Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 12, Issue 3, 2012

Bacterial lipopolysaccharide (LPS, endotoxin) is the major constituent of the outer membrane of Gramnegative bacteria. LPS can cause a variety of immune- and cellular disorders that lead to lethal effects and clinical manifestations of infectious diseases. Several molecular and cellular in vitro techniques, besides synthesis of analogous molecules of the LPS active region, have provided insight in the molecular mechanisms of LPS bioactivity in cellular systems. These advances have facilitated the application of diverse LPS–based molecules in relevant areas such as vaccine technology, allergen immunotherapy, treatment of immune-related diseases/disorders, LPS-related inflammatory processes and sepsis. The purpose of this review is to examine the progress in the generation of new LPS-based molecules and their therapeutic potential.

Prepuberal-onset (PRHH) and postpuberal-onset (PSHH) Hypogonadotropic Hypogondism (HH) refer to a heterogeneous group of patients, showing a broad spectrum of clinical signs and symptoms of androgen deficiency in consideration of the different possible aetiologies and the age at onset. These patients, though, required Gonadotropin treatment (GnTh) by means of administration of both the β Human Chorionic Gonodadotropin (β HCG) and the Follicle Stimulating Hormone (FSH) to obtain mature sperms in the ejaculate aiming to reach fertility levels. However, the response to GnTh is always unpredictable concerning either the effectiveness or the duration of the therapy. Consequently, different studies have been carried out to identify clinical (i.e. cryptorchidism, gynecomastia, testis size, etc) and biochemical markers [serum Testosterone (T) and Inhibin B (IB)] that can be useful to predict the effectiveness of GnTh. Given that the actions of T, even those directed at inducing and maintaining spermatogenesis, are mediated by its interaction with the Androgen Receptor (AR), we measured the AR CAG repeat polymorphism in men with HH, in order to examine whether the CAG polymorphism extensions could co-regulate the GnTh effectiveness. Twenty-three HH subjects were subdivided according to the age at onset (pre- and postpubertal) and treated with the same scheme and doses of GnTh, extending the period of treatment up to 30 months. Thirty-five healthy and fertile men served as a control group (CG). Twelve HH subjects (3 PRHH and 9 PSHH), who reached complete spermatogenesis within 12 months, showed the length of AR CAG repeat number [20 (19-23) = median (interquartile range 25th – 75th percentile)] not statistically different from our CG [20 (19-22)], while CAG repeat number [23 (20-25)] of 11 HH patients (9 PRHH and 2 PSHH) who obtained mature sperms in their ejaculate beyond a year to within 30 months, was significantly higher. Our results suggest that the length of AR CAG repeat polymorphism might affect the response to GnTh in men suffering from HH, in particular in those patients with prepubertal-onset hypogonadism.

Endothelial dysfunction is a common feature in type-2 diabetic patients and is associated with inflammation, increased levels of circulating soluble adhesion molecules and atherosclerosis. Insufficiency of tetrahydrobiopterin leads to uncoupling of the nitric oxide synthase enzyme an endothelial dysfunction. The aim of this study: was to evaluate if there is a relationship between the levels of circulating soluble adhesion molecules and the levels of biopterins in normotensive type-2 diabetic patients. Methods: We studied 30 normotensive type-2 diabetic patients in whom VCAM-1, ICAM-1 and E-selectin were measured by ELISA. Additionally, Biopterins were measured by reverse phase high performance liquid chromatography with fluorescence detection. The levels of circulating adhesion molecules and biopterins were correlated using the Spearman correlation coefficient test. Statistical analysis was performed with ANOVA. Results: We did not find any relationship between absolute values of biopterins and soluble adhesion molecules. However, we observed significant inverse correlations between the BH4/BH2 ratio and VCAM-1 (r= -0.65, p<0.001) with ICAM-1 (r= -0.69, p< 0.001) and with E-selectin (r=-0.64 p<0.001), Conclusion: Our data suggest that systemic levels of adhesion molecules have an inverse association with the BH4/BH2 ratio in type 2 diabetic normotensive patients.

Cancer cachexia is a highly debilitating paraneoplastic disease observed in more than 50% of patients with advanced cancers and directly contributes to 20% of cancer deaths. Skeletal muscle wasting is a prominent feature of the disease and is believed to result from the loss of balance between protein synthesis and degradation. Quality of life and prognosis are severely compromised in patients with cancer cachexia. Despite current knowledge on the mediators involved in cancer cachexia, treatment targeting a single molecule has rendered limited effectiveness. This article aims to review the mediators of cancer cachexia and interventions attempted in the literature and discuss the common pathways leading to protein loss that these mediators modulate during cachexia. We believe that by targeting downstream effectors that are common in these pathways, a better therapeutic approach to reverse muscle wasting and maintain muscle function during cancer cachexia will be achieved.

While overt hypothyroidism is associated with reversible dementia in the elderly, the relationship of subclinical hypothyroidism with cognition remains a controversial issue. Our aim was to investigate the correlation between subclinical hypothyroidism and cognition in the elderly, with particular reference to long term memory and selective attention. We selected 337 outpatients (177 men and 160 women), mean age 74.3 years, excluding the subjects with thyroid dysfunction and those treated with drugs influencing thyroid function. The score of Mini Mental State Examination (MMSE) was significantly lower in the group of patients with subclinical hypothyroidism than in euthyroid subjects (p <0.03). It was observed that patients with subclinical hypothyroidism had a probability about 2 times greater (RR = 2.028, p <0.05) of developing cognitive impairment. Prose Memory Test (PMT) score resulted significantly lower in subjects with subclinical hypothyroidism (p<0.04). Considering the Matrix Test (MT) score, the performance was slightly reduced in subclinical hypothyroidism (NS). Furthermore, TSH was negatively correlated with MMSE (p<0.04), PMT (p<0.05) and MT score (NS). No correlation was found between FT4 and FT3 and MMSE, PMT and MT score. In the elderly, subclinical hypothyroidism is associated with cognitive impairment, and its impact on specific aspects of cognition (long term memory and selective attention) is less evident.

Botulinum neurotoxins (BoNTs) are used in the treatment of many neurological disorders. The primary structure of BoNTs shows a high degree of homology with the tetanus neurotoxin, the toxoid of which is used as a vaccine. Because of the potential cross-reactivity between these toxins, we investigated the effects of Botulinum neurotoxin A (BoNT/A) and tetanus toxoid on peripheral blood mononuclear cells (PBMC) and the corresponding serum antibody levels, in twenty patients who had been treated with BoNT/A. We observed very low PBMC immunostimulation by BoNT/A at the tested dose (15 units/ml), as demonstrated by the low lymphocyte proliferation, and the absence of detectable antibodies cross-reacting with tetanus. However, exposure of PBMC from tetanus-sensitized patients to both neurotoxins showed that BoNT/A exerted a co stimulatory effect on tetanus-stimulated cells. Interestingly, in flow cytometry analysis, BoNT/A seemed to also alter the ratio of naïve (CD45RA) : memory/effector (CD45RO) T lymphocyte subsets, in favour of CD45RO. These preliminary data give a new insight on the potential immune crossreactivity between the two antigens. In view of the wide use of both neurotoxins, these immunotoxic effects merit a more detailed investigation.

Alzheimer's disease (AD) has been traditionally conceptualized as a clinicopathological entity, its definite diagnosis requiring the presence of characteristic pathology together with a dementia clinical picture. The fact that certain AD biomarkers show an acceptable sensitivity and specificity to detect AD pathology has shifted the diagnostic paradigm towards a clinicobiological approach. Neuropathological analysis of AD-affected brains reveals extensive atrophy due to neuronal loss, and accumulation of neurofibrillary tangles and neuritic plaques, surrounded by a tract of neuroinflammation and loss of neurons. Recently, emerging evidence supports the concept that AD is also a disorder of metabolic degeneration. Taken together, the neurochemical changes in the brain from patients with AD indicate multiple disturbances and it seems likely that the changes are secondary to more fundamental changes into the brain. There is a physiological decline of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis with ageing and the possibility that the GH/ IGF-I axis is involved in cognitive deficits has been recognized for several years. The IGF-I is a potent neurotrophic as well neuroprotective factor found in the brain with a wide range of actions in both central and peripheral nervous system. IGF-I is a critical promoter of brain development and neuronal survival and plays a role in neuronal rescue during degenerative diseases. The investigations of GH releasing stimulation tests especially to GHRH in AD are equivocal and in some cases contradictory. When a cholinesterase inhibitor as rivastigmine, a drug for AD, is acutely administered the area under the curve of the GH response to GHRH doubled, showing that rivastigmine is a powerful drug to enhance GH release. Starting with a more accurate diagnosis not of the clinical syndrome, but of underlying molecular defects, that may eventually lead to a personalized, more effective treatment. Hence, the development of novel therapeutic approaches is urgently needed.

Psoriasis is a genetic predisposition with T-cell mediated autoimmune inflammatory skin disorder, characterized by cutaneous inflammation, increased epidermal proliferation, hyperkeratosis, angiogenesis, and abnormal keratinization that affects up to 2 – 3% of the population worldwide. Common therapies that are used for the treatment of psoriasis include topical, systemic, phototherapy, combination, herbal therapy and novel molecules. Topically used agents include Vit D, calcipotriol, corticosteroids, dithranol and retinoids etc. Systemically used agents include methotrexate and cyclosporine etc. Phototherapy includes UV-B, Psoralen plus ultraviolet therapy and excimer laser etc. These therapies have a number of potential problems, such as limited in efficacy, inconvenience, organ toxicity, carcinogenic and broadband immunosuppression. In natural treatment a variety of natural agents such as methanolic extracts of duzhong (Eucommia ulmoides Oliv.), yerba mate (Ilex paraguariensis,) linseed oil, fish oil, and Indigo naturalis etc., that modulates T cell and cytokine action at various steps along with the pathogenic sequence have been developed. But till now there is no more in vivo, dose and its efficacy data has been established. Current therapy includes biologicals, small molecules inhibitor and enzyme inhibitors etc, which serve as novel therapeutic options for psoriasis treatment. All these avoid the side effects of the prebiologically developed systemic agents including hepatotoxicity, nephrotoxicity, and bone marrow suppression. Currently, Denilukin diftitox, Efalizumab, Alefacept, Ustekinumab and Etanercept are approved by the FDA, and others molecules are at clinical stage. Patents issued by the US office are also included in current psoriasis treatment scenario. In the United States, biologicals are widely used for moderate-to-severe psoriasis. But because of the high cost of medication and their availability in injection form, it remains to be seen how widely these agents will be utilized worldwide. Still, developing countries prefer conventional drugs.