Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 11, Issue 1, 2011

Postprandial state is a normal metabolic state throughout the day, due to the fact that the clearance of triglyceride-rich particles, preferably those of intestinal origin, continues for 6-8 hours after each daily meal. In 1979, Zilversmit postulated that atherosclerosis is a postprandial phenomenon. However, only recently the excessive and prolonged metabolic disturbances occurring in the postprandial state have regained interest as a potential cardiovascular risk factor. On the other hand, the molecular mechanisms by which postpandrial lipidaemia and the hyperglycaemia induce vascular damage have been recently described. These mechanisms include endothelial dysfunction, activation of adhesion molecules, activation of coagulation, oxidative stress and gene expression or genetic polymorphisms affecting genes involved in lipoprotein metabolism. Finally, we emphasize the importance of the composition of dietary fat, since it seems that a diet rich in monounsaturated fatty acids protects against the development of insulin resistance and decreases the incidence of type II diabetes mellitus.

The thymus is the central lymphoid structure where T-cell differentiation takes place, and a crucial organ for the maintenance of homeostasis in the immune system. Thymopoiesis includes intrathymic proliferation of T-cell precursors, selection and output of both self-tolerant and competent effector T cells, as well as of natural regulatory T cells (nTreg). In the crosstalk between the neuroendocrine and immune systems, peptide hormones have been more and more implicated in immunomodulation for the last thirty years. The somatotrope growth hormone (GH)/insulin-like growth factor- 1 (IGF-1) axis in particular has been repeatedly shown to play a major regulatory role upon thymus function and T-cell development. This review will focus on the important thymotropic properties of the somatotrope GH/IGF-1 axis, and will try to discriminate these properties in function of the endocrine or paracrine/autocrine pathways involved in their mediation. Most importantly, in light of an increasing number of recent studies, GH and IGF-1 now appear as novel therapeutic agents that could be used for enhancing thymopoiesis in different cases of immune deficiencies, including aging-related immune dysfunction.

Monoclonal antibodies are now major therapeutic agents used to treat many cancers, immunological and other diseases. Two big technological breakthroughs have enabled us to utilize monoclonal antibodies as therapeutic agents; the establishment of monoclonal antibody production technology using hybridomas, and the reduction of immunogenicity by using chimeric, humanized, and fully-human antibodies. These technological improvements have led to the successful launch of more than 25 therapeutic antibodies, such as rituximab, trastuzumab, cetuximab, adalimumab and ustekinumab, which are on the market and contribute to the health of many patients. Despite the clinical success of these antibodies, we have also been faced with demands for improvement of the antibody's therapeutic efficacy as a result of insufficient clinical efficacy seen in many clinical trials. The major mechanisms underlying the therapeutic effects of antibodies are thought to be neutralization of antigen function and/or Fc-mediated functions e.g. antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Among various efforts being made to enhance the intrinsic capacity of therapeutic antibodies, the most promising is Fc engineering, including amino acid mutation, or modification of the Fc-linked oligosaccharide structures to dramatically improve Fc-mediated functions, ADCC, CDC and the FcRnmediated antibody half-life. Some Fc engineered therapeutic antibodies are evaluated in the clinic. This review will focus on the current progress made in the development of Fc engineered antibodies.

Aromatase converts irreversibly androgens into estrogens and is present in the endoplasmic reticulum of various tissues including the mammalian testis. In most of the mammals studied up today, at least in rodents, all testicular cells except peritubular cells express aromatase. Indeed in adult rat germ cells (pachytene spermatocytes and round spermatids) we have demonstrated- the presence of a functional aromatase - and the estrogens output is equivalent to that of Leydig cells. Moreover in the adult rat, transcripts of aromatase vary according to the germ cell type and to the stages of seminiferous epithelium, a maximum being observed at stage I. By contrast with the androgen receptors mainly localized in somatic cells, estrogen receptors (ERs) are described in most of the testicular cells including germ cells. Both estrogen receptors mRNA at levels are higher in purified round spermatids than in pachytene spermatocytes suggesting a putative role of estrogens in the haploid steps of spermatogenesis. Thus, besides the presence of high affinity ERα and/or ERβ, a rapid membrane effect has been recently reported in mouse testis leading to a control of mouse cell proliferation by estradiol. In a recent work we demonstrated that GPR30 (a transmembrane intracellular estrogen receptor) is expressed in adult rat pachytene spermatocytes and that estrogens through both GPR30 and ERα are able to activate the rapid EGFR/ERK/c-jun signaling cascade, which in turn triggers an apoptotic mitochondrial pathway involving an increase in Bax expression and a concomitant reduction of cyclin A1 and B1 gene levels which are involved in the balance between cellular proliferation and apoptosis. As already demonstrated in ArKO mice and from the data collected in ERαKO, estrogens do play an important role in germ cells development and maturation. Thus the role of estrogens (intracrine, autocrine and / or paracrine) in spermatogenesis (proliferation, apoptosis, survival and maturation) and more generally, the male reproduction is now obvious.

Insulin is a circulating peptide hormone that is best known as a critical regulator of glucose levels. It consists of two peptide chains (A and B) that are held together by two disulfide bonds and a third within the A-chain. The first milestone step towards its chemical synthesis was made by Sanger and colleagues who were the first to determine the primary sequence of sheep insulin as well as the precise pairings of the disulfide bonds. However, it was more than ten years before the first total chemical synthesis of bovine insulin was achieved which was via conventional solution phase synthesis of the two individual chains followed by their random combination and folding in solution. Later in that same year, Merrifield applied his newly-developed solid phase peptide synthesis (SPPS) methodology to synthesize bovine insulin within a few days. However the combination of the A- and B-chains invariably led to a low yield of correctly folded peptide. A stepwise disulfide bond formation approach was then introduced by Sieber and co-workers in their complex fragment synthesis of human insulin. In an attempt to overcome the limitations of these approaches, alternative protocols have been subsequently developed, one of which was optimized in our laboratory in which regioselective stepwise formation of the three disulfide bonds is achieved via the use of cysteine S-protecting groups cleaved in different chemical conditions. This review describes the historical course of the advancement of the chemical synthesis of insulin with a particular emphasis on the difficulty and limitations of its assembly.

Adenosine 5'-Triphosphate (ATP) is released from cells acting as an extracellular signaling molecule in an autocrine or paracrine manner. ATP and other nucleotides bind to the plasma membrane P2 family of purinergic receptors resulting in the activation of downstream signaling pathways involved in mitogenesis, differentiation and apoptosis. Thereby, they may have a role in the determination of cell fate. This review focuses on the signal transduction cascades activated by ATP and other nucleotides. In particular, we discuss the mitogen activated protein kinase family (MAPK) and phosphatidyl-inositol 3 kinase (PI3K)/Akt pathways and their involvement in the regulation of cell proliferation, differentiation and apoptosis.

C-peptide, historically considered a biologically inactive peptide, has been shown to exert insulin-independent biological effects on a number of cells proving itself as a bioactive peptide with anti-inflammatory properties. Type 1 diabetes (T1D) patients typically lack physiological levels of insulin and C-peptide. Recombinant insulin administrations, in the absence of C-peptide, correct hyperglycemia but leave an increased risk of developing microvascular complications affecting the small vessels of the eye, the kidneys, and the peripheral nerves. Inflammation is an important factor for the development of diabetes-associated vascular complications, and there is increasing evidence that T1D patients, even at a young age and after short duration of T1D, have circulating activated monocytes and increased plasma levels of inflammatory cytokines. It has been hypothesized that reduced plasma levels or lack of circulating C-peptide might contribute to the development of diabetes-associated vascular complications since C-peptide is able to reduce the inflammatory response associated with T1D. In this review, we present the most-up-to date information on the anti-inflammatory activity of C-peptide at the level of the vascular endothelium exposed to a variety of glucose levels. The anti-inflammatory properties of C-peptide in animal models of endotoxic shock and T1D-associated encephalopathy are also presented. The present evidence favours the view that T1D should be considered a dual-hormone deficiency disorder and emphasizes the possibility that replacement therapy with both insulin and C-peptide in T1D patients may offer an approach to retard or completely prevent the development of diabetes-associated microvascular complications, for which no causal therapy is available today.