Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 11, Issue 1, 2011

Pediatric pain management underwent many changes since the undertreatment of pain in children was reported in the literature in 1980. Increasing data also suggest that long-term behavioural effects can be observed in children, following pain episodes as early as in the neonatal period. Therefore, the knowledge about safe and effective management of pain in children should be applied with greater effectiveness into clinical practice. Other advances in the field include the findings of long-term residual behavioural and metabolic effects induced by pain experienced during the critical periods of development in laboratory animals. Recent data in laboratory animals and clinical data in children suggest that early repeated and/or severe pain and other stressful procedures applied in the perinatal periods may produce not only behavioral, but also important hormonal, immune and metabolic long-term effects. In this paper we shall report data on some metabolic conditions described in adult humans following disruption of hormonal-metabolic programming produced in the peri-natal period. Quite similar signs can be found between animal models and human conditions, most of them being connected with hypothalamus-pituitary-adrenal hormones (HPA) dysfunction. In addition, some signs in animal models, such as overweight and abdominal overweight are prevented by treatment with the μ- and δ-opioid receptor antagonist naloxone during the lactating period. This indicates that some long-term consequences following stress received during the early phases of life in mammals may be bound to the HPA system dysregulation, whereas others are bound to different (e,g., opioid) endogenous brain receptors and/or neuromediators alteration.

Cystic Fibrosis (CF), the most common autosomal lethal disorder in Caucasians, is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although CF is multi-organ disease, the lung pathology is the chief cause of morbidity and mortality of CF patients. The hallmarks of CF lung disease are respiratory infection by opportunistic pathogens and a deranged inflammatory response. However, clinical and experimental data suggest that CF is a hyperinflammatory disorder which can arise in the absence of infection. Laboratory and animal studies suggest that CFTR is involved in regulating some neutrophil and macrophage functions and indicate that altered properties of immune cells may contribute to the dysregulated inflammation in the CF lung. Moreover, recent investigations point out to the involvement of lymphocyte subpopulations in the onset of an altered immune response to pathogens. The development of novel therapies aimed to reduce the inflammatory and regulate immune responses, including stem cell-based treatment, will be presented.

Obesity and type 2 diabetes (T2D) are global problems affecting all age groups and have been characterized as lifestyle disorders. Though no study has clearly proved a direct correlation between obesity and T2D, a number of factors are associated with obesity causing insulin resistance and T2D. The factors such as adipokines and various transcription factors help to maintain a proper metabolic state in the body. Deregulation in any of these signalling balances due to obesity may trigger an inflammatory cascade which could lead to the aforesaid problems of insulin resistance and T2D. In this review, we have discussed the factors that probably link inflammation to obesity-induced insulin resistance and subsequently T2D and the possible therapeutic opportunities to decrease health risk of T2D in future.

Small degradation products of proteins can have regulatory powers in biological systems. We have studied the role of selected oligopeptides derived from the pregnancy hormone human chorionic gonadotropin (hCG) in several (patho)physiological systems. The employed oligopeptides (3 up to 7 amino acids) were designed according to the known nick sites in ‘loop-2’ of β-hCG. These oligopeptides can inhibit severe inflammation, the onset of type I diabetes, renal failure and tumorigenesis. One of the oligopeptides (AQGV) appeared capable of accelerating recuperation after lethal radiation of mice, thereby reducing the number of deaths among the irradiated mice. This particular oligopeptide has already been successfully tested in human Phase I and IIa studies. Regulating oligopeptides are not only released as a specific subset by degradation of the pregnancy hormone hCG, but also during the degradation of other body proteins and possibly also by transcription of so-called ‘non-coding’ mRNA. Based on a system's biology approach we designed a series of oligopeptides with particular physico-chemical properties based on the primary structure of β-catenin and C-reactive protein (CRP). Several of the designed oligopeptides were able to inhibit vital genes involved in cell division in a plant model. We call such oligopeptides with regulating activity ‘peptide- i’ peptides, referring to their ability to interfere with the expression of particular genes, and thus with the expression of the related biological activities. The fact that the selected oligopeptides can inhibit the multiplication of plant cells suggests that these peptides, through evolution, are part of a hitherto unknown conserved regulatory system. Based on the data presented we foresee the development of many new regulatory oligopeptide-based pharmaceuticals, which could be a serious option for addressing new therapeutic challenges.

The Transient Receptor Potential (TRP) channels family consists of seven different subfamilies, namely TRPC (Canonical), TRPV (Vanilloid), TRPM (Melastatin), TRPML (Mucolipin), TRPP (Polycystin), and TRPA (Ankyrin transmembrane protein) and TRPN (NomPC-like) that are related to several physiological and pathological processes. Recent years have witnessed an increased interest of research into the connection between TRP channels and cancer, leading to the discovery of tumor-related functions such as regulation of proliferation, differentiation, apoptotis, angiogenesis, migration and invasion during cancer progression. Among the TRP families, TRPCs, TRPMs and TRPVs are mainly related to malignant growth and progression. Depending on the type and stage of the cancer, regulation of TRPs mRNA and protein expression have been reported; these changes may regulate ion-dependent cell proliferaton and resistance of cancer cells to apoptotic-induced cell death with consequent cancer promoting effects and resistance to chemotherapic treatments. Considerable efforts have been made to fight cancer cells and targeted therapy seems to be the most promising strategy: in this regard, ion channels belonging to the TRP channel superfamily could play an important role. Aim of this review is to summarize data reported so far on the expression and the functional role of TRP channels during cancer growth and progression, and the relationship with clinico-pathological markers. Moreover, the feasibility of TRP channels as target of chemotherapy and the different approaches by which these channels can be targeted will be analyzed in detail. Deeper investigations are required to understand the role TRP channels in cancer in order to develop further knowledge of TRP proteins as valuable diagnostic and/or prognostic markers, as well as targets for pharmaceutical intervention and targeting.

The innate immune system plays an important role systemically and locally in infectious and inflammatory diseases. Vaccines, vaccine adjuvants and anti-inflammatory drugs were developed by understanding mechanisms of the innate immune system and causative factors of infection and inflammatory diseases. Pattern-recognition receptors, such as Toll-like receptors, retinoic acid-inducible gene I (RIG-I)-like helicases and nucleotide-binding oligomerization domain (NOD)-like receptors, and their downstream signals have great potential as targets of therapeutics because they are involved in numerous diseases. Furthermore, proteolytic systems such as autophagy and immunoproteasomes play important roles in the innate immune system, making them potential therapeutic targets also. By taking advantage of the immune system, humankind has made a great effort to develop new therapeutic and preventive medicines. Accordingly, we have reported several studies on the development of vaccines and adjuvants based on novel mechanistic strategies. Additionally, we have elucidated the mechanism underlying an interaction between innate immunity and the endocrine system. This review introduces the possible use of innate immune molecules for the development of immunomodulatory drugs and the involvement of the immune system in endocrine metabolic diseases to discuss future applications of innate immune molecules to therapeutics of various inflammatory diseases.

Human leukocyte antigen G (HLA-G) is a non-classic major histocompatibility complex (MHC) class I molecule that functions as an immune suppressive molecule. HLA-G has direct inhibitory effects on natural killer cells (NK), dendritic cells (DC), T cells and has long-term tolerogenic indirect effects by inducing regulator T cells (Treg). HLA-G has been reported to be involved in various physio-pathological conditions such as reproduction, transplantation, autoimmunity, infectious and malignant diseases. In this context, aberrant expression of HLA-G in malignant diseases including hematological and solid tumors has been extensively investigated and its relevance to clinicoparameters and potential significance in diagnosis, prognosis and immune target therapy has been postulated. We here summarized the HLA-G expression in malignancies and emphasis its clinical relevance to malignant disease diagnosis, prognosis, and its potential in target-based immunotherapy was also discussed.