Nadia M. Hamdy

Effects of Nigella sativa oil and thymoquinone on oxidative stress and neuropathy in streptozotocin-induced diabetic rats.

We examined whether Nigella sativa (NS) oil and its active constituent thymoquinone (TQ) attenuate oxidative stress in the heart and brain in an experimental model of diabetes mellitus using streptozotocin (STZ). Oxidative stress was assessed by measuring cardiac and brain nitric oxide (NO), lipid peroxide levels, glutathione (GSH) and antioxidant enzyme activities, i.e. glutathione-S-transferase (GST) and catalase. Cardiac metabolic damage was estimated by measuring cardiac creatine kinase muscle and brain types (CK-MB). Brain monoamine levels were also evaluated. STZ diabetes induced a significant increase in heart and brain NO and malondialdehyde concentrations compared with the control group. These changes were attenuated by posttreatment of rats with NS oil and TQ. STZ diabetes induced oxidative stress via a significant decrease in GST, GSH and catalase. These lowered levels were improved by either NS oil or TQ administration. Serum CK-MB was decreased in the diabetic rats, which recovered with NS oil and TQ administration. During the course of diabetes, there was a marked increase in norepinephrine and dopamine concentrations and a marked decrease in serotonin concentration compared to the control group. These findings were partly reversed by oral administration of either NS oil or TQ. It is concluded that NS and TQ correct STZ-diabetes-induced alterations in CK-MB and brain monoamines due to their antioxidant properties.

New therapeutic aspect for carvedilol: Antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage

Portal hypertension is a common complication of chronic liver diseases associated with liver fibrosis and cirrhosis. At present, beta-blockers such as carvedilol remain the medical treatment of choice for protection against variceal bleeding and other complications. Since carvedilol has powerful antioxidant properties we assessed the potential antifibrotic effects of carvedilol and the underlying mechanisms that may add further benefits for its clinical usefulness using a chronic model of carbon tetrachloride (CCl4)-induced hepatotoxicity. Two weeks after CCl4 induction of chronic hepatotoxicity, rats were co-treated with carvedilol (10mg/kg, orally) daily for 6weeks. It was found that treatment of animals with carvedilol significantly counteracted the changes in liver function and histopathological lesions induced by CCl4. Also, carvedilol significantly counteracted lipid peroxidation, GSH depletion, and reduction in antioxidant enzyme activities; glutathione-S-transferase and catalase that was induced by CCl4. In addition, carvedilol ameliorated the inflammation induced by CCl4 as indicated by reducing the serum level of acute phase protein marker; alpha-2-macroglobulin and the liver expression of nuclear factor-kappa B (NF-κB). Finally, carvedilol significantly reduced liver fibrosis markers including hydroxyproline, collagen accumulation, and the expression of the hepatic stellate cell (HSC) activation marker; alpha smooth muscle actin. In conclusion, the present study provides evidences for the promising antifibrotic effects of carvedilol that can be explained by amelioration of oxidative stress through mainly, replenishment of GSH, restoration of antioxidant enzyme activities and reduction of lipid peroxides as well as amelioration of inflammation and fibrosis by decreasing collagen accumulation, acute phase protein level, NF-κB expression and finally HSC activation.

Evaluation of C-reactive protein, endothelin-1, adhesion molecule(s), and lipids as inflammatory markers in type 2 diabetes mellitus patients.

This study compared lipids, the product of lipid peroxidation malondialdehyde (MDA), the acute phase reactant high-sensitive C-reactive protein (hsCRP), endothelin-1 (ET-1), P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) between healthy controls, subjects with ischemic heart disease (IHD) and type 2 diabetes mellitus (DM) subjects who did not perform coronary artery bypass graft (CABG) surgery as well as type 2 DM subjects who performed CABG. HbA1c, lipids, MDA, hsCRP, ET-1, P-selectin, ICAM-1, and VCAM-1 levels were significantly higher in the diabetic groups than in either healthy controls or IHD subjects. In the diabetic groups, there was a negative association among hsCRP and HDL-C. ET-1, ICAM-1 levels, and TAG were positively correlated, as do the association between P-selectin, VCAM-1, and HbA1c%. Also a positive relation was found among hsCRP levels and ICAM-1, as well as MDA and ET-1. P-selectin and ICAM-1 were significantly positively correlated. This study indicates that increased level of oxidative stress marker, proinflammatory markers, and their downstream effectors adhesion molecules occur in type 2 DM.

Association of nonalcoholic fatty liver disease with a single nucleotide polymorphism on the gene encoding leptin receptor

Leptin (Lep), a 16‐kDa polypeptide hormone, exerts its action through the leptin receptor (LepRb), a member of the class I cytokine receptor family. Both leptin and LepRb probably have been implicated in pathogenesis of nonalcoholic fatty liver disease (NAFLD). This study was designed to assess the role of soluble leptin and LepRb in NAFLD and to investigate whether leptin receptor gene (LepR) single nucleotide polymorphism (SNP; ID rs6700896) influences NAFLD complicated with or without type 2 diabetes mellitus (T2DM). Blood samples from 90 obese NAFLD cases and 30 lean controls of matched age and sex were recruited in the study. Among the NAFLD patients, 32 were T2DM. Plasma leptin and LepRb levels were measured by enzyme linked immunoassay (ELISA). Lipids profile, glucose metabolic parameters, and insulin concentration were measured for all participants. Body mass index (BMI) and insulin resistance (IR) were calculated as well. Genotyping was done using SNP (rs6700986) for LepR gene. Significant difference was reported between NAFLD with or without T2DM and control regarding biochemical markers and LepR genotype and allele frequencies. Mutant homozygous and heterozygous LepR genotype and mutant allele were significantly higher in mild–severe steatosis and in NAFLD with T2DM when compared with mild steatosis and those without T2DM. Frequencies of mutant LepR polymorphism were significantly associated with IR increment. Elevated leptin level seems to be a feature of steatosis, and it appears to increase as hepatocyte steatosis develops. Moreover, polymorphism of LepR gene contributes to the onset of NAFLD by regulating lipid metabolism and affecting insulin sensitivity.

Levels of Soluble Advanced Glycation End Product-Receptors and Other Soluble Serum Markers as Indicators of Diabetic Neuropathy in the Foot

Objective Advanced glycation end products (AGEs) and the interaction with their receptors (RAGE) play an important role in the pathogenesis of diabetic foot (DF) associated with diabetic neuropathy. Our study examined the association between asymmetric dimethyl arginine (ADMA), fructosamine, nitric oxide (NO), and soluble (s) RAGE levels in serum of diabetic patients with and without neuropathy. Methods Circulating levels of ADMA, fructosamine, NO, and sRAGE, estimated either chemically or by enzyme-linked immunosorbent assay, were examined in 60 type 2 diabetes mellitus (T2DM) overweight/obese (body mass index, 30.5 ± 1.5 kg/m2) male patients and 20 age-matched (55 ± 3 years) obese healthy subjects as control group. The T2DM subjects were categorized as patients without DF (n = 30), and the remaining were patients with DF associated with neuropathy. Results First sRAGE levels were significantly increased in T2DM patients without DF in comparison to healthy controls (1656.6 [1198.8–2065.4] vs 1111.7 [909–1605.3] pg/mL, respectively; P < 0.05). However, in the DF group (1049.6 [783.7–1221.8] pg/mL), its level decreased significantly in comparison to both groups (P < 0.05). However, ADMA and fructosamine were significantly higher in diabetic patients with DF than both T2DM without DF and healthy controls. Moreover, NO was significantly lower in DF than in diabetic patients without DF and controls (5 ± 0.4 and 8 ± 0.4 vs 42 ± 2.5 μmol/L, respectively; P < 0.05). Finally, sRAGE levels were significantly correlated with ADMA, fructosamine, and NO. Conclusions Soluble forms of the receptor for advanced glycation end product could be an endogenous protection factor against occurrence of DF, hence may be of therapeutic value in the treatment of DF.

Clinical value of circulating lipocalins and insulin-like growth factor axis in pancreatic cancer diagnosis.

Objectives Early diagnosis of pancreatic cancer (PC) in diabetic patients is difficult owing to late presentation of symptoms. Hence, finding a marker to identify cancer stage early would be useful to improve survival. We aimed to determine levels of serum retinol binding protein 4 (RBP-4), neutrophil gelatinase–associated lipocalin (NGAL), insulin-like growth factor I (IGF-I), and its binding protein 3 (IGFBP-3) in patients with PC with preexisting type 2 diabetes. Moreover, we assessed their clinical usefulness in PC diagnosis and their association with tumor severity. Methods Twenty-three patients with PC, 32 diabetic patients, and 20 healthy controls were examined. Preoperative and postoperative samples were obtained from 15 patients with PC. Serum insulin, cancer antigen (CA 19-9), RBP-4, NGAL, IGF-I, and IGFBP-3 levels were estimated by enzyme-linked immunosorbent assay. Results Significant elevation in the levels of RBP-4 (60.1 [46.3–71.4] ng/mL), NGAL (142 [80–235] ng/mL), and IGF-I (174 [9.3] ng/mL) together with significant reduction in the level of IGFBP-3 (3669 [299] ng/mL) was found in patients with PC. Moreover, RBP-4 and NGAL levels were reduced in postoperative samples compared with preoperative ones. Receiver operating characteristic curve analysis revealed that they can distinguish PC from non-PC cases with significant area under the curve. Conclusions Retinol binding protein 4, NGAL, IGF-I, and IGFBP-3 are associated with PC in type 2 diabetic patients. They could be useful in distinguishing PC from non-PC cases when used in combination or with cancer antigen.

Influence of vitamin E supplementation on endothelial complications in type 2 diabetes mellitus patients who underwent coronary artery bypass graft

BACKGROUND Diabetes mellitus (DM) is associated with increased risk for complications following coronary artery bypass graft (CABG) surgery, in which tissue damage involves leukocyte-endothelial interactions mediated by endothelin-1 (ET-1) and adhesion molecules (AMs). AIM This study compared lipids and their peroxidation product, malondialdehyde (MDA), high-sensitivity C-reactive protein (hsCRP), ET-1, platelet-selectin (P-selectin), intercellular AM-1 (ICAM-1), and vascular cell AM-1 (VCAM-1) between healthy controls and type 2 DM subjects who did not receive CABG surgery as well as those who did. Vitamin E as an adjunctive therapy in subjects who underwent CABG was evaluated. METHODS ELISA was used to measure hsCRP, ET-1, and AMs. For all subjects, glycosylated hemoglobin (HbA(1c)) and lipid profile were estimated. RESULTS Percentage of HbA(1c), lipids, MDA, hsCRP, ET-1, P-selectin, ICAM-1, and VCAM-1 levels were significantly higher in the diabetic groups than in healthy controls. Vitamin E supplementation for 3 successive months significantly lowered MDA, hsCRP, ET-1, ICAM-1, and VCAM-1 levels by 64%, 47%, 12%, 74%, and 25%, respectively. However, high-density lipoprotein cholesterol (HDL-C) and vitamin E serum levels were increased by 65% and 90.55%, respectively (P<or=.05). Vitamin E cosupplementations correlated restored ET-1, P-selectin, and ICAM-1 levels, which have been functionally damaged by decreased HDL-C, hypercholesterolemia, and hypertriacylglycerolemia, respectively. CONCLUSION This study indicates that increased levels of the proinflammatory markers and AMs occur in type 2 DM. Vitamin E administration appears beneficial in lowering proinflammatory markers and their downstream effectors that played an important role in diabetic complications following CABG.

Adiponectin and sE-selectin concentrations in relation to inflammation in obese type 2 diabetic patients with coronary heart disease.

Adipose tissue can release proinflammatory mediators, namely C-reactive protein (CRP), interleukin 1β (IL-1β), and monocyte chemotactic protein 1 (MCP-1), contributing to vascular injury and insulin resistance (IR). Other mediators namely, adiponectin and nitric oxide (NO) are protective. We enrolled type 2 diabetes mellitus (T2DM) obese male patients without coronary heart disease ([CHD] group II, n = 25) and T2DM obese patients with CHD (group III, n = 25). They were compared with 20 age- and body mass index (BMI)-matched nondiabetic control males (group I). Fasting blood glucose (FBG), glycated hemoglobin (HbA1c%), lipids, insulin, malondialdehyde ([MDA]; lipid peroxidation product), NO, high-sensitivity CRP (hsCRP), IL-1β, MCP-1, adiponectin as well as sE-selectin concentration were significantly different in patients with T2DM and CHD compared with patients without CHD and nondiabetic controls (P = .01). There was a significant negative correlation between adiponectin and E-selectin (P = .0001). Adipose tissue in T2DM obese patients may contribute to the pathogenesis of CHD.

Serum retinol binding protein-4 and neutrophil gelatinase-associated lipocalin are interrelated in pancreatic cancer patients.

Objectives. Pancreatic cancer has an extremely dismal clinical course and high fatality rate. Knowing that, adipokines could regulate insulin resistance, inflammation, immunity and carcinogenesis. Accordingly, an understanding of adipokines in relation to pancreatic cancer could be useful to improve disease outcome. We aimed to determine serum retinol binding protein-4 (RBP-4) and neutophil gelatinase-associated lipocalin (NGAL) levels in pancreatic cancer patients. Moreover, we assessed their association with tumor severity and with each other. Methods. A total of 23 pancreatic cancer patients and 20 healthy controls were enrolled. Fifteen of the pancreatic cancer patients underwent Whipple resection and were examined before and after operation. Serum glucose, insulin, lipid profile, CA19-9, RBP-4 and NGAL were estimated by ELISA. Results. Significant elevation in serum concentrations of RBP-4 (64.4 ± 5.6 ng/ml) and NGAL (142(80–235) ng/ml) at p < 0.001 was found in pancreatic cancer patients. Both RBP-4 and NGAL were significantly lower after operation than before operation. Moreover, NGAL was elevated in advanced pathological T stage. Interestingly, RBP-4 and NGAL levels were positively correlated (r = 0.484, p = 0.05) and they are associated with some of the lipid profile parameters. Conclusions. Elevated serum RBP-4 and NGAL are associated with pancreatic cancer. They were positively interrelated; highlighting the possible interplay between them in pancreatic cancer.

Oxidative Stress and Platelet Activation: Markers of Myocardial Infarction in Type 2 Diabetes Mellitus

We compared lipids, lipid peroxidation product malondialdehyde (MDA), the acute phase reactant high-sensitivity C-reactive protein (hsCRP), interleukin 1β (IL-1β), and platelet selectin (P-selectin) between healthy controls, type 2 diabetes mellitus (DM) participants without myocardial infarction (MI), as well as type 2 DM participants with MI. Malondialdehyde, IL-1β, and P-selectin levels were significantly higher in the diabetic participants with MI than in either healthy controls or diabetic participants without MI. In the diabetic groups, fasting blood glucose (FBG) level, glycated hemoglobin (HbA1c), MDA, hsCRP, and P-selectin were all significantly positively correlated with each other. This study suggests that increased levels of oxidative stress markers, proinflammatory markers, and adhesion molecules contribute to the atherosclerotic process that eventually leads to coronary artery disease in diabetic patients.