Rasha H. Mohamed

The relationship between paraoxonase1-192 polymorphism and activity with coronary artery disease.

OBJECTIVE We tested the association between PON1 polymorphism, PON1 activity, oxidative susceptibility of LDL and coronary artery disease in Egyptians. METHODS PON1 polymorphism, serum PON1 activity, lipoprotein oxidation susceptibility and lipid profile were measured. RESULTS Levels of HDL and paraoxonase activity were significantly decreased in CAD patients compared to control group, and in patients with three vessels compared to those of single or two vessels disease. High-activity allele (R) has a more atherogenic lipid profile than for the low activity allele (Q). PON1 RR genotype has nine fold risks to develop CAD in Egyptians while those with PON1 QR genotype have four fold risks. CONCLUSION The PON1 activity is lower in subject with CAD and there is a significant relationship between activity of PON1 and the severity of coronary atherosclerosis. Also, we provide evidence of a significant association between R allele of the PON1 polymorphism and the development of coronary artery disease.

Epicatechin attenuates doxorubicin-induced brain toxicity: critical role of TNF-α, iNOS and NF-κB.

Doxorubicin (DOX) is considered one of the most important chemotherapeutic agents that is used for the treatment of solid tumors. Its long-term use can cause neurodegenerative disorders due to its prolonged activation of microglia. The present study proved that the use of epicatechin prior to DOX treatment significantly attenuated not only the increase in TNF-α, iNOS and NF-κB expressions but also the increase in TNF-α and total nitrite levels in brain tissue when compared with rats treated with DOX-only. Thus, our study revealed that epicatechin can be used for the treatment of neuroinflammation and also for preventing the development of neurodegenerative disease during antineoplastic therapy because of its protective role in attenuation of neurotoxic pro-inflammatory mediators including TNF-α, NF-κB, and iNOS.

Influence of TRAF1/C5 and STAT4 genes polymorphisms on susceptibility and severity of rheumatoid arthritis in Egyptian population.

Rheumatoid arthritis (RA) is the most common cause of adult inflammatory arthritis. Recent genome-wide association scans have disclosed several single-nucleotide polymorphisms associated with RA susceptibility. The aim of this study was to determine whether the polymorphisms of TRAF1/C5 (tumor necrosis factor (TNF)-receptor associated factor 1)/(complement component 5) and STAT4 (signal transducers and activators of transcription 4) confer susceptibility, activity and severity to RA in Egyptian populations. One hundred and seventy-two RA patients and 160 controls were enrolled in the study. Polymorphisms of TRAF1/C5 and STAT4 genes were determined using restriction fragment length polymorphism-polymerase chain reaction. The TRAF1/C5 A and STAT4 T alleles were significantly associated with RA in Egyptian population. TRAF1/C5 A allele and STAT4 TT genotype were significantly associated with RA severity. In conclusion the mutant alleles or genotypes of both examined polymorphisms are associated with the development of RA in Egyptian population.

Influence of transforming growth factor-β1 and tumor necrosis factor-α genes polymorphisms on the development of cirrhosis and hepatocellular carcinoma in chronic hepatitis C patients

BACKGROUND Host genetic factors may affect clinical outcomes of hepatitis C virus (HCV) infection; however, the possible mechanisms remain largely unknown. This study aimed to evaluate transforming growth factor-β1 (TGF-β1)-509 and tumor necrosis factor-α (TNF-α)-308 genes polymorphisms as a risk factors for cirrhosis and hepatocellular carcinoma (HCC) in chronic hepatitis C patients. MATERIALS AND METHODS Two hundred and eighty HCV patients (152 patients with cirrhosis, 128 patients with HCC) and 160 controls were enrolled in the study. Polymorphisms of TGF-β1-509 and TNF-α-308 gene were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum TGF-β1 and TNF-α were determined using ELISA. RESULTS TGF-β1-509 TT, TNF-α-308 AA and GA genotypes frequencies were significantly increased in cirrhotic and HCC groups. Serum TGF-β1 and TNF-α level were significantly increased in TGF-β1-509 TT and TNF-α-308 AA genotypes respectively. CONCLUSION TGF-β1-509 and TNF-α-308 genes polymorphisms are associated with risk of liver cirrhosis and HCC in patients with chronic HCV infection.

Effect of erythropoietin therapy on the progression of cisplatin induced renal injury in rats

Cisplatin is one of the most important chemotherapeutic agents useful in the treatment of a variety of solid tumors; however, it has several side effects such as nephrotoxicity. In the present study, the effect of rhEPO on acute kidney injury induced by i.p. injection of rats with 9.0 mg/kg cisplatin was studied. It was observed that EPO treated group showed a significantly lower rate in the extent and severity of the histological signs of kidney injury than untreated one. This is attributed to (i) a decrease in the elevated oxidative and nitrosative stress markers, (ii) reduction of the expression of VEGF, HO-1 and iNOS as well as (iii) improvement of Bcl2 immunoreaction in most tubular cells. Thus, EPO may be one of the futures therapeutic possibilities to overcome the side effects of anti-cancer drugs induced acute renal injury through various mechanisms including down regulation of vascular endothelial growth factor (VEGF), hemeoxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) expressions in addition to stimulation of tubular cell regeneration.

Frequent inadequate supply of micronutrients in fast food induces oxidative stress and inflammation in testicular tissues of weanling rats.

Fast food is high in energy density and low in essential micronutrient density, especially zinc (Zn), of which antioxidant processes are dependent. We have tested the hypothesis that frequent fast food consumption could induce oxidative damage associated with inflammation in weanling male rats in relevance to Zn deprivation, which could adversely affect testis function. Zn and iron (in plasma and testicular tissue), plasma antioxidant vitamins (A, E, and C), as well as testicular superoxide dismutase (SOD) and reduced glutathione (GSH), lipid peroxidation indexes (thiobarbituric acid reactive substances (TBARS) and lipoprotein oxidation susceptibility (LOS)), and inflammatory markers (plasma C‐reactive protein (CRP) and testicular tumour necrosis factor‐alpha (TNF‐α)) were determined. Serum testosterone and histological examination of the testis were performed also. We found a severe decrease in antioxidant vitamins and Zn, with concomitant iron accumulation. Zinc deficiency correlated positively with SOD, GSH, anti‐oxidant vitamins and testosterone, and negatively with TBARS, LOS, CRP and TNF‐α, demonstrating a state of oxidative stress and inflammation. We concluded that micronutrient deficiency, especially Zn, enhanced oxidative stress and inflammation in testicular tissue leading to under‐development of testis and decreased testosterone levels.

Increased risk of premature coronary artery disease in Egyptians with ABCA1 (R219K), CETP (TaqIB), and LCAT (4886C/T) genes polymorphism

BACKGROUND Epidemiological studies have shown a strong inverse relationship between high-density lipoprotein (HDL) cholesterol (HDLc) levels and coronary artery disease (CAD), and a low concentration of plasma HDLc is considered an independent risk factor for premature atherosclerosis. Mutations in ATP-binding cassette A1 transporter (ABCA1), cholesteryl ester transfer protein (CETP), and lecithin: cholesterol acyltransferase (LCAT) reduce HDLc in humans. OBJECTIVE To date, no study had tested the association between these polymorphisms and premature CAD (PCAD) in the Egyptian population. Here we searched for ABCA1 (rs2230806), CETP (rs708272), and LCAT (rs5923) mutations in the Egyptian population and investigated the possible association between these gene polymorphisms and PCAD. We aimed to investigate the association between ABCA1, CETP, and LCAT gene polymorphisms and PCAD in Egyptians. METHODS A total of 235 Egyptians-116 with documented PCAD (PCAD group) and 119 controls-were enrolled in the study. RESULTS Mutation carriers with low HDLc had an elevated risk of PCAD (odds ratio [OR] = 11.38 for ABCA1 mutation carriers, P = .000; OR = 5.41 for CETP mutation carriers, P = .000; OR = 5.92 for LCAT mutation carriers, P = .000). Moreover, mutations in ABCA1, CETP, and LCAT were significantly associated with hyperlipidemia in this study. CONCLUSION These observations show that the R allele of ABCA1, the B1 allele of CETP, and the T allele LCAT genes are associated with PCAD in Egyptians. They have more considerable effect on patients with low HDLc.

Leptin, leptin gene and leptin receptor gene polymorphism in heart failure with preserved ejection fraction

Heart failure with a normal ejection fraction (HFNEF) is common in obesity and coronary artery disease (CAD). Both ischemia and reperfusion induce leptin (LEP) and leptin receptor (LEPR) gene expression. We aimed to investigate the possible associations of serum leptin, leptin gene and leptin receptor gene polymorphism with HFNEF in patients with CAD. 100 Egyptian CAD patients with HFNEF and 100 healthy subjects (the control group) were genotyped for LEP and LEPR polymorphism. Leptin levels were measured. Serum leptin levels were significantly increased in patients compared to the control group. There was a significant increase in the leptin gene (AA genotype) and the leptin receptor gene (RR genotype) in HFNEF patients compared to the control group. Leptin levels, leptin gene (AA genotype) and LEPR (RR genotype) were more associated with NYHA III than with NYHA I and II. We thus concluded that HFNEF is associated with increased serum leptin levels, and the LEP AA genotype or LEPR RR genotype carries at least a threefold increased risk of developing HFNEF.

Association of lipoprotein lipase and apolipoprotein C-III genes polymorphism with acute myocardial infarction in diabetic patients

Lipoprotein lipase (LPL) and Apolipoprotein C-III (APOC-III) play an important role in lipid metabolism. The aim of this study was to explore the possible associations of the gene polymorphisms (LPL HindIII, LPL Ser447-Ter and APOC3 SstI), diabetes mellitus, and plasma lipids with myocardial infarction. The polymorphisms were assessed by restriction assay in 200 Egyptian MI patients (100 diabetic and 100 non-diabetic) and 100 healthy controls. This study demonstrated that individuals with the H2H2 genotype or S2 allele have more than three times higher relative risk of suffering from MI than those carrying the H1H1 or S1S1. Type 2 DM mainly lowers HDL-C levels in MI patients who carry H2H2 or S2S2 genotype and increases TC, TG, and LDL levels in MI patients carrying H2H2 or S2S2 genotype compared with non-diabetic MI patients carrying the same genotypes. In S447X polymorphism, it was observed that DM led to loss of the protective lipid profile in MI patients carrying 447XX genotype. These findings suggest that H2H2 or S2S2 genotypes are associated with dyslipidemia and increased risk of myocardial infarction. The S447X polymorphism is associated with a favorable lipid profile. However, the association of diabetes mellitus with these polymorphisms leads to unfavorable lipid profile.

Human C-reactive protein gene polymorphism and metabolic syndrome are associated with premature coronary artery disease

The aim of this study was to investigate the association between C-reactive protein (CRP) gene polymorphism and metabolic syndrome (MetS) with premature coronary artery disease (PCAD). 116 patients with PCAD (58 with MetS and 58 without MetS) and 119 controls were included in the study. CRP gene +1059 G>C polymorphism was analyzed by polymerase chain reaction. Serum hs-CRP was measured using high-sensitivity enzyme-linked immunosorbent assay. Carriers of C allele of the CRP +1059 G>C polymorphism had 3.37 fold increased risk to develop MetS in patients with PCAD. In addition CRP gene and hs-CRP levels were independent risk factors for PCAD and MetS. The present study provides new evidence that the presence of CRP +1059 G>C polymorphism and hs-CRP levels are independent determinants of PCAD and MetS in Egyptians. The results of our study suggest a synergistic effect of CRP C allele with classical risk factors such as hypertension, obesity, dyslipidemia and MetS.