Role of yUbp8 in Mitochondria and Hypoxia Entangles the Finding of Human Ortholog Usp22 in the Glioblastoma Pseudo-Palisade Microlayer.

KAT Gcn5 and DUB Ubp8 are required for respiration and mitochondria functions in budding yeast, and in this study we show that loss of respiratory activity is acquired over time. Interestingly, we show that absence of Ubp8 allows cells to grow in hypoxic conditions with altered mitophagy. Comparatively, the aggressive glioblastoma (GBM) multiforme tumor shows survival mechanisms able to overcome hypoxia in the brain. Starting from yeast and our findings on the role of Ubp8 in hypoxia, we extended our analysis to the human ortholog and signature cancer gene Usp22 in glioblastoma tumor specimens. Here we demonstrate that Usp22 is localized and overexpressed in the pseudo-palisade tissue around the necrotic area of the tumor. In addition, Usp22 colocalizes with the mitophagy marker Parkin, indicating a link with mitochondria function in GBM. Collectively, this evidence suggests that altered expression of Usp22 might provide a way for tumor cells to survive in hypoxic conditions, allowing the escape of cells from the necrotic area toward vascularized tissues. Collectively, our experimental data suggest a model for a possible mechanism of uncontrolled proliferation and invasion in glioblastoma.

Gcn5p and Ubp8p Affect Protein Ubiquitylation and Cell Proliferation by Altering the Fermentative/Respiratory Flux Balance in Saccharomyces cerevisiae.

Protein ubiquitylation regulates not only endocellular trafficking and proteasomal degradation but also the catalytic activity of enzymes. In Saccharomyces cerevisiae, we analyzed the composition of the ubiquitylated proteomes in strains lacking acetyltransferase Gcn5p, Ub-protease Ubp8p, or both to understand their involvement in the regulation of protein ubiquitylation. We analyzed His6Ub proteins with a proteomic approach coupling micro-liquid chromatography and tandem mass spectrometry (µLC-MS/MS) in gcn5Δ, ubp8Δ and ubp8Δ gcn5Δ strains. The Ub-proteome altered in the absence of Gcn5p, Ubp8p, or both was characterized, showing that 43% of the proteins was shared in all strains, suggesting their functional relationship. Remarkably, all major glycolytic enzymes showed increased ubiquitylation. Phosphofructokinase 1, the key enzyme of glycolytic flux, showed a higher and altered pattern of ubiquitylation in gcn5Δ and ubp8Δ strains. Severe defects of growth in poor sugar and altered glucose consumption confirmed a direct role of Gcn5p and Ubp8p in affecting the REDOX balance of the cell.IMPORTANCE We propose a study showing a novel role of Gcn5p and Ubp8p in the process of ubiquitylation of the yeast proteome which includes main glycolytic enzymes. Interestingly, in the absence of Gcn5p and Ubp8p glucose consumption and redox balance were altered in yeast. We believe that these results and the role of Gcn5p and Ubp8p in sugar metabolism might open new perspectives of research leading to novel protocols for counteracting the enhanced glycolysis in tumors.

Gcn5 histone acetyltransferase is present in the mitoplasts.

In Saccharomyces cerevisiae the Lysine-acetyltransferase Gcn5 (KAT2) is part of the SAGA complex and is responsible for histone acetylation widely or at specific lysines. In this paper we report that G CN5 deletion differently affects the growth of two strains. The defective mitochondrial phenotype is related to a marked decrease in mtDNA content, which also involves the deletion of specific regions of the molecule. We also show that in wild-type mitochondria the Gcn5 protein is present in the mitoplasts, suggesting a new mitochondrial function independent from the SAGA complex and possibly a new function for this protein connecting epigenetics and metabolism.

Therapy with climara in surgical menopause.

UNLABELLED: Hormone replacement therapy in surgical menopause is a prophylactic measure that is used for preventing the short and long term effects of the lack of ovarian hormones. MATERIAL AND METHODS: This is a retrospective study conducted between 2004 and 2006 at the Iasi "Elena-Doamna" Hospital of Obstetrics and Gynecology on two series of patients: 46 patients with surgical menopause who received treatment with transdermal estradiol (Climara), and 20 surgical menopause patients not receiving this treatment who served as controls. RESULTS: A decreases in the average levels of total cholesterol, triglycerides and LDL cholesterol and an increase in the HDL cholesterol level were identified in the series receiving Climara compared to the controls. The climacteric symptoms improved in the patients receiving treatment. CONCLUSIONS: Transdermal therapy with estradiol (Climara) is an effective method of treatment in surgically induced menopause.

The importance of EDHF in endothelium-dependent relaxation increases distally in mesenteric arteries depending upon the contracting agent.

AIM: The importance of endothelium-derived hyperpolarizing factor (EDHF) in endothelium-dependent relaxation (EDR) is influenced by multiple factors, including vascular territory and caliber, pre-existing tone and its determining factors. METHOD: Using isometric myography we noticed that in rat mesenteric resistance arteries (RMA2; 2nd order branches) EDHF-mediated relaxation is increased when precontraction is induced by prostaglandin F2 (PGF) compared to phenylephrine (PHE) and we investigated the participation of certain K channels. Here we extend the study on more proximal vascular fragments; from mesenteric arcade and from 1st order branches. RESULTS: The EDHF component of EDR is stronger distally only when precontraction is induced by PHE. Moreover, morphometric analysis shows a strong inverse correlation between the magnitude of EDHF response and arterial caliber. CONCLUSIONS: Other authors have shown that EDHF increases in relative importance distally, but we show that this change in EDR profile depends upon the contracting agent used, with implications regarding the physiological relevance of accumulated data refering to EDHF and nitric oxide as mediators of EDR in resistance arteries.

[Reaction times (RTS) and cognitive visual evoked potentials during reading--a compared study]. / Studiu comparativ între timpii de reactie psihometrici si potentialele evocate vizuale cognitive în lexie.

OBJECTIVE: The main aim of the experiment is to prove the Paivio's theory about the concrete-abstract effect. METHODS: A psychoverbal stimulation interface, created by us, was experimented as an IT extension of an EEG/EMG device dedicated for the human brain Evoked Potentials acquisitions (EPs) and reaction times techniques in reading mechanisms assessment. RESULTS: The shortest reaction time was achieved in tests at which the reading has no access to the meaning of words, for concrete word, in both hemisphere. But, in left hemisphere the reaction times for abstract words was shorter than for the abstract word in right hemisphere. EPs acquisition exhibits more negativity of N400 for concrete word and more reverberation of P650-N750 for abstract words. CONCLUSIONS: The difference in mean reaction times sustain the Paivio's theory and the difference in amplitude of N400, P650-N750 for concrete and abstract nouns show that the electric activities of brain are correlated in time and in amplitude with the same effort of processing the words. The psycho-verbal stimulation interface can be used as a medical research tool for studying and assessment the cognitive processes of reading, memory or learning using the endogenous visual event related potentials and the psychometric reaction times.

[Omega-3 fatty acids and acetylcysteine diet supplementation effects on learning performance]. / Efectele suplimentarii dietei cu acizi grasi polinesaturati omega 3 si acetilcisteina asupra performantei în învatare.

UNLABELLED: Omega-3 fatty acids are essential for human health, are crucial for the brain, body development and also in prevention of cardiovascular diseases. MATERIAL AND METHOD: We used 60 male Wistar fats, weight 180 +/- 20 grams, divided into two study groups: normal control animals (M) and test animals (T) divided in groups I (N3-PUFA), II (ACC) and III (N3-PUFA and ACC). Administration of the substances was made for 36 weeks (nine months), after which the animals were evaluated and subsequently sacrificed for further biochemical analysis. As an evaluation method has been used multiple T maze labyrinth. RESULTS: Group I recorded a time maze percentage decrease from -4.26% to -33.88%. In group II we recorded a decrease time maze percentage from -5.37% to -34.28%. During the experiment, group III recorded a decrease time maze percentage from -5.1% to -32.33% at the end of the experiment. The control group evolution for the maze recorded a decrease in time maze percentage, reaching 17-18% at the end of the experiment. CONCLUSION: By improving the diet with polyunsaturated fatty acids increased exponentially cognitive performance compared with normal diet, low in these acids.

Long-term effects of giving nursing home residents bread fortified with 125 microg (5000 IU) vitamin D(3) per daily serving.

BACKGROUND: In older adults, a serum 25-hydroxyvitamin D [25(OH)D] concentration >75 nmol/L lowers the risk of fracture. An oral intake of 125 microg (5000 IU) vitamin D(3)/d may be required to achieve this target. OBJECTIVE: The objective was to characterize the safety and efficacy of fortifying bread with a biologically meaningful amount of vitamin D(3). DESIGN: In a single-arm design, 45 nursing home residents consumed one bun daily that had been fortified with 125 microg (5000 IU) vitamin D(3) and 320 mg elemental calcium. RESULTS: The initial mean (+/-SD) serum 25(OH)D concentration was 28.5 +/- 10.8 nmol/L. After 12 mo, the 25(OH)D concentration was 125.6 +/- 38.8 nmol/L, and it exceeded 74 nmol/L in 92% of the patients. At every 3-mo follow-up, serum parathyroid hormone was lower than at baseline (P = 0.001). No changes in serum calcium or cases of hypercalcemia were observed at the follow-up assessments. Both mean total urinary calcium and the mean urinary calcium-creatinine ratio increased from baseline at one follow-up time point (P < 0.05). Between baseline and the 12-mo visit, z scores for bone mineral density at the lumbar spine and the hip both increased significantly (P < 0.001). CONCLUSIONS: Fortification of bread with much more vitamin D than used previously produced no evident adverse effects on sun-deprived nursing home residents and improved bone density measures. Fortification of bread with 5000 IU vitamin D(3)/d provided reasonable assurance that vitamin D-deficient older adults attained a serum 25(OH)D concentration greater than the desirable objective of >75 nmol/L. This trial was registered at (ClinicalTrials.gov) as: NCT00789503.

Genetic risk factors in typical haemolytic uraemic syndrome.

BACKGROUND: Haemolytic uraemic syndrome (HUS) is a disorder characterized by thrombotic microangiopathy, which is caused in 'typical forms' by gastrointestinal infections with Escherichia Coli species that produce verotoxins. Several studies have identified negative prognostic factors of the disease, among which prolonged oliguria, neurological involvement and increased leukocytosis have been more consistently reported. We have hypothesized that the genetic background may also predispose to the development of typical forms of HUS and may influence the clinical course of the disease. METHODS: Fourteen polymorphisms, known to influence the coagulation pathway or the activity of the renin-angiotensin system, have been selected and studied in 150 Italian children with typical forms of HUS. Two hundred healthy Italian children were used as controls. RESULTS: The risk of developing HUS was strongly associated with the platelet glycoprotein 1balpha 145M allele (OR 3.08; CI: 1.62-5.85) (P < 0.001). A significant association was also found with polymorphisms located in the adipocyte-derived leucine aminopeptidase and factor V genes. A longer duration of dialysis was moderately associated with increased leukocytosis and with the 807T allele of the platelet glycoprotein 1a gene. High white blood cell count was also strongly associated with the risk of long-term sequelae (OR 2.91, CI: 1.21-6.98) (P < 0.02), whereas the 1166C allele of the angiotensin II type 1 receptor had a significant protective effect (OR 0.28, CI: 0.09-0.83) (P < 0.02). CONCLUSIONS: These results highlight the role of glycoprotein 1balpha in the physiopathology of typical forms of HUS and show that the genetic background plays a role in the susceptibility and severity of the disease.

Effects of dietary flaxseed supplementation on renal oxidative stress in experimental diabetes.

UNLABELLED: Previous results demonstrate that experimental diabetes mellitus is accompanied by increased oxidant stress within glomeruli. Evidence are emerging that dietary flaxseed supplementation can have beneficial effects on oxidative stress. MATERIALS AND METHODS: Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) in male Golden Syrian hamsters, and both diabetic and control groups were fed either standard diet, or standard diet supplemented with flaxseed (15 g/100 g diet), for 20 weeks. At the end of the study, blood samples and renal homogenates were used for determination of oxidative stress markers. RESULTS: STZ-induced diabetes in hamsters substantially increased malondialdehyde levels along with corresponding decrease in the antioxidants levels. Supplementation of flaxseed resulted in the decrease in serum and renal homogenate malondialdehyde levels. The activities of antioxidant enzymes, total glutathione (tGSH) and superoxiddismutase (SOD) were also concomitantly raised to near normal levels by flaxseed supplementation diabetic hamsters. CONCLUSION: Dietary flaxseed supplementation in diabetes mellitus may have beneficial effects on diabetic nephropathy evolution by reducing the levels of oxidative stress and increasing the antioxidant defense systems.

[Nutritional antioxidant effects on endotelial dysfunctions in experimental atherosclerosis by ovariectomy]. / Efectele antioxidantilor nutritionali asupra disfunctiei endoteliale in ateroscleroza experimentala prin ovariectomie.

UNLABELLED: Endothelial dysfunction and atherogenesis involves a general alteration of unicellular layer of the vascular wall structure. Nutritional antioxidants can improve endothelial dysfunction through dietary supplementation with polyunsaturated fatty acids (PUFA N3 and lignans) from flaxseed. The mechanisms by which these nutritional antioxidants have beneficial effects on endothelial function are less known. AIM: The present study examined the effects of the flaxseed supplemented diet, a rich source in PUFA N3 and lignans on the ovariectomy-induced endothelial dysfunction and atherosclerosis. MATERIAL AND METHOD: Forty-two ovariectomized and non-ovariectomized (control) female Wistar rats were used, each one divided in 3 subgroups depending on diet: standard, fat rich or flaxseed supplemented fat rich diet, for 36 weeks. The circulating soluble adhesion molecules of endothelial origin and von Willebrand factor (sVCAM-1, vWF), were measured to assess the endothelial dysfunction. RESULTS: Presence of endothelial dysfunction in ovariectomized animals fed with standard diet associated with a rich PUFA N6 and saturated lipid was proven by the increased plasma concentration of sVCAM-1 and vWE Dietary supplementation with PUFA N3 and lignans (flaxseed) in these animals led to modest decreases of these parameters. CONCLUSION: The results indicate that dietary supplementation with antioxidant activity substances, in presence of estrogen deficiency, especially when it is associated with increased fat intake, may become a mean of prevention and delay of endothelial dysfunction, via anti-inflammatory actions through a reduction of sVCAM-1.

Identification and subcellular localization of a new cystinosin isoform.

Nephropathic cystinosis is a lysosomal disorder caused by functional defects of cystinosin, which mediates cystine efflux into the cytosol. The protein sequence contains at least two signals that target the protein to the lysosomal compartment, one of which is located at the carboxy terminal tail (GYDQL). We have isolated from a human kidney cDNA library a cystinosin isoform, which is generated by an alternative splicing of exon 12 that removes the GYDQL motif. Based on its last three amino acids, we have termed this protein cystinosin-LKG. Contrary to the lysosomal cystinosin isoform, expression experiments performed by transient transfection of green fluorescent protein fusion plasmids in HK2 cells showed that cystinosin-LKG is expressed in the plasma membrane, in lysosomes, and in other cytosolic structures. This subcellular localization of the protein was confirmed by transmission electron microscopy. In addition, immunogold labeling was observed in the endoplasmic reticulum and in the Golgi apparatus. Expression of the protein in renal tubular structures was also directly demonstrated by immunostaining of normal human kidney sections. The plasma membrane localization of cystinosin-LKG was directly tested by [(35)S]cystine flux experiments in COS-1 cells. In the presence of a proton gradient, a marked enhancement of intracellular cystine transport was observed in cells overexpressing this isoform. These data indicate that the expression of the gene products encoded by the CTNS gene is not restricted to the lysosomal compartment. These finding may help elucidate the mechanisms of cell dysfunction in this disorder.

A psycho-verbal stimulation interface for the cognitive evoked potentials acquisition.

UNLABELLED: The psycho-verbal stimulation interface, created by us, represents an IT extension of an EEG / EMG device dedicated for the human brain Evoked Potentials acquisitions (EPs). METHODS: The psycho-verbal stimulation interface was created as a .NET application and was written in the C# language with respect to the OOP paradigm. It uses the TL logic to command the EPs acquisition module. The signal is send on the parallel port (LPT1) to the EPs device by a dedicated hardware interface. The software module was designed as a multi-threading application in order to perform more than one operation once. RESULTS: The stimulus sample can be customized as text, image or both and each stimulus sequence follows also a fully configurable time schema. The application can measure the patient's reaction time to each stimulus sample, which are finally centralized on a list control. The system can save both the test sequences and the EEG diagrams in digital formats; the resulted files can be stored and delivered online using the Telemes web application. CONCLUSIONS: The Telmes project implemented a secured & scalable tele-medical centers network dedicated to the telemonitoring & tele-consulting services, and the psycho-verbal stimulation interface is one of the instruments devoted to these goals. The psycho-verbal stimulation interface can be used as a medical research tool for study the cognitive processes of reading, memory or learning using the endogenous visual event related potentials, as good as a instrument of training the recovery of sensitive language, which can be delivered at home by the neuro-linguist specialist as daily lists programs. The visual evoked potentials and the reaction times collected from the patients can facilitate a prognostic diagnosis of recovery the language.

The effects of dietary flaxseed supplementation on lipid metabolism in streptozotocin-induced diabetic hamsters.

UNLABELLED: Vascular complications, such as atherosclerosis, represent an important cause of morbidity and mortality in diabetic patients. The aim of this study was to investigate the effects of dietary flaxseed supplementation, a rich source of lignans, a-linolenic acid and soluble fiber mucilage on serum and hepatic lipid concentrations in streptozotocin-induced diabetes in hamsters. METHODS: Twenty-four male Golden Syrian hamsters were used in this experiment; diabetes was induced in half of them by intraperitoneal injection of streptozotocin (50 mg/kg body weight), and both diabetic and control groups were divided in 2 subgroups, one fed standard diet, and one fed standard diet supplemented with flaxseed (15%), for 20 weeks. Serum total cholesterol (TC), HDL-cholesterol (HDL-C), triglycerides (TG), cholesterol/HDL-cholesterol ratio and hepatic cholesterol and triglycerides were measured at the end of the experiment. RESULTS: Dietary flaxseed supplementation in diabetic hamsters was associated with significant reductions in serum TC (-24.9%), TC/HDL-C ratio (-60%) and increase in serum HDL-C (+91%) as compared to diabetic group without supplementation. There were no significant differences in serum TG levels between diabetes supplemented with flaxseed and diabetic groups. Also, flaxseed supplementation in diabetes induced significant reductions in hepatic cholesterol (-39.5%) and triglycerides levels (-28.8%). CONCLUSIONS: These results suggest that dietary flaxseed supplementation may reduce the incidence of diabetic macrovascular complications through improvement of lipid profile.

Modulation of human estrogen receptor alpha F promoter by a protein kinase C/c-Src-dependent mechanism in osteoblast-like cells.

The human estrogen receptor alpha (ERalpha) gene is driven by multiple promoters, of which the F promoter alone is found to be active in primary osteoblasts. The study was aimed at identifying new regulatory pathways affecting transcription of the receptor in this cell lineage. We generated human osteoblast-like cells, Saos-2, stably transfected with a luciferase-reporter gene downstream of the human ERalpha F promoter (Saos F-Luc), and assayed the reporter response to differentiation-related signals. Over-confluence, shown to stimulate osteoblast differentiation, caused a time-dependent increase of F-promoter activity and correlated with an inactivation of protein kinase C alpha (PKCalpha ). PKC downregulation, obtained by long-term treatment with phorbol 12-myristate 13-acetate (PMA), resulted in promoter stimulation at similar levels in sub-confluent cells. The F promoter contains a putative PMA-responsive AP-1 site, but AP-1 activation was unremarkable in over-confluent cells. Treatment with PP1, a specific inhibitor of the non-receptor tyrosine-kinase c-Src, which is a negative regulator of osteoblast differentiation, showed that the activity of this kinase inhibits the F promoter. In PP1-treated cells, F-promoter activity was not further increased by PMA. Treatment with the generic kinase inhibitor 4-dimethylaminopyridine (DMAP) resulted in a dose-dependent induction of the promoter, which matched a parallel decrease of active c-Src. The effect was c-Src dependent, as DMAP caused no further promoter induction in PP1-treated cells. Overexpression of exogenous human ERalpha resulted in modest promoter stimulation, which required the ligand-independent activator function 1 of the receptor. In murine primary osteoblasts, additional ERalpha signal was observed upon induction of F promoter. In conclusion, we demonstrated a robust PKC/c-Src-dependent and estrogen-independent mechanism modulating transcription of ERalpha in osteoblasts, probably affecting estrogen responsiveness during cell differentiation.

[Oxidative stress and immune response in eumenorrheic underweight patients]. / Stresul oxidativ si raspunsul imun la pacientele subponderale eumenoreice.

Malnutrition is known to induce a state of immunodeficiency and a predisposition to death from infectious diseases. During fasting or starvation, it appears that oxidative stress is decreased. The goal of our study was to assess the interrelation between nutritional factors, oxidative stress and immune response. The malondialdehyde (MDA)-marker of lipid peroxidation, white blood cell count, differential count and hormonal status (FSH, LH, and cortisol) were followed in eumenorrheic underweight patients. MDA was significantly lower and lymphocyte count was significantly increased in eumenorrheic underweight patients as compared to normal weight patients. Gonadal and adrenal axes were found normal in eumenorrheic underweight patients. Body mass index was positively correlated with MDA and negatively correlated with lymphocyte count. Low levels of lipid peroxidation and non-suppressed immune function in underweight patients may be explained by an increased sensitivity to leptin but further studies are requested.

[Modulation of the platelet function by diet supplemented with flaxseed and vitamin E in diabetic hamsters]. / Modularea functiei plachetare prin suplimentare alimentara cu seminte de in si vitamina E la hamsterii diabetici.

The aim of our study was to assess the platelet aggregation and adhesiveness in diabetic and non-diabetic hamsters receiving or not a diet supplemented with flaxseed (rich in'alpha-linolenic acid) and vitamin E. Forty-eight 6-month old male Golden Syrian hamsters were distributed in either control (non-diabetic) and diabetic group (STZ, 50 mg/kg body weight, i.p.). The control and diabetic groups received one of the following diets 1. control diet (rich in linoleic acid) ; 2. diet supplemented with flaxseed (15% flaxseed); 3. diet supplemented with flaxseed and vitamin E (40 mg/kg body weight); 4. diet supplemented with flaxseed and vitamin E. We measured platelet aggregation and adhesiveness after 20 weeks from the beginning of the experiment. In diabetic hamsters, only the diet supplemented with both flaxseed and vitamin E resulted in significant reduction of platelet aggregation (5.5 +/- 5.2 mOD/min vs. 10.3 +/- 3.8 mOD/min) and adhesiveness (9.7 +/- 3.9% vs. 23.4 +/- 10.6%) as compared to diabetic animals fed with control diet. In non-diabetic animals, flaxseed rich diet alone was efficient in lowering platelet functions as compared to linoleic acid rich diet. Mixed diet containing flaxseed and vitamin E was more effective than flaxseed alone in modulating platelet functions in diabetic hamsters. These observations indicate that vitamin E exerts important effects on determinants of oxidation and platelet functions and potentiates the flaxseed effects in experimental diabetes.

Flaxseed supplementation in hyperlipidemic patients.

UNLABELLED: The aim of this study was to investigate the effect of daily consumption of dietary flaxseed (as a source of linolenic acid, LNA) on plasma lipid concentrations in mildly hyperlipidemic patients. METHODS: 40 hyperlipidemic patients with plasma total cholesterol greater than 240 mg/dL were distributed in 3 groups: 10 patients who received hypo-lipidic diet (diet group), 10 patients who received hypo-lipidic diet plus statins (diet+HL group), 20 patients who received hypo-lipidic diet plus 20 g ground flax-seeds/day (diet+flax group). Body mass index (BMI), serum total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), triglycerides (TG) and cholesterol/HDL-cholesterol ratio were measured at the beginning and after 60 days of treatment. RESULTS: Flaxseed supplementation was associated with significant reductions in TC (-17.2%), LDL-C (-3.9%), TG (-36.3%) and TC/HDL-C ratio (-33.5%). There were no significant differences in absolute change in BMI nor in percentage change in TC, HDL-C, LDL-C, TC/HDL-C ratio between flaxseed and statin groups. CONCLUSIONS: Dietary flaxseed significantly improves lipid profile in hyperlipidemic patients and may favorably modify cardiovascular risk factors.

[Endocrine-metabolic disturbances in chronic stress]. / Tulburari endocrino-metabolice în stresul cronic.

This review focuses on the neuroendocrine infrastructure of the adaptive response to chronic stress and on its concerted effects on behavior, the major endocrine axes and immune systems. Cytokines such as TNF-alpha, IL-1, and IL-6 and other humoral mediators of inflammation are potent activators of central stress-responsive neurotransmitter systems, constituting the afferent limb of a feedback loop from the immune/inflammatory system to the central nervous system. Steroid hormones influence a variety of neuroendocrine events, including brain development, sexual differentiation and reproduction. Hormones elicit many of these effects by binding to neuronal steroid receptors, which are members of a nuclear receptor superfamily of transcriptional activators. Nuclear receptor coactivators enhance the transcriptional activity of steroid receptors.

[The history of experimental diabetes in Iasi ]. / Din traditia diabetologiei experimentale la Iasi.

Department of Pathophysiology, University of Medicine and Pharmacy, Iasi, Romania has a long tradition in studying the diabetes mellitus. The series of experimental studies in diabetes was open by Iulius Nitulescu. His work was focused on the carbohydrate metabolism, and the paper entitled "Sur le metabolisme du sucre chez les vieilliards. L'epreuve de l'hyperglycemie alimentaire" was published in 1933. Later, in 1965, Aurel Sneer introduced the experimental model of diabetes mellitus induced by the alloxan. In 1970, it was for the first time in the medical literature when the importance of lysosomal enzyme discharge was revealed in alloxan-induced diabetes. In the early 70s, the factors conditioning the carbohydrate homeostasis were studied. Starting with 1990, the research was directed to investigate the role of microelements, zinc and magnesium, in the pathogenesis of beta cells injury and chronic complications of diabetes mellitus. Since 1993, our studies have been focused on the role of oxidative stress in the pathogenesis of chronic complications of diabetes mellitus. The effects of exogenous antioxidants, probucol and vitamin E, on the carbohydrate and lipid metabolism, on the markers of oxidative stress, and on the platelet activity were investigated in alloxan-induced diabetes. More than 50 scientifical papers on experimental diabetes and four monographs were published in the last 40 years by the researchers of our department.