Hala O. El-Mesallamy

Vaspin and visfatin/Nampt are interesting interrelated adipokines playing a role in the pathogenesis of type 2 diabetes mellitus.

Recently, vaspin and visfatin/Nampt have been identified as interesting novel adipokines having insulin-sensitizing and insulin-mimetic effects, respectively. However, the relationship between them has not been elucidated; and their circulating levels in type 2 diabetes mellitus (T2DM) have not been adequately studied. Therefore, this study was designed to investigate whether their levels are altered in Egyptian T2DM patients and to study the correlation of these novel adipokines with each other and with insulin resistance, interleukin-6 (IL-6), and other biochemical parameters. The levels of vaspin, visfatin/Nampt, IL-6, insulin, and other parameters were measured in nonobese and obese T2DM patients together with matched healthy nondiabetic control subjects. Vaspin, visfatin/Nampt, and IL-6 levels were measured by enzyme-linked immunosorbent assay, whereas insulin levels were measured by chemiluminescence technique. Vaspin and visfatin/Nampt levels were found to be significantly elevated in nonobese (1.62 ± 0.22 and 25.9 ± 3.44 ng/mL, respectively) and obese T2DM patients (2.76 ± 0.38 and 45.4 ± 4.60 ng/mL, respectively) compared with control subjects (0.42 ± 0.05 and 9.37 ± 1.98 ng/mL, respectively) at P < .01. In addition, vaspin and visfatin/Nampt levels were found to be significantly positively correlated with each other and with other biochemical parameters. In conclusion, both vaspin and visfatin/Nampt might play an important role in the pathogenesis of T2DM. In addition, the 3 adipokines--vaspin, visfatin/Nampt, and IL-6--are significantly interrelated with each other. Other possible mechanisms of action for vaspin should be considered besides the inhibition of unknown substrate proteases.

REST Regulates Oncogenic Properties of Glioblastoma Stem Cells

Glioblastoma multiforme (GBM) tumors are the most common malignant primary brain tumors in adults. Although many GBM tumors are believed to be caused by self‐renewing, glioblastoma‐derived stem‐like cells (GSCs), the mechanisms that regulate self‐renewal and other oncogenic properties of GSCs are only now being unraveled. Here we showed that GSCs derived from GBM patient specimens express varying levels of the transcriptional repressor repressor element 1 silencing transcription factor (REST), suggesting heterogeneity across different GSC lines. Loss‐ and gain‐of‐function experiments indicated that REST maintains self‐renewal of GSCs. High REST‐expressing GSCs (HR‐GSCs) produced tumors histopathologically distinct from those generated by low REST‐expressing GSCs (LR‐GSCs) in orthotopic mouse brain tumor models. Knockdown of REST in HR‐GSCs resulted in increased survival in GSC‐transplanted mice and produced tumors with higher apoptotic and lower invasive properties. Conversely, forced expression of exogenous REST in LR‐GSCs produced decreased survival in mice and produced tumors with lower apoptotic and higher invasive properties, similar to HR‐GSCs. Thus, based on our results, we propose that a novel function of REST is to maintain self‐renewal and other oncogenic properties of GSCs and that REST can play a major role in mediating tumorigenicity in GBM. STEM CELLS 2012;30:405–414

Thymoquinone blocks lung injury and fibrosis by attenuating bleomycin-induced oxidative stress and activation of nuclear factor Kappa-B in rats

Pulmonary fibrosis is one of the most common chronic interstitial lung diseases with high mortality rate after diagnosis and limited successful treatment. The present study was designed to assess the potential antifibrotic effect of thymoquinone (TQ) and whether TQ can attenuate the severity of oxidative stress and inflammatory response during bleomycin-induced pulmonary fibrosis. Male Wister rats were treated intraperitoneally with either bleomycin (15 mg/kg, 3 times a week for 4 weeks) and/or thymoquinone (5mg/kg/day, 1 week before and until the end of the experiment). Bleomycin significantly increased lung weight and the levels of Lactate dehydrogenase, total leucocytic count, total protein and mucin in bronchoalveolar lavage and these effects were significantly ameliorated by TQ treatment. As markers of oxidative stress, bleomycin caused a significant increase in the levels of lipid peroxides and nitric oxide accompanied with a significant decrease in the antioxidant enzyme activity of superoxide dismutase and glutathione transferase. TQ treatment restored these markers toward normal values. TQ also counteracted emphysema in air alveoli, inflammatory cell infiltration, lymphoid hyperplastic cells activation surrounding the bronchioles and the over expression of activated form of nuclear factor kappa-B (NF-B) in lung tissue that was induced by bleomycin. Fibrosis was assessed by measuring hydroxyproline content, which increased markedly in the bleomycin group and significantly reduced by concurrent treatment with TQ. Furthermore, histopathological examination confirmed the antifibrotic effect of TQ. Collectively these findings indicate that TQ has potential antifibrotic effect beside its antioxidant activity that could be through NF-κB inhibition.

Oxidative Stress and Asymmetric Dimethylarginine Are Associated with Cardiovascular Complications in Hemodialysis Patients: Improvements by L-Arginine Intake

Background/Aim: High incidence of cardiovascular disease (CVD) in chronic kidney disease (CKD) patients is a result of an interlaced relation between oxidative stress, endothelial dysfunction (ED) and inflammation. This study tries to investigate the development of these processes in CKD patients receiving conservative treatment or on hemodialysis (HD). We also examined the modulating effect of oral L-arginine in HD patients having CVD. Methods: The study included 12 healthy volunteers and 63 renal patients divided into 15 renal impairment, 18 HD free of CVD, and 30 HD suffering from CVD (HD+CVD). Of the latter, 15 patients were given oral L-arginine (15 g/day, 5 g t.i.d.) for 1 month. Blood levels of asymmetric dimethylarginine (ADMA), malondialdehyde (MDA), and homocysteine and myeloperoxidase activity (MPO) were estimated. Results: ADMA, MDA and homocysteine were significantly elevated in renal impairment group. HD and HD+CVD patients experienced higher levels, along with high MPO activity. Significant reduction by 21, 46, 11, and 26%, respectively, in the aforementioned parameters was observed in HD+CVD patients following L-arginine intake. Conclusion:We recommend considering ADMA, MDA, homocysteine and MPO as potentially important cardiovascular risk factors in CKD patients, and focus the attention to the cardiovascular advantages of L-arginine in these patients.

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.

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.

Expression of inhibitor of apoptosis protein (IAP) livin/BIRC7 in acute leukemia in adults: Correlation with prognostic factors and outcome

The clinical relevance of livin/BIRC7 expression is still controversial in different types of malignancies, therefore this study was designed to evaluate the gene expression of livin in Egyptian adult AML and ALL. Livin expression level was higher in patients with unfavorable prognostic factors at diagnosis in both ALL (p=0.002) and AML (p=0.042) and its level was negatively correlated with event free survival (EFS) and overall survival (OS) in both ALL (p<0.001for both) and AML (p=0.001 and 0.023 respectively). This study suggests that livin expression is a novel prognostic marker in adult acute leukemia and thus needs to be incorporated into the patient stratification and treatment protocols.

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.