Chromium(VI) is a recognized toxicant whose effects have been linked to its reduction to lower oxidation states. Although Cr(VI) is reduced by several systems, it is anticipated that its reduction by nitric oxide synthase (NOS) could have significant effects in endothelial and brain cells that express high constitutive levels of the enzyme. This possibility was examined by electron paramagnetic resonance that showed the formation of a stable Cr(V) species from NOS/Cr(VI). The formation of Cr(V) was calcium/calmodulin-independent indicating that Cr(VI) to Cr(V) reduction occurs at the flavin-containing domain of NOS. Accordingly, Cr(VI) reduction by the reductase domain of NOS and the chimera protein cytochrome-P450-reductase+tail-nNOS also generated Cr(V). Activation of tetrahydrobiopterin (BH(4))-free NOS with calcium/calmodulin diminished Cr(V) steady-state levels while increasing superoxide formation. Since SOD restored Cr(V) to control levels, this result was taken as evidence for a reaction between Cr(V) and superoxide. Supplementation of NOS with BH(4) cofactor not only failed to increase Cr(V) yields but generated superoxide and hydroxyl radical. Since the holoenzyme does not generate superoxide, this reaction indicated that Cr(V) mediates the oxidation of BH(4)-bound to the enzyme. In the presence of L-arginine, however, Cr(VI) neither enhances superoxide release nor inhibits NO formation from fully active NOS. This suggests that L-arginine protects BH(4) from Cr(V)-mediated oxidation. While Cr(V) was inactive toward NO, spin trapping experiments with 5-tert-butoxycarbonyl 5-methyl-1-pyrroline N-oxide and oxygen consumption measurements showed that Cr(V) reacts with superoxide by a one-electron-transfer mechanism to generate oxygen and Cr(IV). Thus, reduction of Cr(VI) to Cr(V) by NOS occurs in resting and fully active states. It is likely that the reaction between Cr(V) and superoxide influences the cytotoxic mechanisms of Cr(VI) in cells.
Some metabolic and humoral deviations found in normotensive offspring from hypertensive families can be modified in the course of years either as a result of ageing or of the clinical manifestation of essential hypertension (EH). The authors compared therefore some metabolic indicators (blood sugar level, IRI, C-peptide and plasma lipids) and humoral factors (plasma catecholamines, renin activity, atrial natriuretic factor and endothelin) in four groups of subjects: 27 young normotensive sons from normotensive families (SNF) and 30 from hypertensive families (SHF) with the findings of normotonics (NT) (n = 21) and patients with EH (n = 21) by 15 years older. Despite a tendency towards higher blood sugar levels in SHF and EH, the basal as well as oGTT stimulated blood sugar values were within the normal range. They were, however, associated with higher IRI and C-peptide concentrations in SHF with a further increase in NT and a much higher increase in EH. This indicates that normal blood sugar homeostasis in these groups is achieved only by an increased insulin secretion. The reduction of the blood sugar/IRI ratio in older NT accentuated in EH, suggests an increasing insulin resistance. In the lipid spectrum the authors found an increase of total cholesterol with advancing age, this being most marked in EH where also a decline of HDL cholesterol was recorded. As to humoral factors, higher catecholamine concentrations were found in SHF. Their increase with advancing age was more marked in EH. The plasma renin activity declined with age in NT as well as in EH.(ABSTRACT TRUNCATED AT 250 WORDS)
Fourteen patients with chronic proliferative glomerulonephritis were given for the period of one year 400 mg acetylsalicylic acid and 225 mg dipyridamole per day. During this treatment the thrombocyte aggregation became normal, however, the mean reduction of antiheparin plasma activity was not statistically significant. Normal synthesis of renal prostacyclin declined significantly as a result of treatment, while the renal thromboxane A2 synthesis remained normal even during treatment. Treatment did not influence proteinuria. The mean annual decline of glomerular filtration was greater during the investigation period than the mean annual decline in previous years, the difference was, however, only at the borderline of statistical significance. The authors did not prove a favourable effect of this treatment in patients with chronic proliferative glomerulonephritis.
Hyperinsulinaemia and insulin resistance are associated with essential hypertension irrespective of obesity and non-insulin-dependent diabetes mellitus. One of the mechanisms whereby hyperinsulinaemia may play a role in the increase in blood pressure, is an increased activity of the sympathetic nervous system. The authors studied the incidence of hyperinsulinaemia, and the possibility of modulating it by 12-week administration of the ACE inhibitor (ACEI) lisinopril (Prinivil by MSD) at a dose of 20-40 mg/day. Compared with normotensive subjects, hypertensives showed a degree of hyperinsulinaemia and insulin resistance (higher blood glucose at higher immunoreactive insulin and C-peptide concentrations, and a higher IRI/blood glucose ratio) as well as manifestations of enhanced sympathetic activity (higher adrenaline levels). Lisinopril had a favourable effect not only on blood pressure but, also, on hyperinsulinaemia and adrenaline levels. It can be reasonably concluded that therapy with ACEI, in addition to its antihypertensive effect, may also favourably modulate some pathogenic and metabolic factors in essential hypertension.
Human paraoxonase 1 (PON1) has been shown to decrease the level of systemic oxidative stress, which is thought to contribute to cancer devel- opment. The aim of this study was to examine the interrelationships between PON1 status and some clinical characteristics in patients with pancreatic cancer (PC). A group of 73 consecutive patients with PC (stage II-IV) and 73 control subjects were exam- ined. Laboratory studies included five polymor - phisms of the PON1 gene (L55M, Q192R, -108C/T, -126C/T, and -162A/G), PON1 arylesterase (PON1-A) and lactonase (PON1-L) activities, as well as some markers of protein metabolism, insulin resistance, and oxidative stress. In comparison with the control group, no difference in the distribution of the PON1 polymorphisms was found in cancer patients, both arylesterase and lactonase activities being signifi- cantly lower (-33, -47 %, respectively, both P < 0.001).
Depressive disorder (DD) is associated with an increased risk of type 2 diabetes mellitus (DM2) and cardiovascular disease (CVD). It was suggested, that metabolic syndrome (MetS), cluster of metabolic and hormonal changes, such as insulin resistence (IR), abdominal obesity, dyslipidemia, arterial hypertension and elevated fasting glycaemia, could stand behind the connection. Recent findings have shown, that adipocytokines leptin and adiponectin might play a role in both depression and MetS.The aim of this pilot study was to observe the plasma concentrations of leptin, adiponectin, leptin-to-adiponectin ratio and indices of IR in women with depressive disorder.The plasma leptin, adiponectin, parameters of lipid and glucose homeostasis and indices of IR were investigated in a group of 38 women with DD. The results were compared with those of 38 healthy women of the control group, matched for age.Depressive women differed significantly from the controls in higher concentrations of plasma leptin (p <0.05), insulin (p <0.01), C-peptide (p <0.01), value of HOMA-IR (p <0.01), and the leptin-to-adiponectin ratio (p <0.05).The QUICKI index of insulin sensitivity was lower (p <0.01). HAM-D score of DD cases correlated negatively with adiponectin (r = - 0.3505; p < 0.05), independently of HOMA-IR. We have not found in DD group any differences between the drug free patients and those treated either with escitaloprame alone or in the combination with mirtazapine.The results of the pilot study presented support the hypothesis that at least part of DD cases has increased leptin serum levels and certain features of MetS. It could be the factor connecting depression with an increased risk of either DM2 or CVD.
We analyzed concentrations of osteopontin (OPN) in patients with pancreatic ductal adenocarcinoma (PDAC) in order to determine firstly whether it is useful to distinguish between PDAC patients and those with chronic non-hereditary pancreatitis (CP) and type 2 diabetes mellitus (T2DM), and secondly whether OPN concentrations depend on the PDAC stage.Groups consisting of 64 patients with PDAC, 71 with CP, 67 with T2DM and 48 healthy controls (CON) were enrolled in the study. Controls were compared with regard to levels of OPN, oxidative stress markers, conventional tumor markers and other biochemical parameters.Levels of OPN were higher in patients with PDAC compared with CP patients (P< 0.001), T2DM (P< 0.001) and CON (P< 0.001). There were increased OPN levels in CP patients in comparison with T2DM (P< 0.001) and CON (P< 0.001). Patients with PDAC in stage IV had higher OPN levels than PDAC patients in stage III (P< 0.01). There was no difference in OPN levels of PDAC patients in stage III compared to patients in stage II.Our pilot study demonstrates the usefulness of estimating OPN levels to differentiate between pancreatic cancer and chronic pancreatitis. Higher OPN levels over 102 ng/ml could be a potential diagnostic biomarker for pancreatic cancer.
The kidney damage in chronic glomerulonephritis develops not only as a result of causal immunopathological evens, but also due to chronic adaptation changes. The study was aimed at identification of active agents, which can serve as markers of proceeding adaptation changes and to determine, if these changes may be determined in patients undergoing the stage of remission of chronic glomerulonephritis.The authors determined renin activity, concentration of atrium natriuretic peptide and endothelin in plasma and elimination of some prostanoids in urine in 33 patients with chronic stabilized glomerulonephritis with normal glomerular filtration and with normal blood pressure and in 21 healthy subjects. Seventeen patients without proteinuria did not receive therapy, 16 patients with minute proteinuria received 100 mg of acetylosalicylic acid daily. In the untreated patients without proteinuria, the elimination of thromboxane in urine was significantly higher than in both other groups. The plasma level of atrium natriuretic peptide in all 33 patients was significantly lower than in the healthy persons.Based on this study the authors believe that adaptation changes proceed even in patients with chronic glomerulonephritis in clinical remission. The increased production of renal thromboxane, which can be successfully blocked by acetylosalicylic acid may be the marker of glomerular changes. A decreased level of atrium natriuretic peptide could reflect tubulointerstitial changes.
