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Biomedical subjects

Ahmed El-Sohemy

Publications and source records attributed to Ahmed El-Sohemy.

At least 19 recordsLinked to original sources
PubMed2007

Coffee, caffeine, and coronary heart disease.

PURPOSE OF REVIEW: This review summarizes and highlights recent advances in current knowledge of the relationship between coffee and caffeine consumption and risk of coronary heart disease. Potential mechanisms and genetic modifiers of this relationship are also discussed. RECENT FINDINGS: Studies examining the association between coffee consumption and coronary heart disease have been inconclusive. Coffee is a complex mixture of compounds that may have either beneficial or harmful effects on the cardiovascular system. Randomized controlled trials have confirmed the cholesterol-raising effect of diterpenes present in boiled coffee, which may contribute to the risk of coronary heart disease associated with unfiltered coffee consumption. A recent study examining the relationship between coffee and risk of myocardial infarction incorporated a genetic polymorphism associated with a slower rate of caffeine metabolism and provides strong evidence that caffeine also affects risk of coronary heart disease. Several studies have reported a protective effect of moderate coffee consumption, which suggests that coffee contains other compounds that may be beneficial. SUMMARY: Diterpenes present in unfiltered coffee and caffeine each appear to increase risk of coronary heart disease. A lower risk of coronary heart disease among moderate coffee drinkers might be due to antioxidants found in coffee.

Beverages↗
PubMed2006

Epigallocatechin-3-gallate increases the formation of mineralized bone nodules by human osteoblast-like cells.

Consumption of green tea, a rich source of epigallocatechin-3-gallate (EGCG), is associated with increased bone mineral density. However, the direct effects of this flavonoid on bone mineralization are not known. The present study demonstrates the effects of EGCG on the formation of mineralized bone nodules by SaOS-2 human osteoblast (HOB)-like cells. EGCG at concentrations of 1-5 microM caused a dose-dependent increase in the number and area of mineralized bone nodules as assessed by both von Kossa and alizarin red staining. EGCG also increased alkaline phosphatase activity, an early marker of osteoblastic differentiation. After 48 h of treatment, EGCG decreased protein levels of Runx2, a transcription factor that regulates osteoblast maturation by inhibiting late-stage differentiation. The observed effects of EGCG on bone formation by HOB-like cells suggest that EGCG may have beneficial effects on bone health.

Alkaline Phosphatase↗
PubMed2006

Cyclooxygenase-2 polymorphisms and risk of systemic lupus erythematosus in Koreans.

Cyclooxygenase-2 (COX-2) is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. Upregulation of COX-2 in human lupus T cells resists anergy and apotosis. We investigated the COX-2 gene for functional variants that may influence susceptibility, clinical outcomes and severity of systemic lupus erythematosus (SLE) in a Korean population. The study included 345 patients with SLE and 400 unrelated healthy controls. Genotyping for the -765G --> C polymorphism of COX-2 was performed by PCR-RFLP analysis. No difference in the distribution of the genotype frequencies between patients and controls was found. COX-2 genotypes were not associated with clinical features except hematologic abnormalities and anti-RNP antibody. We did not detect any association between COX-2 genotype and disease severity in SLE patients. These results suggest that the -765G --> C polymorphism of COX-2 does not play a significant role in the development of SLE in a Korean population. A possible protective effect of the low activity C allele against the production of anti-RNP antibodies merits further investigation.

Adult↗
PubMed2006

Cost-effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate.

OBJECTIVE: To determine whether a strategy based on methylenetetrahydrofolate reductase (MTHFR) genotype screening is more cost-effective than the conventional strategy in reducing the risk of methotrexate (MTX)-related toxicity in patients with rheumatoid arthritis (RA). METHODS: We consecutively enrolled 385 patients with RA (355 female, 30 male) who had received MTX and identified toxicity associated with MTHFR C677T genotypes. We designed a hypothetical decision model to compare the genotype-based strategy with the conventional strategy. The time horizon was set as 1 year, and direct medical costs were used. The measured outcomes were the total expected cost, the effectiveness, and the incremental cost-effectiveness ratio. RESULTS: MTHFR genotype distribution revealed 133 patients (34.6%) with 677CC, 193 (50.1%) with 677CT, and 59 (15.3%) with 677TT. A total of 154 patients (40.0%) exhibited MTX-related toxicity. Compared to RA patients with the CC genotype, the odds ratio (95% confidence interval) for risk of toxicity was 3.8 (2.29-6.33) for the CT genotype, and 4.7 (2.40-9.04) for the TT genotype. In the base-case model, the total expected cost and the probability of continuing MTX medication for the conventional and genotype-based strategies were 851,415 Korean won (710 US dollars) and 788,664 Korean won (658 US dollars), and 94.03% and 95.58%, respectively. CONCLUSION: The MTHFR C677T polymorphism may be an important predictor of MTX-related toxicity in patients with RA. The cost-effectiveness analysis suggests that the genotype-based strategy is both less costly and more effective than the conventional strategy for MTX therapy.

Adult↗
PubMed2006

Coffee, CYP1A2 genotype, and risk of myocardial infarction.

CONTEXT: The association between coffee intake and risk of myocardial infarction (MI) remains controversial. Coffee is a major source of caffeine, which is metabolized by the polymorphic cytochrome P450 1A2 (CYP1A2) enzyme. Individuals who are homozygous for the CYP1A2*1A allele are "rapid" caffeine metabolizers, whereas carriers of the variant CYP1A2*1F are "slow" caffeine metabolizers. OBJECTIVE: To determine whether CYP1A2 genotype modifies the association between coffee consumption and risk of acute nonfatal MI. DESIGN, SETTING, AND PARTICIPANTS: Cases (n = 2014) with a first acute nonfatal MI and population-based controls (n = 2014) living in Costa Rica between 1994 and 2004, matched for age, sex, and area of residence, were genotyped by restriction fragment-length polymorphism polymerase chain reaction. A food frequency questionnaire was used to assess the intake of caffeinated coffee. MAIN OUTCOME MEASURE: Relative risk of nonfatal MI associated with coffee intake, calculated using unconditional logistic regression. RESULTS: Fifty-five percent of cases (n = 1114) and 54% of controls (n = 1082) were carriers of the slow *1F allele. For carriers of the slow *1F allele, the multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of nonfatal MI associated with consuming less than 1, 1, 2 to 3, and 4 or more cups of coffee per day were 1.00 (reference), 0.99 (0.69-1.44), 1.36 (1.01-1.83), and 1.64 (1.14-2.34), respectively. Corresponding ORs (95% CIs) for individuals with the rapid *1A/*1A genotype were 1.00, 0.75 (0.51-1.12), 0.78 (0.56-1.09), and 0.99 (0.66-1.48) (P = .04 for gene x coffee interaction). For individuals younger than the median age of 59 years, the ORs (95% CIs) associated with consuming less than 1, 1, 2 to 3, or 4 or more cups of coffee per day were 1.00, 1.24 (0.71-2.18), 1.67 (1.08-2.60), and 2.33 (1.39-3.89), respectively, among carriers of the *1F allele. The corresponding ORs (95% CIs) for those with the *1A/*1A genotype were 1.00, 0.48 (0.26-0.87), 0.57 (0.35-0.95), and 0.83 (0.46-1.51). CONCLUSION: Intake of coffee was associated with an increased risk of nonfatal MI only among individuals with slow caffeine metabolism, suggesting that caffeine plays a role in this association.

Aged↗
PubMed2006

Cyclooxygenase-2 genotype and rheumatoid arthritis.

OBJECTIVE: To determine the association between cyclooxygenase-2 (COX-2) genotypes and risk and severity of rheumatoid arthritis (RA) in a Korean population. METHODS: A total of 258 Korean patients with RA and 400 control subjects were recruited from Hanyang University Hospital. Subjects were genotyped for the -765G/C polymorphism of the COX-2 gene by RFLP-PCR analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate risk. Severity of RA was assessed by anatomical stage according to Steinbrocker, et al. RESULTS: No association was observed between COX-2 genotype and risk or severity of RA. However, among those without the shared epitope (SE), carriers of the low activity C allele had a lower risk of RA and less severe form of RA than subjects with the G/G genotype. The OR (95% CI) was 0.36 (0.14-0.95) for risk of RA and 0.04 (0.01-0.41) for severity. CONCLUSION: These results suggest that COX-2 genotyping might be useful in predicting the risk and severity of RA in individuals without the SE.

Adult↗
PubMed2005

Catalase and PPARgamma2 genotype and risk of rheumatoid arthritis in Koreans.

Catalase (CAT) and peroxisome proliferator activated receptor-gamma2 (PPARgamma2) are important regulators of oxidative stress and inflammation, and may contribute to the development of rheumatoid arthritis (RA). We investigated the association between CAT and PPARgamma2 genotypes and risk and severity of RA using 474 cases and 400 controls. Genotyping for the -262C-->T polymorphism of CAT and the Pro12Ala polymorphism of PPARgamma2 was performed by PCR-RFLP analysis. Severity of RA was assessed by the anatomical stage according to Steinbrocker, and a Korean language version of a Health Assessment Questionnaire (KHAQ). No association was observed between CAT and PPARgamma2 genotypes and risk of RA. Our results suggest that genetic polymorphisms of CAT and PPARgamma2 do not play a significant role in the susceptibility to RA among Koreans.

Adult↗
PubMed2005

Dietary factors and the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for breast cancer and development.

A role for mevalonate in cancer development has long been suggested by findings that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity is elevated in malignant cells. Increased synthesis mevalonate and mevalonate-derived nonsterol isoprenoids supports increased cell proliferation through the activation of growth-regulatory proteins and oncoproteins, and by promoting DNA synthesis. We have recently shown that mevalonate promotes the growth of human breast cancer cells both in culture and as tumors grown in nude mice. Inhibition mevalonate synthesis, therefore, may be an effective strategy to impair the growth of malignant breast cells. Several dietary compounds with known anti-cancer effects are also reported to inhibit HMG-CoA reductase activity. Here, we review evidence suggesting that inhibition of mevalonate synthesis may mediate the protective effects of cholesterol, plant isoprenoids, genistein, and long-chain n-3 polyunsaturated fatty acids (PUFAs) on experimental breast cancer.

Animals↗
PubMed2005

Statins and cancer development.

There is epidemiologic evidence that the hydrophilic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor pravastatin increases the incidence of some extrahepatic cancers, although this finding has been attributed to chance. We hypothesize that pravastatin is able to promote the development of cancer by causing an induction of HMG-CoA reductase and, hence, mevalonate synthesis in extrahepatic tissues. We have shown that mevalonate, the product of HMG-CoA reductase, promotes the growth of breast cancer cells. Because there is no uptake of pravastatin by most extrahepatic cells, this statin will be unable to mitigate the increase in mevalonate synthesis in extrahepatic tissues that accompanies the decrease in circulating cholesterol caused by its inhibition of hepatic HMG-CoA reductase.

Animals↗
PubMed2005

Glutathione S-transferase M1, T1, and P1 genotypes and rheumatoid arthritis.

OBJECTIVE: To determine the effects of genetic polymorphisms of glutathione S-transferase (GST) M1, GSTT1, and GSTP on risk and severity of rheumatoid arthritis (RA) in a Korean population. METHODS: A total of 258 patients with RA and 400 disease-free controls were enrolled. GST genotypes were determined by RFLP-PCR. HLA-DRB 1 typing and further subtyping of all alleles was performed using sequence-specific oligonucleotide probe hybridization after PCR. Severity of RA among cases was assessed by Steinbrocker anatomical stage. Risk was assessed by calculating the age and sex adjusted odds ratio (OR) and 95% confidence intervals (CI). RESULTS: The OR for risk of RA with the GSTM1-null genotype was 1.40 (95% CI 1.02- 1.92, p = 0.04), and 1.86 (95% CI 1.12- 3.09, p = 0.005) among individuals without the shared epitope (SE). Among patients with RA, the OR for risk of severe RA for the GSTM1-null genotype was 2.45 (95% CI 1.04- 5.77, p = 0.02). No association was observed between the GSTT1 or GSTP1 genotypes and either risk or severity of RA. CONCLUSION: These results suggest that the deletion polymorphism of GSTM1 is associated with increased susceptibility for RA, particularly among individuals who are not carriers of the HLA-DRB 1 SE.

Adult↗
PubMed2004

Regulation of HMG-CoA reductase in MCF-7 cells by genistein, EPA, and DHA, alone and in combination with mevastatin.

We investigated the regulation of HMG-CoA reductase in MCF-7 human breast cancer cells by genistein, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). All three compounds down-regulated reductase activity, primarily through post-transcriptional effects. In mevastatin-treated cells, only genistein and DHA abrogated the induction of reductase activity caused by this competitive inhibitor. Diets rich in soy isoflavones and fish oils, therefore, may exert anti-cancer effects through the inhibition of mevalonate synthesis in the breast. Genistein and DHA, in particular, may augment the efficacy of statins, increasing the potential for use of these drugs in adjuvant therapy for breast cancer.

Anticarcinogenic Agents↗
PubMed2004

Geraniol and beta-ionone inhibit proliferation, cell cycle progression, and cyclin-dependent kinase 2 activity in MCF-7 breast cancer cells independent of effects on HMG-CoA reductase activity.

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the formation of mevalonate, a precursor of cholesterol that is also required for cell proliferation. Mevalonate depletion results in a G1 phase cell cycle arrest that is mediated in part by impaired activity of cyclin-dependent kinase (CDK) 2, and decreased expression of positive regulators of G1 to S phase progression. Inhibition of mevalonate synthesis may, therefore, be a useful strategy to impair the growth of malignant cells. Plant isoprenoids, including beta-ionone and geraniol, have previously been shown to inhibit rodent mammary tumor development, and rodent and avian hepatic HMG-CoA reductase activity. We hypothesized that the putative anti-proliferative and cell cycle inhibitory effects of beta-ionone and geraniol on MCF-7 human breast cancer cells in culture are mediated by mevalonate depletion resulting from inhibition of HMG-CoA reductase activity. Flow cytometric analysis showed a G1 arrest in isoprenoid-treated MCF-7 cells, and also a G2/M arrest at higher concentrations of isoprenoids. These compounds minimally affected the growth of MCF-10F normal breast epithelial cells. Both beta-ionone and geraniol inhibited CDK 2 activity and dose-dependently decreased the expression of cyclins D1, E, and A, and CDK 2 and 4, without changing the expression of p21cip1 or p27kip1. Although both beta-ionone and geraniol also inhibited MCF-7 proliferation, only geraniol inhibited HMG-CoA reductase activity. While these effects were significantly correlated (r2=0.89, P <0.01), they were not causally related, since exogenous mevalonate did not restore growth in geraniol-inhibited cells. These findings indicate that mechanisms other than impaired mevalonate synthesis mediate the anti-proliferative and cell cycle regulatory effects of beta-ionone and geraniol in human breast cancer cells.

Acyclic Monoterpenes↗
PubMed2004

Mevalonate promotes the growth of tumors derived from human cancer cells in vivo and stimulates proliferation in vitro with enhanced cyclin-dependent kinase-2 activity.

Malignant cells are known to have elevated rates of mevalonate synthesis because of increased levels and catalytic efficiency of 3-hydroxy-3-methylglutaryl-CoA reductase. Whether this increased mevalonate synthesis occurs as a consequence of increased requirements for a mevalonate-derived metabolite in response to rapid growth or whether mevalonate promotes the growth of tumor cells is unknown. To address this question, we administered mevalonate via miniosmotic pumps to nude mice inoculated with MDA-MB-435 human cancer cells. After 13 weeks of growth, tumors in mevalonate-treated mice were significantly larger than tumors in saline-treated, control mice (1.52 +/- 0.26 g versus 0.81 +/- 0.27 g respectively, p < 0.05). The cancer cells treated in culture with mevalonate also demonstrated increased proliferation rates associated with accelerated entry of cells into S phase. These cells had enhanced total and cyclin A-immunoprecipitable cyclin-dependent kinase-2 (CDK-2) activity, increased activating phosphorylation of CDK-2, and decreased inhibitory binding of CDK-2 to p21(Cip1). Our findings demonstrate that mevalonate promotes tumor growth and suggest that an increase in mevalonate synthesis in extrahepatic tissues following cholesterol-lowering therapy may explain the elevated risk of cancer shown in some studies.

Animals↗
PubMed2003

Glutathione S-transferase M1, T1, and P1 gene polymorphisms and carotid atherosclerosis in Korean patients with rheumatoid arthritis.

We assessed the contribution of genetic polymorphisms of glutathione S-transferase M1 ( GSTM1), T1 ( GSTT1), and P1 ( GSTP1, Ile105Val) to carotid atherosclerosis in 40 postmenopausal rheumatoid arthritic (RA) women without histories of smoking. We measured mean intima-media thickness (IMT) and plaque of the common carotid arteries by ultrasonography and evaluated relationships among the known risk factors for atherosclerosis, genetic polymorphisms, RA outcomes, and markers of inflammation. Subjects with the GSTT1-0 genotype had greater IMT ( P<0.05). On univariate analysis, carotid IMT was positively associated with age, systolic BP, antihypertensive drug use, and the GSTT1-0 genotype ( P<0.05). When compared to subjects with a double-positive GSTM1/T1 genotype, IMT in those with concurrent lack of the GSTM1 and GSTT1 genes was significantly increased ( P=0.008). This study suggests that the GSTT1-0 genotype might have an interaction with carotid atherosclerosis related to RA in Korean postmenopausal RA women without histories of smoking.

Acyltransferases↗
PubMed2002

Cyclooxygenase-2 inhibitor celecoxib inhibits promotion of mammary tumorigenesis in rats fed a high fat diet rich in n-6 polyunsaturated fatty acids.

The objective of this investigation was to determine whether celecoxib, a highly specific inhibitor of cyclooxygenase-2 (COX-2), inhibits the promotion phase of mammary tumorigenesis in rats fed a high fat diet rich in n-6 polyunsaturated fatty acids (PUFAs) that is known to induce COX-2 expression. Sixty female Sprague-Dawley rats were initially maintained on an AIN-93G diet. At 50 days of age they received a single i.p. injection of methylnitrosourea (MNU). One week later, all rats were switched to a modified AIN-93G diet containing 18% safflower oil plus 3% soybean oil. Half of the rats also began receiving 1500 ppm celecoxib in the diet and the control and experimental diets were continued for a further 23 weeks. Celecoxib significantly decreased both the final tumor incidence (63.3% in the celecoxib group versus 82.2% in the control group, P<0.05) and tumor multiplicity (0.9+/-0.2 tumors/rat in the celecoxib group versus 2.3+/-0.3 tumors/rat in the control group, P<0.05). At the termination of the experiment, body weights were significantly lower in the celecoxib group compared to controls (330.6+/-6.1 versus 401.5+/-10.9 g respectively, P<0.05) although there was no evidence of toxicity and food intakes were not different for the two groups. Fasting serum triglycerides and abdominal adipose tissue accumulation were lower in the celecoxib group compared to controls (49.3+/-4.4 versus 82.8+/-12.6 mg/dL, P<0.05, and 7.2+/-0.3 versus 11.3+/-0.4% of body weight, P<0.01, respectively). These results show that administration of celecoxib to rats in a high fat diet rich in n-6 PUFAs suppresses the promotion of mammary tumorigenesis induced by MNU. This inhibition may be due to the effects of celecoxib on lipid metabolism as well as COX-2.

Animals↗
PubMed2002

Effects of dietary conjugated linoleic acid on the expression of uncoupling proteins in mice and rats.

CLA inhibits mammary cancer and reduces body fat accumulation in rodents. It is not known whether uncoupling proteins (UCP), which are modulators of energy balance and metabolism, play a role in these actions of CLA. To determine the effects of dietary CLA on the expression of UCP in various tissues, 5-wk-old Sprague-Dawley rats and C57Bl/6 mice were fed diets containing 1% CLA for 3 wk. CLA treatment reduced adipose depot weights in both rats and mice but had no significant effects on body weight. There was a species-specific effect of CLA on the expression of UCP. Whereas CLA did not affect the expression of UCP in most tissues in rats, mice fed CLA had increased expression of UCP2 in the mammary gland, brown adipose tissue (BAT), and white adipose tissue (WAT). Furthermore, UCP1 and UCP3 mRNA and protein levels in BAT were significantly lower in CLA-fed mice compared to controls. Skeletal muscle UCP3 mRNA was unchanged, but UCP3 protein levels were significantly increased in mice, suggesting translational or posttranslational regulation of this protein. Results from this study suggest that alterations in the expression of UCP in mice may be related to the previously reported effects of dietary CLA in lowering adiposity and increasing FA oxidation. In rats, however, induction of UCP is not likely to be responsible for fat reduction or for the inhibitory action of CLA on mammary carcinogenesis.

Adipose Tissue, Brown↗
PubMed2002

Individual carotenoid concentrations in adipose tissue and plasma as biomarkers of dietary intake.

BACKGROUND: Plasma and adipose tissue concentrations of carotenoids are thought to reflect short- and long-term intakes of carotenoids, respectively. The ability of adipose tissue carotenoid concentrations to reflect dietary intake in population studies is unknown. OBJECTIVE: We examined the relation between intakes of the major dietary carotenoids and their concentrations in plasma and adipose tissue. DESIGN: A blood sample and an adipose tissue biopsy sample were collected from 115 women and 344 men in Costa Rica after they had fasted overnight, and a dietary interview based on a 135-item food-frequency questionnaire was administered. After carotenoid intake was adjusted for total energy intake and plasma concentrations were adjusted for HDL-, LDL-, and VLDL-cholesterol concentrations, we calculated partial Spearman correlation coefficients that were adjusted for age, sex, smoking, and body mass index. RESULTS: In women, the correlations (r) between intakes and concentrations of alpha-carotene, beta-carotene, beta-cryptoxanthin, and lutein+zeaxanthin were 0.25, 0.29, 0.44, and 0.17, respectively (P < 0.05 for r > or = 0.19), in adipose tissue and 0.26, 0.13, 0.55, and 0.22 in plasma. In men, these values were 0.04, 0.07, 0.23, and 0.06 in adipose tissue and 0.24, 0.22, 0.44, and 0.20 in plasma. In women and men, correlations for lycopene were higher in plasma (r = 0.19 and 0.35, respectively) than in adipose tissue (r = 0.14 and 0.26). The relative abundance of each carotenoid in the diet was similar to its distribution in plasma but not in adipose tissue. CONCLUSION: The usefulness of adipose tissue and plasma carotenoids as biomarkers of intake is similar, although correlations for individual carotenoids vary substantially.

Adipose Tissue↗