The role of P53 and Bcl-2 proteins in 7, 12-dimethylbenz-(a)-anthracene-induced tumor growth.

7, 12- Dimethylbenz-(a)-anthracene (DMBA) has been used for a long time to induce rat mammary gland carcinogenesis. In a previous paper we described the effects of diet, of non-steroidal anti-inflammatory drugs and the combination of these two factors on breast cancer. We also pointed out that DMBA tumor generating process is still poorly understood. The present study attempts to explore whether P53 or the pro-apoptotic protein Bcl-2 are potential targets of DMBA in its induction of breast tumors in the Sprague-Dawley rat breast tumorigenesis model. Our results indicate that the DBMA-induced tumors are apparently the result of P53 inactivation. This inactivation results in tumorigenesis, probably aided by the absence of Bcl-2 in the tumor cells of the Sprague-Dawley rat animal model. We discuss the potential mechanisms by which P53 inactivation results in tumorigenesis.

Cholesterol, cytokines and diseases.

A high level of cholesterol is associated with obesity, cardiovascular diseases and atherosclerosis. Immune response in atherosclerosis is mediated by chemokines which attract monocytes, leading to the innate immune response characterised by the production of cytokines. The immunoregulatory cytokines are an important bridge between innate and adductive immunity. TH1 cytokines are involved as effector T cells in inflammatory response, while TH2 cytokines can be anti-inflammatory such as IL-10 and IL-4. It is well known that statins enhance the production of TH2 cytokines whereas the secretion of TH1 cytokines is suppressed. For this purpose, we studied the significance of anti-inflammatory effect and suppression of inflammation by statins. In this paper we revisited the role of cholesterol and cytokines IL-18, IL-10, IL-12, TNF-α, interferon-γ, and chemokines in inflammatory diseases.

Psychological stress and vitamins.

Conditions of stress and anxiety have complex interactions with insufficient vitamin intake and malnutrition. This study, based on literature research in Medline, analyzes the inter-relationship between vitamins and stress. This report concerns a number of vitamins that have been receiving much attention in earlier reviews of the literature, for their potential to protect against stress-related events, and focus is placed upon recent findings.

Microarray analysis in gynaecology and its findings: a systematic review.

Microarray technology is a promising method for investigating gynaecological benign pathology. This systematic review examined various parameters of the design of these studies, the methods used and the gene outcome in these diseases. Electronic searches were performed in Medline (up to April 2009). An overall representation of important genes for each disease detected was performed. The results showed genes were up-regulated or down-regulated. However, studies suffer from several flaws in their design, the sample size employed and the reporting method. In conclusion, a significant amount of work has been performed on benign gynaecological diseases using microarray technology. New trial designs need to be employed that incorporate microarray reporting standards. New research directions should evolve based on these results.

Impact of IL-18 on inflammation.

IL-18 is produced by many cell types, such as Kupffer cells, keratinocytes, macrophages, dendritic cells, and activated T cells stimulated by LPS. It is an important regulator of both innate and acquired immune responses. IL-18 plays a central role in rheumatoid arthritis since the T cells and macrophages that invade the synovial. These finding support a role for IL-18 in inflammation, allergy and immune diseases.

Hormones of hypothalamic-pituitary-thyroid axis are significant regulators of synthesis and secretion of vitamin K-dependent plasma coagulation factors.

Present data about hormonal regulation of haemostasis are often contradictory and are mostly based on clinical observations. The aim of the current research is to study the effects of the hormones of hypothalamic-pituitary-thyroid (HPT) axis on plasma levels (i.e. on the synthesis and secretion) of vitamin K-dependent coagulation factors in rats. The study was carried out on 65 male Wistar rats, divided into five groups. The animals were injected subcutaneously (s.c.) once daily for three consecutive days as follows: the first group was injected with Thyrotropin releasing hormone (TRH), in a dose of 0.06 mg/kg b.w.; the second group by Thyroid stimulating hormone (TSH), with a dose of 1 MU/kg b.w., the third and the fourth group respectively with Liothyroninum (Triiodothyronin ? T3) and Levothyroxinum (Thyroxin ? T4) with a dose of 0.08 mg/kg b.w. each. The control group rats were injected with saline (the solvent of the hormones), following the same schedule and volume per kg b.w. The necessary quantity of blood was acquired by a cardiac puncture under ether narcosis, and antigen levels of plasma factors II, VII, IX and X (FII:Ag, FVII:Ag, FIX:Ag and FX:Ag) were determined by ELISA kits (Diagnostica Stago, France). TRH, TSH, T3 and T4 significantly decreased the plasma antigen levels of FII and FVII (p<0.001). TRH, T3 and TSH reduced significantly FIX:Ag level( p<0.001 for TRH and T3 and p<0.05 for TSH) while T4 did not exert significant changes ( p>0.05). FX:Ag level was also significantly reduced by TRH, T3 (p<0.001), TSH and T4 (p<0.01). Plasma levels of vitamin K-dependent coagulation factors FІІ:Ag, FVІІ:Ag, FІХ:Ag and FХ:Ag are significantly reduced under the influence of the hormones of hypothalamic-pituitary-thyroid axis which signifies their decreased synthesis and secretion. T4 does not induce substantial changes in FIX:Ag plasma level.

A semi-automated approach towards generating three-dimensional mesh of the heart using a hybrid MRI/histology database.

Both the forward and inverse problems of electrocardiography rely on the precise modelling of the anatomic and electrical properties of the thoracic tissues. This, in turn, requires good knowledge of the electrical anisotropy as well as conductivity inhomogeneity of the heart, lungs and the rest of the thorax. Cardiac electrical anisotropy is related to its microstructure (fibre length, density and orientation). We hereby present detailed three-dimensional (3D) meshes of the thorax and heart, using image data from contiguous 2D magnetic resonance (MR) imaging slices as well as a realistic 3D cardiac fibre orientation model that derives its data from high-resolution ex vivo human heart MR images and from histology specimens of heart tissue. Using specific software, we integrated the 3D thorax and heart meshes in one that addresses the related modelling requirements for the solution of the forward and inverse problems of electrocardiography.

Cholesterol and vitamins: revisited study.

The link between low density lipoprotein and coronary heart disease has been widely studied. Oxidized LDL damages the artery wall, and a diet rich in vitamins and low in saturated fat and cholesterol may reduce this risk. Not only hypercholesterolemia but also low levels of high density lipoprotein cholesterol are critical risk factors for atherosclerosis and related diseases. It has been reported that high doses of B complex vitamin may be useful in lowering blood cholesterol and triglyceride levels in the body, however the use of this compound has been limited by an annoying flush and concern for toxicity. Niacin is a B-complex vitamin with anti-atherosclerotic properties and is an effective medication for raising high density lipoprotein. The combination of niacin with other lipid-lowering drugs, such as statins, reduces the dynamic of atherosclerosis disease. In addition, vitamin E is one of the most important lipid soluble anti-oxidants in humans, and reduces atherosclerosis plaque, coronary artery diseases and myocardial infarction. Vitamin E protects the integrity of membranes by inhibiting lipid peroxidation. In this study we revisited the interrelationship between cholesterol, low density lipoproteins and vitamins.

Atherosclerosis: a classic inflammatory disease.

Atherosclerosis is an inflammatory disease due to a diet high in saturated fat, hypercholesterolemia, obesity, hypoglycemia, etc. mainly mediated by the infiltration of macrophage and T cells into the vascular wall. Once the endothelial is damaged monocytes penetrate the tissue and are transformed in scavenger cells. Upon stimulation of Th1 cells, a group of cytokines is released and contributes to the inflammatory response of atherosclerotic tissue. When macrophages proliferate they amplify inflammatory response through the secretion of growth factors and cytokines such as TNF and IL-1. In addition, chemokines such as RANTES and other C-C chemokines are generated, and matrix metalloprotinease 9 (MMP-9) are produced by activated monocytes. However, the immune system in atherosclerosis still remains unclear. Here, in this study we revisited the inter-relationship between atherosclerosis and inflammation.

Interrelationship between vitamins and cytokines in immunity.

Cytokines are important proteins that modulate immunity and inflammation. Vitamins are also involved in immunity and inflammation. They are found to restore the ability of some cells to produce certain cytokines. Vitamin deficiency appears to affect the mechanism of immune cells, though the impact of reduced cytokine response in vitamin malnutrition is not clear. Vitamin D is involved in many medical conditions, such as infections and inflammation, and mediates innate immunity. Deficiency of vitamin D increases the risk of infectious and inflammatory diseases. In addition, this vitamin modulates Treg function and IL-10 production which is important for therapeutic treatment. Vitamin A increases inflammatory response and is involved in tissue damage; moreover, vitamin A is a key modulator of TGFbeta which can suppress several cytokines. Vitamin E, an anti-ageing compound, is associated with a defect of naive T cells and may inhibit some inflammatory compounds such as prostaglandin generation.

Modulation of NF-kappaΒ signalling pathways by parasites.

NF-kappaB is implicated in lymphocyte development, maturation, proliferation and survival. This inducible transcription factor is widely expressed by virtually all cell types. In mammals, the genes rela, relb, crel, nfkappaΒ1, and nfkappaB encode the five NF-kB protein family members RelA (p65), RelB, c-Rel, p50, and p52, respectively, which form homo- and heterodimeric DNA-binding complexes capable of regulating target gene transcription of specific biological responses differentially. NF-kappaB regulates the expression of a wide variety of genes that play critical roles in innate and adaptive immune responses, is strongly linked to the inhibition of apoptosis, and contributes to tumor growth, metastasis, and chemoresistance. Parasites have targeted several parts of the NF-kappaB pathway, allowing them to interfere with the transcription of immune response genes. The biology of different parasites is critical in influencing the patterns and kinetics of NF-kappaB activity and thereby the development of subsequent immune responses.

Microarray analysis of NF-kappaB signaling pathways in PBMC of mice infected by Trichinella spiralis.

The NF-kappaΒ pathway gene expression profiles were compared between 10, 20 and 39 days after Trichinella spiralis experimental infection in BALB/c mice. Out of 128 genes, 19 (14.8%) genes were present in non-infected and post-infected mice. The expression of 7 (36.8%) genes was downregulated 10 and 20 days post-infection while 3 (15.8%) genes were upregulated 39 days post-infection. The present study lists the candidate genes of the NF-kappaB signaling pathway that were commonly and differentially expressed between the specific points of T. spiralis infection, thus suggesting that these genes need to be further investigated to reveal the mechanism of the T. spiralis modulation of the NF-kappaB signaling pathways.

IL-35, an anti-inflammatory cytokine which expands CD4+CD25+ Treg Cells.

Interleukin 12 (IL 12) p35/p40 is a heterodimeric cytokine which plays a critical role in inflammation, immunity and tissue proliferation, and also plays a relevant function in T helper (Th) cell polarization and Th1 T-cell differentiation. IL-12 family members, IL-12p70, IL-23, IL-27 and IL-35, play an important role in influencing helper T-cell differentiation. EBV-induced gene 3 can be associated with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, also called IL-35. It has been shown that IL-35 has biological activity and able to expand CD4+CD25+ Treg cells, suppress the proliferation of CD4+CD25- effector cells and inhibit Th17 cell polarization. IL-35 has been shown to be constitutively expressed by regulatory T (Treg) cells CD4(+)CD25(+)Foxp3(+) and suggested to contribute to their suppressive activity. IL-35 is a crucial mediator which provokes CD4+CD25+ T cell proliferation and IL-10 generation, another well-known anti-inflammatory cytokine, along with TGFbeta cytokine. These studies suggest that IL-35, together with other successfully discovered cytokine inhibitors, represents a new potential therapeutic cytokine for chronic inflammation, autoimmunity and other immunological disorders.

Vitamins and mast cells.

The immune system is a highly complex, intricately regulated group of cells whose integrated function is essential to health. The mast cell inflammatory response is characterized by an early phase with massive discharge of mediators stored in cytoplasmic secretory granules. Through multigranular/compound exocytosis and a late phase that involves generation of arachidonic acid metabolites and de novo synthesis of cytokines/chemokines and growth factors. Vitamins have been shown to have a protective effect on the body's immune cells. Vitamin C and E are necessary in allergic disease treatment where mast cells are involved. In addition, ascorbic acid and pyridoxine are useful compounds for the treatment of inflammatory disorder of the respiratory airways. Here we revisited the inter-relationship between vitamins and mast cells.

Effects of rich-in-fat diets and highly selective COX-2 inhibitors on 7,12-dimethylbenz-(A)-anthracene-induced tumor growth.

The effects of diet, of non-steroidal anti-inflammatory drugs, or of their combination on carcinogenesis continue to be a case for controversy. Diets that are high in fat have been linked to increased risk of various tumors. At the same time there is substantial, but not conclusive, evidence that the risk of breast and colon cancer correlates with total fat intake rather than a specific type of fat. On the other hand, non-steroidal anti-inflammatory drugs (NSAIDs) have been studied extensively because they appear to delay or inhibit the development of malignant and pre-malignant lesions. 7,12-Dimethylbenz-(a)-anthracene (DMBA) has been used for a long time to induce carcinogenesis in a number of rat animal models. The present study attempts to identify the effects on DMBA-induced tumor growth (a) of diets rich in fat and (b) of the highly selective COX-2 inhibitor Celecoxib, which has been claimed to offer substantial protection against carcinogenesis.

Mast cells and chemokines.

Chemokines are small proteins (8-12 kD polypeptides) secreted by the cells of innate and adaptive immunity that mediate many of the functions of these cells, including recruitment of other cells. They are classified into families: CC, CXC and CX3C. CXC chemoattract mainly on neutrophils and CC act mainly on monocytes, eosinophils and mast cells. Mast cells are important cells in the modulation of allergic and inflammatory diseases. Activation of mast cells with specific IgE antibody and antigens or other active compounds such as Substance P and corticotrophin releasing hormone causes transcription and translation of several different cytokines/chemokines such as tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1 (MIP-1) and GM-CSF, RANTES, MCP-1, CXCL8, along with other proinflammatory compounds, proteases (chymase and tryptase), histamine, leukotrienes and prostaglandin D2. Neutralization of chemokines may reduce inflammatory cell accumulation and may protect against allergy, toxic shock syndrome and inflammatory diseases.

Impact of substance P on cellular immunity.

Much evidence suggests a cross-talking between nerve fibers and the immunity system. The immunomodulation by substance P includes cell activation and proliferation of human cells, with cytokine and chemokine generation and release. Substance P was first isolated by Leeman et al. as an undecapeptide with important neurotransmitter-neuromodulator effects. In addition, substance P was shown to induce and mediate inflammation, angiogenesis, infections, intestinal mucosal immunity and stress. Substance P is able to activate several immune cells, such as CD4+ and CD8+ T lymphocytes, mast cells, NK cells and macrophages. In recent studies we have shown that substance P can activate interleukin-8, a CXC chemokine, demonstrating its involvement in immune cell chemoattraction. We believe that substance P is important in understanding the pathophysiology of inflammation.

Effects of the hormones of the thyroid axis on the vitamin K-dependent plasma factors of blood coagulation (II, VII, IX, and X).

The hormonal regulation of haemostasis is a problem which has not received much attention. The data concerning the influence of hormones from the hypothalamic-pituitary-thyroid axis are scarce, contradictory and based mainly on clinical observations. The objective of the current research is to study the influence of the Thyrotropin releasing hormone (TRH), Thyroid stimulating hormone (TSH), Triiodothyronine (T3) and Thyroxin (T4) on the activity level of the vitamin K-dependent plasma factors of blood coagulation--factor II (F II), factor VII (F VII), factor IX (F IX) and factor X (F X). This study was carried out on 40 male Wistar rats. The necessary quantity of blood was obtained by cardiac puncture under ether narcosis. The indicators studied were activated partial thromboplastin time (aPTT), protothrombin time (PT), F II, F VII, F IX and F X, and were determined by means of Diagnostica Stago tests and with the help of an automatic coagulometer. The hormones studied were: TRH (0.06 mg/kg b.w.), TSH (1 MU/kg b.w.), T3 (0.08 mg/kg b.w.) T4 (0.08 mg/kg b.w.) prolonged aPTT (p<0.001) and PT (p<0.001). TRH and T3 significantly reduced the activity level of factors II, VII, IX and X; T4 only reduced the level of F II (p<0.05), and TSH did not induce significant changes in the haemocoagulation factors studied. The TRH, TSH, T3 and T4 hormones, although elements of one and the same axis, have an ambiguous effect on the vitamin K-dependent factors of blood coagulation. The results obtained show that the determined changes in the activity levels of the vitamin K-dependent plasma factors of blood coagulation are undoubtedly related to the hypocoagulation observed in the intrinsic and extrinsic pathways under the influence of the hormones of the thyroid axis.

Contributions of signal analysis to the interpretation of spirometry.

AIM: Chronic Obstructive Pulmonary Disease (COPD) is taking on catastrophic proportions. However, there is still a need for more objective and quantitative methods for its diagnosis and stratification. The present study explores the effectiveness of signal analysis methodologies as the means to increase the effectiveness of spirometry in diagnosing and stratifying COPD. METHODS: Since expiratory flow at the mouth results from converging airflows, it is possible to use signal analysis to identify changes in the characteristics of airflow along the respiratory tree. This was achieved by non-invasively identifying alterations in the frequency spectrum of the Forced Expiratory Flow (FEF) curve of 108 patients (49 men and 59 women, 12-75 yrs of age) presenting with (a) clinically and spirometrically normal respiratory profile, (b) COPD, (c) restrictive lung disease and (d) interstitial fibrosis. Fundamental to the study design was the notion that the characteristics of the expiratory output of the respiratory system are determined by the bronchial tree and the upper respiratory tract. RESULTS: A number of quantitative measures for the power spectrum of the FEF curve were identified, which permit the definition of specific rules and allow for the accurate classification of, at least, the basic types of respiratory disease. CONCLUSIONS: (a) It is for the first time that airflow resonances are identified in the sub-audible (<20 Hz) range of the power spectrum of the FEF curve. (b) COPD patients present with FEF curves which have different power spectral characteristics from those of healthy individuals (p<0.01), at frequencies lower than 3.66 Hz. (c) In COPD, in restrictive lung disease and in interstitial fibrosis, the lower resonant frequencies of the spectrum of the FEF curve predominate.