Current Drug Targets - Immune, Endocrine & Metabolic Disorders - Volume 1, Issue 3, 2001

Host responses to fungi result from a coordinate interplay between innate and adaptative immune system. Neutrophils and monocytes are involved in the non specific clearance of yeasts (e.g. Candida albicans and Cryptococcus neoformans), while T helper 1 type responses are protective via release of interferon gamma. By contrast, T helper 2 responses (IL-4 and IL-10 release) correlate with disease exacerbation and pathology. IL-12 production which enhances T helper 1 type responses seem to exert a beneficial role in the course of Candida infection. In particular, its production from neutrophilis may support memory T helper 1 cell responses of the fungus. With respect to anti-Candida vaccines several approaches are in progress, such as use of heat-killed Candida albicans in combination with adjuvants, purified peptides and proteins and immunogenic peptide-lipid conjugates. Furthermore, exogenous IL-12 may play an important role in inducing a T helper 1 anticandidal response, also replacing neutrophils in neutropenic patients. At the same time, granulocyte-colony stimulating factor has exhibited therapeutic efficacy in experimental and human models of fungal infection.

It is well known that abnormal immune responses may play a pathogenic role in the H. pylori-related gastropathy. Indeed, as far as humoral immune response is concerned, it is still debated whether specific anti-H. pylori antibodies have a protective or noxious effect in infected hosts. Besides proinflammatory cytokines released from macrophages, such as tumor-necrosis factor-alpha and interleukin-1beta, and IFN-gamma derived from T-helper 1 lymphocytes, also interleukin-10, a product of T-helper 2 lymphocytes with antiinflammatory properties, seems to be surprisingly involved in the pathogenesis of H. pylori-induced gastritis. In addition, lipopolysaccharide derived from the outher membrane of H. pylori acts as a chemoattractant for monocytes and induces release of free radicals, interleukin-1beta, interleukin-6, interleukin-8 and tumor necrosis factor-alpha. On the other hand, H. pylori lipopolysaccharide could be responsible for the increased polyamine concentrations in the gastric mucosa and polyamines, such as putrescine, spermidine and spermine, could be involved in the increased cell proliferation and consequent possible neoplastic transformation of the gastric mucosa.Incubation of peripheral blood mononuclear cells with H. pylori increases significantly the surface expression of CD95 receptor (Fas), thus suggesting that these bacteria are able to induce apoptosis.In animal models, different types of vaccination have been investigated, including stimulation of nasal and rectal lymphoid tissue, as well as adoptive transfer of T cell from donors immunized with H. pylori. However, results obtained are frequently disappointing. In humans, urease of H. pylori was safely used as oral vaccine in the absence or presence of adjuvants with encouraging results. Finally, DNA vaccines could offer in the future advantages for prophylactic H. pylori eradication, especially where population is infected by this microorganism since childhood.

Over the last several years, a great level of interest has rallied behind understanding how the pivotal kinase, 3-phosphoinositide dependent kinase 1 (PDK1) is regulated. PDK1 phosphorylates and activates members of the AGC kinase family shown to be activated downstream of phosphoinositide 3-kinase (PI3K); however, the functional dependency of PDK1 on PI3K for activation of its targets is less clear. The PI3K signaling pathway mediates numerous cellular responses upon growth factor and hormone stimulation. Specifically, PI3K signaling influences many of the metabolic and mitogenic functions of the anabolic hormone, insulin. Thus, the regulation of PI3K and its downstream targets by insulin has become an important topic for investigation. Given its central role as the kinase upstream of those signaling pathways linked to PI3K, the regulation of PDK1 by insulin and other factors is at the height of many of these investigations. Current theories on PDK1 regulation propose substrate conformation and subcellular localization as the primary mediators of PDK1 function. The array of PDK1 substrates suggests, however, that in cells PDK1 may be more tightly regulated. Recent data support phosphorylation as a potential regulatory mechanism that may play an additional role in directing the specificity of PDK1 towards its physiological substrates. The combination of these regulatory mechanisms along with the potential for multiple PDK1 isoforms with select tissue distribution may contribute to the diversified actions of insulin signaling. The targeting of these various aspects of PDK1 regulation may provide for novel therapeutic treatments for diseases such as diabetes and cancer.

Tissue transglutaminase (tTGase, tTG) is known as being implicated in the intracellular cross-linking of proteins occurring in a growing series of physiological conditions including - just to mention the most relevant ones- programmed cell death (apoptosis), cell adhesion, growth, spreading and differentiation, tumor growth, metastasis, cell adhesion, proliferation, differentiation, extra cellular matrix (ECM) stabilization. In the current work we investigated tTG activity and expression of “normal” and potential transformed cytosolic tTG antigens in mammalian cells. Most cell lines studied showed low tTG activity, which in all cases could be enhanced considerably by treating cell cytosol homogenates with trypsin. The results suggested the existence -in transformed cells- of inactive types of tTGase. We purified cytosolic tTG antigens from these cells utilizing a GTP-agarose resin, and we can therefore conclude that “normal” molecular weight (mw) tTG antigens, but also high molecular weight (hmw) and low molecular weight (lmw) tTG antigens from transformed cells, retain GTP-binding ability. The initial results from our study also allowed us to hypothesize that transformed hmw- and lmw- tTG antigens should not be considered as the result of post-translational modifications of normal mw, cytosolic tTG. The potentially low or absent transamidating functionality of cytosolic tTG species in transformed mammalian cells could be responsible for decreased or even abolished programmed cell death, whereas the unaffected GTP-binding functionality of such proteins in these cells might lead to increased signal transduction and possibly proliferation.

Non-steroidal antiinflammatory drugs (NSAIDs) are among the most frequently prescribed medications worldwide. These drugs are effective for the treatment of a wide spectrum of diseases: musculoskeletal disorders, headhache, fever, pain, and others. Their widespread use explains the very high incidence of intolerance reactions range from asthma, rhinitis, to urticaria / angioedema, various skin eruptions and anaphylactic shock.The pathogenesis of intolerance is still unclear: immune-mediated reactions have been reported following the use of pyrazolone derivatives and, less commonly aspirin, anthranilic-acid derivatives and diclofenac. It has been suggested that NSAIDs may induce pseudoallergic reactions, while in case of bronchial asthma the inhibition of cyclooxigenase by NSAIDs has been proposed as a pathogenetic mechanism.The diagnosis of NSAIDs sensitivity can usually be established by history; in fact skin prick tests with NSAIDs have not been successful and no reliable in vitro tests are available. The only definitive diagnostic test is oral test dosing. To identify an alternative NSAIDs in a sensitive patient a tolerance test is performed. Here we review the current state of knowledge concerning NSAIDs sensitivity, including personal data to increase awareness on this issue.

Tumor cells cannot grow as a mass above 2 to 3 mm3 because diffusion is insufficient for oxygen and glucose requirements, unless the tumor induces a blood supply. This mechanism of induction of a new blood supply from pre-existing vascular bed is called angiogenesis. Furthermore, tumor invasiveness and metastasis require neovascularization. In fact, recent published studies suggest that acquisition of the angiogenic phenotype is a common pathway for tumor progression and neovascularization is linked with other molecular steps leading to tumor progression. Angiogenic process is a complex multi-step cascade under the control of positive and negative soluble factors. A paracrine interaction occurs between tumor and endothelial cells. Angiogenesis involves: endothelial cell proliferation, migration and tubule formation with associated changes in the extra-cellular matrix, allowing subsequent new vessel growth toward the tumor. Each of the above steps may represent a target for antiangiogenic therapy. Antiangiogenesis is to be distinguished from direct targeting and destruction of tumor vasculature (vascular targeting). Inhibition of angiogenesis represents one of the more promising, new approaches, to anticancer treatment and its already in early clinical trials. This review takes into consideration: (i) the biological mechanism underlining angiogenesis process (ii) the method to assess tumor angiogenesis activity (iii) inhibition of angiogenesis as an anticancer therapy (iv) the methodology for the clinical development of angiogenesis inhibitors, that should be considered biological response modifiers (v) some angiogenesis antagonists that are in development and leader compounds that are under clinical trial.

Graves disease is the most common form of hyperthyroidism in childhood. Current treatment options include antithyroid medications, surgery, and radioactive iodine. Medical therapy is generally associated with long term remission rates of less than 25percent and a small risk of serious adverse reactions that include hepatic failure and bone marrow suppression. Total thyroidectomy is associated with very high cure rates and a small risk of hypoparathyroidism and recurrent laryngeal nerve damage. When radioactive iodine is used at appropriate doses, there is a very high cure rate without increased risks of thyroid cancer or genetic damage. Because of the theoretical risk of thyroid cancer after thyroid irradiation in individuals less than 20 years of age, relatively high doses of radioactive iodine should be administered to minimize the persistence of residual thyroid tissue.“After 36 years of observation, it seems clear now that this noninvasive form of treatment [radioactive iodine] is safer and more effective than any present method of managing the patient with moderate or severe hyperthyroidism”. Earle M. Chapman [1].

Resistance to the cellular action of insulin, a fundamental pathophysiological defect accompanying the worldwide epidemic of obesity, is closely associated with the development of type 2 diabetes mellitus and the set of cardiovascular risk factors that Constitute the “metabolic” syndrome. The development of novel pharmaceutical agents that help ameliorate insulin resistance will be potentially important not only for the prevention and treatment of diabetes, but also in reducing its associated cardiovascular risk profile. Studies on the cellular role of the protein-tyrosine phosphatase PTP1B have now clearly shown that it serves as a key negative regulator of the tyrosine phosphorylation cascade integral to the insulin signaling pathway. Genetically-modified mice that lack PTP1B protein expression and animals treated with a specific PTP1B antisense oligonucleotide have provided crucial “proof-of-concept” data to show that eradicating or reducing PTP1B enhances insulin signaling and glucose tolerance. PTP1B inhibition also reduces adipose tissue storage of triglyceride under conditions of over-nutrition and was not associated with any obvious toxicity. The effects of the loss of PTP1B in vivo were also remarkably specific for components of the insulin action cascade, in spite of cellular studies suggesting that PTP1B may exert a regulatory influence on a variety of other signaling pathways. Overall, these studies have paved the way for the commercial development of PTP1B inhibitors that may serve as a novel type of “insulin sensitizer” in the management of type 2 diabetes and the cardiovascular / metabolic syndrome.