Sitagliptin protects diabetic rats with acute myocardial infarction through induction of angiogenesis: role of IGF-1 and VEGF.

Angiogenesis is regulated in a tissue-specific manner in all patients, especially those with diabetes. In this study, we describe a novel molecular pathway of angiogenesis regulation in diabetic rats with myocardial infarction (MI) and examine the cardioprotective effects of different doses of sitagliptin. Male rats were divided into 5 groups: normal vehicle group, diabetic group, diabetic + MI, diabetic + MI + 5 mg/kg sitagliptin, and diabetic + MI + 10 mg/kg sitagliptin. Isoproterenol in diabetic rats resulted in significant (p < 0.05) disturbance to the electrocardiogram, cardiac histopathological manifestations, and an increase in inflammatory markers compared with the vehicle and diabetic groups. Treatment with sitagliptin improved the electrocardiogram and histopathological sections, upregulated vascular endothelial growth factor (VEGF) and transmembrane phosphoglycoprotein protein (CD34) in cardiac tissues, and increased serum insulin-like growth factor 1 (IGF-1) and decreased cardiac tissue homogenate for interleukin 6 (IL-6) and cyclooxygenase 2 (COX-2). A relationship was found between serum IGF-1 and cardiac VEGF and CD34 accompanied by an improvement in cardiac function of diabetic rats with MI. Therefore, the observed effects of sitagliptin occurred at least partly through an improvement in angiogenesis and the mitigation of inflammation. Consequently, these data suggest that sitagliptin may contribute, in a dose-dependent manner, to protection against acute MI in diabetic individuals.

Effect of mesenchymal stem cells and melatonin on experimentally induced peripheral nerve injury in rats.

Injury of a peripheral nerve (PNI) leads to both ischemic and inflammatory alterations. Sciatic nerve injury (SNI) represents the most widely used model for PNI. Mesenchymal stem cell-based therapy (MSCs) has convenient properties on PNI by stimulating the nerve regeneration. Melatonin has cytoprotective activity. The neuroprotective characteristics of MSCs and melatonin separately or in combination remain a knowledge need. In the rats-challenged SNI, therapeutic roles of intralesional MSCs and intraperitoneal melatonin injections were evaluated by functional assessment of peripheral nerve regeneration by walking track analysis involving sciatic function index (SFI) and two electrophysiological tests, electromyography and nerve conduction velocity, as well as measurement of antioxidant markers in serum, total antioxidant capacity (TAC) and malondialdehyde, and mRNA expression of brain derived neurotrophic factor (BDNF) in nerve tissues in addition to the histopathological evaluation of nerve tissue. Both individual and combination therapy with MSCs and melatonin therapies could effectively ameliorate this SNI and promote its regeneration as evidenced by improving the SFI and two electrophysiological tests and remarkable elevation of TAC with decline in lipid peroxidation and upregulation of BDNF levels. All of these led to functional improvement of the damaged nerve tissues and good recovery of the histopathological sections of sciatic nerve tissues suggesting multifactorial synergistic approach of the concurrent usage of melatonin and MSCs in PNI. The combination regimen has the most synergistic neuro-beneficial effects in PNI that should be used as therapeutic option in patients with PNI to boost their quality of life.

Plasma thrombin-activatable fibrinolysis inhibitor levels and Thr325Ile polymorphism as a risk marker of myocardial infarction in Egyptian patients.

OBJECTIVE: The objective of this study was to investigate whether thrombin activatable fibrinolytic inhibitor (TAFI) Thr325Ile polymorphism and TAFI antigen (Ag) levels could constitute a risk marker of myocardial infarction (MI) in Egyptian patients. STUDY POPULATION AND RESULTS: The study included forty-six patients with acute MI (mean age 55.7 +/- 8.1 years, 33 men, 13 women) compared with age and sex-matched healthy volunteers (n = 54) as a control group. Clinical examination, laboratory investigations, electrocardiography (ECG) and/or echocardiography were done. TAFI Thr325Ile (reference sequence: rs1926447) polymorphism was genotyped in both studied groups using TaqMan SNP (single nucleotide polymorphism) genotyping assay. The genotypes of the high-risk allele [Thr/Ile (CT) and Ile/Ile (TT)] were significantly more frequent in patients compared with the control group (54.4% and 32.6% vs. 51.8% and 5.6%, respectively) and were also associated with an increased risk of MI [OR = 4.95, (95% CI: 1.80 - 13.63); P = 0.0001]. Ile325 allele carriers were more frequent in cases than in control subjects (60.0% vs. 31.5%) [OR = 3.26, (95% CI = 1.82 - 5.83), P = 0.001]. The Thr325Ile SNP significantly correlated with TAFI antigen levels with the C/C genotype corresponding with the highest and the T/T genotype with the lowest TAFI antigen levels (P < 0.001). No statistically significant relation was found between TAFI Thr325Ile polymorphism and either the type or the site of MI. CONCLUSIONS: TAFI Thr325Ile and its respective plasma protein level could have a contribution to MI risk in the Egyptian population.This could be helpful in refining a risk profile for coronary heart disease (CHD) patients.

Comparing the effects of inorganic nitrate and allopurinol in renovascular complications of metabolic syndrome in rats: role of nitric oxide and uric acid.

INTRODUCTION: The epidemic of metabolic syndrome is increasing worldwide and correlates with elevation in serum uric acid and marked increase in total fructose intake. Fructose raises uric acid and the latter inhibits nitric oxide bioavailability. We hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome and treatment of hyperuricemia or increased nitric oxide may improve it. MATERIAL AND METHODS: Two experiments were performed. Male Sprague-Dawley rats were fed a control diet or a high-fructose diet to induce metabolic syndrome. The latter received either sodium nitrate or allopurinol for 10 weeks starting with the 1(st) day of fructose to evaluate the preventive role of the drugs or after 4 weeks to evaluate their therapeutic role. RESULTS: A high-fructose diet was associated with significant (p < 0.05) hyperuricemia (5.9 ±0.5 mg/dl), hypertension (125.2 ±7.8 mm Hg), dyslipidemia and significant decrease in tissue nitrite (27.4 ±2.01 mmol/l). Insulin resistance, as manifested by HOMAIR (20.6 ±2.2) and QUICKI (0.23 ±0.01) indices, as well as adiposity index (12.9 ±1.1) was also significantly increased (p < 0.1). Sodium nitrate or allopurinol was able to reverse these features significantly (p < 0.05) in the preventive study better than the therapeutic study. CONCLUSIONS: Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid. Either sodium nitrate or allopurinol can prevent this pathological condition by different mechanisms of action.