Predominant monomorphism of the RIT2 and GPM6B exceptionally long GA blocks in human and enriched divergent alleles in the disease compartment.

Across human protein-coding genes, the human neuron-specific genes, RIT2 and GPM6B, contain the two longest GA short tandem repeats (STRs) of 11 and 9-repeats, respectively, the length ranges of which are functional, and result in gene expression alteration. Here we sequenced the RIT2 and GPM6B STRs in 600 human subjects, consisting of late-onset neurocognitive disorder (n = 200), multiple sclerosis (n = 200), and controls (n = 200). Furthermore, we selected two large human databases, including the general-population-based gnomAD ( https://gnomad.broadinstitute.org ) and a mainly disease-phenotype-archiving database, TOPMed ( https://www.nhlbiwgs.org ), to compare allele frequencies in the general populations vs. the disease compartment. The RIT2 and GPM6B GA-repeats were monomorphic in the human subjects studied, at lengths of 11 and 9-repeats, respectively, and were predominantly human-specific in formula. Exception included a 9/11 genotype of the RIT2 GA-STR in an isolate case of female multiple sclerosis. Exceedingly rare alleles of the two GA repeats were significantly enriched in TOPMed vs. the gnomAD. We report prime instances of predominant monomorphism for specific lengths of STRs in human, and possible enrichment of rare divergent alleles in the disease phenotype compartment. While STRs are most attended because of their high polymorphic nature, STR monomorphism is an underappreciated feature, which may have a link with natural selection and disease.

Evolving evidence on a link between the ZMYM3 exceptionally long GA-STR and human cognition.

The human X-linked zinc finger MYM-type protein 3 (ZMYM3) contains the longest GA-STR identified across protein-coding gene 5' UTR sequences, at 32-repeats. This exceptionally long GA-STR is located at a complex string of GA-STRs with a human-specific formula across the complex as follows: (GA)8-(GA)4-(GA)6-(GA)32 (ZMYM3-207 ENST00000373998.5). ZMYM3 was previously reported among the top three genes involved in the progression of late-onset Alzheimer's disease. Here we sequenced the ZMYM3 GA-STR complex in 750 human male subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 268) and matched controls (n = 482). We detected strict monomorphism of the GA-STR complex, except of the exceptionally long STR, which was architecturally skewed in respect of allele distribution between the NCD cases and controls [F (1, 50) = 12.283; p = 0.001]. Moreover, extreme alleles of this STR at 17, 20, 42, and 43 repeats were detected in seven NCD patients and not in the control group (Mid-P exact = 0.0003). A number of these alleles overlapped with alleles previously found in schizophrenia and bipolar disorder patients. In conclusion, we propose selective advantage for the exceptional length of the ZMYM3 GA-STR in human, and its link to a spectrum of diseases in which major cognition impairment is a predominant phenotype.

Ghrelin did not change coronary angiogenesis in diet-induced obese mice.

Ghrelin is a 28 amino acids peptide that initially was recognized as an endogenous ligand for growth hormone secretagogue receptor (GHSR). Recently, a number of studies demonstrated that ghrelin is a cardiovascular hormone with a series cardiovascular effect. The main objective of this study was to investigate the effect of systemic ghrelin administration on angiogenesis in the heart and its correlation with serum leptin levels in normal and diet-induced obese mice. 24 male C57BL/6 mice were randomly divided into four groups: normal diet (ND) or control, ND+ghrelin, high-fat-diet (HFD) or obese and HFD+ghrelin (n=6/group). Obese and control groups received HFD or ND, respectively, for 14 weeks. Then, the ghrelin was injected subcutaneously 100µg/kg twice daily. After 10 days, the animals were sacrificed, blood samples were taken and the hearts were removed. The angiogenic response in the heart was assessed by immunohisochemical staining. HFD significantly increased angiogenesis in the heart expressed as the number of CD31 positive cells than standard diet. Ghrelin did not alter angiogenesis in the heart in both obese and control groups, however, it reduced serum nitric oxide (NO) and leptin levels in obese mice. There was a strong positive correlation between the number of CD31 positive cells and serum leptin concentration (r=0.74). Leptin as an angiogenic factor has a positive correlation with angiogenesis in the heart. Although systemic administration of ghrelin reduced serum leptin and NO levels in obese mice, however, it could not alter coronary angiogenesis.

Association between the cytotoxic T-lymphocyte antigen-4 mutations and the susceptibility to systemic lupus erythematosus; Contribution markers of inflammation and oxidative stress.

The cytotoxic T lymphocyte antigen-4 (CTLA-4) also known as CD152 (cluster of differentiation 152) is a crucial negative regulator of the immune system. This protein receptor provides negative signals in order to suppress T-cell activation and immune attack against self-antigens, although its role is unclear.  The ability of CTLA-4 to limit T cell-mediated immune response has made it a major target in treatment of tumors and autoimmune diseases such as systemic lupus erythematosus (SLE). In this study, we investigated whether CTLA-4 G-1661A and CTLA-4 T-1722C mutations are associated with SLE. So one hundred nine SLE patients and 101 gender and age-matched unrelated healthy controls were recruited for this case-control study. The promoter mutations were detected by PCR-RFLP, neopterin, malondialdehyde (MDA) and serum lipid concentration were determined by HPLC and enzyme assay, respectively. RESULT: We found that both codominant (AA vs. GG) and recessive (AA vs. GA+GG) CTLA-4 G-1661A mutation significantly decreased the risk of SLE by 1.7 and 3.7 times, respectively.  Interestingly, SLE patients with AA genotypes of CTLA-4 G-1661A have lower neopterin and MDA concentration compared with GA+GG genotypes. The overall distribution of CTLA-4 T-1722C genotypes and alleles in SLE patients were similar to those in control group. In conclusion, our findings showed, that there is an association between systemic inflammatory markers, oxidative stress and the CTLA-4 G-1661A GG+AG genotypes, MDA and neopterin which are the most conventional risk factors for coronary heart disease, therefore these mutations may be consider as a risk factor for susceptibility to heart disease in SLE patients.

Physalis alkekengi and Alhagi maurorum ameliorate the side effect of cisplatin-induced nephrotoxicity.

Cisplatin is frequently being used for the treatment of different tumors, although the application of this agent is associated with nephrotoxicity. Here, we explored the antioxidant and anti-inflammatory activities of Physalis alkekengi and Alhagi maurorum; 400 mg kg(-1) per day P. alkekengi and 100 mg kg(-1) per day A. maurorum were administered in rats, orally for 10 days after a single dose of 7 mg kg(-1) intraperitoneal cisplatin. The concentrations of creatinine, urea-nitrogen, and relative and absolute excretion of sodium/potassium were evaluated before/after therapy. Levels of malondialdehyde (MDA) and ferric-reducing antioxidant power (FRAP) were measured to assess the oxidative stress induced by cisplatin. Moreover, tissues sections were used for histological analyses and evaluation of the degree of tissue damage. Cisplatin increased serum levels of creatinine and urea-nitrogen, relative/absolute excretion of sodium/potassium, and MDA, whereas decreased FRAP level. Interestingly, P. alkekengi or A. maurorum were able to reduce the level of the renal function markers as well as the levels of sodium/potassium. This effect was more pronounced by P. alkekengi. Moreover, cisplatin induced pathological damage in kidney, whereas treatment with these agents improved this condition. Our findings demonstrate the potential therapeutic impact of P. alkekengi and A. maurorum for improving cisplatin-induced nephrotoxicity, supporting further investigations on the novel potential clinical application of these agents for patients being treated with cisplatin to ameliorate cisplatin-induced nephrotoxicity.

Morphometric and hormonal study of the effect of utrica diocia extract on mammary glands in rats / Estudio morfométrico y hormonal del efecto de extracto de utrica diocia en glándulas mamarias en ratas

Urtica diocia is a multipurpose herb in traditional medicine. Its hydroalcoholic extract (20, 50 and 100 mg/kg) administered interaperitoneally to Wistar female rats for 21 consequent days resulted in significant increase in the number of alveoli of mammary glands in doses of 20 and 50 mg/kg. Changes in serum prolactin and alveolar diameter were not significant in comparison with control group. Also, there was an increase in serum prolactin and alveolar diameter in doses of 20 and 50 mg/kg. Utrica diocia extract has positive effects on mammary glands.

Urtica diocia es una hierba de usos múltiples en la medicina tradicional. Su extracto hidroalcohólico (20, 50 y 100 mg/kg) administrado por vía intraperitoneal en ratas hembras Wistar de 21 días resultaron en un aumento significativo en el número de alvéolos de las glándulas mamarias en dosis de 20 y 50 mg/kg. Los cambios en la prolactina sérica y el diámetro alveolar no fueron significativos en comparación con el grupo control. Además, hubo un aumento en la prolactina sérica y en el diámetro alveolar en dosis de 20 y 50 mg/kg. El extracto de Urtica diocia tiene efectos positivos sobre las glándulas mamarias.

Gamma-secretase inhibitor does not modulate angiogenesis in colon adenocarcinoma in obese mice.

BACKGROUND: Notch is a signaling molecule which plays a role in angiogenesis and γ-secretase is required for processing of Notch. In this study, we investigated the effect of γ-secretase inhibitor (DAPT) on tumor angiogenesis in diet-induced obese mice. METHODS: 18 mice were divided into three groups; control, obese (diet-induced) and obese+DAPT. After 15 weeks, the obese mice were subjected for tumor induction of CT26 colon adenocarcinoma cells (5 x 105 cells). When the tumor size reached approximately 350 ± 50 mm3, half of the obese animals received DAPT (10mg/kg/day) subcutaneously. Blood samples were taken after 14 days and the tumors harvested for immunohistochemical staining and capillary density were reported as CD31 positive cells/mm2. RESULTS: The obese animals had higher serum leptin and NO concentrations, while, serum VEGF and VEGFR-1 concentrations were not different compare to control group. Administration of DAPT in obese mice significantly reduced serum VEGFR-1 and leptin concentrations and increased serum NO level (p < 0.05). Capillary density in the tumors of obese animals was not different compare to control groups. DAPT administration could not alter capillary density in the tumors. CONCLUSION: Administration of DAPT in obese mice altered serum angiogenic factors, however, it could not modulate tumor angiogenesis in diet-induced obese mice (Fig. 4, Ref. 26).

Systemic administration of ghrelin did not restore angiogenesis in hindlimb ischemia in control and diet-induced obese mice.

BACKGROUND: Ghrelin is a novel growth hormone releasing peptide that mainly regulates food intake and energy homeostasis, however, recently, it is indicated that it may be closely related with physiological and/or pathological angiogenesis. OBJECTIVES: The objective of the present study was to evaluate the effect of systemic ghrelin administration on angiogenesis in hindlimb ischemia in normal and diet-induced obese mice. METHODS: 24 male C57BL/6 mice were fed with high-fat diet (HFD) or standard for 14 weeks. Then, the mice underwent unilateral hindlimb ischemia. Next, each group was divided into the two subgroups: treatment with ghrelin (100 µg/kg, twice daily, Sc) or without treatment. After 10 days, the animals were sacrificed, blood samples were taken and the gastrocnemius muscles removed. RESULTS: There was no significant difference in capillary/fiber ratio in hind limb ischemia between obese and control groups. Administration of ghrelin reduced serum nitric oxide (NO) and leptin and increased vascular endothelial growth factor (VEGF) concentrations in obese mice, however, did not change the capillary/fiber ratio in ischemic legs. CONCLUSION: Systemic administration of ghrelin did not restore angiogenesis in hindlimb ischemia in control and diet-induced obese mice (Fig. 4, Ref. 35).

The effect of walnut on the weight, blood glucose and sex hormones of diabetic male rats / Efecto del nogal sobre el peso, glucosa en la sangre y hormonas sexuales de ratas macho diabéticas

Diabetes leads to reproductive dysfunctions by producing free radicals. It seems that using walnut can be effective in the damage induced by diabetes. The aim of the present study was to evaluate the effects of walnut consumption on sex hormones in diabetic Wistar male rats induced by STZ (streptozotocin). Diabetes animals were induced by STZ (60 mg/kg). Rats were randomly divided into 5 groups (n=6), including normal diet and healthy (Sham), Diabetic by normal diet (control) and diabetic by 6, 9 and 12% walnut in their diet (experimental groups), and were examined for 6 weeks. Body weight, blood glucose (3 times), and sex hormones (testosterone, FSH and LH) were measured. Overall, in terms of the mean index, there was a significant difference in the percentage of weight changes between the groups (p<0.001). Blood glucose (3 times) significantly increased in experimental and control groups in comparison with sham group (p<0.001). FSH concentration significantly decreased in control group (p<0.05) and testosterone hormone decreased in experimental and control groups compared to sham group (p<0.05). Oral administration of walnut seems to prevent severe weight loss in the experimental models of diabetic rats and exerts appropriate and useful changes in blood glucose level as well as positive effects on the secretion of sex hormones.

La diabetes conduce a disfunciones reproductivas mediante la producción de radicales libres. Parece que el uso del nogal puede ser eficaz para contrarestar el daño inducido por la diabetes. El objetivo fue evaluar los efectos del consumo de nueces sobre las hormonas sexuales en ratas Wistar macho diabéticas, inducidas por estreptozotocina (STZ). La diabetes en los animales fue inducida por STZ (60 mg/kg). Los animales fueron divididos aleatoriamente en 5 grupos (n= 6 ): saludable con dieta normal (Sham), diabéticos con dieta normal (control) y diabéticos con consumo de nogal en 6, 9 y 12% en su dieta (grupos experimentales), quienes se examinaron durante 6 semanas, donde se midieron el peso corporal, glucosa en la sangre (3 veces) y hormonas sexuales (testosterona , FSH y LH). En general, en términos del índice promedio, hubo una diferencia significativa en el porcentaje de cambios de peso entre los grupos (p<0,001). La glucosa en sangre aumentó significativamente en los grupos experimentales y de control en comparación con el grupo Sham (p<0,001). La concentración de FSH se redujo significativamente en el grupo control (p<0,05); la testosterona disminuyó en los grupos experimentales y control en comparación con el grupo sham (p<0,05). La administración oral de nogal parece prevenir la pérdida severa de peso en los modelos experimentales de ratas diabéticas y ejerce cambios apropiados y útiles en el nivel de glucosa en la sangre, así como efectos positivos sobre la secreción de hormonas sexuales.

Changes of serum angiogenic biomarkers and their correlations with serum leptin concentration.

AIM: Obesity is considered as a major health problem. Angiogenic vessels by providing oxygen, nutrients and growth factors trigger growth and survival signals in adipocytes. We aimed to investigate the effect of high-fat diet (HFD) on serum angiogenic biomarkers including vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGFR1), nitric oxide (NO) concentrations and their correlations with serum leptin level in obese and control groups. METHODS: Twenty male C57BL/6 mice were randomly assigned into the control and obese groups. Obese group received HFD for 15 weeks. At the end of experiment, blood samples were collected for blood glucose, serum insulin, VEGF, sVEGFR1, NO and leptin level measurements and correlation between serum angiogenic factors and leptin levels were analyzed. RESULTS: HFD induced higher serum NO and leptin levels compared to the control group, while, it did not affect serum VEGF and sVEGFR1 concentrations. There was a strong positive correlation between serum leptin and NO levels (r=0.78), however, a weak correlation was found between serum leptin and VEGF and VEGFR-1 concentrations. CONCLUSION: It seems that the angiogenic activities in obese mice are through the mechanisms that were not regulated by VEGF or VEGF receptors rather; other factors such as leptin and NO are involved (Tab. 1, Fig. 4, Ref. 32).

Limbs' postischemic revascularization is not improved by losartan treatment in diabetic rats.

OBJECTIVE: Most physiological actions of angiotensin II (Ang II) on cardiovascular system are mediated by angiotensin type 1 receptor (AT1R). Since peripheral artery disease is one of the most important complications of diabetes, in this study, we aimed to investigate the effect of losartan, an AT1R blocker, on skeletal muscle angiogenesis in diabetic hind limb ischemic rats. METHODS: Twenty four male Wistar rats were randomly divided into four groups as follow: diabetic sham; diabetic sham + losartan (15 mg/kg/day); diabetic hindlimb ischemia; diabetic hindlimb ischemia + losartan. For induction of diabetes, streptozotocin was injected (55 mg/kg; i.p.). The animals were sacrificed after 21 days and the serum concentrations of vascular endothelial growth factor (VEGF), soluble VEGF receptor-1 (sFlt-1), nitric oxide (NO), capillary density, and capillary to fiber (cap/fib) ratio in ischemic legs were evaluated. RESULTS: The serum NO concentrations were significantly decreased, sFlt-1 concentrations increased, and VEGF concentrations did not significantly change after experiment in diabetic sham and diabetic hind limb ischemic rats. Administration of losartan did not induce significant changes in serum NO, sFlt-1, and VEGF concentrations (p>0.05). Capillary density and cap/fib ratio in ischemic leg of diabetic rats were not affected by losartan treatment (p>0.05). CONCLUSION: AT1R blocker, losartan, was not able to restore neovascularization in the ischemic leg of diabetic animals. Therefore, based on the present data, the losartan cannot be considered for treatment or prevention of peripheral artery disease in diabetic subjects.

Myocardial capillary density in normal and diabetic male rats: Effect of bezafibrate.

Cardiovascular disease is the common cause of mortality in diabetic subjects. Recently, it is indicated that peroxisome proliferator-activated receptors (PPARs) agonists have beneficial effect on cardiovascular system especially on angiogenesis. PPARs have three isotypes: PPARα, PPARß/δ and PPARγ. In this study, we evaluated the effect of bezafibrate as pan PPAR agonist on myocardial capillary density in type I diabetic rats. Eighteen male wistar rats were randomly divided into three groups (n=6 each): control, diabetic and diabetic+bezafibrate (400 mg/kg/day) by gavage every day. Diabetes was induced by a single dose of streptozotocin (55 mg/kg), intraperitoneally. After 21 days, capillary density in the myocardial tissue was evaluated by immunohistochemical staining and reported as capillaries per mm(2). Blood samples were taken before and after the experiment. Diabetes was associated by lower serum nitric oxide (NO) concentration and reduced myocardial capillary density compared to control group (121.71 ± 13.32 vs. 158.78 ± 11.08 /mm(2); P<0.05). Administration of bezafibrate significantly increased serum NO level and improved angiogenesis in myocardial tissue of diabetic animals (170.24 ± 15.76 vs.121.71 ± 13.32 /mm(2); P<0.05). There was a positive correlation between serum NO concentration and myocardial capillary density (r=0.90). Activation of all isotypes of PPAR by bezafibrate improves heart capillary density in diabetic animals and it seems that it can be considered for treatment or prevention of coronary heart disease in diabetic subjects.

Systemic ghrelin administration alters serum biomarkers of angiogenesis in diet-induced obese mice.

Introduction. Ghrelin is a gastrointestinal endocrine peptide that was initially identified as the endogenous ligand of growth hormone secretagogue receptor; however, recently, the cardiovascular effect of this peptide has been indicated. In this study, we investigated the effect of ghrelin administration on serum biomarkers of angiogenesis including leptin, nitric oxide (NO), vascular endothelial growth factor (VEGF), and its soluble receptor (VEGF receptor 1 or sFlt-1) in control- and diet-induced obese mice. Methods. Male C57BL/6 mice were randomly divided into four groups, normal diet (ND) or control, ND + ghrelin, high-fat-diet (HFD) or obese and HFD + ghrelin (n = 6/group). Obese and control groups received either HFD or ND for 15 weeks. Then, the ghrelin was injected subcutaneously 100 µg/kg twice daily for 10 days. At the end of experiment, blood samples were collected for blood glucose, serum insulin, VEGF, sFlt-1, NO, and leptin measurements. Results. The obese animals had higher serum NO and leptin concentrations without changes in serum VEGF and sFlt-1 levels compared to control. Administration of ghrelin significantly increased serum VEGF and decreased serum leptin and NO concentrations in HFD group. Conclusion. Since ghrelin changes serum biomarkers of angiogenesis, it seems that it gets involved during states with abnormal angiogenesis.

Comparing the long-term retention of a physiology course for medical students with the traditional and problem-based learning.

The rapid improvements in medical sciences and the ever-increasing related data, however, require novel methods of instruction. One such method, which has been given less than due attention in Iran, is problem-based learning (PBL). In this study, we aimed to evaluate the impact of study skills and the PBL methods on short and long-term retention of information provided for medical students in the course of respiratory physiology and compare it with traditional learning method. In this study, 39 medical students from Medical School of Kerman University of Medical Sciences, Kerman, Iran (2006-2010) were enrolled in the study and allocated randomly in three equal groups (13 in each group). All groups underwent a pre-test to be assessed for their basic information regarding respiratory physiology. Two groups were instructed using the traditional method, and one group used PBL. Among the two groups of the traditional method, one was instructed about study skills and the other was not. Once the PBL group took the study skill workshop, they were aided by tutors for their education. In the final term test, those students who had learned study skills and were instructed with the traditional method scored higher compared to other groups (p < 0.05). However, in the 1 year (p < 0.05) and 4 year (p < 0.01) interval examinations, the PBL group achieved significantly higher scores. Despite the fact that PBL had no positive effect on the final term exam of our students, it yielded a more profound and retained understanding of the subject course. Moreover, considering the positive effect of study skills on long-term student scores, we recommend students to receive instructions regarding the appropriate study skills when initiated into universities.

Protective effects of subchronic caffeine administration on cisplatin induced urogenital toxicity in male mice.

In Cisplatin treated group, the degeneration intensity of the kidneys the diameter of seminiferous tubules as well as the apoptotic index in testes and kidney were increased. In Caffeine+Cisplatin treated groups, the total body weight, the weight of testes and kidneys and also the histopathological data did not show significant differences. The motility of sperm in cisplatin group reduced but in Caffeine+Cisplatin groups this parameter was increased. These data suggest that caffeine recovers toxicity induced by cisplatin in both kidneys and testes of mice.

Prevalence of Toxocara Spp. eggs in Public Parks in Tehran City, Iran.

BACKGROUND: The objective of the present research was to determine the frequency of Toxocara spp. eggs in soil samples of public parks, in the city of Tehran, Iran. METHODS: A total of 600 soil samples were taken from 120 parks between Aprils to November, 2008. Soil samples were collected from 5 distinct sites in the parks. The samples were washed with saline solution and the collected sediment from each park were equally divided and examined by floatation and Petri dish methods for Toxocara eggs. RESULTS: Ten percent were contaminated with Toxocara spp. eggs. The number of observed Toxocara eggs in each microscopic field was varied from 1-3. No significant differences were observed between floatation and Petri dish methods. CONCLUSION: Our public parks showed a high risk of toxocariasis and the need for preventive studies.

Pan-PPAR Agonist, Bezafibrate, Restores Angiogenesis in Hindlimb Ischemia in Normal and Diabetic Rats.

Introduction. The aim of this study was to investigate the effect of bezafibrate as a pan-PPAR agonist on angiogenesis and serum nitrite, the main metabolite of nitric oxide (NO), vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) concentrations in hindlimb ischemia model of normal and type I diabetic rats. Methods. 28 male Wistar rats were divided into control and diabetic groups. Then, all rats underwent unilateral hindlimb ischemia. After recovery, they were randomly assigned to one of the following experimental groups: (1) control; (2) control + bezafibrate (400 mg/kg/day); (3) diabetic; (4) diabetic + beztafibrate. After three weeks, blood samples were taken and capillary density was evaluated in the gasterocnemius muscle of ischemic limb. Results. Bezafibrate increased capillary density and capillary/fiber ratio in ischemic leg of diabetic and control rats (P < 0.05). Serum VEGF and VEGFR-2 concentrations did not alter after bezafibrate administration, however, serum nitrite concentration was significantly higher in bezafibrate-treated groups than non-treated groups (P < 0.05). Discussion. It seems that bezafibrate, as a pan PPAR agonist, restores angiogenesis in hindlimb ischemic diabetic animals and is useful for prevention and/or treatment of peripheral artery disease in diabetic subjects.

Role of peroxisome proliferator-activated receptor ß agonist on angiogenesis in hindlimb ischemic diabetic rats.

INTRODUCTION: Studies indicated that PPARß agonists play a role in modulation of angiogenesis. In this study, we evaluated the effect of specific PPARß agonist, GW0742, on angiogenesis and serum vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), and nitrite concentrations in hindlimb ischemia in normal and diabetic rats. METHODS: Hindlimb ischemic rats were divided into four groups: control, diabetic, control, and diabetic treated with GW0742 (n=7 each). Diabetes was induced by injection of streptozotocin (55mg/kg, ip). GW0742 was injected 1day after surgery (1mg/kg, sc). After 21days, blood samples were taken, and gastrocnemius muscles were harvested for immunohistochemistry. RESULTS: GW0742 significantly increased serum nitrite and VEGFR-2 concentrations and VEGF-to-VEGFR-2 ratio in control and diabetic rats. Capillary density was lower in diabetic animals compared to the control, and GW0742 significantly restored the capillary density in the control and diabetic hindlimb ischemic rats. CONCLUSION: PPARß agonists restore skeletal muscle angiogenesis and can be considered for prevention and/or treatment of peripheral vascular complications in diabetic subjects.

Effect of chronic L-Arginine supplementation on aortic fatty streak formation and serum nitric oxide concentration in normal and high-cholesterol fed rabbits.

Several reports indicated the beneficial effects of short-term L-Arginine (L-Arg) administration on atherosclerosis processes. The aim of this study was to evaluate the effect of chronic L-Arg supplementation on serum lipid profile, aortic Fatty Streak (FS) formation, and serum Nitric oxide (NO) concentration in Normal Diet (ND) and High-Cholesterol Diet (HCD) fed rabbits. 24 male rabbits were randomly divided into four groups (n=6 in each group) (i): ND for seven months; (ii): ND for 1 month plus ND + L-Arg for six months; (iii): HCD (1%) for 1 month plus HCD (0.5%) for six months; (iv): HCD (1%) for 1 month plus HCD (0.5%) + L-Arg for six months. At the end of the study, histological evaluation of aortic FS formation was performed. Blood samples were taken for serum lipid profile and NO concentrations. L-Arg did not change serum total cholesterol, triglyceride, LDL and LDL/HDL ratio in normal and hypercholesterolemic rabbits (p>0.05). Histological examination of thoracic aortae revealed that the HCD group had higher FS formation compared to the ND group (2.1 ± 0.16 vs. 0 ± 0; respectively; p<0.05) and L-Arg supplementation did not attenuate FS formation in the HCD group (1.93 ± 0.17 compare to 2.1 ± 0.16; p>0.05). Serum NO level in the HCD group was higher than ND groups (p<0.05). Chronic L-Arg supplementation did not alter serum NO concentration either in the hypercholesterolemic or in the ND group (p>0.05). It seems that chronic L-Arg supplementation does not have beneficial effects on aortic fatty streak formation, serum lipids and NO concentrations in this model of experimental hypercholesterolemia.