Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 12, Issue 4, 2012

Gram negative sepsis remains a high cause of mortality and places a great burden on public health finance in both the developed and developing world. Treatment of sepsis, using antibiotics, is often ineffective since pathology associated with the disease occurs due to dysregulation of the immune system (failure to return to steady state conditions) which continues after the bacteria, which induced the immune response, have been cleared. Immune modulation is therefore a rational approach to the treatment of sepsis but to date no drug has been developed which is highly effective, cheap and completely safe to use. One potential therapeutic agent is VIP, which is a natural peptide and is highly homologous in all vertebrates. In this review we will discuss the effect of VIP on components of the immune system, relevant to gram negative sepsis, and present data from animal models. Furthermore we will hypothesise on how these studies could be improved in future and speculate on the possible different ways in which VIP could be used in clinical medicine.

The pathogenesis of inflammatory bowel syndrome (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC) is poorly understood. However, an inflammatory component is a common hallmark. It has been suggested that CD principally involves Th1 and/or Th17 cells, while UC is considered to be more Th2 driven. Because vasoactive intestinal peptide (VIP) has emerged in the last decade as a putative candidate for the treatment of inflammatory diseases with a Th1 component, it may as well serve as a therapeutic target in CD. In addition, experiments using mice deficient in VIP or its receptors have revealed that the endogenously-produced VIP may participate in the regulation of immunity. The aim of the present review is to summarize the quite considerable array of data which suggests that the VIP-receptor system plays a key role in modulating multiple molecular and cellular players involved in IBD.

A hallmark in most neurological disorders is a massive neuronal cell death, in which uncontrolled immune response is usually involved, leading to neurodegeneration. The vasoactive intestinal peptide (VIP) is a pleiotropic peptide that combines neuroprotective and immunomodulatory actions. Alterations on VIP/VIP receptors in patients with neurodenegerative diseases, together with its involvement in the development of embryonic nervous tissue, and findings found in VIP-deficient mutant mice, have showed the relevance of this endogenous peptide in normal physiology and in pathologic states of the central nervous system (CNS). In this review, we will summarize the role of VIP in normal CNS and in neurological disorders. The studies carried out with this peptide have demonstrated its therapeutic effect and render it as an attractive candidate to be considered in several neurological disorders linked to neuroinflammation or abnormal neural development.

Vasoactive intestinal peptide (VIP) is a well-known immunoregulatory neuropeptide produced by the immune system in response to inflammation, autoimmunity or alloantigens as a natural endogenous mechanism of induction of tolerance. VIP has been proven therapeutically effective in various experimental models of autoimmune disorders and recently in human sarcoidosis. Numerous studies clearly show that VIP exerts its immunomodulatory effects by downregulating both inflammatory and Th1 responses. Recent evidences suggest that new actors enter in scene to play a role in this scenario of tolerance. By inducing antigen-specific regulatory T cells and tolerogenic dendritic cells, VIP seems to reinforce/reinstall immune tolerance, especially under autoimmune conditions. Transplantation is also a condition where VIP-related therapies emerge as promising tools for clinical application. Induction of alloantigen-specific tolerance is critical to achieve organ transplant tolerance and to avoid graft-versus-host responses following allogeneic hematopoietic transplantation. This review will focus on describing the capacity of VIP to induce suppressive/regulatory immune cells and how we can manage this cell-based therapeutic strategy to induce transplant tolerance in subjects free of immunosuppressive drugs.

Vasoactive intestinal peptide (VIP) conveys various physiological effects in the digestive tract, nervous and cardiovascular system, airways, reproductive system, endocrine system, and more. A family of specific membrane bound receptors, termed VPAC1, VPAC2, and PAC1, bind VIP and trigger the effects. Many of them are of clinical interest. To date more than two thousand publications suggest the use of VIP in diseases like asthma, erectile dysfunction, blood pressure regulation, inflammation, endocrinology, tumours, etc. Despite this considerable potential, the peptide is not regularly used in clinical settings. A key problem is the short half life of inhaled or systemically administered VIP due to rapid enzymatic degradation. This shortcomings could be overcome with stable derivates or improved pharmacokinetics. A promising strategy is to use biocompatible and degradable depots, to protect the peptide from early degradation and allow for controlled release. This review focuses on aspects of clinical applications of VIP and the idea to use formulations based on biodegradable particles, to constitute a dispersible VIP-depot. Smart particle systems protect the peptide from early degradation, and assist the sustainable cell targeting with VIP for therapeutic or imaging purposes.

The involvement of both oxidative stress and hyperlipaemia in atherosclerosis development is well established. Oxidative burst is an innate immune response to infection, the latter being associated also with marked changes in lipid and lipoprotein metabolism, aimed to neutralize endotoxin toxic effects. On the other hand, lipid overload may increase lipopolysaccharide circulating levels and oxidative stress. Whilst these changes may be beneficial from the perspective of host defense, if they become chronic, they likely increase the risk of atherosclerosis. In particular, oxidation of lipoproteins, resulting from an imbalance of the pro- and antioxidant equilibrium, is involved in the pathologic process of atherosclerosis, changing cellular functions. Lipid oxidation, induced by leukocytes derived reactive oxygen species, can amplify foam cell formation through oxidized low density lipoproteins LDL (oxLDL) formation and uptake. The main enzymes, operating during oxidative burst, involved in LDL oxidation are NADPH oxidase and myeloperoxidase. In vitro studies have shown that oxLDL are able to induce many proatherogenic processes, including modulation of oxidative burst. OxLDL may also induce maturation of dendritic cells and regulate the shift from classical (M1) to alternative (M2) macrophage activation and from T helper 1 to T helper 2 response, suggesting that these could act as a bridge between innate and adaptative immunity, both involved in plaque development. Understanding the relationship between oxLDL and leukocyte oxidative burst helps to explain the involvement of innate immune responses in the early phases of atherosclerosis. The present review focuses on this interplay.

Changing demographics have made aging and age-related chronic diseases an enormous and growing biomedical and societal challenge. The biological processes of aging may involve a role for the gut microbiota. Aspects of host physiology such as immune homeostasis and energy balance are profoundly influenced by the microbiota. Immune dysregulation characterizes old age and constitutes a major pathomechanism underlying frailty and age-associated chronic diseases. A growing body of literature implicates age-related perturbations in the gut microbial ecology as contributing to a global inflammatory state in the elderly. A better understanding of the nature and determinants of the host-microbe relationship in old age has the potential to translate into strategies that promote healthy aging and extend life span. This review summarizes our current understanding of the configuration of the age-related gut microbiota and its likely role in determining the immune phenotype in the elderly. It also highlights the specific components of the microbiota that can be targeted to modulate the age-related chronic inflammation.

Royal jelly is a food for queen and larvae honeybees. 10-Hydroxy-trans-2-decenoic acid (10H2DA; “royal jelly acid”) is the principal lipid component in royal jelly. Several pharmacological activities of 10H2DA have been reported: anti-tumor, anti-biotic, immunomodulatory, estrogenic and neurogenic. We recently revealed an inhibitory effect of 10H2DA in innate immune signals. Despite appreciable advances in studies on innate immune signals after the identification of Toll-like receptors as innate immune receptors, few studies have reported the effect of 10H2DA on innate immune signals. In this review, we focus on recent advances in the evaluation of the biological activities of 10H2DA (especially immunomodulatory activities). We also discuss the molecular mechanisms underpinning these biological activities, which could lead to new therapeutic targets for the treatment of immune disorders.

Familial Adenomatous Polyposis, Cowden’s Syndrome, and Peutz-Jeghers Syndrome are well known as Intestinal Polyposis Syndromes, inherited conditions characterized by the development of polyps of the gastro-intestinal tract in association with extra-intestinal manifestations, in particular malignant tumors at different sites. Thyroid carcinoma is sometimes a part of the clinical picture of these syndromes. The aim of this paper is to review the literature dealing with the association between differentiated thyroid carcinomas and Intestinal Polyposis Syndromes in order to point out peculiar aspects, providing suggestions for the screening and the management of thyroid tumors in these patients.