Serum zinc concentrations in the maintenance hemodialysis patients.

Zinc is necessary for growth and cells' division. Its deficiency may seriously affect antioxidant defense system and is usually related to renal failure, gastrointestinal diseases and alcoholism. It is very important to know zinc status in dialyzed patients and to prevent hypo- or hyperzincemia. Serum samples from 89 patients with chronic terminal renal failure on regular hemodialysis were withdrawn for the estimation of zinc concentrations immediately before and after dialysis. Serum zinc concentrations showed to be highly dependent on hemodialysis. In 57 (64%) patients, serum zinc concentrations decreased, sometimes from very high to normal values. In remaining 32 (36%) patients serum zinc concentrations tended to increase, but remained within normal range. Zinc supplementation may be recommended only in the patients with proven zinc deficiency, but for all chronic renal failure patients it is questionable.

Metal tissue kinetics in regenerating liver, thymus, spleen, and submandibular gland after partial hepatectomy in mice.

Liver regeneration after partial hepatectomy (pHx) is a well-defined process, which involves the concerted action of extra- and intracellular factors resulting in induction of cell replication and its inhibition at the time when the entire liver mass is restored. Concomitantly, the breakdown of previously maintained tolerance and the exposure of self-antigens lead to the activation of preimmune and immune repertoires, which participate in surveillance against aberrant cells and the re-establishment of previous morphostasis. Because, in these events, important biological function might have tissue minerals that are affecting the structural integrity and enzyme activities, transduction signals, transcription and replication factors during cell proliferation and apoptosis, as well as the development and maintenance of immune functions and cytokine production, in this study we analyzed tissue dynamics of zinc, iron, magnesium, and calcium in the liver, thymus, spleen, and submandibular gland in intact and pHx mice on the 1st, 2nd, 7th, and 15th d after one-third pHx, using microwave digestion and inductivity coupled plasma spectrometry. The data showed that pHx induces significant and interconnected changes in all of the estimated metals not only in the regenerating liver but also in the lymphatic tissues and submandibular gland, indicating their importance for the control of growth processes.

Thymic alterations induced by partial hepatectomy: Upregulation of glycoprotein 96, CD91 and TLR2 and generation of regulatory T cells.

Glycoprotein 96 (gp96) is an endoplasmic reticulum (ER)-resident heat shock protein. It controls the folding of nascent membrane-spanning and secretory proteins, participates in stress-induced unfolded protein response (UPR) and in pathways leading to proteolysis of damaged proteins through ER-associated degradation pathways and chaperone-mediated autophagy. In addition, gp96 controls the steroid biosynthesis and Ca²âº homeostasis and participates in insulin-IGF/signaling pathways. Besides, owing to its peptide chaperone capacity and ability to interact with antigen-presenting cells, gp96 has been implicated in priming of innate and adaptive immunity. In an attempt to visualize the intensity of ER-stress in thymus and possible participation of gp96 in generation of auto-reactive T cell clones that were detected in regenerating liver, in this study we investigated the dynamics of gp96 expression in partially hepatectomized (pHx) and sham Hx mice. Simultaneously, we detected the thymic expression of receptors responsible for endocytosis of gp96-chaperoned peptides (CD91) and intracellular activation of ER-stress pathways (TLR2), as well as the expression of TGF-ß and the distribution of CD4+CD25+FoxP3+ cells. The data have shown that both pHx and sham Hx induced an accelerated apoptosis and hypoplasia in thymus. Partial Hx induced, however, a higher expression of gp96, the translocation of the CD91, TLR2 and TGF-ß immunostaining from medulla to cortex and an appearance of Treg cells. The data show that pHx triggers in thymus the ER-stress and UPR response and suggest that gp96 participates in the generation of natural Treg cells, which might be involved in the control of liver regeneration in the periphery.

[Recent findings regarding physiological characteristics and effects of renal dopamine]. / Novije spoznaje o fizioloskim svojstvima i ucincima bubreznog dopamina.

During the past decade, it has become evident that dopamine acts not only as a classical neurotransmitter in the central and peripheral nervous system but also as an autocrine, paracrine and/or endocrine substance in peripheral, non-neuronal tissues. This work is aimed to review some of the recent aspects related to the physiological features and effects of renal origin dopamine. Renal dopamine is synthesized in the proximal tubule epithelial cells. Newly formed dopamine leaves the cellular compartment by crossing the apical cell border and the basolateral membrane side. Dopamine exerts its intrarenal action via specific cell surface receptors, differentially expressed along the nephron and other structural components of renal tissue. These receptors have been classified into five types. D1 and D5 receptors are linked to stimulation, while D2, D3 and D4 receptors are linked to inhibition of adenylyl cyclase. Renal dopamine affects electrolyte and fluid balance by regulation of renal excretion of electrolytes and water through actions on renal hemodynamics and tubular, epithelial transport. The importance of intrarenally produced dopamine as a natriuretic hormone is reflected by its capacity to inhibit the majority of sodium transporters (Na+K+ATPase, Na+/H+-exchanger) in the entire nephron. Numerous clinical and animal, experimental observations suggest that dopamine coordinates the effects of antinatriuretic and natriuretic factors and indicate that the intact renal dopamine system is of major importance for maintenence of sodium homeostasis and systemic blood pressure. Sodium retention leads to an increase in renal dopamine tonus. This function is, due to deficient renal dopamine production and/or a D1 receptor G-protein coupling defect, lost in human essential hypertension and in some animal models of genetic hypertension. A better knowledge of molecular bases of these changes may contribute to the development of specific diagnostic and therapeutic approaches in essential as well as secondary forms of hypertension.

Heat shock protein Gp96 as potential regulator of morphostasis after partial hepatectomy in mice.

Gp96 (also known as glucose-regulated protein 94, endoplasmin) is the endoplasmic reticulum (ER)-resident protein, which belongs to the heat shock protein HSP90 family. It is upregulated in response to glucose starvation and other stressful stimuli that disrupt protein synthesis in the ER. There, it is acting as a molecular chaperon involved in the correction of unfolded proteins, in the activation of proteasome-dependent ER-associated degradation of the misfolded proteins, and in activation of protein translations that modulate the polypeptide traffic into the ER. In addition, it has been implicated in antigen presentation and MHC class I and II upregulation, in the activation and maturation of dendritic cells and proinflammatory cytokine secretion, as well as in chaperoning of integrins and Toll-like receptors, acting as a "danger signal" to the innate and adaptive immunity. Moreover, owing to its specific function in Ca2+ homeostasis and in the insulin- IGF/signaling pathways, it has been proposed that gp96 might participate in mechanisms that are critical for cell growth, differentiation, and responses to ER stress. Emphasizing that gp96, as a natural adjuvant for chaperoning antigenic self peptides into the immune surveillance pathways, may also be involved in the maintenance of morphostasis and self tolerance, in this survey we show that high levels of upregulation of gp96 in regenerating liver and thymus are followed by signs of transient autoimmunity, augmented apoptosis in thymus, and the presence of autoreactive NKT and regulatory T cells that might be involved in the control of rapid liver growth induced by partial hepatectomy.

Heat shock protein-GP96 as an innate sensor of damage and activator of autoreactive NKT and regulatory T cells during liver regeneration.

Tissue disintegration after injury leads, in the endoplasmic reticulum (ER), to activation of adaptive pathways known as the ER stress response. It is directed to the correction of unfolded proteins and to the activation of proteasome-dependent ER-associated degradation of the misfolded proteins, but induces also a rapid activation of natural and adaptive immunity, since a ER resident heat shock protein-gp96 acts not only as a molecular chaperone, but also as a strong adjuvant, able to cross-present the antigenic peptides onto MHC class I or MHC class II pathways. Analyzing its potential role in processes of normal growth, in mice subjected to 1/3 partial hepatectomy (pHx) we determined the tissue expression of gp96 protein and mRNA in regenerating liver, thymus and spleen, determining simultaneously the phenotypic profile and spontaneous cytotoxic activity of intrahepatic and splenic mononuclear lymphatic cells (MNLC) against NKT- and NK-cells sensitive targets (syngeneic thymocytes and YAC-1) in wild, perforin and FasL deficient mice. The data have shown that pHx induces fast overexpression of gp96 protein and mRNA in hepatocytes, spleen and thymus, with accumulation of CD3intermediate/NK1.1+/CD69+ cells (liver) and Foxp3+CD4+CD25+ cells (liver and thymus). Simultaneously, intrahepatic MNLC acquired the FasL-dependent cytotoxic potential against NKT-sensitive targets and both, intrahepatic and splenic MNLC, acquired the perforin-dependent cytotoxic potential against NK-sensitive targets, implying that during the disturbance of morphostasis gp96 serves as a natural adjuvant for chaperoning antigenic self peptides into the immune surveillance pathways, resulting in activation of autoreactive NKT and regulatory cells, as well as NK cells. Moreover, cell cycle analysis revealed that G2+M phase of regenerating hepatocytes in PKO mice was translocated from the 1st to the 7th p. o. day, as well as that hepatocytes from FasL deficient mice were arrested in G0/G1 phase.