Route-dependent effects of cadmium/cadmium and magnesium acute treatment on parameters of oxidative stress in rat liver

The study was designed to evaluate and compare the effects of single oral (or) and intraperitoneal (i.p.) cadmium (Cd) administration on parameters of oxidative stress in liver of rats. Furthermore, investigation on protective effects of magnesium (Mg) or and i.p. pretreatment on the same parameters was performed. Wistar rats were administrated oral dose of Cd (30 mg Cd/kg b.w.)/Cd+Mg (30 mg Cd/kg b.w., 50 mg Mg/kg b.w.) or i.p. dose of Cd (1.5 mg Cd/kg b.w.)/Cd+Mg (1.5 mg Cd/kg b.w., 3 mg Mg/kg b.w.) and sacrificed after 24 h. In liver homogenates superoxide anion, malondialdehyde, non-protein sulfhydryl groups, total sulfhydryl groups content, and superoxide dismutase activity were determined. Cadmium intoxication caused the increase of superoxide anion and malondialdehyde levels and had negative effect on investigated parameters of antioxidant defense system, except on total sulfhydryl groups. The negative effect was more emphasized after i.p. Cd administration. Oral Mg pretreatment induced more pronounced positive effect than Mg given intraperitoneally that can be attributed, at least partly, to Cd and Mg interactions on the level of GIT. On the basis of the obtained results it can be concluded that both Cd and Cd+Mg effects on parameters of oxidative stress in rats liver are route-dependent.     

The clinical significance of the spectrum of interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians

OBJECTIVES: To assess the clinical significance of the interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians. METHODS: The clinical phenotypes associated with compound heterozygosity for the CAP+1 (A-->C) mutation with other beta-thalassemia mutations, together with the potential effect of the genetic modifiers alpha-thalassemia and the Xmn-1(G)gamma C-->T polymorphism were studied in 30 patients. The frequency of the CAP+1 (A-->C) polymorphism was determined and an analysis of the red cell indices, HbA(2) levels, iron status, and alpha-globin genes was carried out in 35 heterozygotes. RESULTS: Based on an analysis of 1075 beta-thalassemia alleles the CAP+1 (A-->C) mutation constituted 3.2% of north Indians. There was a wide spectrum of phenotypic severity in compound heterozygotes; 18 of 30 were transfusion dependent. There was a very high frequency of the -/- genotype of the Xmn-1(G)gamma polymorphism in compound heterozygotes. Analysis of 35 heterozygotes indicated that approximately half were hematologically normal and therefore genuine 'silent' carriers. CONCLUSIONS: Compound heterozygotes for CAP+1 (A-->C) and other severe beta-thalassemia alleles are phenotypically severe enough to necessitate appropriate therapy and counseling. The unexpected severity of these interactions may be due, in part, to the high frequency of beta-thalassemia alleles associated with the Xmn-1(G)gamma- allele in Indian populations. It is concluded that the CAP+1 (A-->C) mutation can pose serious difficulties in screening and counseling programs in populations in which it occurs at a significant frequency.     

Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity

Acetyl-CoA carboxylase (ACC) is a key enzyme of fatty acid metabolism with multiple isozymes often expressed in different eukaryotic cellular compartments. ACC-made malonyl-CoA serves as a precursor for fatty acids; it also regulates fatty acid oxidation and feeding behavior in animals. ACC provides an important target for new drugs to treat human diseases. We have developed an inexpensive nonradioactive high-throughput screening system to identify new ACC inhibitors. The screen uses yeast gene-replacement strains depending for growth on cloned human ACC1 and ACC2. In “proof of concept” experiments, growth of such strains was inhibited by compounds known to target human ACCs. The screen is sensitive and robust. Medium-size chemical libraries yielded new specific inhibitors of human ACC2. The target of the best of these inhibitors was confirmed with in vitro enzymatic assays. This compound is a new drug chemotype inhibiting human ACC2 with 2.8 μM IC₅₀ and having no effect on human ACC1 at 100 μM.     

Metabolic and pharmacokinetic evaluation of a novel 3-hydroxypyridinone iron chelator, CP502, in the rat.

A recently synthesized 3-hydroxypyridinone derivative with an amido function at the 2-position, CP502 (1,6-dimethyl-3-hydroxy-4-(1H)-pyridinone-2-carboxy-(N-methyl)-amide hydrochloride), exhibited high in vitro iron chelating potency (pFe3+ =21.7). It was targeted as a new iron-chelating candidate for further development in early pre-clinical testing. To evaluate its pharmacokinetics, including oral bioavailability, metabolic and disappearance profiles, studies were conducted in Sprague Dawley male rats. A single 150 mg/kg intravenous and oral dose was given to male Sprague Dawley rats (N=6, B.Wt. 250g). The rats were placed in metabolic cages and fasted overnight before the dosing. Venous blood samples (200 microL per withdrawal) were collected at defined time points before (blank) and up to 28 h post administration. Urine and feces were collected before dosing (blank) and in 24 h intervals up to 72 h post administration. Plasma CP502 concentration versus time profiles were consistent with two-compartment distribution, and the oral bioavailability approached 100%. Total clearance and mean residence time (i.v.) were 1.02 L/kg/h and 1.10 h, respectively. Simultaneous computer fitting yielded V1 and Vss estimates of 0.96 L/kg and 1.74 L/kg, respectively. CP502 was mainly excreted unchanged via urine (45.29+/-9.40 % of total dose) or as glucuronide (6.46+/-1.22% of total dose). High iron chelation potential and favorable pharmacokinetic and metabolic profiles indicate that CP502 is a promising candidate for further development.     

Tamoxifen stimulates calcitonin-producing thyroid C-cells and prevents trabecular bone loss in a rat model of androgen deficiency

Thyroid C-cells produce calcitonin (CT), a hypocalcemic hormone, that acts as an inhibitor of bone resorption. In this study, we investigated the effects of tamoxifen (TAM) as a selective estrogen receptor modulator on thyroid C-cells, trabecular bone and biochemical markers of bone metabolism in an animal model of androgen deficiency, represented by middle-aged orchidectomized (Orx) rats. Fifteen-month-old male Wistar rats were divided into: Orx and sham-operated (SO) groups. Rats from one Orx group were injected subcutaneously with TAM citrate (Orx + TAM; 0.3 mg kg⁻¹ b.w.), while the rats from SO and a second Orx group received vehicle alone, once a day for 3 weeks. The peroxidase–antiperoxidase method was applied for localization of CT in C-cells. Thyroid C-cells were morphometrically and ultrastructurally analyzed. An ImageJ image-processing program was used to measure bone histomorphometric parameters. Blood serum samples were analyzed for CT, osteocalcin (OC), calcium (Ca²⁺) and phosphorus (P). Urinary Ca²⁺ concentrations were measured. TAM treatment significantly increased thyroid C-cell volume (V_c) and serum CT when compared with vehicle-treated Orx rats. Analysis of trabecular microarchitecture of the tibia showed that administration of TAM significantly increased cancellous bone area, trabecular thickness and trabecular number, whereas trabecular separation was significantly decreased compared with vehicle-treated Orx rats. Serum OC and urinary Ca²⁺ concentrations were significantly lower in comparison with the control Orx group. These results indicate that in our rat model of androgen deficiency, TAM stimulated calcitonin-producing thyroid C-cells and increased trabecular bone mass.     

Epidemiology of hypertension in Serbia: results of a National Survey

Background

We evaluated the prevalence of high blood pressure and the level of awareness, treatment, and control of hypertension in a Serbian population.

Methods

A cross-sectional study of an adult population was carried out across Serbia in 2006. The study involved 14 204 adults aged 20 years or older. Interviews and measurements of blood pressure were performed at participants’ homes.

Results

Overall, 47% of the Serbian adult population had hypertension: 25.3% had stage 1 hypertension and 18.1% had stage 2 hypertension. Only 58.0% of the hypertensive population were aware that they had the disease, and 60.4% were receiving medical treatment. Among those receiving medical treatment, only 20.9% had a blood pressure within the normal range. One in 10 participants with hypertension were not treated because, among other reasons, they thought treatment was unnecessary (55.3%) or they lacked money for medication (19.3%).

Conclusions

The prevalence of undiagnosed and untreated hypertension is high in the adult population of Serbia. Further action is required to hasten detection and treatment of high blood pressure. Attention should be directed toward educational programs that improve knowledge, attitudes, and awareness of hypertension among adults.Key words: hypertension, adult population, Serbia