Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 13, Issue 2, 2013

Introduction: Hypocalcemia is a common and poorly understood finding in critically ill patients. The current study was designed to assess the association of ionized calcium, vitamin D, phosphorus and Parathyroid hormone levels in a cohort of patients with and without kidney dysfunction admitted for sepsis or non-infectious causes. Methods: Prospective cohort clinical and biochemical study. Results: We confirmed that hypocalcemia and hypovitaminosis D are a common finding in critically ill patients. Parathyroid hormone levels significantly rise in septic shock. In the recovery phase, however, despite persistent hypocalcemia, Parathyroid hormone levels abruptly decrease in patients with kidney dysfunction, but not in patients with normal renal function. Conclusions: The systemic inflammatory response syndrome probably leads to inappropriately high Parathyroid hormone levels during septic shock. In the recovery phase, Parathyroid hormone levels decrease, but calcium levels remain low, displaying evidence that the parathyroid is not responding as expected. Since Parathyroid hormone receptors and calcium-sensing receptors have been described in immune cells and other cell types, we propose that these effects may have a plethora of other deleterious effects, with important implications to the pathogenesis of septic shock.

The objective of this study was to determine, in a female swine model of leptin resistance (Iberian pig), the effect of an obesogenic diet, with high saturated fat content, during the juvenile period, on the appearance of early obesity and its possible effects on metabolic syndrome-related parameters and reproductive features (puberty attainment). Thus, from 130 to 245 days-old, seven Iberian gilts had ad libitum access to food enriched with saturated fat whilst six females acted as controls and had ad libitum access to a commercial maintenance diet. Results showed that a high fat intake-level during the juvenile period induces early obesity with lower body weight and size but a higher body fat-content. Such obesity was related with impairments of glucose regulation predisposing for insulin resistance, but also with an earlier onset of puberty. However, there were no signs of hypertriglyceridemia and hypertension; the gilts diminish their intake level and modify their metabolic features by increasing insulin secretion. In conclusion, Iberian gilts freely eating saturated fat diets during the juvenile period have the prodrome of metabolic syndrome but, during their juvenile period, are still able to develop an adaptive response to the diet.

The present study has been designed to investigate the combined effect of daidzein (caveolin inhibitor), hemin (hemoxygenase activator) and BMS182874 (endothelin receptor antagonist) in diabetic nephropathy in wistar rats. Diabetic nephropathy was induced by administering single dose of streptozotocin in wistar rats. DN was clinically assessed by the estimation of various biochemical parameters and histopathological studies of renal tissue. DN was assessed by measuring serum creatinine, blood urea nitrogen, proteinuria, renal cortical collagen content, lipid profile, serum nitrite/nitrate ratio, renal TBARS and reduced glutathione levels. The combination of daidzein, hemin and BMS182874 showed significant improvement in (BUN, serum creatinine, proteinuria, urinary output, kidney weight/ body weight, renal cortical collagen content, nitrite/ nitrate level, renal TBARS, reduced glutathione) renal parameters studied for DN in comparison with single drug administration as well as a combination of two drugs. L-NAME (NG-nitro- L-arginine methyl ester) a selective eNOS inhibitor abolished the ameliorative effect of combination of daidzein, hemin and BMS182874 in DN in rats. It may therefore be concluded that Daidzein in combination with hemin may enhance the level of renal nitric oxide by decreasing the expression of caveolin. BMS182874 shows renoprotection by inhibiting RAAS system and through reactivation of NO synthesis. These findings may provide mechanistic insights to explain renoprotective effect of this combined therapy in diabetes.

Introduction: Cytokines play a crucial role in the pathogenesis of autoimmune thyroid disease, and recent studies have demonstrated an association between cytokine gene polymorphisms and Graves’ Disease (GD) in different ethnic groups. The aim of the present study was to investigate the relationship of interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), and interferon-gamma (INF-γ) gene polymorphisms in the development of GD in Turkish population. Material and Methods: A total of 224 subjects were included in the study comprising of 100 patients with GD (70 female, 30 male; mean age, 43.9 ±13.8 years) and 124 healthy subjects (81 female, 43 male); mean age, 37.8 ±10.2 years) without antithyroid autoantibodies or family history of autoimmune disorders. Genotyping was conducted by using PCR and sequence-specific primers. Results: Statistical analysis showed a significant association between high TNF-α -308GA and IL-6 -174CC gene polymorphisms in patients with GD compared to control subjects (p=0.016, p=0.044, respectively). However, no significant differences were observed between GD and control subjects for IL-10, TGF-β, and INF-γ gene polymorphisms. Conclusion: TNF-α-308GA and IL-6 -174CC gene polymorphisms are involved in susceptibility to GD in Turkish population. The polymorphism hypothesis in pro-inflammatory cytokines might be involved in predisposition to GD.

The skeleton is constantly being remodelled through the simultaneous resorption of bone and formation of new bone. Significant effects on bone metabolism are produced due to cancer treatment especially of breast and prostate origin, even in the absence of bone metastases. These pathological changes are known as cancer treatment-induced bone loss. Bone mass loss and osteoporosis may cause an increased risk of fractures due to a reduction in bone volume and microarchitectural deterioration. On the other hand, the skeleton is both the most common organ affected by metastatic cancer and the site that produces the greatest morbidity for patients. Recent advances in our understanding of bone biology and the pathways by which cancer metastasizes and spreads to bone have contributed to the development of several important new drugs targeting these processes. This article summarizes our current knowledge and recommendations to advanced biology of metastasis, focusing on breast and prostate cancer.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear transcription factor which is involved in the differentiation of fibroblasts to adipocytes in vitro. PPAR-γ also plays a pivotal role in inflammation and macrophage activation. Furthermore, type 2 diabetes mellitus (T2DM), a condition in which an individual’s ability to respond to insulin is lowered, is treated by drugs called thiazolidinediones (TZDs) that are known to activated PPAR-γ, thus augmenting insulin signaling and glucose uptake by adipose tissue. Unfortunately, these otherwise effective drugs are responsible for side effects such as obesity and cardiovascular diseases. The ligand-binding ability of PPAR-γ is different from other nuclear receptors since it can bind to a wide variety of ligands. Although a number of compounds have been shown to activate PPAR-γ, knowledge of its endogenous ligands and their physiological functions is lacking. The known ligands were either ambiguous or found to produce ill effects in vivo. In this review we discuss the structure and functions of PPAR-γ, ligands discovered so far, and focus on the importance of identification of physiologically relevant endogenous ligands.

CD4+ T-cells are central players orchestrating antigen-specific immunity and tolerance. Importantly, dendritic cells (DCs) are responsible for priming T-cells and for promoting their differentiation from naive T-cells into appropriate functional cells. Because of their fundamental roles in controlling immunity, activation and differentiation of DCs and CD4+ T-cells require tight regulatory mechanisms. Several studies have shown that dopamine, not only mediates interactions into the nervous system, but it can also contribute to the modulation of immunity. Here, we review the emerging role of this neurotransmitter as a regulator of DCs and CD4+ T-cells physiology and its consequent involvement, in the regulation of immune response. We specially focus the analysis in the role of dopamine receptor D5 expressed on DCs and CD4+ T-cells in the modulation of immunity. We also discuss how alterations in the dopamine-mediated regulation of immunity could contribute to the onset and development of immune-related disorders.

Aims: Lactic acid bacteria (LAB) are known to have antitumoral properties, although the intrinsic mechanisms responsible for the execution of this activity are poorly understood. Here, we investigated the ability of concentrated supernatants from Lactobacillus plantarum to promote cell death in a human promyelocytic cell line. Methods and Results: We aim to test the hypothesis that concentrated supernatants from Lact. plantarum at 5, 50 or 100 μg/ml for 24 h exert cytotoxic effects on HL-60 cells. Accumulation of reactive oxygen species (ROS) was diminished and nuclear staining with Hoechst 33342 and propidium iodide (PI) determined a necrotic induction in a concentrationdependent sequence. Concentrated supernatants did not modify or reduced the activity of caspase-3. The assessment of phosphatidylserine externalization by annexin V/PI double staining led to a necrotic state, but the treatment did not produce a dissipation of mitochondrial membrane potential (ΔΨm), whereas cell cycle analysis revealed that concentrated supernatants failed to significantly enhance the population of HL-60 cells in the hypodiploid (sub-G1) fraction. Conclusions: Concentrated supernatants from Lact. plantarum are capable of inducing necrosis rather than apoptosis at high doses in a promyelocytic cell line. Significance and Impact of the Study: Here, we demonstrate the cytotoxic properties of concentrated supernatants from Lact. plantarum on a tumor cell line, and then, to open the possibility to analyze the chemical composition to elucidate the bioactive molecules.

It is known that in severe acquired brain injuries there is process of neuroinflammation, with the activation of a local and general stress response. In our study we considered six patients with disorders of consciousness (five in vegetative state and one in minimal consciousness state) in subacute phase, which had both a clinical assessment and a functional imaging (fMRI): in all these patients we analised blood levels of osteopontin (OPN), a cytokin involved in neuroinflammation but also in neurorepair with a still discussed role. Besides we studied the lymphocyte subsets and blood levels of some hormones (ADH, ACTH, PRL, GH, TSH, fT3, fT4). We found a positive correlation between the levels of serum osteopontin (higher than normal in all subjects) and the severity of the brain injury, especially for prognosis: actually, the patient with the lowest level has emerged from minimal consciousness state, while the one with the highest level has died a few days after the evaluation. The lymphocyte subset was altered, with a general increase of CD4+/CD3+ ratio, but without a so strict correlation with clinical severity; the only hormone with a significant increase in the worse patients was prolactin. In fMRI we detected some responses to visual and acoustic stimuli also in vegetative states, which had no clinical response to this kind of stimulation but generally have had a better prognosis. So we conclude that osteopontin could be a good marker of neuroinflammation and relate to a worse prognosis of brain injuries; the lymphocyte alterations in these disorders are not clear, but we suspect an unbalance of CD4 towards Th2; PRL is the best endocrinological marker of brain injury severity; fMRI surely plays an important role in the detection of subclinical responses and in prognostic stratification, that is still to define with more studies and statistical analysis.