Interactions between Zn and Cu in LEC rats, an animal model of Wilson's disease

The effect of oral Zn treatment was studied in the liver and kidneys of 26 male Long-Evans Cinnamon (LEC) rats (mutant animals, 5 weeks old) in relation to both the interaction between Zn and Cu and the localisation and concentration of metallothionein (MT). Rats receiving 80 mg zinc acetate daily by gavage and control rats receiving no treatment were killed after 1 or 2 weeks. By immunohistochemical and analytical chemical techniques we revealed that treated rats had higher levels of MT in the hepatic and renal cells compared to untreated ones. Tissue Zn concentrations were significantly higher in treated rats compared to untreated whereas Cu concentrations decreased in the liver and kidneys as indicated by analytical chemical analyses. MT levels also decreased with treatment period. A histochemical procedure, obtained using autofluorescence of Cu-metallothioneins, confirms these findings: after 2 weeks, the signal decreased in both the liver and kidney sections. This gives a greater understanding of the mechanism of Cu metabolism in the two tissues considered. These results suggest that Zn acts both to compete for absorption on the luminal side of the intestinal epithelium and to induce the synthesis of MT.     

Cardiotonic steroids: potential endogenous sodium pump ligands with diverse function

The highly conserved cardiotonic steroid (CS) binding site present on the ubiquitous membrane sodium pump, sodium, potassium-ATPase, appears to have been conserved by no force other than its capacity to bind CS: a family that includes plant-derived cardiac glycosides and putative endogenous vertebrate counterparts. Binding of ligand is inhibited by increased extracellular potassium. This implies functional coordination because inhibition of the sodium pump would be counterproductive when extracellular potassium is elevated. The interesting biology of the CS binding site continues to stimulate investigations into the identity of endogenous ligands, their role as pump regulators at the cellular level, and as mediators of body fluid balance and blood pressure regulation. In addition to inhibition of sodium and potassium transport, there is considerable recent evidence suggesting that the sodium pump may act as a cell signaling receptor activated by CS binding and responding by coordination of intracellular signaling pathways that can be dependent on and also independent of the reduction in transmembrane ion flux resulting directly from pump inhibition. This signaling may influence cell survival, growth, and differentiation. Recent insight into the biology of pump regulation by CS is reviewed.     

In vitro production of ovarian steroids in yellow perch (Perca flavescens): effects of photothermal manipulation, gonadotropin and phorbol ester

We investigated the capacity of ovaries of yellow perch to produce steroid hormones in vitro and the ovarian response to gonadotropin and phorbol ester during the annual reproductive cycle. The effects of photothermal manipulation on perch gonadal steroidogenesis and its regulation have also been examined. Initially, all females kept indoors were exposed to the same water temperature and photoperiod. By the end of August, following the first sampling, fish were submitted to different photothermal regimes. Group A was maintained under photothermal conditions characteristic for southern Ohio. Group B was submitted to a condensed light/temperature regime designed to accelerate physiological changes that depend on photothermal stimuli. In group A, basal in vitro production of ovarian estradiol (E2) was the highest in October and November, and hCG significantly stimulated E2 secretion during the entire period of vitellogenesis (October-January). In this group, the highest production of basal testosterone (T) was observed before spawning. hCG-stimulated production of T was highest at the beginning of vitellogenesis. Gonadotropin stimulated T production before spawning, a time when gonadotropin was unable to stimulate E2 production. Phorbol ester (PDBu) stimulated E2 and T production during vitellogenesis at the same time points as hCG did (E2: December, January; T: December). hCG-stimulated T production was not mimicked by PDBu in April. Condensing of the photothermal cycle resulted in diminished ovarian production of E2 during vitellogenesis. Moreover, the fish submitted to a condensed photothermal cycle demonstrated augmented T production during the postvitellogenic stage of ovarian development. Ovaries of group B did not respond to PDBu. Generally, the seasonal fluctuations in ovarian capacity to produce E2 and T as well as in gonadal responsiveness to gonadotropin observed in female yellow perch illustrate the dynamic nature of ovarian endocrine function. The lack of response to gonadotropin with regard to E2 production prior to spawning is not due to insensitivity to gonadotropin, but rather due to some deficiency in steroidogenesis (e.g. reduced aromatase activity). It appears also that ovarian steroidogenesis and its regulation are dependent on annual changes of photothermal conditions.     

Structure of CcmG/DsbE at 1.14 A resolution: high-fidelity reducing activity in an indiscriminately oxidizing environment

CcmG is unlike other periplasmic thioredoxin (TRX)-like proteins in that it has a specific reducing activity in an oxidizing environment and a high fidelity of interaction. These two unusual properties are required for its role in c-type cytochrome maturation. The crystal structure of CcmG reveals a modified TRX fold with an unusually acidic active site and a groove formed from two inserts in the fold. Deletion of one of the groove-forming inserts disrupts c-type cytochrome formation. Two unique structural features of CcmG-an acidic active site and an adjacent groove-appear to be necessary to convert an indiscriminately binding scaffold, the TRX fold, into a highly specific redox protein.     

Free fatty acid-induced peripheral insulin resistance augments splanchnic glucose uptake in healthy humans

To investigate the effect of elevated plasma free fatty acid (FFA) concentrations on splanchnic glucose uptake (SGU), we measured SGU in nine healthy subjects (age, 44 +/- 4 yr; body mass index, 27.4 +/- 1.2 kg/m(2); fasting plasma glucose, 5.2 +/- 0.1 mmol/l) during an Intralipid-heparin (LIP) infusion and during a saline (Sal) infusion. SGU was estimated by the oral glucose load (OGL)-insulin clamp method: subjects received a 7-h euglycemic insulin (100 mU x m(-2) x min(-1)) clamp, and a 75-g OGL was ingested 3 h after the insulin clamp was started. After glucose ingestion, the steady-state glucose infusion rate (GIR) during the insulin clamp was decreased to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in GIR during the period after glucose ingestion from the ingested glucose load. [3-(3)H]glucose was infused during the initial 3 h of the insulin clamp to determine rates of endogenous glucose production (EGP) and glucose disappearance (R(d)). During the 3-h euglycemic insulin clamp before glucose ingestion, R(d) was decreased (8.8 +/- 0.5 vs. 7.6 +/- 0.5 mg x kg(-1) x min(-1), P < 0.01), and suppression of EGP was impaired (0.2 +/- 0.04 vs. 0.07 +/- 0.03 mg x kg(-1) x min(-1), P < 0.01). During the 4-h period after glucose ingestion, SGU was significantly increased during the LIP vs. Sal infusion study (30 +/- 2 vs. 20 +/- 2%, P < 0.005). In conclusion, an elevation in plasma FFA concentration impairs whole body glucose R(d) and insulin-mediated suppression of EGP in healthy subjects but augments SGU.     

Heat-shock protein 90 complexes in resting and thrombin-activated platelets

The orexins are peptides which were recently isolated from the rat hypothlamus. They play a role in energy homeostasis and regulation of feeding as well as in other functions such as the sleep-wake cycle. The involvement of glucocorticoids in stress processes as well as in body weight regulation is well known. In the present paper, we investigated the role of glucocorticoids on hypocretin (Hcrt)/orexin (OX) pathway in Sprague-Dawley rats. We confirmed by in situ hybridization that prepro-Hcrt/OX mRNA expression is restricted to the lateral hypothalamus area with extension to the perifornical nucleus and the posterior hypothalamic area. Lateral hypothalamic prepro-Hcrt/OX mRNA expression was decreased by 50% after adrenalectomy (99.8+/-5.0 vs 49.2+/-4.4 nCi/g, p<0.01). Peripheral glucocorticoid treatment (dexamethasone) restored its expression to normal levels (105.4+/-6.1 nCi/g). The present data provide direct evidence that Hcrt/OX expression in the lateral hypothalamus is modulated by the glucocorticoids status. As the Hcrt/Ox system is closely interactive with the corticotropin-releasing hormone and neuropeptide Y systems, we propose that hypocretin/orexins peptides constitute a very sensitive key relay for mediating both stress and feeding behavior.     

Adiponectin concentrations as a criterion of metabolic control in persons with type 2 diabetes mellitus?

Adiponectin (ADP) is an adipocytokin with many antiatherogenic properties; its decreased level is associated with numerous atherogenic diseases and syndromes (e.g. diabetes mellitus (DM), dyslipidemia, endothelial dysfunction, hypertension, and obesity). Decreased ADP values in blood may be an independent risk factor of atherosclerotic (ATS) complications. AIM OF THE STUDY: 1) Do persons with type 2 diabetes have lower ADP values than individuals without DM but with a high risk of ATS complications? 2) Do ADP values differ between persons with well controlled and persons with uncontrolled type 2 diabetes? We examined 109 patients of the Metabolic Center of Hospital Sternberk. Out of them, 58 had type 2 diabetes, others were individuals with variously expressed risk factors of early atherosclerosis (obesity, hypertension, age, family history, smoking, dyslipidemia, etc.). In all persons under this study the following parameters were determined in peripheral venous blood: adiponectin, resistin, leptin, ObRe, cholesterol, HDL-cholesterol, triacylglycerols, glucose, HbA1c, creatinine, urea, ALT, AST, CRP, homocysteine, thrombocyte aggregation after CPG induction. The whole group was divided according to the presence of type 2DM into two subgroups; persons with diabetes were divided into the well controlled and uncontrolled subgroups. All data obtained were processed statistically using the software SPSS for Windows and Medcalc. The adiponectin/BMI index correlated negatively with HbA1c value (correlation coefficient -0.37, p = 0.00053), triacylglycerols (-0.4, p = 0.000001), P-glucose (-0.3, p = 0.0017), uricemia (-0.35, p = 0.0007) and positively with HDL-cholesterol value (0.6, p=0.00001). Women had higher adiponectin values than men. Persons with hypertension and with diabetes mellitus, individuals with atherogenic lipotype or persons with inflammation signs had lower values than individuals without these diseases and syndromes. Persons with wellcontrolled diabetes mellitus had higher values than persons with uncontrolled diabetes (medians of the adiponectin/BMI index 9.7 vs. 6.7, p < 0.01). Persons with type 2 diabetes mellitus have lower ADP values than persons with a high ATS risk without diabetes mellitus. Persons with wellcontrolled diabetes mellitus (DM) and with satisfactory compensation have significantly higher ADP levels (independently of other metabolic parameters of DM control). ADP may be a new marker of metabolic control in persons with a high risk of atherosclerotic complications.     

Pathobiology of androgenetic alopecia

Human hair morphogenesis is a dynamic process caused by the remodelling of the skin. Hair growth is cyclic in mammals consisting of three distinct stages: an active stage (anagen), a regressive stage (catagen), and a resting stage (telogen). One disorder in this process is gradual balding of the scalp called androgenetic alopecia. Little is known about the cell biological or molecular mechanisms involved and thus very little treatment is currently available. In this review we focus on the most significant parameters affecting hair growth which participate in baldness.