Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 9, Issue 1, 2009

Diabetes mellitus (diabetes) is suffered by more than 180 million people and is responsible for approximately 2.9 million deaths each year. This mortality rate is expected to increase by 50 % in the next decade. Due to the inconvenience of the traditional treatment of diabetes by subcutaneous administration of insulin injection, various attempts are made in the production, purification, formulation and methods of delivery of insulin. However, despite advances in recent years, these attempts have met with limited success. Various alternative routes such as rectal, ocular, nasal, pulmonary and oral have been exploited. The pulmonary route offers great potential for the delivery of polypeptide drugs due to the large surface area for insulin absorption in the respiratory tract. But due to its low bioavailability, oral route is intensely investigated for the insulin delivery. Microencapsulation, as one of the delivery systems utilising oral route, has shown some potential progress in insulin delivery; though it is at an early stage yet it has proved to be quite encouraging providing new less toxic immunosuppressive agents. Microencapsulation may prove to be an attractive delivery system for controlled release of insulin and beneficial for therapeutic, bio-efficient and bio-effective drug delivery. In this review we discuss the possible alternative routes for insulin delivery (ocular, nasal, pulmonary and oral) and advantages and disadvantages of each. Furthermore we consider the different drug delivery strategies available (aerosols, dry powder inhalers, synthetic beta cells, hydrogels and microcapsules) and their current and potential applications with respect to the different insulin delivery routes.

Interferon-beta (IFN-β) therapy has a central place in the management of multiple sclerosis (MS). The three recombinant IFN-β preparations currently available have shown benefit on activity measures (relapses and active lesions apparent on magnetic resonance imaging), while therapy advantages on progression measures (disability and total lesion burden) are less consistent. Moreover, IFN-β is effective only in a percentage of patients, since in many of them neutralizing anti-IFN-β antibodies develop after 6-18 months of treatment, leading to loss of drug bioactivity. Comparative data across studies made with different IFN-β preparations suggest that the optimal choice of IFN-β subtype, preparation and dose regimen are important determinants of efficacy. Because IFN-β actions depend on the activation of IFN-inducible genes, in addition to the direct quantification of anti-IFN-β antibodies, several other methods for the measure of IFN-β biologic activity have been recently developed. Among these, the determination of the IFN-β-inducible gene product Myxovirus protein A (MxA) has proven to be the most reliable one. Another still open point is the role of the differential expression of IFN-β receptor (IFNAR) components, since IFNAR2 subunit can be synthesized in three isoforms: functional, truncated non-functional and soluble. While this and other important issues require further studies, this article reviews and discusses the importance, potential and limits of the methods currently available to monitor IFN-β therapy in MS patients.

Women before menopause are at relatively lower risk of cardiovascular disease (CVD) compared with agematched men and after menopause this gender advantage disappears. Androgen has been known to be an independent factor contributing to the higher male susceptibility to CVD, through adverse effects on lipids, blood pressure, and glucose metabolism. High androgen levels also contribute to CVD development in women with polycystic ovary syndrome as well as androgen abusing athletes and body builders. On the other hand, decline in androgen levels, as a result of ageing in men, is associated with hypertension, diabetes and atherosclerosis. Postmenopausal women, particularly those with oophorectomy are generally in low levels of sex hormones and androgen insufficiency is independently associated with the higher incidence of atherosclerosis in postmenopausal women. Androgen testosterone therapy (ATT) has been commonly used to improve well-being and libido in aging men with low androgen levels. The therapy has been demonstrated also to effectively reduce atherogenesis in these people. The use of ATT in postmenopausal women has increased in recent years and to date, however, the cardiovascular benefits of such therapy in these women remain uncertain. This review focuses on research regarding the impact of endogenous androgens and ATT on the cardiovascular physiology and CVD development in postmenopausal women.

Type 2 diabetes is associated with insulin resistance, endothelial dysfunction and accelerated atherosclerotic diseases. Though underlying mechanisms remain to be unraveled, p38 mitogen-activated protein kinase (MAPK) appears to play important roles in their pathogenesis. As a member of the MAPK family, it regulates the activities of many transcription factors and proteins/enzymes and thus has a wide-spectrum of biological effects. Patients with insulin resistance and/or type 2 diabetes have high levels of plasma free fatty acids, inflammatory cytokines, and/or glucose, and overactivation of the cardiovascular renin-angiotensin system, all are capable of activating p38 MAPK. p38 MAPK plays a central role in hepatic glucose and lipid metabolism, leading to increased hepatic glucose production and decreased hepatic lipogenesis. The roles of p38 MAPK in insulin-mediated glucose uptake in skeletal muscle and adipose tissue remain controversial. p38 MAPK also mediates inflammatory processes and cell apoptosis. Recent evidence suggests that p38 MAPK may be the key node linking cardiovascular insulin resistance, endothelial dysfunction and the pathogenesis of atherosclerotic diseases through its influences on monocytes/macrophages, vascular endothelial cells, and vascular smooth muscle cells in type 2 diabetes. In addition, p38 MAPK also contributes significantly to cardiac injury during ischemiareperfusion.

In some mRNA sequences, namely those of formyl peptide receptors and chemokine CXC receptors 4, it has been observed that the second nucleotide (nt) of the coding triplets is significantly more highly conserved than the first nt and the correlation between the conservation indexes of the first two nt is positive and significantly higher than the “basic” correlation usually found between adjacent nt. A theoretical analysis demonstrated that random mutations in the first nt preserve hydrophobicity in 73 % of triplets coding for hydrophobic amino acids (aa) and hydrophilicity in 77 % of triplets coding for hydrophilic aa, while random mutations in the second nt preserve hydrophobicity in 18 % of triplets coding for hydrophobic aa and hydrophilicity in 53 % of triplets coding for hydrophilic aa. When the triplets which had changed their hydropathic aa coding character underwent a second random mutation in the previously unmutated first or second nt, an additional 11 % of the originally hydrophobic-coding triplets reverted to hydrophobicity and an additional 14 % of the originally hydrophilic-coding triplets reverted to hydrophilicity. This analysis provides a rationale for why a higher number of mutations in the second nt are presumably negatively selected and a number of double mutations in the first and second nt presumably are positively selected, in cases when a mutation in one of the two is not reverted.

β-D-glucans belong to a group of natural, physiologically active compounds, generally called biological response modifiers. Glucans represent highly conserved structural components of cell walls in yeast, fungi, or seaweed. Despite long history of research, the exact mechanisms of glucan action remain unsolved. The present review starts with the history of glucans. Next, the detailed information about the possible glucan sources is followed by a description of the mechanisms of action. Physiological functions of glucan suggest the possible use of glucans not only as non-specific immunomodulator, but also as its possible future use as a drug.

Peroxisome proliferator activator-receptor (PPAR)-γ is a ligand-activated transcriptional factor belonging to a steroid receptor superfamily. PPAR-γ plays a role in both adipocyte differentiation and carcinogenesis. Up-date, PPAR-γ is expressed in various cancer tissues, and PPAR-γ ligand induces growth arrest of these cancer cells. In this study, we examined the expression of PPAR-γ in human urological cancer (including renal cell carcinoma, bladder tumor, prostate cancer and testicular cancer) by RT-PCR and immunohistochemistry, and we also examined the effect of PPAR-γ ligand in these cells by MTT assay, flow cytometry and hoechest staining. PPAR-γ expression was significantly more extensive and intense in malignant tissues than in normal tissues. PPAR-γ ligand induced the reduction of malignant cell viability through early apoptosis. These results demonstrated that generated PPAR-γ in urological cancer cells may play an important role in carcinogensis and become a new target therapy in the treatment of urological cancer.

The ‘histone code’ is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular “code” recognised and used by non-histone proteins to regulate specific chromatin functions. One modification which has received significant attention is that of histone acetylation. The enzymes which regulate this modification are described as histone acetyltransferases or HATs, and histone deacetylases or HDACs [1]. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The proinflammatory environment is increasingly being recognised as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential & current development of histone deacetylases for the treatment of diseases for which a proinflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the proinflammatory environment.

No new drugs have been approved for the treatment of systemic lupus erythematosus (SLE) by the Food and Drug Administration for the last 30 years. One barrier has been the lack of validated biomarkers and surrogate endpoints. Validation of SLE biomarkers in the past have been methodologically flawed. We put forth a conceptual framework and five critical criterion for validating putative biomarkers and bio-surrogates in this heterogeneous multi-system disease with protean manifestations. Using the example of a putative biomarker for end-stage lupus nephritis, we performed computer simulations for planning a biomarker bio-repository to support the validation process. “Random time window” sampling where a biomarker is obtained in an interval randomly selected from the total follow-up time for that subject creates survival bias. This can be avoided by the “fixed calendar window” design, in which biomarkers are measured within the same, pre-specified period for all cohort members who remain at risk during that period. In lupus nephritis where the incidence rate of end-stage renal disease is relatively low, to accumulate 300 instances of end-stage renal disease, at risk patients would have to be followed for about 5,000 person-years, implying 500 subjects followed, on average, for about 10 years. Increasing the number of biomarker determinations per subject from one to five reduces the required number of subjects by 10-15%, while further increases in the number of observations per subject yielded much smaller gains. The large numbers of subjects required for a bio-repository, makes it essential to maximize the efficiency of study designs and analyses and provides the strongest rationale for collaboration and the use of standardized measures to ensure comparability.