Association between Urinary Levels of Interleukin-6, Interleukin-10 and Tumor Necrosis Factor-Alpha with Glomerular and Tubular Damage Indicators in Patients with Type 2 Diabetes.

BACKGROUND: This study investigated the association between urinary levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha (TNF-α) with estimated glomerular filtration rate (eGFR), urinary albumin/creatinine ratio (uACR), and urinary neutrophil gelatinase-associated lipocalin (uNGAL) in patients with type 2 diabetes (T2D). METHODS: Urinary concentrations of IL-6, IL-10, TNF-α, ACR, and NGAL were measured in 121 patients with T2D. RESULTS: Urinary IL-6 and TNF-α increased 45.5% and 49.4% in the highest uACR quartile compared to lowest quartile. Urinary IL-10 levels decreased 40.9% in the highest uACR quartile compared to the lowest quartile. Urinary IL-6 and TNF-α were 75.3% and 81.6%, higher in the highest uNGAL quartile compared to the lowest quartile. Urinary IL-10 concentration was 69.8% lower in patients from the highest uNGAL quartile compared to lowest quartile. CONCLUSIONS: Urinary IL-6, IL-10, and TNF-α were associated with indicators of glomerular and tubular injuries in patients with T2D.

High serum uric acid is associated with oxidation of nucleosides in patients with type 2 diabetes.

Uric acid presents different roles in an organism, since it can act as an antioxidant or a pro-oxidant molecule. High serum uric acid levels may cause damage to several structures, including nucleic acids and its components. Therefore, in this study the association between increased serum uric acid concentrations and oxidation of nucleosides was investigated by assessment of urinary 8-hydroxydeoxyguanosine (8-OHdG) in patients with type 2 diabetes (T2D) and in healthy individuals. Urinary 8-OHdG and biochemical parameters were assessed in 61 patients who were initially grouped into 2 groups based on the median serum uric acid levels (<5.3 mg/dL and ≥5.3 mg/dL). Urinary 8-OHdG was higher in patients with T2D and serum uric acid levels ≥5.3 mg/dL, when compared with the patients with serum uric acid levels <5.3 mg/dL; however, co-occurrence of high serum uric acid with high urinary 8-OHdG was not observed in healthy individuals. A significant positive correlation between 8-OHdG and uric acid (r = 0.40, P < 0.01) was observed in patients with T2D. High serum uric acid levels were associated with high urinary 8-OHdG levels in patients with T2D, and this association was independent of gender, hypertension, body mass index, and serum creatinine.

Urinary inflammatory cytokines as indicators of kidney damage in type 2 diabetic patients.

BACKGROUND: The aim of this study was to investigate whether urinary levels of interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) are altered in normoalbuminuric patients with type 2 diabetes mellitus (T2DM), and whether these cytokines are able to identify diabetic kidney disease (DKD) among these patients. METHODS: This study included 125 T2DM patients classified into 3 groups according to urinary albumin/creatinine ratio (uACR): uACR <10mg/g creatinine, uACR 10-30mg/g creatinine and uACR >30mg/g creatinine. Urinary inflammatory cytokines were measured. RESULTS: The urinary IL-6 concentrations increased from uACR <10 (97.2±26.4pg/ml) to uACR 10-30 (113.6±28.0pg/ml) and to uACR >30mg/g creatinine (163.5±25.6pg/ml) (P<0.05 and P<0.001, respectively) patients. The urinary IL-10 concentrations decreased in these uACR ranges [100.0 (58.0-141.0) pg/ml vs. 62.0 (54.5-71.5) pg/ml vs. 42.0 (32.0-48.0) pg/ml] (P<0.05 and P<0.001, respectively). All urinary cytokines demonstrated good ability to identify DKD (areas under curves >0.9). CONCLUSIONS: Urinary inflammatory cytokines, especially IL-6 and IL-10, may assist in the identification of DKD in T2DM patients, even in the absence of micro- and macroalbuminuria.

Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as indicators of tubular damage in normoalbuminuric patients with type 2 diabetes.

OBJECTIVES: Renal dysfunction has been reported in normoalbuminuric patients, demonstrating the necessity to improve the diagnostic and prognostic tools for diabetic kidney disease (DKD) investigation. Therefore, the aim of this study was to investigate whether the urinary levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) are increased in type 2 diabetes mellitus (DM) patients with normal or mildly increased albuminuria. DESIGN AND METHODS: In this study, 117 type 2 DM patients classified into three groups according to urinary albumin/creatinine ratio (uACR): uACR<10mg/g creatinine, uACR 10-30mg/g creatinine and uACR>30mg/g creatinine were enrolled. Urinary concentrations of KIM-1 (uKIM-1) and NGAL (uNGAL) were measured. RESULTS: uKIM-1 levels increased progressively from uACR<10mg/g creatinine (69.0±20.8pg/ml) to uACR 10-30mg/g creatinine (106.1±41.2pg/ml) and to uACR>30mg/g creatinine (166.0±31.9pg/ml) (P<0.001). In addition, uNGAL levels increased progressively from uACR<10mg/g creatinine (29.5±8.8ng/ml) to uACR 10-30mg/g creatinine (51.7±10.9ng/ml) and to uACR>30mg/g creatinine (71.0±9.6ng/ml) (P<0.001) patients. Similarly, both uKIM-1 and uNGAL adjusted by urinary creatinine were increased in patients with uACR 10-30mg/g creatinine. Significant and positive correlations were observed between uACR, uKIM-1 and uNGAL. CONCLUSIONS: uKIM-1 and uNGAL were increased in type 2 DM patients with normal or mildly increased albuminuria, which indicates that tubular and glomerular injuries may be occurring even at the earliest stage of DKD.

Complex interaction of deferasirox and Pythium insidiosum: iron-dependent attenuation of growth in vitro and immunotherapy-like enhancement of immune responses in vivo.

Pythium insidiosum iron acquisition mechanisms are unknown. We previously showed that the iron chelator deferasirox had weak activity in vitro and in rabbits with experimental pythiosis. Here we show that deferasirox causes damage to P. insidiosum hyphae in vitro, but that activity is diminished in the presence of exogenous iron. The tissue activity of the proinflammatory enzyme adenosine deaminase and the histological pattern observed in pythiosis lesions of rabbits treated with deferasirox were similar to the ones in animals treated with immunotherapy.

Syzygium cumini is more effective in preventing the increase of erythrocytic ADA activity than phenolic compounds under hyperglycemic conditions in vitro

Syzygium cumini (S. cumini) is a plant known for its antidiabetic properties. The aim of this study was to evaluate the effect of Sc aqueous leaf extract (ASc) on adenosine deaminase (ADA) activity in erythrocytes (RBCs) exposed to high glucose concentrations (30 mM) in vitro. We also investigated the effects of the main phenolic compounds found in ASc (gallic acid, rutin, and chlorogenic acid) and the effects of insulin, caffeine, and dipyridamole, which are substances involved in the adenosine metabolism, on ADA activity in vitro. Blood samples were obtained from healthy volunteers and a suspension of RBCs was used for the determination of ADA activity. The results showed that: (1) the effect of ASc on ADA activity was more significant than the combination of phenolic compounds; (2) insulin, caffeine, or dipyridamole prevented high glucose increase of ADA activity at doses as low as 50 μU/mL, 25 μM, and 1 μM, respectively; (3) the inhibitory effect caused by ASc on erythrocyte ADA activity remained practically the same after the combination of the extract with insulin or caffeine; (4) when RBCs were exposed to ASc plus dipyridamole, this chemical attenuated the effect of ASc on ADA activity, suggesting an antagonism or a competition with ASc by the same site of action. Therefore, ASc was more effective in preventing the increase in ADA activity than phenolic compounds, suggesting that ASc may collaborate to improve endothelial dysfunction, antioxidant, anti-inflammatory, and antithrombotic properties of adenosine by affecting its metabolism. The results of this study help to provide evidence of the empirically supported benefits of the use of S. cumini in diabetes

Syzygium cumini is more effective in preventing the increase of erythrocytic ADA activity than phenolic compounds under hyperglycemic conditions in vitro.

Syzygium cumini (S. cumini) is a plant known for its antidiabetic properties. The aim of this study was to evaluate the effect of Sc aqueous leaf extract (ASc) on adenosine deaminase (ADA) activity in erythrocytes (RBCs) exposed to high glucose concentrations (30 mM) in vitro. We also investigated the effects of the main phenolic compounds found in ASc (gallic acid, rutin, and chlorogenic acid) and the effects of insulin, caffeine, and dipyridamole, which are substances involved in the adenosine metabolism, on ADA activity in vitro. Blood samples were obtained from healthy volunteers and a suspension of RBCs was used for the determination of ADA activity. The results showed that: (1) the effect of ASc on ADA activity was more significant than the combination of phenolic compounds; (2) insulin, caffeine, or dipyridamole prevented high glucose increase of ADA activity at doses as low as 50 µU/mL, 25 µM, and 1 µM, respectively; (3) the inhibitory effect caused by ASc on erythrocyte ADA activity remained practically the same after the combination of the extract with insulin or caffeine; (4) when RBCs were exposed to ASc plus dipyridamole, this chemical attenuated the effect of ASc on ADA activity, suggesting an antagonism or a competition with ASc by the same site of action. Therefore, ASc was more effective in preventing the increase in ADA activity than phenolic compounds, suggesting that ASc may collaborate to improve endothelial dysfunction, antioxidant, anti-inflammatory, and antithrombotic properties of adenosine by affecting its metabolism. The results of this study help to provide evidence of the empirically supported benefits of the use of S. cumini in diabetes.

Antinociceptive effect of Mirabilis jalapa on acute and chronic pain models in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The infusion or decoction of Mirabilis jalapa leaves is used in traditional medicine in Brazil to treat inflammatory and painful diseases. Thus, the present study was designed to investigate whether the leaf ethyl acetate (Eta) fraction from Mirabilis jalapa exhibits antinociceptive effect in clinically relevant pain models in mice. Furthermore, we have investigated the role of cholinergic system in the antinociceptive action produced by Eta in mice. MATERIALS AND METHODS: The effect of Eta administered orally (10mg/kg, p.o.) in mice was verified on the painful hypersensitivity (mechanical allodynia) in models of chronic inflammation (subcutaneous injection of complete Freund's Adjuvant-CFA in the plantar surface of the right hind paw), postoperative (paw surgical incision) and neuropathic (partial sciatic nerve ligation) pain. In the chronic inflammation model, we further verified the effect of Eta treatment on paw edema and interleukin-1ß (IL-1ß) levels. We also investigated the role of muscarinic and nicotinic receptors in the antiallodynic action produced by Eta as well as the possible action of Eta on in vitro and ex vivo acetylcholinesterase activity in CFA treated animals. Furthermore, we verified the effect of Eta treatment on the parameters of liver and kidney lesion (level of urea, and activity of aspartate aminotransferase and alanine aminotransferase). RESULTS: Eta produced marked reduction in the allodynia caused by CFA, surgical incision and partial sciatic nerve ligation. However, Eta did not alter the paw edema or the increase of IL-1ß levels produced by CFA. The antinociceptive effect of Eta was reversed by the pre-treatment of animals with the antagonists of muscarinic (atropine, 5mg/kg, s.c) or nicotinic (mecamylamine, 0.001mg/kg, s.c.) receptors. Eta did not alter in vitro acetylcholinesterase activity in blood or spinal cord samples, but it reversed the increase in the acetylcholinesterase activity observed in the spinal cord samples from mice injected with CFA. Moreover, Eta did not alter the indicators of liver or kidney lesion. CONCLUSIONS: Based on its use in traditional medicine, the results of the present study confirmed the antinociceptive properties of Eta in clinically relevant pain models. Also its effect on the CFA-induced chronic inflammation seems to be related to acetylcholinesterase inhibition and cholinergic system.

Exposição aguda ao Metilmercúrio em ratos em desenvolvimento: mini-revisão / Acute exposition of developing rats to Methylmercury: a mini-review

Mercúrio (Hg) está presente no ambiente em três diferentes formas químicas: elementar (Hg0), inorgânico e orgânico, sendo que a sua distribuição, toxicidade e metabolismo são dependentes de sua forma química. A exposição oral ao consumo de peixes e alimentos contaminados é a principal forma de exposição humana ao metilmercúrio (MeHg), um poluente ambiental que é absorvido por ingestão, inalação e através da pele. O MeHg é um potente neurotóxico, especialmente para o cérebro em desenvolvimento. Neste estudo, foram examinados os principais efeitos da exposição ao MeHg durante o desenvolvimento salientando os mecanismos bioquímicos envolvidos nestes processos. Também foram apresentados recentes resultados sobre o uso de extratos de plantas medicinais que atenuaram os efeitos adversos deste metal. Deste modo, estes dados reforçam a toxicidade do MeHg durante o desenvolvimento e sugerem possíveis caminhos para futuras intervenções terapêuticas.

Mercury (Hg) is present in the environment in three different chemical forms: elemental, inorganic and organic Hg. The distribution, toxicity and metabolism of Hg are linked to its chemical form. The oral exposition following fish and food contaminated is the main route of contamination of humans to the methilmercury (MeHg), an environmental pollutant which is absorbed by ingestion, inhalation and through the skin. MeHg is a strong neurotoxic molecule, especially for the developing brain. In this study, the main effects of the MeHg exposition and the biochemical parameters involved in this process were examined. The results of the use of plant extracts which attenuate the adverse effects of this metal are also presented here. Therefore, these data reinforce the MeHg toxicity during the development and suggest alternative ways for future therapeutic approaches.

Plasma malondialdehyde levels and risk factors for the development of chronic complications in type 2 diabetic patients on insulin therapy.

BACKGROUND: We assessed plasma malondialdehyde (MDA) levels as a biomarker of lipid peroxidation in type 2 diabetic patients on insulin therapy. Associations among MDA levels and some risk factors for the development of chronic complications of diabetes were also evaluated. METHODS: MDA, fasting glucose, fructosamine, urinary albumin, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, creatinine, uric acid, serum albumin, lactate, high sensitive C reactive protein (hsCRP), and vitamin E were measured in 53 type 2 diabetic patients and 26 healthy subjects. RESULTS: MDA levels were higher in type 2 diabetes insulin users (12.8 +/- 3.0 micromol/L) and type 2 diabetes no insulin users (10.3 +/- 2.1 micromol/L) compared to control subjects (8.2 +/- 2.1 micromol/L). Fasting glucose, fructosamine, urinary albumin, and hsCRP were higher in all type 2 diabetic patients compared to controls. Significant correlations were observed between MDA and fasting glucose (r = 0.685, p < 0.001), fructosamine (r = 0.526, p < 0.001), urinary albumin (r = 0.516, p < 0.001), and the duration of type 2 diabetes (r = 0.401, p = 0.005). CONCLUSIONS: MDA levels increased in type 2 diabetes, especially in patients on insulin therapy. Chronic hyperglycemia and other biomarkers, such as urinary albumin, were correlated with MDA levels, suggesting the involvement of lipid peroxidation in the pathogenesis of diabetes complications.

Purinergic system ecto-enzymes participate in the thromboregulation of patients with indeterminate form of Chagas disease.

Chagas disease (CD) is a chronic and endemic illness caused by the parasite Trypanosoma cruzi. Microvascular disturbances play an important role in the progress of the disease. The purinergic signaling system participates in regulatory functions, such as immunomodulation, neuroprotection, and thromboregulation. This study aimed to investigate the activities of purinergic system ecto-enzymes present on the platelet surface and the platelet aggregation profile from patients with indeterminate form of Chagas disease (IFCD). Thirty patients diagnosed with IFCD and 30 healthy subjects were selected. Ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase), ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP), ecto-5'-nucleotidase (E-5'-NT) and ecto-adenosine deaminase (E-ADA) activities were measured in platelets isolated from these individuals as well as the platelet aggregation. Results demonstrated an increase of 21 % in the E-NPP activity and 30 % in the E-5'-NT activity in IFCD group (P < 0.05); however, a decrease of 34 % in the E-ADA activity was determined in the same group (P < 0.001). A significant decrease of 12.7 % and 12.8 % in the platelet aggregation of IFCD group in two different concentrations of ADP (5 and 10 µM) was observed, respectively (P < 0.05). Increased E-NPP and E-5-NT activities as well as decreased E-ADA activity in platelets of patients with IFCD contributed to decrease platelet aggregation, suggesting that the purinergic system is involved in the thromboregulation process in these patients, since adenosine (the final product of ATP hydrolysis) has cardioprotective and vasodilator effects that prevent the clinical progress of the disease.

Activities of adenine nucleotide and nucleoside degradation enzymes in platelets of rats infected by Trypanosoma evansi.

Nucleotide and nucleoside-degrading enzymes, such as nucleoside triphosphate diphosphohydrose (NTPDase), 5'-nucleotidase and adenosine deaminase (ADA) are present in the surface membranes of platelets, involved in clotting disturbances of Trypanosoma evansi-infected animals. Thus, this study was aimed at evaluating the activities of these enzymes in platelets of rats experimentally infected with T. evansi. Animals were divided into four groups, according to the level of parasitemia. Blood samples were collected on days 3 (group A: at the beginning of parasitemia), 5 (group B: high parasitemia) and 15 (group C: chronic infection), post-infection. Group D (control group) was composed of non-infected animals for platelet count, separation and enzymatic assays. Animals from groups A and B showed marked thrombocytopenia, but platelet count was not affected in chronically infected rats. NTPDase, 5'-nucleotidase and ADA activities decreased (p<0.05) in platelets from rats of groups A and B, when compared to the control group. In group C, only NTPDase and 5'-nucleoside activities decreased (p<0.001). The correlations between platelet count and nucleotide/nucleoside hydrolysis were positive and statistically significant (p<0.05) in groups A and B. Platelet aggregation was decreased in all infected groups, in comparison to the control group (p<0.05). It is concluded that the alterations observed in the activities of NTPDase, 5'-nucleotidase and ADA in platelets of T. evansi-infected animals might be related to thrombocytopenia, that by reducing the number of platelets, there was less release of ATP and ADP. Another possibility being suggested is that changes have occurred in the membrane of these cells, decreasing the expression of these enzymes in the cell membrane.

Activity of the enzyme adenosine deaminase in serum, erythrocytes and lymphocytes of rats infected with Trypanosoma evansi.

In Trypanosoma evansi infections changes in the haemogram are commonly observed, and the enzyme adenosine deaminase (ADA) plays an important role in the production and differentiation of blood cells. Thus, the aim of this study was to evaluate the activity of ADA in serum, erythrocytes and lymphocytes of rats infected with T. evansi compared to non-infected rats. Thirty adult rats were used, divided into 3 uniform groups. The animals in groups A and B were infected intraperitoneally with 2 x 106 trypomastigotes/rat. Rodents from group C (control group), were not-infected. Blood collection was performed on days 4 and 20 post-infection (p.i.) in order to obtain acute and chronic infection stages of disease. The blood was used to assess the activity of ADA. In the blood, reduced haematocrit and increased lymphocytes were correlated with ADA activity in erythrocytes and lymphocytes. We observed reduction of ADA activity in serum and erythrocytes in rats infected with T. evansi compared to non-infected rats (P < 0.05). ADA activity in lymphocytes was decreased after 4 days, when the parasitaemia was high and increased after 20 days, when the number of circulating parasites was low. In conclusion, our results showed that the ADA activity was altered in serum, lymphocytes and erythrocytes of rats, concomitantly with haematological parameters, in experimental infection by T. evansi.

Trypanosoma evansi: adenosine deaminase activity in the brain of infected rats.

The study was undertaken to evaluate changes in the activity of adenosine deaminase (ADA) in brains of rats infected by Trypanosoma evansi. Each rat was intraperitoneally infected with 10(6) trypomastigotes either suspended in fresh (group A; n = 13) and cryopreserved blood (group B; n = 13). Thirteen animals were used as control (group C). ADA activity was estimated in the cerebellum, cerebral cortex, striatum and hippocampus. No differences (P > 0.05) in ADA activity were observed in the cerebellum between infected and non-infected animals. Significant (P < 0.05) reductions in ADA activity occurred in cerebral cortex in acutely (day 4 post-infection; PI) and chronically (day 20 PI) infected rats. ADA activity was significantly (P < 0.05) decreased in the hippocampus in acutely infected rats, but significantly (P < 0.05) increased in the chronically infected rats. Significant (P < 0.05) reductions in ADA activity occurred in the striatum of chronically infected rats. Parasites could be found in peripheral blood and brain tissue through microscopic examination and PCR assay, respectively, in acutely and chronically infected rats. The reduction of ADA activity in the brain was associated with high levels of parasitemia and anemia in acute infections. Alterations in ADA activity of the brain in T. evansi-infected rats may have implications for pathogenesis of the disease.

Syzygium cumini extract decrease adenosine deaminase, 5'nucleotidase activities and oxidative damage in platelets of diabetic patients.

Diabetes mellitus, a chronic metabolic disorder, has assumed epidemic proportions and its long-term complications can have devastating consequences. The oxidative stress in diabetes was greatly increased due to prolonged exposure to hyperglycemia and impairment of oxidant/antioxidant equilibrium. Syzygium cumini is being widely used to treat diabetes by the traditional practitioners over many centuries. Adenosine deaminase (ADA) and 5'-Nucleotidase (5'NT) are enzymes of purine nucleoside metabolism that play an important role in the regulation of adenosine (Ado) levels. In this study, we investigated the effect of Syzygium cumini aqueous leaves extract (ASc) on ADA and 5'NT activities and on parameters of oxidative stress under in vitro conditions, using platelets of patients with Type 2 diabetes mellitus. Platelet-Rich Plasma (PRP) was assayed by ADA, 5'NT, Catalase (CAT), Superoxide Dismutase (SOD) activities and Thiobarbituric acid reactive substances (TBARS) levels. We observed that ADA, 5'NT activities and TBARS levels were significantly higher when compared to the control group, and ASc (100 and 200 µg/mL) prevented these effects. Our study demonstrates that ASc was able to remove oxidant species generated in diabetic conditions and modulates in the Ado levels. Then, ASc may promote a compensatory response in platelet function, improving the susceptibility-induced by the diabetes mellitus.

The activity and expression of NTPDase is altered in lymphocytes of multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating neurological disease, which is presumed to be a consequence of infiltrating lymphocytes that are autoreactive to myelin proteins. ATP and adenosine contribute to fine-tuning immune responses and NTPDase (CD39) and adenosine deaminase (ADA) are important enzymes in the control of the extracellular levels of these molecules at the site of inflammation. We evaluated the activity and expression of NTPDase and adenosine deaminase (ADA) activity in lymphocytes from patients with the relapsing-remitting form of MS (RRMS). METHODS: This study involved 22 patients with RRMS and 22 healthy subjects as a control group. The lymphocytes were isolated from blood and separated on Ficoll density gradients and after isolation the NTPDase and ADA activities were determined. RESULTS: The NTPDase activity and expression were increased in lymphocytes from RRMS patients when compared with the control group (p<0.05). In addition, a decrease in ADA activity was observed in lymphocytes from these patients when compared to the control group (p<0.05). CONCLUSIONS: The regulation of ATP and adenosine levels by NTPDase and ADA activities may be important to preserve cellular integrity and to modulate the immune response in MS.

Evaluation of ischemia-modified albumin in myocardial infarction and prostatic diseases.

BACKGROUND: Ischemia-modified albumin (IMA) has been shown to be a rapidly rising and sensitive biochemical marker for the diagnosis of myocardial ischemia. In this study, we evaluated the levels of IMA in myocardial infarction and prostate diseases, as well as the influence of HDL cholesterol levels on C-reactive protein (CRP) and IMA levels. METHODS: A total of 27 patients with myocardial infarction (MI), 102 patients with benign prostatic hyperplasia (BPH), 84 patients with prostate cancer (PCA), and 21 healthy subjects were enrolled in this study. IMA levels were measured in whole studied patients. Cardiac troponin I (cTnI), cholesterol, HDL cholesterol, and CRP were measured in MI and control groups. RESULTS: IMA values were significantly higher in patients with MI (0.5215+/-0.0241 ABSU) and BPH (0.4150+/-0.0156 ABSU) in comparison to control subjects (0.3381+/-0.0194 ABSU). IMA and CRP were higher in MI group, especially in patients with HDL cholesterol levels lower than 38 mg/dL. The ability of IMA to discriminate myocardial infarction was higher than CRP. Significant correlations between CRP and HDL, CRP and IMA, and HDL and IMA were reported. CONCLUSIONS: IMA and CRP increase in myocardial damage, and the decrease of HDL cholesterol appears to enhance the inflammatory response. IMA also increase in benign prostate hyperplasia and this finding suggests that the diagnosis of prostate diseases must be considered on evaluation of IMA as a marker of cardiac ischemia.

(45)Ca(2+) influx in rat brain: effect of diorganylchalcogenides compounds.

In nervous tissue, the calcium (Ca(2+)) release induces neurotransmitter exocytosis and synaptic plasticity in neurons and is essential for Ca(2+) waves and oscillations in astrocytes. In this work, we have investigated the effect of organocalchogens on calcium influx in synaptosomal preparations under basal and depolarizing conditions. Acute administration of ebselen caused a significant increase of 34% (p < 0.05) Ca(2+) influx, when under basal conditions but showed no effect on potassium stimulated calcium conditions by brain synaptosomes. Diphenyl ditelluride (PhTe)(2) increased (45)Ca(2+) influx by 40% (p < 0.05) under depolarizing conditions, while diphenyl diselenide (PhSe)(2) had no effect on the brain synaptosomes studied. In addition, we characterized an "in vitro" model with the purpose of studying Ca(2+) movements in slices. In this model, we examined the effect of diorganylchalcogenides using brain hippocampal slices, which showed the decrease of calcium influx with the three drugs studied. These findings showed that there are different effects of diorganylchalcogenides in the different models evaluated. It is possible that these differential effects result from the action of neural signal transduction pathways at different levels, possibly involving neurotransmitter release and channel targeting.

Evidence that 3-hydroxyglutaric acid interacts with NMDA receptors in synaptic plasma membranes from cerebral cortex of young rats.

Neurological symptoms are common in patients with glutaric acidemia type I (GA-I). Although the pathophysiology of this disorder is not yet fully established, 3-hydroxyglutaric acid (3-HGA), which accumulates in affected patients, has recently been demonstrated to be excitotoxic to embryonic chick and neonatal rat neurons probably via NMDA glutamate receptors. In the present study, we investigated the in vitro effects of 3-HGA on the [(3)H]glutamate and [(3)H]MK-801 (dizocilpine) binding to rat synaptic plasma membranes from cerebral cortex of young rats in order to elucidate the interactions of 3-HGA with glutamate receptors and its possible contribution to the in vitro excitotoxic properties of 3-HGA. 3-HGA (10-100 microM) significantly decreased Na(+)-dependent (up to 62%) and Na(+)-independent (up to 30%) [(3)H]glutamate binding to synaptic membranes, reflecting a possible competition between glutamate and 3-HGA for the glutamate transporter and receptor sites, respectively. Since a decrease in Na(+)-independent glutamate binding might represent an interaction of 3-HGA with glutamate receptors, we next investigated whether 3-HGA interacts with NMDA receptors by adding NMDA alone or combined with 3-HGA and measuring Na(+)-independent [(3)H]glutamate binding to synaptic membranes (binding to receptors). We verified that 3-HGA and NMDA, at 10 and 100 microM concentrations, decreased glutamate binding by up to 20 and 45%, respectively, and that the simultaneous addition of both substances did not provoke an additive effect, implying that they bind to NMDA receptors at the same site. Furthermore, the binding of the NMDA-channel blocker [(3)H ]MK-801 was significantly increased (approximately 32-40%) by 10 and 100 microM 3-HGA, implying that 3-HGA was able to open the NMDA channel allowing MK-801 binding, which is a characteristic of NMDA agonists. On the other hand, glutamate had a much higher stimulatory effect on this binding (180% increase), reflecting its strong NMDA agonist property. Furthermore, the simultaneous addition of 3-HGA and glutamate provoked an additive stimulatory effect on [(3)H]MK-801 binding to the NMDA receptor. These data indicate that, relatively to glutamate, 3-HGA is a weak agonist of NMDA receptors. Finally, we demonstrated that 3-HGA provoked a significant increase of extracellular calcium uptake by cerebral cortex slices, strengthening therefore, the view that 3-HGA activates NMDA receptors. The present study therefore, demonstrates at the molecular level that 3-HGA modulates glutamatergic neurotransmission and may explain previous findings relating the neurotoxic actions of this organic acid with excitotoxicity.