Evaluation of Glucose Metabolism and Cardiovascular Risk Factors in Prepubertal Girls with Premature Pubarche

Objective: Premature pubarche (PP) is a risk factor for metabolic syndrome (MS). The aim was to evaluate if glucose-insulin metabolism, cardiovascular risk factors, familial cardiovascular risk factors (FCVRF) created a risk for insulin resistance (IR) and if PP was a risk factor alone for MS in normal weight prepubertal girls with PP. Methods: Thirty-five prepubertal, non-obese girls with PP with normal birth weight and 35 age-matched control girls were evaluated for FCVRF, anthropometric measurements, blood pressure, lipid profile, fasting blood glucose-insulin, hemoglobin A1c (HbA1c), sex hormone binding globulin (SHBG), leptin, adiponectin, tumor necrosis factor-alpha (TNF-α), androgen levels, and bone age. Oral glucose tolerance test was performed in PP participants. Homeostasis model of assessment of IR (HOMA-IR), fasting glucose/insulin ratio, atherogenic index (AI), and free androgen index (FAI) were calculated. PP participants were further stratified by FCVRF. Results: HbA1c, lipid profile, testosterone, leptin, adiponectin, TNF-α, HOMA-IR, glucose/insulin ratio, AI, and fasting glucose-insulin levels were similar. In the PP group FAI was significantly higher (p=0.001), whereas SHBG was significantly lower (p=0.010) than the control group. Leptin levels of FCVRF+ and FCVRF- subgroups were 15.2±9.1 and 9.7±7.2 ng/mL, respectively and the difference was significant (p=0.016). Conclusion: As PP does not appear to be a risk factor alone for impaired glucose metabolism and IR in prepubertal non-obese girls with normal birth weight, it is our opinion that it is unnecessary to examine in detail such cases before puberty. Low SHBG levels in the PP group and high leptin levels in FCVRF+ subgroup might suggest that these may be predictive for MS in the future.

Asymmetric dimethylarginine in experimental breast cancer; action of Vitamin C and E.

OBJECTIVE: To investigate the arginase-nitric oxide synthase paradox through asymmetric dimethylarginine, symmetric dimethylarginine and nitric oxide levels, and to see the effect of antioxidant vitamins on this mechanism of cancer action. METHODS: The animal-based study was conducted at Trakya University, Turkey, in 2008, and comprised mice that were divided into five equal groups. Group 1 had healthy controls, while in the other four groups breast cancer was induced. Group 2 received saline solution, group 3 received 200 mg/kg/day vitamin C (tumour +vit C), group 4 received 300 mg/kg/day vitamin E (tumour +vitE) and group 5 received both 200 mg/kg/day vitamin C and 300 mg/kg/day vitamin E (tumour +vit C+vit E) for 15 days intra-peritoneally.Arginine, asymmetric dimethylarginine, symmetric dimethylarginine and nitric oxide levels were determined in each group. RESULTS: The 50 mice in the study were divided into five groups of 10(20%) each. Plasma arginine levels were significantly decreased, asymmetric dimethylarginine and symmetric dimethylarginine levels were increased, while plasma nitric oxide level was significantly decreased in group 2. There was no statistically significant difference in treatment groups for all parameters (p>0.05 each). CONCLUSIONS: Understanding of the mechanism may help to develop new anti-cancer agents.

Effect of rosuvastatin on arginase enzyme activity and polyamine production in experimental breast cancer.

BACKGROUND: Breast cancer is the most common malignant tumour of women around the world. As a key enzyme of the urea cycle, arginase leads to the formation of urea and ornithine from L-arginine. In the patients with several different cancers, arginase has been found to be higher and reported to be a useful biological marker. AIMS: The aim of this study was to investigate the effect of rosuvastatin on serum and cancer tissue arginase enzyme activity, and ornithine and polyamine (putrescine, spermidine, spermine) levels. STUDY DESIGN: Animal experiment. METHODS: In this study, 50 male Balb/c mice were used. Erchlich acid tumour cells were injected into the subcutaneous part of their left foot. The mice were divided into five groups: healthy control group, healthy treatment, tumour control, treatment 1 and treatment 2. Then, 1 mg/kg and 20 mg/kg doses of rosuvastatin were given intraperitoneally. Serum and tissue arginase enzyme activities and tissue ornithine levels were determined spectrophotometrically. HPLC measurement of polyamines were applied. RESULTS: Increased serum arginase activity and polyamine levels were significantly decreased with rosuvastatin treatment. In the tumour tissue, arginase activity and ornithine levels were significantly decreased in treatment groups compared to the tumour group. Tissue polyamine levels also decreased with rosuvastatin treatment. CONCLUSION: We suggest that rosuvastatin may have some protective effects on breast cancer development as it inhibits arginase enzyme activity and ornithine levels, precursors of polyamines, and also polyamine levels. This protective effect may be through the induction of nitric oxide (NO) production via nitric oxide synthase (NOS). As a promising anticancer agent, the net effects of rosuvastatin in this mechanism should be supported with more advanced studies and new parameters.

VEGFR-1, Bcl-2, and HO-1 Ratios in Pregnant Women With Hypertension.

BACKGOUND/AIM: Preeclampsia (PE) is a multisystem disease resulting in high maternal-fetal morbidity and mortality. The aim of the study was to investigate antiangiogenesis-associated alterations in antiapoptotic and antioxidative proteins in PE. METHOD: Of the 46 patients with PE, 25 (54.3%) were with gestational hypertension (GH), 12 (26%) were with mild, and 9 (19.5%) were with severe PE. The serum levels of vascular endothelial growth factor receptor 1 (VEGFR-1), heme oxygenase 1 (HO-1), and B-cell lymphoma/leukemia (Bcl-2) levels were measured by enzyme-linked immunosorbent assay. RESULTS: In the severe PE group, the VEGFR-1 serum levels (27.3 ± 16.8 vs 13.3 ± 10.7 ng/mL, P = .023) were higher, but the Bcl-2 levels (1.5 ± 0.2 vs 2.1 ± 1.7 ng/mL, P = .047) were lower than the levels in the GH-mild PE group (P = .047). Also, VEGFR-1/Bcl-2 ratio in the severe PE group was significantly higher (P = .003) than the ratio in the GH-mild PE group. CONCLUSION: The Bcl-2 and HO-1 proteins seem to have important roles in the antiangiogenic environment of preeclampsia.

The Protective Effect of Curcumin on Ionizing Radiation-induced Cataractogenesis in Rats.

OBJECTIVE: The aim of the study was to determine the protective effect of curcumin against ionizing radiation-induced cataract in the lens of rats. MATERIAL AND METHODS: Rats were divided into six groups. Group 1: Control, Group 2: Dimethyl sulfoxide (DMSO), Group 3: DMSO+curcumin, Group 4: Irradiation, Group 5: Irradiation+DMSO, Group 6: Irradiation+DMSO+curcumin. A 15 Gy total dose was given to 4, 5, 6 groups for radiation damage. Curcumin (100 mg/kg) was dissolved in DMSO and given by intragastric intubation for 28 days. At the end of the experiment, lenses were graded and enucleated. The lenticular activity of the antioxidant enzymes, total antioxidant and glutathione peroxidase (GSH-Px), and the malondialdehyde (MDA) were measured. RESULTS: 100% Cataract was seen in the irradiation group. Cataract rate fell to 40% and was limited at grade 1 and 2 in the curcumin group. In the irradiation group, antioxidant enzyme levels were decreased, MDA levels were increased. There was an increase in antioxidant enzyme levels and a significant decrease in MDA in the group which was given curcumin. CONCLUSION: Curcumin has antioxidant and radioprotective properties and is likely to be a valuable agent for protection against ionizing radiation. Hence, it may be used as an antioxidant and radioprotector against radiation-induced cataractogenesis.

Tissue damage in rat ovaries subjected to torsion and detorsion: effects of L-carnitine and N-acetyl cysteine.

We aimed to evaluate histopathological changes, to detect HIF-1alpha staining intensities and to determine MDA levels in rat ovaries, which were subjected to torsion and detorsion and treated with L -carnitine or N-acetyl cysteine (NAC). Forty-eight prepubertal female Sprague-Dawley rats were divided into five groups (n = 8): 1, control; 2, ischemia; 3, reperfusion; 4, L -carnitine; and 5, NAC groups. In groups 3, 4 and 5, an ischemic period of 3 h was followed by reperfusion for 24 h. In groups 4 and 5, ischemia was performed and either L -carnitine or NAC was infused intraperitoneally 30 min before reperfusion. Ovarian tissues were examined histopathologically; tissue MDA levels and serum IL-6 levels were determined biochemically. HIF-1alpha was applied to all ovaries immunohistochemically. Total tissue damage scores, tissue MDA levels and HIF-1alpha scores, were significantly higher in group 2 (all P < 0.001) than group 4, and group 3 than group 4 (P < 0.001, P = 0.05 and P < 0.001, respectively). They were also significantly higher in group 2 (all P < 0.001) than group 5. When group 3 is compared to group 5, total tissue damage scores and tissue MDA levels were significantly higher in the former (P < 0.01 and P < 0.001, respectively). Serum IL-6 levels were significantly higher in group 2 when compared to groups 1, 4 and 5 (all P < 0.01). The degree of tissue damage of the torsioned ovaries decreased after a reperfusion period of 24 h in the torsioned ovaries. However, ovaries of both L -carnitine and NAC groups showed better recovery than the reperfusion group.

Breast cyst fluid plasmin activity and its effect on TGF-beta2 activation.

There are two types of breast cyst and women with apocrine breast cyst may have a higher risk of developing breast cancer than cyst lined by flattened epithelium. Transforming growth factor-beta's growth inhibitory effect on epithelial cells suggests a potential protective role in breast cancer. The aim of this study was to investigate the presence of plasmin in both breast cyst groups and the possible role of plasmin on transforming growth factor beta activation. Presence of high plasmin level may indicate its importance on activation process, but some other proteases may also involve in this activation mechanism.

Protective effects of L-carnitine and alpha-lipoic acid in rats with adjuvant arthritis.

Free radicals play an important role in the pathophysiology of adjuvant arthritis. The purpose of this study was to assess the efficacy of L-carnitine (LC) and alpha-lipoic acid (alpha-LA) which are known to have antioxidant effects, in the treatment of adjuvant arthritis. Arthritis model was created by the administration of complete Freund's adjuvant (CFA) in 32 of 40 male Sprague-Dawley rats. The rats were divided into five groups. Rats in Group I served as controls and received 0.1 ml kg(-1) saline. Group II received only 0.1 ml of CFA and served as the CFA-control for the other groups. Groups III-V, after being injected with CFA, were treated with LC, alpha-LA or diclofenac, respectively. Levels of malondialdehyde (MDA) and glutathione (GSH) were measured in plasma samples. Enzyme activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured. The paws of rats were evaluated histopathologically to investigate the anti-inflammatory effects. TNF-alpha levels were measured for the evaluation of inflammation. In Group II plasma MDA increased, levels of glutathione decreased, enzyme activities of SOD and GPx decreased. Histopathological damage increased in the paws of the rats in this group. MDA levels decreased in Groups III-V when compared with Group II. GSH levels significantly increased in Group III and IV than Group V. SOD activity of Group IV was higher than Group III and V. TNF-alpha levels were significantly lower in Group IV and V. LC and alpha-LA seemed to have protective effects against oxidative damage in adjuvant arthritis model.

Protective role of carnitine in breast cancer via decreasing arginase activity and increasing nitric oxide.

Breast cancer remains one of the most common types of cancer. High levels of arginase and ornithine in different carcinomas may indicate their relation to cancer. Carnitine is a cofactor required for the transformation of free long-chain fatty acids into acetyl-carnitines. We have examined the protective effect of carnitine and the possibility that it disturbs arginase-nitric oxide (NO) interaction. Histopathological examination, arginase activity, ornithine and NO levels were determined in tumour tissues. Mitotic cells significantly decreased in the treatment group. Tissue arginase activity and ornithine levels decreased significantly with carnitine. NO levels were significantly higher in the treatment group. One of the possible mechanisms of carnitine's protective role in tumour progression might be its promotion of NO. This mechanism could decrease the production of tumour-promoting agents, polyamines, and increase the production of NO, thereby exerting a protective effect on cancer development.

Prostatic acid phosphatase in breast cyst fluid.

Prostatic Acid Phosphatase (PAP) is mostly found in the epithelial cells and secretions of the prostate gland. It has also been found to be present in several tissues and biological fluid. Gross cystic breast disease is the commonest benign breast condition and several studies have shown that women with palpable breast cysts may have a higher risk of developing breast cancer. There are two types of breast cyst and women with apocrine breast cyst may have a higher risk of developing breast cancer than women with breast cysts lined by flattened epithelium. The growth inhibitory effect of transforming growth factor beta (TGF-beta) on epithelial cells suggests a potential protective role in breast cancer. TGF-beta is secreted as a high molecular weight complex in a biologically inactive or latent form and activation of TGF-beta is necessary for the exertion of its effects on target cells. Prostate specific antigen (PSA) has been found in breast cyst fluid (BCF) and it may have a protective effect on the development of several carcinomas by activating TGF-beta. As a similar molecule to PSA, PAP may also involve in this mechanism. We investigated the presence of PAP in two groups of BCF using an ELISA kit. PAP was found to be present in BCF but there was not a statistically significant difference between the two cyst groups. The presence of PAP in BCF may suggest its possible role in the development of breast cancer from cystic breast diseases. A possible role of PAP on TGF-beta activation needs further investigation.

Melatonin reduces nitric oxide via increasing arginase in rhabdomyolysis-induced acute renal failure in rats.

Melatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger. In addition to a direct scavenging effect on nitric oxide (NO), its inhibitory effect on nitric oxide synthase (NOS) activity has been also reported. L-arginine is the substrate for both NOS and arginase. It has been suggested that there is a competition between arginase and NOS and that they control each other's level. NO plays a crucial role in the pathogenesis of myoglobinuric acute renal failure (ARF). In this study, the authors aimed to investigate the effect of melatonin on arginase activity, ornithine, and NO levels on the myoglobinuric ARF formed by intramuscular (i.m.) injection of hypertonic glycerol. Forty rats were randomly divided into four groups. Rats in SHAM were given saline, and those in groups ARF, ARF-M5, and ARF-M10 were injected with glycerol (10 mL/kg) i.m. Concomitant and 24 hours after glycerol injection for the ARF-M5 and ARF-M10 groups, melatonin--5 mg/kg and 10 mg/kg, respectively--was administrated intraperitoneally. Forty-eight hours after the glycerol injection, kidneys of the rats were taken under anesthesia. Arginase activity, ornithine, and NO levels in the kidney tissue were determined. Melatonin had an increasing effect on kidney tissue arginase activities and ornithine levels while decreasing NO concentration. It is possible that besides the direct scavenging effect, the stimulatory effect of melatonin on arginase activity may result in an inhibition of NOS activity and, finally, a decrease in the kidney NO level.

Effects of N-acetylcysteine on arginase, ornithine and nitric oxide in renal ischemia-reperfusion injury.

BACKGROUND: Renal ischemia-reperfusion (I/R) is a complex syndrome involving several mechanisms such as renal vasoconstrictions, extensive tubular damage and glomerular injury. N-Acetylcysteine (NAC), a potent antioxidant by itself, may serve as a precursor for glutathione synthesis. The aim of this study was to investigate the possible effects of NAC on liver and kidney tissue arginase activity, ornithine and plasma nitric oxide levels during the I/R injury of kidney. METHODS: Twenty-four female Sprague-Dawley rats divided into three groups: group 1; was given saline intraperitoneally (i.p.). Saline to group 2 and NAC (300 mg kg(-1)) to group 3 were injected i.p. 30 min before induction of ischemia. Groups 2 and 3; subjected to bilateral renal ischemia (60 min) followed by reperfusion (24 h). After the reperfusion period, the rats were sacrificed and liver and kidney tissue arginase activities, ornithine and plasma nitric oxide (NO) levels were determined. RESULTS: NAC had an increasing effect on both of liver and kidney tissue arginase activities and ornithine levels while decreasing plasma NO concentration. CONCLUSION: The stimulatory effect of NAC on arginase activity may result in an inhibition of the plasma NO level. Moreover, it could be possible that one of the protective mechanisms of NAC might be through the stimulation on the both liver and kidney tissue ornithine levels.