prevalence due to the increasing age of human populations. A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease. Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons.

Coenzyme Q10 and colorectal neoplasms in aged patients.

G Palazzoni — 2006-11-06T18:22:49-00:00

Rays, Vol. 22, No. 1 Suppl. (r 1997), pp. 73-76.

Coenzyme Q10 (CoQ10), a quinone located in cellular membranes, is a compound with mitochondrial bioenergetic functions whose antioxidant activity has recently been defined. CoQ10 content in colorectal neoplasms is significantly higher than in normal colorectal mucosa. While older patients (aged over 70 years) have also a significantly higher CoQ10 content, not observed in younger patients (aged under 70 years), the normal mucosa, instead; shows constant CoQ10 levels in both groups. For the same local stage (T), an increase in lymph node involvement (N) was observed in older patients as compared to younger ones, but not in distant metastases (M) with the same 5-year survival. These results justify the same therapeutic approach for patients older or younger than 70 years.

Coenzyme Q10 enrichment decreases oxidative DNA damage in human lymphocytes.

M Tomasetti — 2006-11-06T18:15:55-00:00

Free Radic Biol Med, Vol. 27, No. 9-10. (November 1999), pp. 1027-1032.

Ubiquinol-10, the reduced form of coenzyme Q10, is a powerful antioxidant in plasma and lipoproteins. It has been suggested that endogenous ubiquinol-10 also exerts a protective role even towards DNA oxidation mediated by lipid peroxidation. Even though the antioxidant activity of coenzyme Q10 is mainly ascribed to ubiquinol-10, a role for ubiquinone-10 (the oxidized form), has been suggested not only if appropriate reducing systems are present. To investigate whether the concentration of ubiquinol-10 or ubiquinone-10 affects the extent of DNA damage induced by H2O2, we supplemented in vitro human lymphocytes with both forms of coenzyme Q10 and evaluated the DNA strand breaks by Comet assay. The exposure of lymphocytes to 100 microM H2O2 resulted in rapid decrease of cellular ubiquinol-10 content both in ubiquinol-10-enriched and in control cells, whereas alpha-tocopherol and beta-carotene concentration were unchanged. After 30 min from H2O2 exposure, the amount of DNA strand breaks was lower and cells' viability was significantly higher in ubiquinol-10-enriched cells compared with control cells. A similar trend was observed in ubiquinone-10-enriched lymphocytes when compared with control cells. Our experiments suggest that coenzyme Q10 in vitro supplementation enhances DNA resistance towards H2O2-induced oxidation, but it doesn't inhibit directly DNA strand break formation.

Coenzyme Q10, antioxidant status and ApoE isoforms.

M Battino — 2006-11-06T18:15:26-00:00

Biofactors, Vol. 18, No. 1-4. (2003), pp. 299-305.

The aim of this study was to inquire the antioxidant status in plasma and lipoproteins isolated from normal subjects possessing different ApoE genotypes. For this purpose we investigated blood samples from 106 healthy blood donors: the distribution of ApoE alleles (E2/E2 = 0.9%, E2/E3 = 10.4%, E2/E4 = 2.8%, E3/E3 = 71.7%, E3/E4 = 12.3% and E4/E4 1.9% with 1, 11, 3, 76, 13, and 2 subjects respectively for each genotype) was in agreement with previous data. Almost no differences were found in the concentrations of both coenzyme Q10 (CoQ10) and vitamin E for the different genotypes. Concentration of CoQ10 in isolated lipoproteins was also similar, in the different genotypes, when referred to cholesterol; CoQ10 in LDL was higher for the E3/E3 subjects when referred to protein. Neither CoQ10 nor vitamin E correlated with paraoxonase (PON) activity or cholesteryl-ester hydroperoxides (CHP). Furthermore, there was no correlation between the same lipophilic antioxidants and CHP levels. The only E2 homozygous subject found had high levels of PON and low levels of CHP; the two E4/E4 subjects had low PON activity together with low levels of CHP.

Coenzyme Q10 affects expression of genes involved in cell signalling, metabolism and transport in human CaCo-2 cells.

DA Groneberg — 2006-11-06T18:14:33-00:00

Int J Biochem Cell Biol, Vol. 37, No. 6. (June 2005), pp. 1208-1218.

Coenzyme Q10 is an essential cofactor in the electron transport chain and serves as an important antioxidant in both mitochondria and lipid membranes. CoQ10 is also an obligatory cofactor for the function of uncoupling proteins. Furthermore, dietary supplementation affecting CoQ10 levels has been shown in a number of organisms to cause multiple phenotypic effects. However, the molecular mechanisms to explain pleiotrophic effects of CoQ10 are not clear yet and it is likely that CoQ10 targets the expression of multiple genes. We therefore utilized gene expression profiling based on human oligonucleotide sequences to examine the expression in the human intestinal cell line CaCo-2 in relation to CoQ10 treatment. CoQ10 caused an increased expression of 694 genes at threshold-factor of 2.0 or more. Only one gene was down-regulated 1.5-2-fold. Real-time RT-PCR confirmed the differential expression for seven selected target genes. The identified genes encode proteins involved in cell signalling (n = 79), intermediary metabolism (n = 58), transport (n = 47), transcription control (n = 32), disease mutation (n = 24), phosphorylation (n = 19), embryonal development (n = 13) and binding (n = 9). In conclusion, these findings indicate a prominent role of CoQ10 as a potent gene regulator. The presently identified comprehensive list of genes regulated by CoQ10 may be used for further studies to identify the molecular mechanism of CoQ10 on gene expression.

Clinical aspects of coenzyme Q10: an update.

GP Littarru — 2006-11-06T18:13:30-00:00

Curr Opin Clin Nutr Metab Care, Vol. 8, No. 6. (November 2005), pp. 641-646.

PURPOSE OF REVIEW: Coenzyme Q10 is administered for an ever-widening range of disorders, therefore it is timely to illustrate the latest findings with special emphasis on areas in which this therapeutic approach is completely new. These findings also give further insight into the biochemical mechanisms underlying clinical involvement of coenzyme Q10. RECENT FINDINGS: Cardiovascular properties of coenzyme Q10 have been further addressed, namely regarding myocardial protection during cardiac surgery, end-stage heart failure, pediatric cardiomyopathy and in cardiopulmonary resuscitation. The vascular aspects of coenzyme Q10 addressing the important field of endothelial function are briefly examined. The controversial issue of the statin/coenzyme Q10 relationship has been investigated in preliminary studies in which the two substances were administered simultaneously. Work on different neurological diseases, involving mitochondrial dysfunction and oxidative stress, highlights some of the neuroprotective mechanisms of coenzyme Q10. A 4-year follow-up on 10 Friedreich's Ataxia patients treated with coenzyme Q10 and vitamin E showed a substantial improvement in cardiac and skeletal muscle bioenergetics and heart function. Mitochondrial dysfunction likely plays a role in the pathophysiology of migraine as well as age-related macular degeneration and a therapy including coenzyme Q10 produced significant improvement. Finally, the effect of coenzyme Q10 was evaluated in the treatment of asthenozoospermia. SUMMARY: The latest findings highlight the beneficial role of coenzyme Q10 as coadjuvant in the treatment of syndromes, characterized by impaired mitochondrial bioenergetics and increased oxidative stress, which have a high social impact. Besides their clinical significance, these data give further insight into the biochemical mechanisms of coenzyme Q10 activity.

An update of Coenzyme Q10 implications in male infertility: biochemical and therapeutic aspects.

A Mancini — 2006-11-06T18:13:01-00:00

Biofactors, Vol. 25, No. 1-4. (2005), pp. 165-174.

This review is focused upon the role of coenzyme Q(10) in male infertility in the light of a broader issue of oxidative damage and antioxidant defence in sperm cells and seminal plasma. Reactive oxygen species play a key pathogenetic role in male infertility besides having a well-recognized physiological function. The deep involvement of coenzyme Q(10) in mitochondrial bioenergetics and its antioxidant properties are at the basis of its role in seminal fluid. Following the early studies addressing its presence in sperm cells and seminal plasma, the relative distribution of the quinone between these two compartments was studied in infertile men, with special attention to varicocele. The reduction state of CoQ(10) in seminal fluid was also investigated. After the first in vitro experiments CoQ(10) was administered to a group of idiopathic asthenozoospermic infertile patients. Seminal analysis showed a significant increase of CoQ(10) both in seminal plasma and in sperm cells, together with an improvement in sperm motility. The increased concentration of CoQ(10) in seminal plasma and sperm cells, the improvement of semen kinetic features after treatment, and the evidence of a direct correlation between CoQ(10) concentrations and sperm motility strongly support a cause/effect relationship. From a general point of view, a deeper knowledge of these molecular mechanisms could lead to a new insight into the so-called unexplained infertility.

Coenzyme Q10 evaluation in pituitary-adrenal axis disease: preliminary data.

A Mancini — 2006-11-06T18:12:14-00:00

Biofactors, Vol. 25, No. 1-4. (2005), pp. 197-199.

In previous works we have demonstrated plasma CoQ10 alterations in pituitary diseases, such as acromegaly or secondary hypothyroidism. However, pituitary lesions can induce complex clinical pictures due to alterations of different endocrine axes controlled by pituitary itself. A further rationale for studying CoQ10 in pituitary-adrenal diseases is related to the common biosynthetic pathway of cholesterol and ubiquinone. We have therefore assayed plasma CoQ10 levels in different conditions with increased or defective activity of pituitary-adrenal axis (3 subjects with ACTH-dependent adrenal hyperplasia, 2 cases of Cushing's disease and 1 case of 17-alpha-hydroxylase deficiency; 10 subjects with secondary hypoadrenalism, including three subjects with also secondary hypothyroidism). CoQ10 levels were significantly lower in isolated hypoadrenalism than in patients with adrenal hyperplasia and multiple pituitary deficiencies (mean +/- SEM: 0.57 +/- 0.04 vs 1.08 +/- 0.08 and 1.10 +/- 0.11 microg/ml, respectively); when corrected for cholesterol levels, the same trend was observed, but did not reach statistical significance. These preliminary data indicate that secretion of adrenal hormones is in some way related to CoQ10 levels, both in augmented and reduced conditions. However, since thyroid hormones have an important role in modulating CoQ10 levels and metabolism, when coexistent, thyroid deficiency seems to play a prevalent role in comparison with adrenal deficiency.

Coenzyme Q10 and exercise training in chronic heart failure.

R Belardinelli — 2006-11-06T18:04:18-00:00

Eur Heart J, Vol. 27, No. 22. (November 2006), pp. 2675-2681.

AIMS: There is evidence that plasma coenzyme Q(10) (CoQ(10)) levels decrease in patients with advanced chronic heart failure (CHF). However, it is not known whether oral CoQ(10) supplementation may improve cardiocirculatory efficiency and endothelial function in patients with CHF. METHODS AND RESULTS: We studied 23 patients in NYHA class II and III (20 men, three women, mean age 59+/-9 years) with stable CHF secondary to ischaemic heart disease [ejection fraction 37+/-7%], using a double-blind, placebo-controlled cross-over design. Patients were assigned to each of the following treatments: oral CoQ(10) (100 mg tid), CoQ(10) plus supervised exercise training (ET) (60% of peak VO(2), five times a week), placebo, and placebo plus ET. Each phase lasted 4 weeks. Both peak VO(2) and endothelium-dependent dilation of the brachial artery (EDDBA) improved significantly after CoQ(10) and after ET as compared with placebo. CoQ(10) main effect was: peak VO(2)+9%, EDDBA +38%, systolic wall thickening score index (SWTI) -12%; ET produced comparable effects. CoQ(10) supplementation resulted in a four-fold increase in plasma CoQ(10) level, whereas the combination with ET further increased it. No side effects were reported with CoQ(10). CONCLUSIONS: Oral CoQ(10) improves functional capacity, endothelial function, and LV contractility in CHF without any side effects. The combination of CoQ(10) and ET resulted in higher plasma CoQ(10) levels and more pronounced effects on all the abovementioned parameters. However, significant synergistic effect of CoQ(10) with ET was observed only for peak SWTI suggesting that ET amplifies the already described effect of CoQ(10) on contractility of dysfunctional myocardium.

Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors.

SA Mortensen — 2006-11-06T18:02:39-00:00

Mol Aspects Med, Vol. 18 Suppl (1997)

Coenzyme Q10 (ubiquinone) the essential mitochondrial redox-component and endogenous antioxidant, packaged into the LDL + VLDL fractions of cholesterol, has been suggested as an important anti-risk factor for the development of atherosclerosis as explained by the oxidative theory. Forty-five hypercholesterolemic patients were randomized in a double-blind trial in order to be treated with increasing dosages of either lovastatin (20-80 mg/day) or pravastatin (10-40 mg/day) over a period of 18 weeks. Serum levels of coenzyme Q10 were measured parallel to the levels of cholesterol at baseline on placebo and diet and during active treatment. A dose-related significant decline of the total serum level of coenzyme Q10 was found in the pravastatin group from 1.27 +/- 0.34 at baseline to 1.02 +/- 0.31 mmol/l at the end of the study period (mean +/- S.D.), P < 0.01. After lovastatin therapy the decrease was significant as well and more pronounced, from 1.18 +/- 0.36 to 0.84 +/- 0.17 mmol/l, P < 0.001. Although HMG-CoA reductase inhibitors are safe and effective within a limited time horizon, continued vigilance of a possible adverse consequence from coenzyme Q10 lowering seems important during long-term therapy.

Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study.

G Ghirlanda — 2006-11-06T18:00:29-00:00

J Clin Pharmacol, Vol. 33, No. 3. (March 1993), pp. 226-229.

Inhibitors of HMG-CoA reductase are new safe and effective cholesterol-lowering agents. Elevation of alanine-amino transferase (ALT) and aspartate-amino transferase (AST) has been described in a few cases and a myopathy with elevation of creatinine kinase (CK) has been reported rarely. The inhibition of HMG-CoA reductase affects also the biosynthesis of ubiquinone (CoQ10). We studied two groups of five healthy volunteers treated with 20 mg/day of pravastatin (Squibb, Italy) or simvastatin (MSD) for a month. Then we treated 30 hypercholesterolemic patients in a double-blind controlled study with pravastatin, simvastatin (20 mg/day), or placebo for 3 months. At the beginning, and 3 months thereafter we measured plasma total cholesterol, CoQ10, ALT, AST, CK, and other parameters (urea, creatinine, uric acid, total bilirubin, gamma GT, total protein). Significant changes in the healthy volunteer group were detected for total cholesterol and CoQ10 levels, which underwent about a 40% reduction after the treatment. The same extent of reduction, compared with placebo was measured in hypercholesterolemic patients treated with pravastatin or simvastatin. Our data show that the treatment with HMG-CoA reductase inhibitors lowers both total cholesterol and CoQ10 plasma levels in normal volunteers and in hypercholesterolemic patients. CoQ10 is essential for the production of energy and also has antioxidative properties. A diminution of CoQ10 availability may be the cause of membrane alteration with consequent cellular damage.

Dietary soy sphingolipids suppress tumorigenesis and gene expression in 1,2-dimethylhydrazine-treated CF1 mice and ApcMin/+ mice.

H Symolon — 2006-11-05T12:33:47-00:00

J Nutr, Vol. 134, No. 5. (May 2004), pp. 1157-1161.

Dietary supplementation with milk sphingolipids inhibits colon tumorigenesis in CF1 mice treated with a colon carcinogen [1,2-dimethylhydrazine (DMH)] and in multiple intestinal neoplasia (Min) mice, which develop intestinal tumors spontaneously. Plant sphingolipids differ structurally from those of mammals [soy glucosylceramide (GlcCer) consists predominantly of a 4,8-sphingadiene backbone and alpha-hydroxy-palmitic acid], which might affect their bioactivity. Soy GlcCer was added to the AIN-76A diet (which contains <0.005% sphingolipid) to investigate whether it would also suppress tumorigenesis in these mouse models. Soy GlcCer reduced colonic cell proliferation in the upper half of the crypts in mice treated with DMH by 50 and 56% (P < 0.05) at 0.025 and 0.1% of the diet (wt/wt), respectively, and reduced the number of aberrant colonic crypt foci (an early marker of colon carcinogenesis) by 38 and 52% (P < 0.05). Min mice fed diets containing 0.025 and 0.1% (wt/wt) soy GlcCer developed 22 and 37% fewer adenomas (P < 0.05), respectively. The effects of dietary sphingolipids on gene expression in the intestinal mucosal cells of Min mice were analyzed using Affymetrix GeneChip microarrays. Soy GlcCer affected the expression of 96 genes by > or = 2-fold in a dose-dependent manner, increasing 32 and decreasing 64. Decreases in the mRNA expression of two transcription factors associated with cancer, hypoxia-induced factor 1 alpha (HIF1 alpha) and transcription factor 4 (TCF4), were confirmed by quantitative RT-PCR. In conclusion, soy GlcCer suppressed colon tumorigenesis in two mouse models; hence, plant sphingolipids warrant further investigation as inhibitors of colon cancer. Because soy contains relatively high amounts of GlcCer, sphingolipids may partially account for the anticancer benefits attributed to soy-based foods.

High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability.

TN Bongers — 2006-11-02T16:51:50-00:00

Stroke, Vol. 37, No. 11. (November 2006), pp. 2672-2677.

BACKGROUND AND PURPOSE: Elevated von Willebrand factor (vWF) concentrations are associated with an increased risk of ischemic heart disease. Several factors influence vWF antigen levels and activity, including blood group, genetic variability, acute-phase response, and proteolysis by A Disintegrin and Metalloprotease with ThromboSpondin motif (ADAMTS13), a determinant of proteolytic cleavage of vWF. We assessed how these factors affect the relation between vWF and the occurrence of stroke to understand the underlying mechanism. METHODS: In a case-control study of 124 first-ever ischemic stroke patients and 125 age- and sex-matched controls, we studied vWF antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCo), ADAMTS13 activity, the -1793C/G polymorphism in the vWF gene, and C-reactive protein. RESULTS: vWF antigen and activity levels were significantly higher in cases than in controls. The relative risk of ischemic stroke was highest in individuals in the upper quartile of vWF:Ag (odds ratio, 3.2; 95% CI, 1.4 to 7.5) and vWF:RCo (odds ratio, 2.1; 95% CI, 0.9 to 4.8) compared with individuals in the lowest quartiles. In individuals with ADAMTS13 in the lowest quartile, the relative risk of stroke was 1.7 (95% CI, 0.7 to 3.9) compared with the highest quartile. C-reactive protein, ADAMTS13, and genetic variation did not affect the association between vWF and the relative risk of stroke, whereas blood group did affect the association. CONCLUSIONS: vWF antigen and activity are associated with the occurrence of acute ischemic stroke. This relation is unaffected by the severity of the acute-phase response or by genetic variation or degradation.

ABO blood group and diet prescription for weight loss

CS Johnston — 2006-11-02T10:52:35-00:00

The FASEB Journal, Vol. 20, No. A581. (2006)

The ABO blood group phenotype has been related to risk of myocardial infarction and type 2 diabetes mellitus, but there is no evidence that ABO blood group influences diet prescription for effective weight loss. We examined retrospectively whether ABO blood group was associated with weight loss potential on high-protein (HP), calorie-restricted diets. Healthy, overweight subjects (n=11 blood group O; n=7 blood group A) consumed experimental diets composed of common foods including meat (HP: ~30% energy from protein and 30–55% energy from fat) for 6 weeks in tightly controlled feeding trials. Body mass and metabolic indices were measured at weeks 0 and 6. At baseline, body mass (95±6 [mean±SE] and 94±11 kg), fat mass (38±4 and 39±8 kg), LDL cholesterol (133±8 and 129±14 mg/dL), and fasting insulin (23±1 and 25±5 mU/L) did not vary by blood group (O and A respectively). However, fasting glucose tended to be higher in blood group O versus A (98±3 versus 91±2 mg/dL; p=0.065). After 6 weeks of diet adherence, mean body mass was reduced significantly in both blood groups (–6%), and mean blood indices were favorably affected in all subjects: LDL cholesterol was reduced 6% (p=0.612) and 16% (p=0.027), and fasting insulin was reduced 20% (p=0.087) and 25% (p=0.031) in blood groups O and A respectively. These data suggest that HP diets are effective for weight loss and healthy outcomes in overweight individuals with either the O or A blood group phenotype. These data do not support the contention of a popular diet book that individuals with the A blood group phenotype should adhere to low-protein, vegetarian diets for health and weight management.

Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin.

M Aspholm-Hurtig — 2006-11-01T15:54:02-00:00

Science, Vol. 305, No. 5683. (23 July 2004), pp. 519-522.

Adherence by Helicobacter pylori increases the risk of gastric disease. Here, we report that more than 95% of strains that bind fucosylated blood group antigen bind A, B, and O antigens (generalists), whereas 60% of adherent South American Amerindian strains bind blood group O antigens best (specialists). This specialization coincides with the unique predominance of blood group O in these Amerindians. Strains differed about 1500-fold in binding affinities, and diversifying selection was evident in babA sequences. We propose that cycles of selection for increased and decreased bacterial adherence contribute to babA diversity and that these cycles have led to gradual replacement of generalist binding by specialist binding in blood group O-dominant human populations.

Hypertension, type 2 diabetes, and blood groups in a population of African ancestry.

B Nemesure — 2006-10-30T18:51:53-00:00

Ethn Dis, Vol. 16, No. 4. (2006), pp. 822-829.

OBJECTIVE: To evaluate the possible relationship of hypertension and diabetes with the ABO, Rhesus, and Duffy blood groups, which are known markers of African ancestry. DESIGN: Population-based study. SETTING AND PARTICIPANTS: A random sample of 1253 Barbados residents, > or = 40 years of age. MAIN OUTCOME MEASURES: Hypertension was defined as a systolic blood pressure >140 mm Hg or a diastolic blood pressure >90 mm Hg or use of antihypertensive treatment; type 2 diabetes was defined as a glycosylated hemoglobin level >10% and/or a history of treatment in those >30 years of age. RESULTS: In logistic regression analyses, elevated diastolic blood pressure was positively associated with years of age (odds ratio [OR] 1.03, 95% confidence interval CI 1.02-1.05), the Rhesus D+ antigen (OR 2.68, 95% CI 1.21-5.97) and body mass index (OR 1.53, 95% CI 1.19-1.96), but negatively associated with the ABO blood group A allele (OR 0.68, 95% CI .48-.97). A separate logistic regression model indicated that the likelihood of diabetes increased with years of age (OR 1.03, 95% CI 1.01-1.04), hypertension (OR 1.56, 95% CI 1.10-2.20), body mass index (OR 1.68, 95% CI 1.29-2.20), and waist-hip ratio (OR 1.36, 95% CI 1.05-1.75), but decreased with presence of the Rhesus C+ antigen (OR .66, 95% CI .44-.97). CONCLUSIONS: The associations of diabetes and hypertension to these blood groups support possible genetic influences on both conditions in this and similar African-origin populations; however, further investigations in other settings are necessary to more fully elucidate these findings.

Antibody Prevalence and Titer to Norovirus (Genogroup II) Correlate with Secretor (FUT2) but Not with ABO Phenotype or Lewis (FUT3) Genotype.

MM Larsson — 2006-10-30T18:50:19-00:00

J Infect Dis, Vol. 194, No. 10. (15 November 2006), pp. 1422-1427.

Background. Histo-blood group antigens and secretor status have been associated with susceptibility to Norovirus infections, which suggests that antibody prevalence and titer might correlate with these phenotypes.Methods. Plasma samples (n=105) from Swedish blood donors that had been genotyped for secretor (FUT2) and Lewis (Le; FUT3) genotypes and phenotyped for ABO and Le blood groups were analyzed for immunoglobulin G antibody prevalence and titers to norovirus genogroup (GG) II.4.Results. The results showed that nonsecretors (se(428)se(428)) and Le(a+b-) individuals not only had significantly lower antibody titers than did secretors (P<.0001) and Le(a-b+) individuals (P<.0002) but were also significantly more often antibody negative (P<.05). Antibody titers in secretors were not significantly different between individuals of different Le (FUT3) genotypes or different ABO phenotypes.Conclusions. Nonsecretors and Le(a+b-) individuals are significantly less prone to be infected with GGII noroviruses. This new information extends previous knowledge and supports the hypothesis that nonsecretors are relatively but not absolutely resistant to norovirus infections.

Peanut consumption and reduced risk of colorectal cancer in women: a prospective study in Taiwan.

CC Yeh — 2006-10-04T17:23:18-00:00

World J Gastroenterol, Vol. 12, No. 2. (14 January 2006), pp. 222-227.

AIM: To examine whether peanut consumption is associated with a reduced risk of colorectal cancer in a prospective cohort with a 10-year follow-up. METHODS: In 1990-1992, residents (12026 men and 11917 women aged 30 to 65 years) in 7 townships, Taiwan, were interviewed and recruited into a cancer-screening cohort and annually followed up. Colorectal cancer cases in this cohort were identified from cancer registry and death certificates. Incidence rates of this disease by the end of 2001 were calculated by gender for the primary study variable and covariates. The dietary intake was assessed by means of weekly food frequency measures, including frequently consumed food groups and folk dishes including sweet potato, bean products, peanut products, pickled foodstuffs, nitrated or smoked foodstuffs. RESULTS: During the study period, 107 new colorectal cancer cases (68 men and 39 women) were confirmed. The multivariate Cox's proportional hazard model showed that the relative risk (RR) of peanut consumption was 0.73 [95% confidence interval (CI) = 0.44-1.21] for men and 0.42 (95% CI = 0.21-0.84) for women. However, frequent intake of pickled foodstuffs was harmful for women (RR = 2.15, 95% CI = 0.99-4.65). The risk of colorectal cancer was also elevated among cigarette smokers but not significant (P<0.05). CONCLUSION: This study suggests that frequent intake of peanut and its products may reduce colorectal cancer risk in women, demonstrating the anti-proliferating effect of peanut intake.

Anti-diabetic property of ethanolic extract of Andrographis paniculata in streptozotocin-diabetic rats.

XF Zhang — 2006-09-28T20:46:48-00:00

Acta Pharmacol Sin, Vol. 21, No. 12. (December 2000), pp. 1157-1164.

AIM: To investigate the anti-diabetic effect of a crude ethanolic extract of Andrographis paniculata in normal and streptozotocin (STZ)-induced diabetic rats. METHODS & RESULTS: Oral administration of the extract at different doses (0.1, 0.2, and 0.4 g/body weight) significantly reduced the fasting serum glucose level in STZ-diabetic rats compared to the vehicle (distilled water), but not in normal rats. This effect was dose-dependent. A similar result was seen with metformin (0.5 g/body weight). In the glucose tolerance test, an oral administration of the extract at the same doses suppressed the elevated glucose level in normal and diabetic rats, as did metformin. The effects were also dose-respondent. In the long-term experiment, the extract (0.4 g/body weight), metformin (0.5 g/body weight), and vehicle were given twice daily to diabetic rats for 14 d. On d 15, fasting serum glucose levels were found to be significantly lower in the extract- and metformin-treated groups (P < 0.001) than in the vehicle-treated group. The mean food and water intakes over 14 days were significantly lower in the extract-treated group (P < 0.05, P < 0.01, respectively) and also in the metformin-treated group (both P < 0.001) when compared to the vehicle-treated group. No significant change in insulin level was observed among the 3 groups of diabetic rats. The extract, like metformin, maintained the leptin levels after 14-d treatment, whereas this level was significantly decreased (P < 0.05) in the vehicle-treated group. The activity of hepatic glucose-6-phosphatase (G-6-Pase) was significantly reduced by the extract as well as by metformin (both P < 0.05). No significant difference in hepatic glycogen stores was noted among the 3 groups. The extract caused 49.8% reduction of fasting serum triglyceride levels, compared to 27.7% with metformin. However, neither the extract nor metformin significantly affected serum cholesterol level. CONCLUSION: The ethanolic extract of A paniculata possesses antidiabetic property. Its antidiabetic effect may be attributed at least in part to increased glucose metabolism. Its hypotriglyceridemic effect is also beneficial in the diabetic state.

Left–right asymmetry in the vertebrate embryo: from early information to higher-level integration

Ángel Raya — 2006-03-17T12:03:17-00:00

Nature Reviews Genetics, Vol. 7, No. 4., pp. 283-293.

The genetics of human longevity.

M Capri — 2006-09-23T18:01:19-00:00

Ann N Y Acad Sci, Vol. 1067 (May 2006), pp. 252-263.

Aging is due to a complex interaction of genetic, epigenetic, and environmental factors, but a strong genetic component appears to have an impact on survival to extreme ages. In order to identify "longevity genes" in humans, different strategies are now available. In our laboratory, we performed association studies on a variety of "candidate" polymorphisms in Italian centenarians. Many genes/polymorphisms gave negative results, while others showed a positive association with human longevity and a sometimes-positive association with unsuccessful aging (myocardial infarction, Alzheimer's disease, and type 2 diabetes). Results regarding genes involved in inflammation (IL-1 cluster, IL-6, IL-10, TNF-alpha, TGF-beta, TLR-4, PPARgamma), insulin/IGF-1 signaling pathway and lipid metabolism (apolipoproteins, CETP, PON1), and oxidative stress (p53, p66(shc)) will be described. In addition, a strong role of the interaction between nuclear and mitochondrial genomes (mtDNA haplogroups and the C150T mutation) emerged from our findings. Thus, the genetics of human longevity appears to be quite peculiar in a context where antagonistic pleiotropy can play a major role and genes can have a different biological role at different ages.

A2A adenosine receptor protects tumors from antitumor T cells.

A Ohta — 2006-09-22T05:44:58-00:00

Proc Natl Acad Sci U S A, Vol. 103, No. 35. (29 August 2006), pp. 13132-13137.

The A2A adenosine receptor (A2AR) has been shown to be a critical and nonredundant negative regulator of immune cells in protecting normal tissues from inflammatory damage. We hypothesized that A2AR also protects cancerous tissues by inhibiting incoming antitumor T lymphocytes. Here we confirm this hypothesis by showing that genetic deletion of A2AR in the host resulted in rejection of established immunogenic tumors in approximately 60% of A2AR-deficient mice with no rejection observed in control WT mice. The use of antagonists, including caffeine, or targeting the A2 receptors by siRNA pretreatment of T cells improved the inhibition of tumor growth, destruction of metastases, and prevention of neovascularization by antitumor T cells. The data suggest that effects of A2AR are T cell autonomous. The inhibition of antitumor T cells via their A2AR in the adenosine-rich tumor microenvironment may explain the paradoxical coexistence of tumors and antitumor immune cells in some cancer patients (the "Hellstrom paradox"). We propose to target the hypoxia-->adenosine-->A2AR pathway as a cancer immunotherapy strategy to prevent the inhibition of antitumor T cells in the tumor microenvironment. The same strategy may prevent the premature termination of immune response and improve the vaccine-induced development of antitumor and antiviral T cells. The observations of autoimmunity during melanoma rejection in A2AR-deficient mice suggest that A2AR in T cells is also important in preventing autoimmunity. Thus, although using the hypoxia-->adenosine-->A2AR pathway inhibitors may improve antitumor immunity, the recruitment of this pathway by selective drugs is expected to attenuate the autoimmune tissue damage.

Naegeli-Franceschetti-Jadassohn Syndrome and Dermatopathia Pigmentosa Reticularis: Two Allelic Ectodermal Dysplasias Caused by Dominant Mutations in KRT14.

J Lugassy — 2006-09-18T17:36:37-00:00

Am J Hum Genet, Vol. 79, No. 4. (October 2006), pp. 724-730.

Naegeli-Franceschetti-Jadassohn syndrome (NFJS) and dermatopathia pigmentosa reticularis (DPR) are two closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation, thickening of the palms and soles (palmoplantar keratoderma), abnormal sweating, and other subtle developmental anomalies of the teeth, hair, and skin. To decipher the molecular basis of these disorders, we studied one family with DPR and four families with NFJS. We initially reassessed linkage of NFJS/DPR to a previously established locus on 17q11.2-q21. Combined multipoint analysis generated a maximal LOD score of 8.3 at marker D17S800 at a recombination fraction of 0. The disease interval was found to harbor 230 genes, including a large cluster of keratin genes. Heterozygous nonsense or frameshift mutations in KRT14 were found to segregate with the disease trait in all five families. In contrast with KRT14 mutations affecting the central alpha -helical rod domain of keratin 14, which are known to cause epidermolysis bullosa simplex, NFJS/DPR-associated mutations were found in a region of the gene encoding the nonhelical head (E1/V1) domain and are predicted to result in very early termination of translation. These data suggest that KRT14 plays an important role during ontogenesis of dermatoglyphics and sweat glands. Among other functions, the N-terminal part of keratin molecules has been shown to confer protection against proapoptotic signals. Ultrastructural examination of patient skin biopsy specimens provided evidence for increased apoptotic activity in the basal cell layer where KRT14 is expressed, suggesting that apoptosis is an important mechanism in the pathogenesis of NFJS/DPR.

Epigenetics and DNA methylation come of age in toxicology.

RE Watson — 2006-09-18T15:58:36-00:00

Toxicol Sci, Vol. 67, No. 1. (May 2002), pp. 11-16.

A wide variety of chemical and physical agents have the potential to produce adverse effects by causing heritable changes to the genome, resulting in heritable alterations in phenotype. These are often assumed to be a consequence of mutation. However, mutagenesis is not the only mechanism underlying heritable alterations to the genome. It is important to understand that there may also be an epigenetic basis for this. DNA methylation is the epigenetic mechanism that this review focuses upon. We indicate how altered methylation may play a key role in a variety of chemical-induced toxicities, including, but not limited to, carcinogenesis, and we point out how an assessment of methylation status can provide important information as a component of an overall safety assessment.

Endocrine disrupters and female reproductive health.

JA McLachlan — 2006-09-18T15:57:48-00:00

Best Pract Res Clin Endocrinol Metab, Vol. 20, No. 1. (March 2006), pp. 63-75.

There is growing evidence of the impact of estrogenic contaminants in the environment. Studies have shown that male fish in detergent-contaminated water express female characteristics, turtles are sex-reversed by polychlorinated biphenyls (PCBs), male frogs exposed to a common herbicide form multiple ovaries, pseudohermaphroditic offspring are produced by polar bears, and seals in contaminated water have an excess of uterine fibroids. Endocrine-disrupting chemicals (those found in the external environment that can mimic or inhibit endogenous hormones) mostly exhibit estrogenic effects, but a few are anti-estrogenic or anti-androgenic. Many of these compounds are industrial contaminants, such as pesticides and plasticizers, and others are natural phytoestrogens found in plants such as soy and in herbal supplements. Recent work shows that human development can also be feminized by exposure to estrogenic chemicals. Estrogen is the key hormone in the initiation (puberty) and the end (menopause) of reproductive life in women and thus of considerable importance in women's health. The same chemicals that affect wildlife may affect breast growth and lactation, and could have a role in uterine diseases such as fibroids and endometriosis. New studies provide a mechanism of action for estrogenic chemicals and other endocrine disrupters at the molecular level (called epigenetics) that may help explain the long-term effects of endocrine disruption.

Epigenetics, evolution, endocrine disruption, health, and disease.

D Crews — 2006-09-18T15:57:11-00:00

Endocrinology, Vol. 147, No. 6 Suppl. (June 2006)

Endocrine-disrupting chemicals (EDCs) in the environment have been linked to human health and disease. This is particularly evident in compounds that mimic the effects of estrogens. Exposure to EDCs early in life can increase risk levels of compromised physical and mental health. Epigenetic mechanisms have been implicated in this process. Transgenerational consequences of EDC exposure is also discussed in both a proximate (mechanism) and ultimate (evolution) context as well as recent work suggesting how such transmission might become incorporated into the genome and subject to selection. We suggest a perspective for exploring and ultimately coming to understand diseases that may have environmental or endocrine origins.

Tissue distribution of blood group membrane proteins beyond red cells: Evidence from cDNA libraries.

Markus T Rojewski — 2006-09-12T16:57:54-00:00

Transfus Apher Sci (4 September 2006)

The proteins of blood group systems are expressed on red blood cells (RBC) by definition. We searched nucleotide databases of human expressed sequence tags (EST) to collate the distribution of 22 distinct membrane proteins in cells and tissues other than RBC. The documented blood group genes are: MNS, Rh, Lutheran, Kell, Duffy, Kidd, Diego, Yt, Xg, Scianna, Dombrock, Colton, Landsteiner-Wiener, Kx, Gerbich, Cromer, Knops, Indian, Ok, Raph, John-Milton-Hagen and Gill. The genes were grouped according to their overall and their relative expression in embryo and adults. We describe the distribution of EST in cells, tissues and cell lines with a focus on non-RBC tissues.

THE BLOODGEN PROJECT: TOWARD MASS SCALE GENOTYPING FOR HUMAN BLOOD GROUP ANTIGENS

D Avent — 2005-01-20T00:29:54-00:00

(7 September 2006)

Background: During the past 20 years there has been a significant increase in the knowledge surrounding the molecular basis of blood group antigenicity. This has permitted the implementation of molecular diagnostics as an adjunct technology in the modern Transfusion medicine laboratory. Recent advances in high-throughput genotyping now make the replacement of blood group serology by molecular genotyping a distinct possibility, and will lead to a reduction in alloimmunisation due to incompatible transfusions if implemented on a mass scale. Aims: We have developed as an EC funded framework V consortium a gene chip that is capable of defining the major clinically significant blood group alleles in a single test kit format. Alleles of the ABO, RH, KEL, FY, JK, DI, MNS, DO and CO systems have been included on the BloodGen testing platform, which includes 96 blood group alleles, and eventually will include all platelet and perhaps HLA alleles of clinical significance. The Bloodgen project will become commercially available within the next two years, as a product of Progenika SA (www.progenika.com). Methods: Multiplex (MPX) PCRs which amplify all alleles of clinical significance have been developed in a two-tube format (ABO/RH and all others). When fragmented and labelled, they are hybridised to a gene chip which has 40 copies of probes for each allele. When washed using a hybridisation station and scanned on laser and white light scanners, the images of the chips are analysed by software specifically developed for scoring blood group genotypes. Certain partial D phenotypes will be scored by drop out of RHD signals from the relevant regions of the chip. Results: Using sophisticated scoring algorithms, the Blood Group Genotype for an individual can be scored with over 99.5% accuracy. We have screened a large cohort of rare phenotype red cells with common blood group phenotypes and Rh variant phenotypes, with almost complete concordance with genotype scoring. We are proceeding to test a large panel of 3000 phenotyped samples in order to submit the BloodGen product for CE marking purposes. Summary/Conclusions: The BloodGen project (www.bloodgen.com) clearly demonstrates the feasibility of performing mass scale genotyping for all patients and donors. Comprehensive genotyping will lead to a reduction in alloimmunisation and will greatly assist the selection of units for multiply transfused donors, and to large scale implementation of electronic cross matching. Our objective is to provide a technical platform to enable the mass-scale genotyping of initially the European blood supply and patients, and eventually worldwide. Mass scale genotyping for a variety of genetic diseases will become obligatory for neonates ‘ we envisage that Blood Group genotyping of all individuals at birth will become part of this process, and this information will be important for the provision of a safe blood supply and wellbeing of that individual throughout their life as patient and donor.

Lectindb: a plant lectin database

Nagasuma Chandra — 2006-09-05T09:44:49-00:00

Glycobiology, Vol. 16, No. 10. (1 October 2006), pp. 938-946.

Lectins, a class of carbohydrate-binding proteins, are now widely recognized to play a range of crucial roles in many cell-cell recognition events triggering several important cellular processes. They encompass different members that are diverse in their sequences, structures, binding site architectures, quaternary structures, carbohydrate affinities, and specificities as well as their larger biological roles and potential applications. It is not surprising, therefore, that the vast amount of experimental data on lectins available in the literature is so diverse, that it becomes difficult and time consuming, if not impossible to comprehend the advances in various areas and obtain the maximum benefit. To achieve an effective use of all the data toward understanding the function and their possible applications, an organization of these seemingly independent data into a common framework is essential. An integrated knowledge base (Lectindb, http://nscdb.bic.physics.iisc.ernet.in) together with appropriate analytical tools has therefore been developed initially for plant lectins by collating and integrating diverse data. The database has been implemented using MySQL on a Linux platform and web-enabled using PERL-CGI and Java tools. Data for each lectin pertain to taxonomic, biochemical, domain architecture, molecular sequence, and structural details as well as carbohydrate and hence blood group specificities. Extensive links have also been provided for relevant bioinformatics resources and analytical tools. Availability of diverse data integrated into a common framework is expected to be of high value not only for basic studies in lectin biology but also for basic studies in pursuing several applications in biotechnology, immunology, and clinical practice, using these molecules. 10.1093/glycob/cwl012

Blood Group A and B Antigen Expression in Human Kidneys Correlated to A1/A2/B, Lewis, and Secretor Status.

Michael Breimer — 2006-08-30T17:58:13-00:00

Transplantation, Vol. 82, No. 4. (27 August 2006), pp. 479-485.

BACKGROUND.: In the revived interest in crossing ABO barriers in organ transplantation renal A/B antigen expression has been correlated with donor ABO, Lewis, and secretor subtype to predict antigen expression. METHODS.: A/B antigen expression was explored by immunohistochemistry in LD renal biopsies. Donor A1/A2/B, Lewis, and secretor status were determined by serology and polymerase chain reaction. RESULTS.: In the renal vascular bed, three distinct A antigen expression patterns with a major, minor, and minimal staining distribution, and intensity (designated as types 3+, 1+ and (+) respectively) were identified. Type 3+ had a strong A antigen expression in the endothelium of arteries, glomerular/peritubular capillaries and veins. The type 1+ showed an overall weaker antigen expression, whereas type (+) had faint staining of peritubular capillaries only. In all cases, distal tubular epithelium was focally stained, whereas proximal tubules were negative. Type 3+ were all from blood group A1 subtype individuals while A2 cases expressed either a 1+ or (+) pattern. The secretor gene did not appear to influence renal A antigen expression. All B kidneys examined showed a B antigen pattern slightly weaker but otherwise similar to A type 3+. CONCLUSION.: Renal vascular A antigen expression correlates to donor A1/A2 subtypes, whereas B individuals show one singular antigen pattern. From antigen perspective, A1 and B donors are a "major" and A2 individuals a "minor" antigen challenge in ABO-incompatible renal transplantation.