Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 19, Issue 2, 2019

Background and objective: Klinefelter Syndrome (KS) is the most common sex chromosome aneuploidy (47, XXY) and cause of male hypergonadotropic hypogonadism. It is characterized by an extreme clinical heterogeneity in presentation, including infertility, hypogonadism, language delay, metabolic comorbidities, and neurocognitive and psychiatric disorders. Since testosterone is known to have organizational, neurotrophic and neuroprotective effects on brain, the condition of primary hypogonadism could play a role. Moreover, given that KS subjects have an additional X, genes on the extra-chromosome could also exert a significant impact. The aim of this narrative review is to analyze the available literature on the relationship between KS and neuropsychiatric disorders. Methods: To extend to the best of published literature on the topic, appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined. Results: Both morphological and functional studies focusing on the brain showed that there were important differences in brain structure of KS subjects. Different psychiatric disorders such as Schizophrenia, autism, attention deficit hyperactivity disorder, depression and anxiety were frequently reported in KS patients according to a broad spectrum of phenotypes. T supplementation (TRT) was not able to improve the psychotic disorders in KS men with or without overt hypogonadism. Conclusion: Although the risk of psychosis, depression and autism is increased in subjects with KS, no definitive evidence has been found in studies aiming at identifying the relationship between aneuploidy, T deficit and the risk of psychiatric and cognitive disorders in subjects affected by KS.

Background and Objective: Coeliac disease (CD) is a chronic autoimmune intestinal disorder characterized by intolerance to gluten, a protein contained in certain cereals. The main physiopathological basis of CD is the progressive destruction of intestinal villi caused by gluten ingestion by genetically-susceptible individuals. Patients who receive a diagnosis of CD must make significant changes to their daily habits and this can affect their quality of life. The objective of this review is to summarize the evidence regarding the economic, physical and social limitations which can affect the quality of life in patients with CD. Results: Different factors such as physical changes, psychological effects, interpersonal relationships, emotions and economic difficulties can affect the quality of life of these patients. Observations suggest that, in general, women with CD experience a greater deterioration in their quality of life than men. Lastly, complications in daily life are also associated with the reduced availability of gluten-free products which also usually cost more than standard products. Conclusions: Continuous health education and care regarding socio-economic issues should be continuously developed and provided to people with CD.

Background: Despite a number of innovations in anti-diabetic drugs and substantial improvement in diabetes care, the number of people with diabetes continues to increase, suggesting further need to explore novel approaches to prevent diabetes. Type 2 diabetes (T2DM) is characterized by beta cell dysfunction and insulin resistance. However, insulin resistance, usually a consequence of obesity, is often emphasized and the role of beta cell dysfunction in T2DM is less appreciated. Objective and Results: This paper summarizes recent evidence showing the importance of beta cell dysfunction in T2DM and refines the “beta cell workload hypothesis”, emphasizing the importance of beta cell preservation for the prevention and management of T2DM. Conclusion: It is hoped that this novel concept will foster a better understanding of the pathophysiology of T2DM by not only medical staff and patients with diabetes, but also the general population, and encourage more people to adhere to a healthy lifestyle, eventually resulting in “stopping diabetes”.

Background: Secondary lymphoid organs (SLO) are distributed in many districts of the body and, especially, lymph nodes, spleen and gut-associated lymphoid tissue are the main cellular sites. On the other hand, tertiary lymphoid organs (TLO) are formed in response to inflammatory, infectious, autoimmune and neoplastic events. Developmental Studies: In the present review, emphasis will be placed on the developmental differences of SLO and TLO between small intestine and colon and on the role played by various chemokines and cell receptors. Undoubtedly, microbiota is indispensable for the formation of SLO and its absence leads to their poor formation, thus indicating its strict interaction with immune and non immune host cells. Furthermore, food antigens (for example, tryptophan derivatives, flavonoids and byphenils) bind the aryl hydrocarbon receptor on innate lymphoid cells (ILCs), thus promoting the development of postnatal lymphoid tissues. Also retinoic acid, a metabolite of vitamin A, contributes to SLO development during embryogenesis. Vitamin A deficiency seems to account for reduction of ILCs and scarce formation of solitary lymphoid tissue. Translational Studies: The role of lymphoid organs with special reference to intestinal TLO in the course of experimental and human disease will also be discussed. Future Perspectives: Finally, a new methodology, the so-called “gut-in-a dish”, which has facilitated the in vitro interaction study between microbe and intestinal immune cells, will be described.

Objective: Hyperlipemia represents an independent risk factor in the development of atherosclerosis in patients undergoing type 2 diabetes mellitus (DM). Moreover, the pharmacological treatment of dyslipemia in patients undergoing type 2 DM (e.g. by means of statins), is accompanied by relevant side effects and oral supplementation with natural antioxidants, such as Citrus polyphenols, has recently been suggested to improve cardioprotection in such patients. However, due to the poor gastrointestinal absorption of polyphenols, novel formulations have recently been developed for getting a better bioavailability of polyphenolic rich fractions of citrus species extract rich in polyphenols. Methods: Here, we investigated the effect of standard bergamot polyphenolic fraction (BPF®) as well as of its phytosomal formulation (BPF Phyto), in patients with type 2 DM and hyperlipemia. A randomized, double blind, placebo-controlled study was carried out in 60 patients suffering from type 2 DM and mixed hyperlipemia. Patients were divided into three groups: one receiving placebo, the second receiving standard BPF and the third BPF Phyto. Results: In the groups receiving BPF and BPF Phyto, a significant reduction of fasting plasma glucose, serum LDL cholesterol and triglycerides accompanied by increased HDL cholesterol was observed. This effect was associated with significant reduction of small dense atherogenic LDL particles, as detected by means of proton NMR Spectroscopy, thus confirming the hypolipemic and hypoglycemic effect of bergamot extract both when using standard formulation as well as BPF Phyto. No differences were seen in the therapeutic response among groups receiving BPF and BPF Phyto, thus suggesting a substantial bioequivalence in their hypoglycemic and hypolipemic profile. However, when comparing the pharmacokinetic profile of naringin (the major component of BPF) and its metabolites, in patients treated with BPF Phyto, an at least 2,5 fold increase in its absorption was found, confirming in human studies the better profile of BPF Phyto compared to standard BPF. Conclusion: These data suggest that better absorption and tissue distribution of BPF Phyto formulation represents an innovative approach in supplementation treatments of cardiometabolic disorders.

Introduction: Inhibition of Toll-like receptors (TLRs) signaling plays a crucial role in suppressing the inflammation and available data presenting G2013 as an immunomodulatory agent, therefore, we designed this study to answer whether G2013 can affect the signaling pathway of TLR2 and TLR4. Methods: Cytotoxicity study of G2013 was performed by MTT assay. HEK293 TLR2 and HEK293 TLR4 cell lines were cultured and treated with low dose (5μg/ml) and high dose (25μg/ml) of G2013 for 24 hours. Gene expressions of MyD88, Tollip, and NF-ΚB were defined by quantitative real-time PCR. Results: The cytotoxicity assay showed that the concentrations lesser than 125μg/ml of G3012 had no apparent cytotoxicity, however, the concentrations of 5μg/ml and 25μg/ml could suppress the mRNA expression of MyD88, Tollip and NF-ΚB in HEK293 TLR2 and HEK293 TLR4 cell lines. Conclusion: in our study, we verified the linkage between the immunosuppressive property of G2013 and TLR2, TLR4 signaling cascade; but so far, the specific target of G2013 and its molecular mechanism has not been detected yet. We recommend further studies on other Patten Recognition Receptors (PRRs)and other mechanisms of inflammation like oxidative stress to be conducted in the future.

Background: Diabetic peripheral neuropathy (DPN) is one of the most common complications of Type 2 diabetes mellitus (T2DM). This study was conducted to investigate the possible association between interleukin-1β (IL-1β) rs16944 /IL-1 receptor antagonist (IL-1Ra) VNTR variants and genetic susceptibility to DPN in a Turkish cohort. Methods: A total of 200 subjects were enrolled in this study, 98 patients with DPN and 102 cases of age and sex-matched healthy controls. Genotyping was performed for all individuals using PCR-RFLP analysis. Results: IL-1β rs16944 CC genotype had a 3.20-fold increased risk for DPN (p=0.0003, OR=3.20, 95% Cl:1.72-5.96). IL-1β rs16944 CT genotype was higher in healthy control than patients (p=0.004). IL-1β rs16944 C allele was higher in the patient group compared to controls while T allele was lower in patients than controls (p=0.003). IL-1Ra VNTR a1/a1 and a2/a2 genotypes were lower in DPN patients while a1/a2 genotype was higher in patients (p=0.045). The patients carrying a1/T haplotype had decreased risk of DPN than control groups (p=0.004). The patients carrying a2/a2 genotype had lower HDL level (p=0.039). The subjects carrying a2/a2 genotype had higher total cholesterol level while the subjects carrying a1/a2 genotype had lower total cholesterol (p=0.026 and p=0.037, respectively). IL-1Ra a1 allele was associated with higher HDL level (p=0.041). Conclusion: Findings of this study indicated that the IL-1β rs16944 and IL-1Ra VNTR variants are probably to be associated with susceptibility DPN risk in a Turkish cohort.

Background/Objectives: The aim of this work was to evaluate the current vitamin D status in healthy pregnant women and their newborns living in Greece and assess possible associations between 25(OH)D and anthropometric features of their fetuses and newborns. Materials & Methods: 81 healthy women were monitored during pregnancy. Biochemical markers related to bone metabolism, 25(OH)D and PTH levels were measured in serum samples of mothernewborn pairs at 1st trimester of pregnancy and at delivery in mothers, in cord blood and at the 3rd day of life of newborns. Results: Maternal 25(OH)D levels at the 1st trimester of pregnancy (22.6±9.2ng/ml) were significantly higher than those at delivery (19.2±9.2ng/ml) (p<0.001). Furthermore, umbilical 25(OH)D levels (21.3±9.3ng/ml) were higher than maternal at delivery (p=0.005) and neonatal levels (19.4±10.4 ng/ml) (p=0.021). Only 57.3% of the mothers at the first trimester and 46.7% at delivery as well as 55.8% of the fetuses and 38.5% of the neonates had adequate vitamin D levels (25(OH)D≥30ng/ml). A significant positive correlation was found between fetal femur length at the 22nd week of gestation and maternal 25()D at the 1st trimester of pregnancy (r=0.36, p=0.048) while body length was significantly higher in newborns whose mothers had sufficient 25(OH)D levels (51.5±2.1cm) compared with those whose mothers had insufficient or deficient 25(OH)D levels at delivery (50.6±2.0cm) (p=0.047). Conclusion: The study confirms inadequate levels of vitamin D in pregnant women in Greece associated with inadequate vitamin D levels of their fetuses and newborns.

Objective: To investigate whether serum vitamin D levels have an effect on pseudoexfoliation (PEX) glaucoma/syndrome development and on the control of glaucoma in these cases. Method: A total of 31 cases with PEX glaucoma, 34 cases with the PEX syndrome and 43 control subjects of similar age and sex were included in the study. Vitamin D levels were compared between the groups and also between the cases where glaucoma surgery was performed or not. Results: PEX glaucoma group consisted of 17 males and 14 females, PEX syndrome group of 27 males and 7 females, and the control group of 27 males and 16 females. The mean age was 70.9±8.9 years, 72.1±7.3 years, and 67.9±9.1 years in PEX glaucoma, syndrome and control group, respectively. Mean vitamin D levels were 9.4±7.7 ng/mL, 7.9±6,1 ng/mL, 11.5±14.2 ng/mL in PEX glaucoma, syndrome and control group, respectively (p>0.05). The mean serum vitamin D level was 8.04±4.7 ng/mL in those who underwent glaucoma surgery and 10.1±8.7 ng/mL in those who didn't undergo glaucoma surgery in PEX glaucoma group (p>0.05). No difference was found between the PEX glaucoma subgroups in terms of the mean deviation when classified according to vitamin D levels (<10 ng/mL, ≥10 ng/mL) (p>0.05). Conclusion: Although we found no statistically significant difference between the PEX syndrome/ glaucoma, and control group in terms of serum vitamin D levels, serum vitamin D levels were lower in PEX syndrome and glaucoma group than control group. Our results indicate that serum vitamin D levels have no effect on the development of PEX glaucoma/syndrome or the control of the disorder in cases with PEX glaucoma. However, these results need to be supported with further studies on a larger number of patients and with longer follow-up.

Background and Objective: α-Tocopherol is the active form of vitamin E which has various biological functions. However, the exact molecular mechanism of its action is not fully understood. Thus, the main objective of the current study is to determine the contribution of α-tocopherol in counteraction of the apoptogenic signaling pathways induced by deltamethrin in murine thymocytes and splenocytes. Methods and Results: Deltamethrin (25 μM) induces apoptosis at 18 h through the activation of reactive oxygen species, caspases and depletion of glutathione in thymocytes and splenocytes. MTT assay results have shown that α-tocopherol (10 and 50 μg/ml) when added along with Deltamethrin (25μM), increases the viability of thymocytes and splenocytes in a concentration-dependent manner. The α-tocopherol treatment reduces the early markers of cell death (ROS and caspase3 activation) significantly. Further, the depleted GSH by deltamethrin has also been restored by α-tocopherol. At 18 h, α-tocopherol (50 μg/ml) significantly reduced the Deltamethrin induced cell death. In additional, phenotyping and cytokines assay have demonstrated that alpha-tocopherol significantly ameliorated the altered immune functions. Conclusion: These findings indicate that α-tocopherol shows immunoprotective effects in Deltamethrin induced splenic and thymic apoptosis by inhibiting oxidative stress and caspasedependent apoptogenic pathways.

Background & Aims: Insulin resistance is the real determinant of both Nonalcoholic fatty liver disease (NAFLD) and diabetes, and can facilitate the accumulation of triglycerides in the liver. Overexpression of hepassocin (HPS) increased the accumulation of hepatic fat and NAFLD activity scores (NAS) in mice. The aim of this study was to investigate the relationship between hepassocin and steatosis of the liver in diabetic patients with or without NAFLD in humans. Methods: The study enrolled 60 patients plus 20 healthy controls that were divided into 4 groups: Group I: included 20 patients who were diagnosed as diabetes mellitus type 2, Group II: included 20 patients who were diagnosed as nonalcoholic fatty liver disease (NAFLD), Group III: included 20 patients who were diagnosed as diabetes type 2 and NAFLD, and Group IV (control group): included 20 healthy person or controls who were matched in age and sex with patients group. All patients and controls were subjected to full history taking, thorough clinical examination, laboratory investigations including measurement of serum hepassocin in peripheral blood by ELISA technique. Results: There was a significant overexpression of serum hepassocin in patients with type 2 diabetes and NAFLD patients (Group 3) more than diabetic patients (Group 1) and even more than non-alcoholic fatty liver disease (Group 2). Conclusion: This study provides evidence that increased HPS may facilitate increased hepatic lipid accumulation with NAFLD and type 2 diabetes.

Background and Objective: Warionia saharae Benth & Coss, a plant belonging to Asteraceae family, is used for its anti-diabetic properties in Morocco. The objective of this study was to evaluate the effect of tannins extracted from Warionia saharae (W. saharae) on blood glucose levels and lipid profile in normal and streptozotocin(STZ)-induced diabetic rats. Methods: Tannins (TE) were extracted from W. saharae using Soxhlet apparatus and different organic solvents. Single and once daily repeated oral administration of TE (10 mg/kg) for 15 days were used to evaluate the glucose and lipid-lowering activity in normal and diabetic rats. Furthermore, glucose test tolerance, liver histopathological examination and in vitro antioxidant activity of TE were carried out in this study. Results: The results showed that TE was able to exert antihyperglycemic and lowering total cholesterol effects as well as improvement of the high-density lipoprotein (HDL)-cholesterol serum level after 15 days of treatment. Furthermore, TE improved glucose tolerance, histopathological status of liver in diabetic rats and demonstrated interesting antioxidant activity. Conclusion: In conclusion, the present investigation revealed that TE possesses potent antidiabetic and antihyperlipidemic activities as claimed in different ethnopharmacological practices.

Background: VSL#3 has been extensively investigated and is currently recommended for the prevention and treatment of chronic pouchitis and ulcerative colitis. Nonetheless, in vitro and in vivo studies have recently shown variability in the VSL#3 efficacy often attributed to the manufacturing process. Objective: The aim was to comparatively study the in vitro effects of two VSL#3 preparations produced in different sites (named US- and Italy-made VSL#3) on CaCo-2 epithelial barrier model in terms of trans-epithelial electrical resistance (TEER), dextran flux and expression of Tight Junctions (TJ) proteins i.e. zonulin-1 (ZO-1) and occludin, in the absence or presence of a heat stress-related damage of monolayer. Methods: TEER was evaluated on CaCo-2 differentiated monolayers. Epithelial permeability of polarized monolayers was assessed by measuring the FITC-labeled dextran flux from the apical to basolateral chambers. ZO-1/occludin levels were analyzed by western blot analysis. A set of experiments was performed to compare the effects of both VSL#3 on TEER values, dextran flux and ZO-1/occludin expression in CaCo-2 monolayers after heat stress exposure. Results: US- and Italy-made VSL#3 have opposing effects on TEER values, dextran flux, and ZO- 1/occludin expression, being all these parameters negatively influenced just by Italy-made product. US-made probiotic did not affect baseline TEER, dextran flux and ZO-1 expression and strongly increased occludin levels. Of note, pre-treatment of monolayer with US-made VSL#3, but not Italy-made product, totally prevented the heat-induced epithelial barrier integrity loss. Conclusion: Our data trigger the need for reassessing efficacy or safety of the Italy-made VSL#3 considering intestinal epithelial barrier plays an important role in maintaining host health.

Background: Dapagliflozin, sodium glucose cotransporter 2 inhibitor, has potential side effects on electrolyte imbalance as it has diuretic effects which include decreasing glucose reabsorption, increasing glucosuria and natriuresis. We aimed to determine the possible effects of dapagliflozin on electrocardiogram (ECG) in patients with type 2 DM. Material and Methods: This retrospective study consisted of 49 patients (25 female, 24 male). Patients who had inadequate glycemic control besides using several oral antidiabetics, subsequently endorsed with dapagliflozin, were included in the current study. Results: Meantime interval from treatment initiation to control was 10.5 ± 5.03 weeks. Body mass index, glucose, HbA1C, eGFR, LDL-C, heart rate, systolic and diastolic blood pressures were found to be significantly lower at control admission (p<0.05). Creatinine and QT interval were significantly higher at control admission (p<0.05). Baseline Tpe duration and baseline Tpe/QT ratio were found to be significantly correlated with Tpe/QT difference (p<0.05). In linear regression analysis, baseline Tpe/QT ratio was found to be the sole independent predictor of Tpe/QT difference (p<0.05). Conclusion: Initiation of dapagliflozin treatment seems to be safe, up to several months, in terms of serum electrolytes and ECG findings in patients with type 2 DM with a probable improvement.

Background and Objective: Giant pituitary adenomas (GPAs) are benign tumours with a diameter ≥ 4 cm [1]. They can cause symptoms and signs due to the possible hyper-secretion of one or more pituitary hormones, and involvement of the surrounding structures whereas the compression of the pituitary itself can lead to hypopituitarism. Methods: We report on a young woman with acromegaly due to an inoperable giant GH-secreting pituitary adenoma extending to right cavernous sinus, right orbital cavity, ethmoid, right maxillary sinus, sphenoid sinus, clivus and right temporal fossa, in which medical treatment with Octreotide- LAR was able to promptly relieve headache and bilateral hemianopsia due to optic chiasm involvement, improve acromegaly symptoms and, over the time, control tumor expansion, improving fertility and therefore allowing the patient to become pregnant. Results: Octreotide-LAR therapy was withdrawn during pregnancy and the patient did not experience complications and gave birth to a healthy son. On magnetic resonance, the size of the tumor at the end of pregnancy and in the subsequent follow up was not increased. Conclusion: The history we report, therefore, confirms previous experiences reporting a possible favourable outcome of pregnancy in patients affected by acromegaly and adds further information about the behaviour of giant pituitary tumors in patients underwent pregnancy.

Background and Objective: Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis that can be limited to the skin but may also affect other organs. Often, its cause is unknown. LCV has previously been reported to occur with the reactivation of human herpesvirus 6 (HHV-6). Here, we report a second instance of HHV-6 reactivation in a 43-year-old woman with idiopathic cutaneous LCV.

Case Description: In this case, the patient was immunocompetent, and testing revealed that she had inherited chromosomally integrated human herpesvirus 6 variant A (iciHHV6-A) with a parallel skin infection of HHV-6B. The integrated ciHHV-6A strain was found to be transcriptionally active in the blood, while HHV-6B late antigen was detected in a skin biopsy. The patient’s rash was not accompanied by fever nor systemic symptoms and resolved over four weeks without any therapeutic intervention.

Conclusion: In light of the transcriptional activity documented in our case, further examination of a possible role for HHV-6 in the etiology of LCV is warranted.

Background: Medullary thyroid cancer (MTC) accounts for 5% of all thyroid cancers and occurs either sporadically or in a hereditary pattern. Routine calcitonin (CT) measurement is suggested for MTC screening in patients with nodular thyroid disease. Patient Findings: A 45 years-old woman incidentally discovered, with neck ultrasound, the presence of thyroid micronodules. Fine-needle aspiration (FNA) on thyroid prevailing nodule did not demonstrate cellular atypia. During follow-up, FNA was repeated on the previously analyzed nodule suspicious for Hürthle cell nodule suspicious for follicular neoplasm and on another hypoechoic right nodule which showed cellular atypia. CT was <2 pg/ml (normal values <18.2 pg/ml), anti-thyroid antibodies were positive and the patient showed a normal thyroid function. The patient also was diagnosed with primary hyperparathyroidism with an enlarged parathyroid gland behind the right thyroid lobe. Therefore, she underwent total thyroidectomy and a selective parathyroidectomy was performed. Histology showed an encapsulated microMTC (pT1aNxMx) associated with diffuse C-cell hyperplasia and lymphocytic thyroiditis. The neoplasm was positive for calcitonin and chromogranin A and negative for thyroglobulin. A right parathyroid adenoma was also diagnosed. One month after surgery basal and stimulated CT were <2 ng/ml. Genetic analysis did not reveal mutation of RET proto-oncogene. Twelve months after surgery, neck ultrasonography, chest and abdomen computed tomography did not demonstrated residual/recurrent disease with undetectable serum CT. Conclusion: In the literature, few MTC cases with normal serum CT have been reported. Although MTC without elevated plasma CT is extremely rare, normal or low CT levels, do not entirely exclude this diagnosis.

Background: Dysphagia affects one in twenty-five adults yearly in the United States. Objective: While dysphagia may be common, the prevalence of dysphagia may be underestimated primarily due to under-reporting. Dysphagia may be caused by intraluminal, intrinsic, extrinsic, or motility disorders. Method/Results: We present a case of dysphagia caused by extra-thoracic extrinsic compression due to bra use. Conclusion: Despite many published reports on dysphagia caused by other diagnoses, we occasionally overlook extrinsic abdominal compression as the cause for dysphagia.