bluuebunny/crossref_metadata_2025 huggingface dataset:
Phospholipase A2 modulates respiratory burst developed by neutrophils in patients with rheumatoid arthritis
Authors: Bostan Marinela , Galatiuc C. , Hirt M. , Constantin M.C. , Brasoveanu L.I. , Iordachescu Dana
Published: May 2007

Activated by bacterial peptides, phorbol esters, calcium ionophores and other agonists, neutrophils (PMNs) release the proinflammatory mediator, arachidonic acid (AA) via the intervention of phospholipase A2 (PLA2). AA may play an essential role in activation of NADPH‐oxidase, which is involved in the generation of superoxide anion by neutrophils. The present study is focused on the involvement of PLA2 in the respiratory burst developed by PMNs isolated from patients with rheumatoid arthritis (RA). PLA2 exists in very high levels in diseases such as rheumatoid arthritis and may cause acute inflammatory and proliferative changes in synovial structures. The respiratory burst was evaluated as superoxide anion release, using an amplified chemiluminiscence method. The assays were performed using PMNs untreated or treated with different doses of stimulatory reagents (phorbol 12‐myristate‐13‐acetate (PMA), calcium ionophore (A23187)). Our data suggested that PMA stimulated the production of superoxid anion in a dose‐response manner, as compared with A23187, which did not induce a significant release of superoxide anion in PMNs‐RA. The exogenous addition of AA significantly amplified the superoxide anion release by PMNs‐RA stimulated with PMA and to a lesser extent, by PMNs stimulated with A23187. AA has also reversed the inhibitory effect of arachidonyl‐trifluorometylketone and E‐6‐(bromomethylene)tetrahydro‐3‐(1‐naph‐thalenyl)2H‐pyran‐2‐one (BEL) on the superoxide anion release by PMNs‐RA. In conclusion, the differential responses to these two agents suggested that different isoforms of PLA2 were activated by A23187 or PMA, and support the idea that activation of these different PLA2 served distinct functions of PMNs. Therefore, the inhibition of PLA2 enzymes might be of great importance in the immunotherapy of rheumatoid arthritis.
Expression and significance of new tumor suppressor gene PTEN in primary liver cancer
Authors: Dong‐Dong Lu , Xi‐Ran Zhang , Xiang‐Rong Cao
Published: May 2007

Objective: To investigate expression and significance of PTEN gene in primary hepatocellular carcinoma (HCC). Methods: Immunohistochemical peroxidase‐conjugated streptavidin (SP) method was used to detect expression of PTEN gene in 120 cases of primary HCC and its adjacent tissue 10 cases of normal liver tissue. The relationship between expression of tumor suppressor gene of PTEN and the percentage of lymph node metastasis of HCC was analyzed. Results: It was shown that PTEN gene was expressed in all 10 cases of normal liver tissues and paracancerous liver tissues. The staining was localized mainly in cytoplasm. Expression of PTEN in 120 cases of HCC were as follows: 12.5% were negative, 17.5% were weak positive, and 70% were strong positive. At time of diagnosis, 33/120 (27.5%) presented lymph node metastasis. Lymph node metastases were present in 80% (12 out of 15) PTEN negative HCC, 57.14% (12 out of 21) PTEN weak positive HCC and only 10.71% (9 out of 84) PTEN intense positive HCC, (P<0.05). Therefore, PTEN tumor suppresor gene malfunction seems to be involed in mtastasing capacity of HCC. Conclusion: This study suggests that PTEN gene was deleted or weakly expressed in primary hepatocellar carcinoma, which is probably related to its tumorigenesis.
Plasma membrane potential interferes with the respiratory burst of peripheral granulocytes
Authors: Livescu Alexandra , Manda Gina , Constantin Carolina , Neagu Monica , Iordachescu Dana
Published: May 2007

Membrane potential is involved in the regulation of several immune functions developed by granulocytes. The Na+/K+ gradient across the plasma membrane, mainly generated by the Na+/K+ pump, plays a key role in the maintenance of membrane potential. This study is focused on the correlation between plasma membrane potential and the in vitro receptor ‐ triggered respiratory burst of normal human peripheral granulocytes. The respiratory burst was measured as superoxide anion release by the cytochrome c reduction test and plasma membrane potential was modulated by experimental changes of the extracellular potassium concentration. Results show a differentiated cellular response, depending on the in vivo activation state and on the signals received in vitro by granulocytes via CR3 or FcγR. Alteration of the membrane potassium gradient modulates the respiratory burst of unstimulated and CR3‐activated cells, whilst it does not seem to significantly interfere with the signals delivered by FcγR.
Inflammatory mechanisms associated with brain damage induced by kainic acid with special reference to the interleukin‐1 system
Authors: Oprica M. , Eriksson C. , Schultzberg M.
Published: May 2007

The evidence of inflammatory processes in the clinical manifestations and neuropathological sequelae of epilepsy have accumulated in the last decade. Administration of kainic acid, an analogue of the excitatory amino acid glutamate, induces a characteristic behavioural syndrome and a reproducible pattern of neurodegeneration in several brain areas, closely resembling human temporal lobe epilepsy. Results from studies using the kainic acid model indicate that manipulation of pro‐ and anti‐inflammatory cytokines can modify the outcome with regard to the behavioural syndrome as well as the neuropathological consequences. Interleukin‐1 is one of the most important cytokines and has several actions in the brain that are critical for the host defense against injury and infection, and it is involved in the initiation of early stages of inflammation. It is believed that interleukin‐1 plays a pivotal role in the neuroinflammation associated with certain forms of neurodegeneration, including cerebral ischemia, trauma and excitotoxic brain injury. In this review, we have summarized the experimental data available with regard to the involvement of the interleukin‐1 system in kainic acid‐induced changes in the brain and emphasized the modulatory role of interleukin‐1β in this model of epilepsy.
Immunohistochemical analysis of differentiation in static and mixed prostate cancer spheroids
Authors: Song Hong , O'Connor Kim C. , David Odile , Giordano Carrie L. , Pappas‐LeBeau Helena , Clejan Sanda
Published: May 2007

Neoplastic multicellular spheroids are in vitro models of solid tumors employed in drug testing and basic research. This study compares differentiation in static and mixed prostate cancer spheroids. Staining intensity of prostate specific antigen (PSA) was down‐regulated upon mixing from 0.21 ± 0.03 to 0.13 ± 0.03 in LNCaP multicellular spheroids, and from 0.13 ± 0.04 to 0.03 ± 0.02 in DU 145 multicellular spheroids. This was accompanied by 65% increase in the expression of cytokeratins 8 and 18 in DU 145 spheroids. PSA expression extended 60 μm within static spheroids and was disrupted in mixed culture. Diminished PSA expression and spatial organization suggests a more aggressive cancer. Higher cytokeratin expression could result from either differentiation towards a luminal phenotype or activation of the Ras pathway during dedifferentiation. THus, the existing paradigm of differentiation established for normal tissue does not apply for our neoplastic spheroids. Cell dedifferentiation is attributed to improved interstitial transport and synthesis of extracellular matrix.
Cyclooxygenase‐2 modulates cellular growth and promotes tumorigenesis
Authors: Trifan O. C. , Hla T.
Published: May 2007

Cyclooxygenase (COX)‐2 and the prostaglandins resulting from its enzymatic activity have been shown to play a role in modulating cell growth and development of human neoplasia. Evidence includes a direct relationship between COX‐2 expression and cancer incidence in humans and animal models, increased tumorigenesis after genetic manipulation of COX‐2, and significant anti‐tumor properties of non‐steroidal anti‐inflammatory drugs in animal models and in some human cancers. Recent data showed that COX‐2 and the derived prostaglandins are involved in control of cellular growth, apoptosis, and signal through a group of nuclear receptors named peroxisome proliferator‐activated receptors (PPARs). In this article we will review some of the findings suggesting that COX‐2 is involved in multiple cellular mechanisms that lead to tumorigenesis.
Protein folding
Authors: Basharov M. A.
Published: May 2007

The problem of protein folding is that how proteins acquire their native unique three‐dimensional structure in the physiological milieu. To solve the problem, the following key questions should be answered: do proteins fold co‐ or post‐translationally, i.e. during or after biosynthesis, what is the mechanism of protein folding, and what is the explanation for fast folding of proteins? The two first questions are discussed in the current review. The general lines are to show that the opinion, that proteins fold after they are synthesized is hardly substantiated and suitable for solving the problem of protein folding and why proteins should fold cotranslationally. A possible tentative model for the mechanism of protein folding is also suggested. To this end, a thorough analysis is made of the biosynthesis, delivery to the folding compartments, and the rates of the biosynthesis, translocation and folding of proteins. A cursory attention is assigned to the role of GroEL/ES‐like chaperonins in protein folding.
Regulation of apoptosis by Bcl‐2 family proteins
Authors: Burlacu Alexandrina
Published: May 2007

For multicellular organisms, the rigorous control of programmed cell death is as important as that of cell proliferation. The mechanisms involved in the regulation of cell death are not yet understood, but a key component is the family of caspases which are activated in a cascade and are responsible for the apoptotic‐specific changes and disassembly of the cell. Although the caspases represent a central point in apoptosis, their activation is regulated by a variety of other factors. Among these, Bcl‐2 family plays a pivotal role in caspases activation, by this deciding whether a cell will live or die. Bcl‐2 family members are known to focus much of their response to the mitochondria level, upstream the irreversible cellular damage, but their functions are not yet well defined. This review summarizes the recent data regarding the Bcl‐2 proteins and the ways they regulate the apoptosis.
Catalytic antibodies in healthy humans and patients with autoimmune and viral diseases
Authors: Nevinsky G. A. , Buneva Valentina N.
Published: May 2007

Antibodies have been first characterized as proteins produced by the immune system solely for binding other molecules, called antigens, with the goal of eliciting immune response. In this classical conception, antibodies act similarly to enzymes in specific binding to different molecules but cannot catalyze their chemical conversion. However, in 1986 the first monoclonal catalytic antibodies against a chemically stable analog of the transition state of a reaction were obtained and termed abzymes (Abzs). At present, artificial monoclonal Abzs catalyzing more than 100 distinct chemical reactions have been obtained. The discovery of IgG specifically hydrolyzing intestinal vasoactive peptide in the blood serum of asthma patients stimulated studies of natural Abzs. Numerous Abzs discovered afterwards in sera of patients with various autoimmune diseases, viral disorders, or in the milk of healthy mothers, are capable of hydrolyzing proteins, DNA, RNA, polysaccharides, or nucleotides, as well as to phosphorylate proteins and lipids. The phenomenon of catalysis by auto‐Abzs is more and more in research focus. In this review we summarize new data on Abzs applications in basic science, medicine and biotechnology.
Attenuation of changes in Gi‐proteins and adenylyl cyclase in heart failure by an ACE inhibitor, imidapril
Authors: Sethi R. , Shao Q. , Takeda N. , Dhalla N. S.
Published: May 2007

Cardiac dysfunction in animals with congestive heart failure due to myocardial infarction (MI) is known to be associated with a wide variety of defects in receptor and post‐receptor mechanisms. Since the heart function have been shown to be improved by treatment with different angiotensin converting enzyme (ACE) inhibitors, we examined the effects of imidapril, an ACE inhibitor, on changes in post‐receptor mechanisms involving adenylyl cyclase (AC) and G proteins in the failing heart. Heart failure in rats was induced by occluding the coronary artery and 3 weeks later the animals were treated daily with 1 mg/kg (orally) imidapril for 5 weeks. The animals were assessed for their left ventricular function and crude membranes were isolated from the viable left ventricle and examined for AC activities as well as G‐protein activities and expression. Animals with heart failure exhibited depressions in ventricular function and AC activities in the absence or presence of forskolin, NaF and Gpp(NH)p. The AC activity in the presence of pertussis toxin was increased whereas that in the presence of cholera toxin was decreased in the failing heart. Protein contents and mRNA levels for Gi‐proteins were increased whereas those for Gs‐proteins were unaltered in the infarcted heart. All these changes due to MI were prevented by imidapril treatment. The results indicate that the depressed cardiac function in the failing heart may partly be due to the direct effects of changes in AC and Gi proteins.
Correlation between the predicted and the observed biological activity of the symmetric and nonsymmetric cyclic urea derivatives used as HIV‐1 protease inhibitors. A 3D‐QSAR‐CoMFA method for new antiviral drug design
Authors: Avram Speranta , Svab I. , Bologa C. , Flonta Maria‐Luiza
Published: May 2007

The predicted inhibition constant (Ki) and the predicted inhibitor concentration (IC90) of the HIV‐1 protease (HIV‐1 PR) inhibitors: symmetric and nonsymmetric ‐ benzyl, ketone, oxime, pyrazole, imidazole, and triazole cyclic urea derivatives, were obtained by the 3D‐CoMFA (Comparative Molecular Field Analysis) method. The CoMFA statistical parameters: cross‐validate correlation coefficient (q2), higher than 0.5, and the fitted correlation coefficient (r2), higher than 0.90 validated the predicted biological activities. The best predictions were found for the trifluoromethyl ketoxime derivative (log 1/Ki predict = 8.42), the m‐pyridineCH2 pyrazole derivative (log 1/Ki predict = 9.77) and the 1,2,3 triazole derivative (log 1/Ki predict = 7.03). We attempted to design a new potent HIV‐1 protease inhibitor by addition of o‐benzyl to the (p‐HOPhCH2) pyrazole 12f derivative inhibitor. A favorable steric area surrounded the o‐benzyl, suggesting a possible new potent HIV‐1 protease inhibitor.
Effect of chromium picolinate on histopathological alterations in STZ and neonatal STZ diabetic rats
Authors: Shinde Urmila A. , Goyal R. K.
Published: May 2007

Earlier studies from our laboratory have indicated insulin sensitizing action of chromium picolinate as the mechanism of its anti‐diabetic activity in experimental models of type I and type II diabetes. In the present investigation, we have evaluated the effects of chronic administration of chromium picolinate on the functional and histological alterations of streptozotocin (STZ)‐induced diabetes in rats. Type I diabetes was induced by intravenous injection of STZ (40 mg/kg) in adult rats, whereas, type II diabetes was induced by intraperitoneal injection of STZ (90 mg/kg) in 2‐day old rat pups which in adulthood develop abnormalities resembling type II diabetes. Chromium picolinate was administered at 8 μg/ml in drinking water for 6 weeks and was found to improve glucose tolerance and increase insulin sensitivity of STZ‐diabetic rats. This treatment decrease elevated serum creatinine and urea levels as well as elevated serum levels of hepatic enzymes of both groups of diabetic rats. Histopathological studies of kidney and liver show decrease in the intensity and incidence of vacuolations, cellular infiltration and hypertrophy of STZ and nSTZ (neonatal STZ) diabetic rats. Chronic treatment with chromium picolinate however, did not alter the normal function or morphology of control rats. Chronic chromium picolinate at the therapeutic doses that improved glucose tolerance, was observed to have no hepatotoxic or nephrotoxic potential. It was rather found to improve renal and hepatic function and to reduce abnormalities associated with STZ‐diabetes. Chromium picolinate could play an important role in the long term management of diabetes mellitus.
Ischemia induces short‐ and long‐term remodeling of synaptic activity in the hippocampus
Authors: Crepel Valérie , Epsztein J. , Ben‐Ari Y.
Published: May 2007

One of the most vulnerable areas to ischemia or hypoglycemia is CA1 hippocampal region due to pyramidal neurons death. Glutamate receptors are involved together with protein‐kinase C and nitric oxide synthase. Long‐term potentiation (LTP) is generated in anoxic or hypoglycemic conditions via activation of NMDA while inhibition of these receptors atenuates this response. Protein‐kinase C and nitric oxide synthase are involved in anoxic LTP mechanism. Postischemic neurons are hyperexcitable in CA3 area while CA1 pyramidal neurons degenerate and dissapear. Changes of glutamate receptors triggered by ischemia and hypoglycemia are discussed in this review.
Endotoxin translocation in two models of experimental acute pancreatitis
Authors: Vasilescu C. , Herlea V. , Buttenschoen K. , Beger H. G.
Published: May 2007

To test the hypothesis that endotoxin is absorbed from the gut into the circulation in rats with experimental acute pancreatitis we studied two different animal models. In the first model necrotizing pancreatitis was induced by the ligation of the disatl bilio‐pancreatic duct while in the second, experimental oedematous acute pancreatitis was induced by subcutaneous injections of caerulein. In both experiments, in the colon of rats with acute pancreatitis endotoxin from Salmonella abortus equi was injected. Endotoxin was detected by immunohistochemistry in peripheral organs with specific antibodies. The endotoxin was found only in rats with both acute pancreatitis and endotoxin injected into the colon and not in the control groups. The distribution of endotoxin in liver at 3 and 5 days was predominantly at hepatocytes level around terminal hepatic venules, while in lung a scattered diffuse pattern at the level of alveolar macrophages was identified. A positive staining was observed after 12 hours in the liver, lung, colon and mesenteric lymph nodes of rats with both caerulein pancreatitis and endotoxin injected into the colon. We conclude that the experimental acute pancreatitis leads to early endotoxin translocation from the gut lumen in the intestinal wall and consequent access of gut‐derived endotoxin to the mesenteric lymph nodes, liver and lung.
Phenotypic characterization of mouse embryonic fibroblasts lacking heat shock factor 2
Authors: Paslaru Liliana , Morange M. , Mezger Valérie
Published: May 2007

In murine cells, the heat shock response is regulated by a transcription factor, HSF1, which triggers the transcription of heat shock genes. HSF2 has been shown to be involved in meiosis and mouse brain development. We characterized the effects of the absence of HSF2 in mouse embryonic fibroblasts (MEFs). The temperature threshold of the heat shock response appeared lowered in Hsf2‐/‐ MEFS as monitored by the synthesis of heat shock protein HSP70. In contrast to unstressed wild type MEFS, HSP70 and HSF1 are localized in the nucleus of unstressed Hsf2‐/‐ MEFS, a characteristic of stressed cells. HSF1 is not activated for DNA‐binding at unstressed temperature in Hsf2‐/‐ MEFS. Therefore, the absence of HSF2 induces some but not all of the characteristics of the stress response. In addition, Hsf2‐/‐ MEFS exhibited proliferation defects, altered morphology, remodeling of the fibronectin network.
The influence of sodium metavanadate on the process of diabetogenesis in BB rats
Authors: Cheta D. , Orasanu Gabriela , Nicolaie T. , Iordachescu Dana , Buligescu S. , Constantin C. , Hassanain M. , Coman Anca , Enache Mihaela , Negru Raluca , Tica Valeria , Timofte Delia , Gutu Daniela , Panaite C.
Published: May 2007

Vanadium has been shown to be beneficial in the oral treatment of animal models of type 1 and type 2 diabetes. The aim of the study was to evaluate the short‐term effects of sodium metavanadate in prediabetic BB‐DP rats. To do this, 96 rats were divided into 4 equal groups. Groups VI, V2, V3 were treated with sodium metavanadate (0.1, 0.2 and 0.3 mg/ml respectively) and sodium chloride (0.5 mg/ml) in drinking water for 7 days. Group C received only sodium chloride (0.5 mg/ml). Blood glucose (BG), glycosuria, ketonuria, body weight and insulinemia were determined. The age of onset of diabetes was significantly higher for groups V2, V3 compared to group C, (p < 0.05) and depends on the metavanadate concentration (V3 vs. V1, p=0.006). The incidence of diabetes was lower in the rats treated with metavanadate than in the control group, but this difference was not statistically significant. In diabetic rats, the BG at the onset was higher in group C than in groups V, p < 0.05. Insulinemia, at the onset of the treatment as well as immediately after its cessation showed a drop in the treatment groups, proportionally to the dosage of vanadium, but later increased slowly and continuously until the end of the experiment. In conclusion, metavanadate delays the development of diabetes in BB‐DP rats, but does not prevent its onset. A milder form of diabetes occurs in diabetic rats treated with metavanadate. The effects depend on the metavanadate concentration and 0.2 mg/ml is preferable.
Endothelial cells from hematopoietic stem cells are functionally different from those of human umbilical vein
Authors: Paunescu V. , Suciu Erika , Tatu C. , Plesa Adriana , Herman Diana , Siska Ioana Raluca , Suciu C. , Crisnic Daniela , Nistor Daciana , Tanasie Gabriela , Bunu Carmen , Raica M.
Published: May 2007

Hematopoietic stem cells have a remarkable plastic capacity, which allows them to differentiate into various cells, such as immune cells, nervous cells, muscle cells, bone and cartilaginous cells. The aim of this study was to show the capacity of stem cells to differentiate into endothelial cells, in culture, after addition of endothelial cells growth suplement (ECGS). We also compared the behavior of these cells with that of endothelial cells obtained from human umbilical vein (HUVEC). CD34+ cells obtained by immunomagnetic separation from human umbilical cord and placental blood were used. After 12‐15 days of culture in a medium containing ECGS, the cells showed morphological changes characteristic to endothelial cells and immunocytochemical analysis revealed the presence of CD31 surface antigen and von Willebrand factor. The flow‐cytometric analysis of endothelial cells adhesion molecules (ECAM) showed that endothelial cells derived from CD34+ cells expressed CD54/ICAM‐1 9.65 ± 0.2% and CD106/VCAM 7.73±0.3%, values similar to those expressed by HUVECs. After TNF incubation, ECAM expression increased only in HUVECs. These data demonstrate that a fraction of circulating CD34+ cells may develop some endothelial cell characteristics when cultured with ECGS, but they are functionally different from HUVECs.
Interleukin‐17 in acute myeloid leukemia
Authors: Wróbel T. , Mazur G. , Jazwiec Bozena , Kuliczkowski K.
Published: May 2007

There are several reports that angiogenesis plays important roles in hematological malignancies including acute myeloid leukemia (AML). Human interleukin‐17 (IL‐17) is a proinflammatory cytokine produced by activated CD4 T cells. IL‐17 plays a potential role in T cell mediated angiogenesis. The role of IL‐17 in pathologic angiogenesis has not been evaluated yet. The aim of the study was to determine plasma level of IL‐17 in patients with AML. IL‐17 levels were measured by ELISA in plasma samples taken from 68 adult patients with AML before chemotherapy was administered. In addition 20 out of 68 patients were reanalysed after achieving complete remission (CR). Ten samples from healthy volunteers were evaluated as the control. In this study we have demonstrated that serum level of IL‐17 is not elevated in AML patients. These results suggest that angiogenesis in AML is not mediated by CD4 T cells. To our knowledge this is the first report about IL‐17 serum level in acute leukemias. We are currently evaluating IL‐17 levels in others haematological malignancies.
New asthma drugs acting on gene expression
Authors: Popescu F.‐D.
Published: May 2007

New asthma drugs acting on transcription are transcription factor agonists (dissociated steroids, peroxisome proliferator‐activated receptor gamma agonists), transcription factor inhibitors (NF‐kB / AP‐1 inhibitors, STAT6 inhibitors), inhibitors of protein kinases acting on transcription factors (p38 MAP kinase inhibitors), and chromatin modifying agents. Pharmacological approach of translation in asthma includes therapeutic ribozymes and antisense oligonucleotides targeting receptors (adenosine A1 receptor, alpha chain of IL‐5 receptor, common beta chain of IL‐3/IL‐5/GM‐CSF receptor), cytokines (IL‐4, IL‐5, SCF), signal transduction molecules (Syk, Lyn), transcription factors (STAT‐6, GATA‐3). Some of these drugs acting on gene expression have the potential to improve therapeutic benefits compared with traditional drugs.
Molecular pathology in the diagnosis and treatment of non‐Hodgkin's lymphomas
Authors: Krause J. R. , Shahidi‐Asl Mahnaz
Published: May 2007

The non‐Hodgkin's lymphomas encompass a wide spectrum of hematologic neoplasms that exhibit different clinical and biological features. Lymphomas classically have been initially assessed based on their cytologic and histologic features. Morphology alone is often inadequate as similar appearing neoplasms may be immunophenotypically and molecularly heterogeneous. Molecular diagnostic methods can provide an additional level of testing that not only helps refine diagnoses but can provide prognostic information. New methods are being refined that may provide information to establish precise diagnostic profiles, provide targets for therapy and provide more sensitive methods for monitoring the success of treatment. Molecular methods will be increasingly utilized and eventually required as the accepted method of diagnosis and for monitoring the disease. Understanding of the molecular abnormality and the pathogenesis of the neoplasm hopefully will lead to therapeutic intervention aimed at the specific molecular defect or its product. The molecular pathology of the non‐Hodgkin's lymphomas is discussed.
Renal cortex remodeling in nitric oxide deficient rats treated with enalapril
Authors: Barbuto Noemi , Almeida Jorge Reis , Pereira Leila Maria Meirelles , Mandarim‐de‐Lacerda Carlos Alberto
Published: May 2007

The kidney NO synthase is one of the most important renal controlling systems. This paper aims the quantification of renal cortical components involved in blood pressure regulation under NOs blockade. Spontaneous hypertensive rats (SHRs) are submitted to chronic blockade of NOs by L‐nitro‐arginine‐methyl‐ester (L‐NAME) and an ACE inhibitor (enalapril) in comparison with the normotensive Wistar rats. Twenty SHRs and 5 Wistar rats were divided in 5 groups and observed for 21 days for blood pressure (BP) and serum creatinine: control Wistar (5) (C‐W), control SHR (5) (C‐SHR), L‐SHR (5) ‐ received L‐NAME 30 mg/kg/day, L+E‐SHR (5) ‐ received L‐NAME and Enalapril maleate 15 mg/kg/day, E‐SHR (5) ‐ received Enalapril maleate. A quantitative morphometric study (glomerular density, QA[g1], interstitium volume density, Vv[i], tubular surface and length densities, Sv[t] and Lv[t]) were performed at the end. The BP reached 226±15 mmHg in L‐SHR group. The BP difference between the L‐SHR and the C‐SHR groups was significant from the first week while the E‐SHR group became significant from the second week. At the end of the experiment the BP of the E‐SHR group was similar to the BP in the C‐W group. The QA[g1] was similar among C‐SHR, L‐SHR and L+E‐SHR groups and no difference was found between E‐SHR and C‐W groups. In the L‐SHRs serum creatinine was greatly increased, and microscopy showed thickening of arteriolar tunica media with an increase of the wall‐to‐lumen ratio, perivascular fibrosis, inflammatory infiltrated, tubular atrophy and interstitial fibrosis with focal segmental glomerulosclerosis. The use of enalapril was not completely efficient in reducing BP and morphological injury when the hypertension of SHRs was increased with the NOs blockade suggesting that NO deficiency‐induced hypertension is not entirely mediated by the RAAS.
Topical superoxide dismutase reduces post‐irradiation breast cancer fibrosis
Authors: Campana F. , Zervoudis S. , Perdereau B. , Gez E. , Fourquet A. , Badiu C. , Tsakiris G. , Koulaloglou S.
Published: May 2007

Fibrosis following breast radiotherapy for mammary cancer is a frequent undesired effect with objective (esthetic) and subjective (pain) consequences. Forty‐four patients with clinical radiofibrosis following conservative treatment of breast cancer were evaluated for the local antifibrosis effect of copper zinc superoxide dismutase [SOD(Cu/Zn)]. Extracted SOD(Cu/Zn) in a concentration of 3,600 units/mg was applied as ointment to the fibrotic affected area, b.i.d. for 90 days, in a total dose of 40 mg. The radiofibrosis intensity was scored on the basis of clinical criteria (pain and the fibrosis area) before and after SOD(Cu/Zn) treatment. SOD(Cu/Zn) was found to be effective in reducing radiation induced fibrosis by a lowering pain score in 36/39 patients and a decrease of the fibrotic area size in half cases, after 6 months. The intensity and changes of breast fibrosis were assessed also by mammography and, for the topographical distribution of subcutaneous temperature, by infrared thermography. Mammography density suggested decreased fibrosis in one third of patients. Thermography showed that fibrosis was accompanied by two zones clinically indistinctive: a central area with maximum thermal activity, called “Maximal Thermic zone” (MTZ) and a peripheral area with less thermal activity but higher than in the surrounding normal tissue, “Transitional Thermic Zone” (TTZ). Both MTZ and TTZ were significantly decreased in 36/44 patients after SOD(Cu/Zn) treatment. Clinical changes persisted all along the study. Treatment was well tolerated except for one case of local allergic reaction, and no important side effects. Molecular mechanisms involved are discussed. Further studies are running to confirm and explain these results.
β‐secretase‐cleaved amyloid precursor protein in Alzheimer brain: a morphologic study
Authors: Sennvik Kristina , Bogdanovic N. , Volkmann Inga , Fastbom J. , Benedikz E.
Published: May 2007

β‐amyloid (Aβ) is the main constituent of senile plaques seen in Alzheimer's disease. Aβ is derived from the amyloid precursor protein (APP) via proteolytic cleavage by proteases β‐ and β‐secretase. In this study, we examined content and localization of β‐secretase‐cleaved APP (β‐sAPP) in brain tissue sections from the frontal, temporal and occipital lobe. Strong granular β‐sAPP staining was found throughout the gray matter of all three areas, while white matter staining was considerably weaker. β‐sAPP was found to be localized in astrocytes and in axons. We found the β‐sAPP immunostaining to be stronger and more extensive in gray matter in Alzheimer disease (AD) cases than controls. The axonal β‐sAPP staining was patchy and unevenly distributed for the AD cases, indicating impaired axonal transport. β‐sAPP was also found surrounding senile plaques and cerebral blood vessels. The results presented here show altered β‐sAPP staining in the AD brain, suggestive of abnormal processing and transport of APP.
Redox regulation of angiotensin II siganling in the heart
Authors: Das Dipak K. , Maulik Nilanjana , Engelam Rjichard M.
Published: May 2007

A large number of studies have demonstrated the role of angiotensin II in cardiac preconditioning against ischemic reperfusion injury. Generally, angiotensin II is a detrimental factor for the heart, and its inhibition with an ACE inhibitor provides cardioprotection. This review provides an explanation for such paradoxical behavior of angiotensin II. Angiotensin II can potentiate the induction of the expression of a variety of redox‐sensitive factors including p38 MAPK, JNK and Akt, IGF‐IR, EGF‐R, and HO‐1 as well as redox‐regulated genes and transcription factors such as NF??B. It becomes increasingly apparent that during the earlier phase, the heart attempts to adapt itself against the detrimental effects of angiotensin II by upregulating several cardioprotective genes and proteins. These genes and proteins are redox‐regulated and the antioxidants or ROS scavengers block their expressions. Interestingly, an identical pattern of cardioprotective proteins and genes are expressed in the preconditioned heart, which are also inhibited with ROS scavengers. It is tempting to speculate that the induction of the expression of the redox‐sensitive cardioprotective proteins is the results of adaptation of the heart against the oxidative stress resulting from angiotensin II; and preconditioning is the net result of harnessing its own protection during ischemic and/or oxidative stress through its ability to trigger redox signaling.
Ca2+ and mitochondria as substrates for deficits in synaptic plasticity in normal brain ageing
Authors: Toescu E. C. , Verkhratsky A.
Published: May 2007

Normal brain ageing is associated with a degree of functional impairment of neuronal activity that results in a reduction in memory and cognitive functions. One mechanism proposed to explain the age‐dependent changes was the “Ca2+ hypothesis of ageing” but data accumulated in the last decade revealed a number of inconsistencies. Two important questions were raised: (a) which are, if any, the most reliable age‐associated change in neuronal Ca2+ homeostasis and (b) are these changes primary, and thus determinant of the ageing phenotype, or are they secondary to other changes in the physiology of the aged neurones. After a brief review of the evidence accumulated for the age‐induced changes in synaptic plasticity, we assess the proposal that these changes are, ultimately, determined by changes in the metabolic state of the aged neurones, that are manifest particularly after neuronal stimulation. In this context, it appears that the changes in mitochondrial status and function are of primary importance.
Inorganic phosphate homeostasis and the role of dietary phosphorus
Authors: Takeda Eiji , Yamamoto Hironori , Nashiki Kunitaka , Sato Tadatoshi , Arai Hidekazu , Taketani Yutaka
Published: May 2007

Inorganic phosphate (Pi) is required for cellular function and skeletal mineralization. Serum Pi level is maintained within a narrow range through a complex interplay between intestinal absorption, exchange with intracellular and bone storage pools, and renal tubular reabsorption. The crucial regulated step in Pi homeostasis is the transport of Pi across the renal proximal tubule. Type II sodium‐dependent phosphate (Na/Pi) cotransporter (NPT2) is the major molecule in the renal proximal tubule and is regulated by Pi, parathyroid hormone and by 1,25‐dihydroxyvitamin D. Recent studies of inherited and acquired hypophosphatemia [X‐linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor‐induced rickets/osteomalacia (TIO)], which exhibit similar biochemical and clinical features, have led to the identification of novel genes, PHEX and FGF23, that play a role in the regulation of Pi homeostasis. The PHEX gene, which is mutated in XLH, encodes an endopeptidase, predominantly expressed in bone and teeth, but not in kidney. FGF‐23 may be a substrate of this endopeptidase and may therefore accumulate in patients with XLH. In the case of ADHR mutations in the furin cleavage site, which prevent the processing of FGF‐23 into fragments, lead to the accumulation of a “stable” circulating form of the peptide which also inhibits renal Pi reabsorption. In the case of TIO, ectopic overproduction of FGF‐23 overwhelms its processing and degradation by PHEX, leading to the accumulation of FGF‐23 in the circulation and inhibition of renal Pi reabsorption. Mice homozygous for severely hypomorphic alleles of the Klotho gene exhibit a syndrome resembling human aging, including atherosclerosis, osteoporosis, emphysema, and infertility. The KLOTHO locus is associated with human survival, defined as postnatal life expectancy, and longevity, defined as life expectancy after 75. In considering the relationship of klotho expression to the dietary Pi level, the klotho protein seemed to be negatively controlled by dietary Pi.
The comparison of different protocols for expansion of umbilical‐cord blood hematopoietic stem cells
Authors: Chivu Mihaela , Diaconu Carmen C. , Bleotu Coralia , Alexiu Irina , Brasoveanu Lorelei , Cernescu C.
Published: May 2007

Hematopoiesis is maintained by the activity of multipotent stem cells, which have the dual capacity to self‐renew and to differentiate into all of the blood cell lineages. The major challenge of stem cells based regenerative therapy is to expand ex vivo the primitive compartment to increase transplantable stem cells number. The present study was designed to evaluate several culture systems for in vitro maintenance of umbilical cord blood stem cells. The influences of different growth conditions such as stromal feeder layer, cytokines supplement and placental conditioned medium (PCM) have been evaluated over a relatively short period of time on CD34+ cell expansion and maintenance of clonogenic progenitors. When cells were expanded on feeder layer in the presence of added cytokines and PCM on average a 2.96‐fold increase of CD34+CD71‐ and a 3.13‐fold increase of CD34+HLA‐DR‐ was observed. The total number of colony forming cells (35±2.65) indicated also that the yield of clonogenic progenitors obtained with a combination of all factors was two folds higher than each of these factors alone and ten time above control (3.67± 2.52). In conclusion, the results of our study clearly show that the ex vivo expansion of hematopoietic progenitor cells obtained from human umbilical cord blood is dependent on controlled experimental conditions, which might be helpful when designing culture systems for clinical applications.
Scanning of β‐globin gene for identification of β‐thalassemia mutation in Romanian population
Authors: Talmaci R. , Traeger‐Synodinos J. , Kanavakis E. , Coriu D. , Colita D. , Gavrila L.
Published: May 2007

β‐Thalassemia is uncommon (0.5%) in the Romanian population, but it must be considered in the differential diagnosis of hypochromic anemia. The molecular characterization of β‐thalassemia is absolutely necessary for molecular diagnosis, as well as any genetic epidermiological study in this region. Molecular analyses consist of mutation detection by molecular scanning of β‐globin gene. This gene has 3 exons and 2 introns, involved in β‐thalassemic pathogenesis. Clinical application of DNA analysis on β‐thalassemic chromosomes allowed characterization of 29 persons with different β‐thalassemia mutations among 58 patients with anemia. The experimental strategy was based on sequential PCR amplification of most of the β‐globin gene and running on denaturing gradient gel electrophoresis of amplification products. Definitive characterization of mutations in samples identified with shifted DGGE patterns was performed ARMS‐PCR and/or PCR‐restriction enzyme analysis methods. Eight different β‐thalassemia alleles were identified, the most common being IVS I‐110 (G‐A) and cd 39 (C‐T). Comparison of overall frequency of mutations in the neighboring countries, shows that these results are in the frame of overall distribution of these mutations in Mediterranean area, especially in Greece and in Bulgaria. Molecular diagnosis is useful for differentiating mild from severe alleles, for genetic counseling, as well as for mutation definition in carriers, identified by hematological analysis necessary for prenatal testing and genetic counseling.
Type 1 diabetes genetic susceptibility encoded by HLA DQB1 genes in Romania
Authors: Guja C. , Guja L. , Nutland S. , Rance H. , Sebastien M. , Todd J. A. , Ionescu‐Tirgoviste C.
Published: May 2007

Most cases of type 1 diabetes (T1DM) are due to an immune‐mediated destruction of the pancreatic beta cells, a process that is conditioned by multiple genes and environmental factors. The main susceptibility genes are represented by the class II HLA‐DRB1 and DQB1 alleles. The aim of our study was to reconfirm the contribution of HLA‐DQB1 polymorphisms to T1DM genetic susceptibility for the Romanian population. For this, 219 Romanian T1DM families were genotyped at high resolution for HLA DQB1 using the PCR‐SSOP method (Polymerase Chain Reaction ‐ Sequence Specific Oligonucleotide Probes). Allele transmission to diabetics and unaffected siblings was studied using the Transmission Disequilibrium Test (TDT). We found an increased transmission of DQB1 *02 (77.94% transmission, PTDT= 7.18 × 10−11) and DQB1*0302 (80.95% transmission, PTDT= 2.25 × 10−10) alleles to diabetics, indicating the diabetogenic effect of these alleles. Conversely, DQB1*0301, DQB1*0603, DQB1*0602, DQB1*0601 and DQB1*05 alleles are protective, being significantly less transmitted to diabetics. In conclusion, our results confirmed the strong effect of HLA‐DQB1 alleles on diabetes risk In Romania, with some characteristics which can contribute to the low incidence of T1DM in this country.
Kinetic logic: a tool for describing the dynamics of infectious disease behavior
Authors: Martinet‐Edelist Claire
Published: May 2007

Most of the infectious diseases imply biological regulations controlled by several feedback loops or circuits. Kinetic logic, which is a method easily accessible to biologists or physicians, and which takes time and thresholds of activity into account, seems a convenient method for building simplified models related to this field. This implies usually qualitative predictions concerning the dynamics of such biological systems, leading to a movement back and forth between experimentation or observation and logical description. Here, we illustrate this simple modelling method in building elementary models concerning prion infection to demonstrate how to proceed. We also discuss and summarize how this method has been used for studying several viral diseases. As an example, we show how predictions related to the rhabdovirus cycle, were experimentally verified.
The involvement of endothelial progenitor cells in tumor angiogenesis
Authors: Ribatti Domenico
Published: May 2007

Endothelial progenitor cells (EPCs) have been isolated from peripheral blood CD34, VEGFR‐2, or AC 133 (CD133) antigen‐positive cells, which may home to site of neovascularization and differentiate into endothelial cells in situ. Endothelial cells contribute to tumor angiogenesis, and can originate from sprouting or co‐option of neighbouring pre‐existing vessels. Emerging evidence indicate that bone marrow‐derived circulating EPCs can contribute to tumor angiogenesis and growth of certain tumors. This review article will summarize the literature data concerning this new role played by EPCs in tumor angiogenesis.
Double transgenic mice with Type 1 diabetes mellitus develop somatic, metabolic and vascular disorders
Authors: Radu D. L. , Georgescu Adriana , Stavaru Crina , Carale Alina , Popov Doina
Published: May 2007

The double transgenic mice (dTg) were obtained by mating: (i) transgenic mice expressing the hemagglutinin of influenza virus under the insulin promoter with (ii) transgenic mice expressing specific T lymphocytes with receptor for the immunodominant epitope of the same virus. In this study we show that dTg mice developed type 1 diabetes mellitus associated with hyperglycemia, low level of plasma insulin, glucosuria, weight loss and ∼ 90% mortality (at 3 months biological age). The membrane of red blood cells was more sensitive to osmotic shock in diabetic mice, compared to non‐diabetic mice, assessing systemic oxidative stress. Both vasoconstriction and vasorelaxation of the renal arteries decreased significantly in diabetic mice (compared to the control group of non‐diabetic mice) related to the phenotypic change of endothelium and smooth muscle cells within the artery wall. This animal model, may be used in developing various strategies to study pancreatic β‐cell function, as well as for a better metabolic control conducting to a reduced risk of vascular complications.
Vesicle traffic through intercellular bridges in DU 145 human prostate cancer cells
Authors: Vidulescu Cristina , Clejan Sanda , O'Connor Kim C.
Published: May 2007

We detected cell‐to‐cell communication via intercellular bridges in DU 145 human prostate cancer cells by fluorescence microscopy. Since DU 145 cells have deficient gap junctions, intercellular bridges may have a prominent role in the transfer of chemical signals between these cells. In culture, DU 145 cells are contiguous over several cell diameters through filopodial extensions, and directly communicate with adjacent cells across intercellular bridges. These structures range from 100 nm to 5 μm in diameter, and from a few microns to at least 50–100 μm in length. Time‐lapse imagery revealed that (1) filopodia rapidly move at a rate of microns per minute to contact neighboring cells and (2) intercellular bridges are conduits for transport of membrane vesicles (1–3 μm in diameter) between adjacent cells. Immunofluorescence detected alpha‐tubulin in intercellular bridges and filopodia, indicative of microtubule bundles, greater than a micron in diameter. The functional meaning, interrelationship of these membrane extensions are discussed, along with the significance of these findings for other culture systems such as stem cells. Potential applications of this work include the development of anticancer therapies that target intercellular communication and controlling formation of cancer spheroids for drug testing.
Apoptosis of pancreatic acinar cells in acute pancreatitis: is it good or bad?
Authors: Bhatia M.
Published: May 2007

Acute pancreatitis is a disease of variable severity in which some patients experience mild, self‐limited attacks while others manifest a severe, highly morbid, and frequently lethal attack. The events that regulate the severity of acute pancreatitis are, for the most part, unknown. Several recent studies have suggested that the acinar cell response to injury may be an important determinant of disease severity. In these studies, mild acute pancreatitis was found to be associated with extensive apoptotic acinar cell death while severe acute pancreatitis was found to involve extensive acinar cell necrosis but very little acinar cell apoptosis. These observations have led to the hypothesis that apoptosis might be a favorable response to acinar cell and that interventions which favor induction of apoptotic, as opposed to necrotic, acinar cell death might reduce the severity of an attack of acute pancreatitis. This review aims to discuss our current understanding of the contribution of acinar cell apoptosis to the severity of acute pancreatitis.
Endothelial progenitor cells: past, state of the art, and future
Authors: Iwami Yo , Masuda Haruchika , Asahara Takayuki
Published: May 2007

Recent evidences suggest that endothelial progenitor cells (EPCs) derived from bone marrow (BM) contribute to de novo vessel formation in adults occurring as physiological and pathological responses. Emerging preclinical trials have shown that EPCs home to sites of neovascularization after ischemic events in limb and myocardium. On the basis of these aspects, EPCs are expected to develop as a key strategy of therapeutic applications for the ischemic organs. Such clinical requirements of EPCs will tentatively accelerate the translational research aiming at the devices to acquire the optimized quality and quantity of EPCs. In this review, we attempt to discuss about biological features of EPCs and speculate on the clinical potential of EPCs for therapeutic neovascularization.