Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) - Volume 14, Issue 2, 2014

We have shown that the 1,25D3-MARRS receptor is necessary for the rapid, pre-genomic effects of 1,25(OH)2D3 on phosphate and/or calcium absorption in chick intestines. However, a clear understanding of the proteins involved in the signaling mechanisms by which the 1,25D3-MARRS receptor facilitates 1,25(OH)2D3-mediated phosphate or calcium uptake, as well as other cellular effects, is still under investigation. We used co-immunoprecipitation studies and mass spectroscopy to identify actin and keratin as proteins that interact with the 1,25D3-MARRS receptor. Using confocal microscopy, we visualized 1,25(OH)2D3- MARRS receptor localizations relative to actin and/or keratin distribution in chick enterocytes. Cells cultured in media containing phenol red had the 1,25D3-MARRS receptor and actin localized largely in the nucleus, which was dispersed upon addition of (OH)2 1,25(OH)2D3. In the absence of phenol red, staining was cytoplasmic. Addition of steroid caused diminished staining at 10 s and 30 s, with a return of intensity between 1 and 5 min. Nuclear staining was observed after 1 min. We found that F-actin concentrations are maximal when 1,25D3-MARRS receptor localizations within enterocytes are low suggesting that cyclical conversions of F-actin to G-actin are involved in the 1,25(OH)2D3-mediated redistribution of the 1,25D3-MARRS receptor within the cell. We also found that keratin distribution remains constant with 1,25(OH)2D3 exposure when Factin depolymerizes into G-actin, which suggests that actin and keratin work in concert to facilitate hormonemediated redistribution of the 1,25D3-MARRS receptor. We subsequently investigated whether the cyclical redistribution was related to either 1,25(OH)2D3-stimulated phosphate or calcium uptake, but no congruent pattern was found.

Leprosy, caused by Mycobacterium leprae is a granulomatous disease of the peripheral nervous system, causing permanent damage to the nerves, skin and limbs. It mainly affects the people living below the poverty. The current immunization strategies against leprosy like the BCG vaccine face several limitations and thus there is a need for an effective counter measure. The main aim was to design a vaccine with a genetically modified strain of the non-pathogenic Mycobacterium smegmatis which over-expressed the immunedominant protein that would induce a strong, non-toxic cell-mediated immune response, and the production of memory cells would lead to successful immunization against leprosy.

Research performed during the last decades clearly demonstrated that the endocytic pathways act as a fine spatio-temporal regulator of the cell signaling. It is now accepted that the principal sorting signal for most of the endocytic cargos is the post-translational modification with ubiquitin (Ub). Indeed, nonproteolytic ubiquitination of the cargo protein (e.g., monoubiquitination) triggers its internalization and its incorporation into specific endocytic vesicles through which cargo is destined either to lysosomes for degradation, to plasma membrane for recycling or to other intracellular fates. Thus, cargo ubiquitination and intracellular trafficking are intrinsically connected and contribute to the regulation of many cellular functions. The nuclear receptor estrogen receptor α (ERα) regulates the physiological effects triggered by 17β-estradiol (E2). It is now clear that the ERα drives the nuclear (gene transcription) and extra-nuclear (activation of signaling kinase cascades) E2-dependent effects because it has a wide intracellular localization both in the nucleus, in the cytoplasm and at the plasma membrane of the E2 target cells. Remarkably, many laboratories, including our own, have reported that ERα is monoubiquitinated and receptor monoubiquitination is required for the receptor- dependent regulation of E2 cellular effects and that an endocytic intracellular trafficking of the ERα can occur. Thus, this evidence suggests the possibility of a Ub-based endo-membrane shuttling of the activated ERα for the regulation of the E2-triggered effects. In light of these novel discoveries, this review will focus on the role of the endocytic trafficking pathways in E2:ERα signaling by particularly highlighting how endocytic proteins and non-degradative ubiquitination could impact on the modulation of E2-dependent physiological processes.

17β-estradiol (E2) plays a crucial role in the maintenance of body homeostasis including the balance between cell survival and apoptosis. Intriguingly, estrogen receptor subtypes (i.e., ERα and ERβ) trigger opposite pathways which drive E2 target cells to proliferation (via ERα) or apoptosis (via ERβ). Recently, we identified neuroglobin (NGB) as an E2 inducible heme-protein involved in hormone regulation of cell proliferation and apoptosis in neuronal and non-neuronal cell lines. In particular, E2 increases NGB protein level mainly in the mitochondria preventing the release of cytochrome c after an oxidative stress injury. Here, the mechanisms underlying E2-induced NGB up-regulation, the involvement of signal transduction pathways and of specific ER subtypes will be discussed in order to propose a possible new E2-dependent scenario at the root of cell survival and cell death balance.

Oral appliance (OA) is known to be beneficial to improve the severity of obstructive sleep apnea. However, its effect on sleep quality in patients with OSA has to be elucidated. Ten patients with OSA underwent two polysomnography (PSG) sessions, one without OA and another with OA. We found that OAattendant sleep was associated with decreased stage 1 sleep (N1), increased stage 2 sleep (N2), and decreased arousal index compared to the non-OA condition. We concluded that sleeping with the OA is beneficial to sleep quality.

Iron deficiency anemia (IDA) is the commonest nutritional problem responsible for 50% cases of anemia worldwide. An extensively searched literature revealed that Iron deficiency anemia is found to be the most common nutritional disorder among Pakistani population. Early Identification of IDA and administering the appropriate therapy are of paramount importance in its management. The study is aimed to determine the serum hepcidin level in IDA patients and its correlation with serum ferritin, iron and hemoglobin. Methods: This was a pilot study including 25 patients of Iron deficiency anemia (IDA). Patients were enrolled from Life Line medical and Diagnostic Centre from May 2014 to August 2014. All patients of age > 13 years with given written consent were enrolled. Complete blood count and Iron profile/ studies were conducted. Out of twenty five patients with iron deficiency anemia, 14 patients (56%) were female while 11(44%) were male. The mean hemoglobin concentration was 8.544 ± 1.54 g/dL, serum ferritin was 9.09±1.35 ng/dL and serum iron was 27.2±6.78μg/dL. The mean serum hepcidin level of patients was 13.2± 1.03ng/ml. Three iron deficiency parameters were correlated with serum hepcidin level. Serum ferritin had technically weak positive correlation with serum hepcidin (r = 0. 021, determination coefficient R= 0.048). Serum iron also had weak positive correlation with serum hepcidin (r = 0. 25, determination coefficient R= 0.066). Serum iron also had weak positive correlation with serum hepcidin (r = 0. 25, determination coefficient R= 0.066). Hemoglobin had a negative correlation with serum hepcidin (r = -0.06, determination coefficient R= 0.004). This pilot study showed weak positive correlation between serum hepcidin with serum iron and serum ferritin level in patients with iron deficiency anemia. Study further showed negative correlation between hemoglobin levels with serum hepcidin. Further large scale studies are required to confirm this correlation along with determination of serum hepcidin as a diagnostic marker for iron deficiency anemia.

Objective: The study aimed to verify that ingestion of multiple dietary supplement containing lutein, astaxanthin, cyanidin-3-glucoside and docosahexaenoic acid (DHA) would improve accommodative ability of aged and older subjects who were aware of eye strain on a daily basis. Methods: A randomized double-blind placebo-controlled parallel group comparison study was conducted for 48 participants aged 45 to 64 years who complained of eye strain. The subjects took multiple dietary supplement containing 10 mg of lutein, 20 mg of bilberry extract and 26.5 mg of black soybean hull extract (a total of 2.3 mg of cyanidin-3-glucoside in both extracts), 4 mg of astaxanthin, and 50 mg of DHA (test supplement) or placebo for four consecutive weeks. Near-point accommodation (NPA) and subjective symptoms were evaluated both before and after four weeks’ intake. Results: The variation of the NPA of both eyes from baseline to 4 weeks’ post-intake in the test supplement group was significantly higher than in the placebo group (1.321±0.394 diopter (D) in the test supplement group and 0.108±0.336 D in the placebo group, p=0.023). The multiple dietary supplement group showed improvement in the NPA. Regarding subjective symptoms, significant improvement of “stiff shoulders or neck” and “blurred vision” was also found in the test supplement group compared to the placebo group (p<0.05). There were no safety concerns in this study. Conclusion: This study shows that multiple dietary supplement containing lutein, astaxanthin, cyanidin-3- glucoside, and DHA has effect to improve accommodative ability and subjective symptoms related to eye fatigue.