Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 18, Issue 6, 2018

Background and Objective: Fat accumulation in the pancreas has remained a relatively unknown disease since it was initially described in 1926. However, it has gained increasing attention in the past two decades with the emergence of the obesity epidemic. Pancreatic steatosis is a general term used for fat accumulation in the pancreas. It is further classified into fatty replacement, fatty infiltration, lipomatous pseudo-hypertrophy, non-alcoholic fatty pancreas disease (NAFPD) and non-alcoholic fatty steatopancreatitis (NASP). NAFPD is defined as obesity-associated accumulation of fat in the pancreas without significant alcohol consumption. Data on the prevalence of NAFPD are limited due to a lack of standardized screening tests. Methods: MEDLINE/PubMed was searched to find relevant studies and abstracts on pancreatic steatosis. Results: Pancreatic fat can be quantified by various imaging techniques including ultrasonography, computed tomography, magnetic resonance imaging and magnetic resonance spectroscopy. The pathophysiology of NAFPD has not been completely understood. Chronic exposure of β-cells to hyperglycemia and higher levels of free fatty acids results in increased intracellular triglyceride accumulation, which ultimately causes reduced insulin secretion, insulin resistance, cell apoptosis and subsequent fatty replacement. This vicious cycle likely is a determining factor in the development of diabetes mellitus and metabolic syndrome. There is no approved pharmacologic therapy for NAFPD. Caloric restriction might have a role in normalization of β-cell function by reducing pancreatic fat content. Troglitazone (blend of telmisartan and sitagliptin) has demonstrated effectiveness in animal models but is still in experimental stages. Conclusion: The cause and effect relationship between the metabolic syndrome and NAFPD has not yet been established. Further studies are required to study the effect of NAFPD on glucose hemostasis.

Background and Objective: Anaplastic thyroid carcinoma is rare, but represents the deadliest type of thyroid cancer that is characterised by a rapid course. Diagnosis is usually made at a late stage, when more than half of the patients have distant metastasis. Our main purpose is to review the current information on anaplastic thyroid aetiology and risk factors that might contribute to an earlier diagnosis as well as to give new perspectives regarding the most recent treatment options and future directions. Results: The treatment options are mainly palliative and lack efficacy. In particular, the multikinase inhibitors, BRAF inhibitors and other directed agents aim to stabilize the tumour growth and might enable a radical surgery with curative intent. Conclusion: With the mutational landscape investigation and the discovery of new targets, new directed treatments are being tried. Considering the current tendency to be more conservative regarding the multinodular goiter approach and some differentiated thyroid carcinomas treatment, it is vital to understand that it might evolve to anaplastic cancers.

Background: Occupational asthma occurs in a significant number of adult unset forms of asthma. Even after exposure cessation, persistent asthma is frequent. Although recognized as important, nutrition, specifically vitamin D intake, was rarely evaluated in occupational asthma. Objective: To assess the vitamin D intake in occupational asthma patients and the relation with body mass index, co-morbidities related to vitamin D deficit, lung function and quality of life. Results: We found a reduced vitamin D intake in both irritant and allergic asthma, in obese and nonobese patients. The average intake in non-obese patients, although higher, did not reach statistical significance. We also found lower vitamin D intake in the mild asthma group versus the severe group, marginally reaching the significance level (p=0.056) at the median test. Regression analysis in asthma subpopulations revealed a different pattern of correlation, with a stronger relationship between the BMI and the impact score in irritant asthma and a closer link between vitamin D intake and symptoms score (p= 0.027) in the allergic asthma group. Conclusion: The relation between obesity and vitamin D on clinical scores and lung function seems to be different according to the asthma phenotype. However, our study supports the usefulness of nutritional interventions in all occupational asthma patients, targeting both the reduction of the fat mass and the achievement of the recommended daily intake of vitamin D. When analyzing the impact of the weight loss effect on asthma evolution, the vitamin D status should also be considered as an influencer.

Background & Aims: Esophageal varices (EV) are a major complication of portal hypertension in cirrhotic patients. Screening is essential for all patients with cirrhosis. Performing non-invasive methods for screening is a cost-effective and time-saving measure. The aim of this work is to evaluate whether insulin resistance (IR) assessed by HOMA-IR score can predict the presence of EV or not. Methods: This cross-sectional study was carried out on sixty Egyptian cirrhotic HCV patients divided into 3 groups: Group I: 20 cirrhotic patients without esophageal varices, Group II: 20 cirrhotic patients, with small esophageal varices and Group III: 20 cirrhotic patients with large esophageal varices. Fasting insulin level was measured and HOMA- IR score was calculated. Abdominal ultrasound and Fibroscan were done to all patients. Results: Insulin resistance assessed by HOMA –IR score showed a statistically significant difference among the three groups (P<0.001) with a cutoff value equal to or more than 3.40. It could significantly predict EV (AUROC= 0.841) with high sensitivity of 75 %, and excellent specificity 80%. Liver stiffness measurement (LSM) with a cutoff value 40.95 kPa could significantly predict EV (AUROC= 0.629) with sensitivity 75 %, specificity 50 %. Conclusion: HOMA-IR score is a new independent predictor of the presence of EV.

Background and Objective: Mentha spicata is a medicinal plant with several beneficial effects on health. The objective of this study was to evaluate the antidiabetic effect of this plant in the experimental diabetic state. Methods: In this work, the effect of Mentha spicata (L.) (M. spicata) aerial part aqueous extract (A.P.A.E) at a dose of 20 mg/kg body weight on blood glucose levels has been demonstrated in normal and streptozotocin (STZ) diabetic rats. Additionally, a preliminary phytochemical screening for various bioactive constituents was realized and a dosage of polyphenols and flavonoid has been done. Moreover, the histopathological changes in liver and pancreas have been evaluated both in normal and STZ diabetic rats. The effect of M. spicata aqueous extract to improve glucose tolerance in normal rats was also evaluated. Results: In normal rats, both a single and repeated administration of the A.P.A.E (20 mg/kg) had not shown a significant reduction in blood glucose levels. However, repeated oral administration of M. spicata aqueous extract showed a significant blood glucose lowering effect (p<0.0001) in STZ diabetic rats. The blood glucose lowering activity of A.P.A.E was comparable to glibenclamide treatment at the dose used. Also, a histopathological study has showed the better act of M. spicata in pancreas and liver. Moreover, the oral glucose tolerance test demonstrated the ability of the aqueous extract (20 mg/kg) to improve the increase in blood glucose levels in normal treated rats. In the current study, no significant changes in body weight in normal and STZ rats have been shown. In addition, the preliminary phytochemical screening of M. spicata A.P.A.E. showed the presence of several beneficial compounds including polyphenols, flavonoids, anthraquinones, tannins, saponins, sterol, glucides, glycosides, terpenoids and reducing sugars. Furthermore, the result of dosage of some bioactive compounds present in this plant showed an important value of polyphenol (424.37±43.93 mg EAG) and showed also a non-negligible content of flavonoid. (9.74 ±0.39 mg EQ/g of extract). Conclusion: In conclusion, aqueous M. spicata extract exhibits an interesting antidiabetic effect in streptozotocin rats.

Background and Objective: Previous studies revealed the association between serum Nterminal pro-brain natriuretic peptide (NT-proBNP) level and chronic kidney diseases (CKD) in general population. However, little is known about the association between serum NT-proBNP level and incident CKD in patients with type 2 diabetes. Thus, we investigated the impact of serum NT-proBNP level on incident CKD in patients with type 2 diabetes. Method: We enrolled 211 type 2 diabetic patients without CKD in this cohort study. CKD was diagnosed as estimated glomerular filtration rate <60 ml/min/1.73 m2. We divided the patients into three groups according to the tertiles of serum NT-proBNP level. Univariates and multivariate hazard ratios (HRs) for the incident CKD were calculated by Cox regression analyses. Results: Over the median follow-up period of 7 years, 56 patients developed incident CKD. Log NTproBNP was positively associated with incident CKD (HR 3.70, 95%CI 1.72-8.18, p <0.001). Compared with the lowest level of serum NT-proBNP tertile (≤36 pg/mL), the highest level of serum NTproBNP tertile (≥84 pg/mL) showed increased risk of incident CKD after adjusting age, sex, body mass index, hemoglobin A1c, creatinine, smoking, usage of hypertension drug and urinary albumin excretion at baseline examination (adjusted HR2.37, 95% CI 1.09-5.48, p = 0.028). Conclusion: Serum NT-proBNP level is an independent biomarker for incident CKD in patients with type 2 diabetes.

Background: One mechanism that underlies protection from autoimmunity and avoidance of uncontrolled inflammation is the controlled contraction of lymphocyte expansion during the immune response. We identified regulatory rheumatoid factor (regRF), the production of which is associated with resistance to and remission of experimental autoimmune diseases. RegRF is anti-idiotypic antibodies to lymphocyte receptors against autoimmune disease-inducing antigens; at the same time, it is specific to epitopes in the hinge Fc fragments of IgG. Objective: The aim of this study is to test the hypothesis that regRF prevents autoimmunity by limiting the expansion of lymphocytes. Methods: To test this hypothesis, we used a model of experimental autoimmune encephalitis. Results: We found that in the lymph nodes that drain the injection site in rats producing regRF in response to immunization with myelin basic protein (MBP) the proportion of CD4+lymphocytes was lower than in rats in which MBP-immunization did not induce higher regRF levels. RegRF-containing plasma obtained from MBP-immunized rats induces complement-dependent killing of MBP-activated lymphocytes. Activated MBP-specific lymphocytes are not sensitive to the regRF-containing plasma of intact rats. Conclusion: The regRF produced during the immune response is a specific control factor for the expansion of antigen-activated CD4+lymphocytes.

Background and Objective: Side effects of some drugs may be useful in certain cases. In this work, we studied the inhibitory effects on Lipases of some medications as: Folic Acid which is taken by pregnant women, Colchicine and Febuxostat which is used as treatment of gout disease. These cases are linked to obesity, where women (BMI ≥ 30) have twice higher odds of having an NTDaffected pregnancy than the normal weight women, and the Gout disease frequently occurs in combination of a Metabolic syndrome. The risk of gout increases with the increase of the mass index. In silico studies were aimed to determine the mechanism of inhibition and different interactions for two enzymes: Candida rugosa lipase and human pancreatic lipase. Methods: In the first part of this study, we studied the inhibition activity of these medications on lipase activity of Candida rugosa in vitro. Autodock vina was used for molecular docking with 50 runs and 1000 obtained solutions. The saved interactions were with His449 and Ser209 for the three molecules. Results: The results show that these drugs have an important inhibition activity with IC50 values 0.64 mg/ml for Folic acid and 0.66 mg/ml for Febuxostat. The results of in silico show competitive, Noncompetitive and uncompetitive inhibition for folic acid, febuxostat and colchicine respectively for two enzymes with different repetition ratios of hydrogen bonds. Conclusion: These observations support a higher intake of dietary folate, and febuxostat for losing weight to decrease NTD risk and prevent hyperuricemia and recurrent gout attacks.

Background: Acute lymphoblastic leukemia (ALL) is the commonest childhood cancer. Transferrin receptor 1 (CD71) is a trans-membrane glycoprotein which has important role in iron homeostasis by acting as a gatekeeper regulating iron uptake from transferrin and is an attractive target for anti-cancer agents, particularly those that aim to induce lethal iron deprivation in malignant hematopoietic cells. Aim of the Work: To assess the prognostic value of Transferrin receptor -1 (CD71) in children with newly diagnosed ALL. Patients and Methods: This study was carried out on 75 patients with newly diagnosed ALL. Transferrin receptor-1 expression was analyzed on the bone marrow blasts by flow cytometry at time of diagnosis with positive CD71 expression is considered when ≥20% of malignant cells express this marker while negative expression is considered when <20% of malignant cells express this marker. Results: Transferrin receptor-1 positive expression was detected in 45 patients (60%) while negative expression was found in the remaining 30 patients (40%). CD71 expression was significantly higher on T- ALL patients compared with B-ALL patients. Positive CD71 expression at diagnosis was significantly associated with bad clinical and laboratory prognostic factors as lymphadenopathy, higher white blood cell count, higher hemoglobin level, lower platelets count, and higher blast cells in peripheral blood and bone marrow and higher lactate dehydrogenase levels'. There were significant differences in disease free survival (DFS) and overall survival (OS) between positive and negative CD71 expression groups with significantly shorter DFS and OS in positive CD71 expression group compared to negative group. Conclusion and Recommendations: ‘Positive Transferrin receptor -1 (CD71) expression in patients with ALL is adverse prognostic factor and should be taken in consideration in designing future therapeutic strategies based on patient- specific risk factors’.

Background and Objective: BLyS (B-Lymphocyte stimulator) is over-expressed in several tumoral settings, with direct or indirect effects on neoplastic proliferation and possibly representing a therapeutic target. In this study, we explored the role of BLyS in a large population of patients with neuroendocrine tumors (NETs). Methods: The study analyzed the stored sera of 124 consecutive unselected patients with NETs: 36 lung carcinoids (24 typical, 12 atypical), 47 gastroenteric tract and 41 pancreatic (30 non-functioning and 11 functioning: 9 insulinomas, 2 glucagonomas). In 23 cases, BLyS was repeatedly assessed during the follow-up and the disease was monitored (progression, stabilization or remission) according to the RECIST criteria. Patients were compared to 92 age and sex-matched blood donors (BDs). Serum levels of BLyS and Chromogranin A (CgA) were analyzed by ELISA. Results: NET patients showed significantly higher BLyS levels than BDs (1274±809 pg/ml vs. 587±173 pg/ml; p<0.0001). BLyS correlated weakly with CgA (r=0.19 and p=0.035) but did not correlate with Ki67, grading, metastasis, histological type and site. In patients with sustained remission after surgery, BLyS and CgA both showed a gradual reduction over time. Patients with progressing disease showed higher BLyS levels compared to stable patients (1524±694 pg/ml vs. 1168± 373 pg/ml; p= 0.033). BLyS serum levels remained stable in remission and therapy-controlled patients, while increased in the follow-up of progressing cases. Conclusion: Higher BLyS levels identify patients with a more severe disease, characterized by progression despite treatments, possibly representing a factor implicated in the proliferation of the neoplastic cells or in sustaining the neoplastic environment.

Introduction: Bisphenol A (BPA) is suspected to cause hormonal imbalance in humans. Dietary factors are known to bring changes in hormonal profile. In order to study chemico-biological interaction of iron deficiency on toxicity outcome of BPA exposure, we studied the modulatory effects of iron deficiency on the hormone levels in rats chronically-exposed to BPA. Methods: Weanling rats maintained on normal and iron-deficient diets were exposed to low level of BPA at 0, 1, 5 and 10 ppm for six months through drinking water. The serum levels of thyroidstimulating hormone (TSH), testosterone, progesterone and estradiol were measured in the animals by enzyme-linked immunosorbent assay kit. Histopathology was performed to check the pathological changes in gonads. Results: No significant change was observed in TSH, progesterone and estradiol levels at 1 and 5 ppm BPA. However, at 10 ppm BPA a significant increase in TSH level was observed in the animals maintained on an iron-deficient diet of either sex. BPA caused a significant change in testosterone level even at 5 and 10 ppm doses in animals of either sex. However, in male rats 1 ppm dose also showed a significant effect in the animals maintained on iron deficient diet. Changes in the histoarchitecture of the testes at high dose of BPA (10 ppm) were more remarkable in anemic rats. Conclusion: These results suggest that iron deficiency has no generalized effect on hormonal levels in BPA-treated animals and trends indicate a more remarkable effect in male animals at hormonal and tissue levels.

Background: There is a paucity of information in the literature on the effect of Cnidoscolus aconitifolius on the hematological, coagulation activities, electrolyte balance and antioxidant activities of humans or animals. Objectives: To determine the ameliorative potentials of methanol fractions of Cnidoscolus aconitifolius on hematological, coagulation, electrolyte, hepatic and renal antioxidant activities of streptozotocininduced diabetic rats using standard techniques. Method: Thirty rats, distributed into five groups of six rats each were used for this study. Groups 1 and 2 (normal and diabetic controls) received 1 ml/kg normal saline. Groups 3 and 4 received methanol fractions of Cnidoscolus aconitifolius (at 250 and 500 mg/kg). Group 5 was administered glibenclamide (2.5 mg/kg). Results: The diabetic control had decreased (P<0.05) white blood cells, red blood cells, hemoglobin, packed cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, lymphocytes, eosinophils, thrombin time, prothrombin time, activated partial thromboplastin time, sodium, potassium, bicarbonate ions, hepatic and renal superoxide dismutase, catalase and glutathione peroxidase activities; increased (P<0.05) neutrophils, fibrinogen and platelets counts, chloride ion levels compared with the normal control while their monocytes were not different (P>0.05) from that of the normal control. Basophils were not detected in all the groups that were studied. The methanol fraction at 500 mg/kg was more potent than the methanol fraction at 250 mg/kg or glibenclamide (at 2.5 mg/kg) in ameliorating the hematological parameters, serum electrolytes and oxidative stress in the hepatic and kidney tissues of the diabetic rats suggesting its potentials in the management of diabetic complications. Conclusion: Finally, the biological properties demonstrated by the methanol fraction could be attributed to the presence of octadecanoic acid, n-hexadecanoic acid, eicosanoic acid, tetradecanoic acid and n-hexadecanoic acid in it as previously reported.

Background: Low vitamin D levels have been associated with autoimmune disorders and, then, with the Hashimoto's autoimmune thyroiditis (AT), the most common autoimmune disease. Obesity is characterized by lower vitamin D levels and higher risk to develop autoimmune diseases. The aim of the study was to examine the possibility of an association between AT and decreased 25(OH) vitamin D (25(OH)D) levels in a cohort of otherwise healthy overweight and obese subjects. Materials and Methods: Two hundred sixty one overweight subjects (mean age: 40.9 + 15.6 years, 200 women and 61 men) were enrolled for this study. All of them did not show any clinically evident metabolic or chronic diseases (i.e. hypertension, diabetes mellitus, renal failure, etc.) and did not use any kind of drug. Serum fasting levels of 25(OH)D, anti-thyroid peroxidase (TPO-Ab) and antithyroglobulin (TG-Ab) antibodies, free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), glucose, uric acid and lipids (triglycerides, total, HDL and LDL cholesterol) were measured. Demographic, anthropometric and clinical parameters (age, body mass index (BMI), waist circumference, blood pressure) were also assessed. Results: Fifty five percent of all subjects (144/261) showed vitamin D deficiency (≤ 20 ng/ml), and 17% of all individuals had AT (45/261). The percentage of subjects having vitamin D deficiency was significantly higher among those with AT (31 of 45, 69%) than in those without AT (113 of 216, 52%) (χ2= 4.1, p = 0.042). TSH levels were significantly higher in subjects with AT as compared to those without AT (M-W = 7715.5, p < 0.0001). The final logistic model of a multivariate analysis, performed with AT as the dependent variable and sex, age, BMI category, 25(OH)D category, and HDLcholesterol and TSH levels as the independent ones, showed that patients with AT were more likely to have deficiency of 25(OH)D (p = 0.031) and higher TSH (p < 0.005) levels. Seventy six percent of patients with vitamin D deficiency (110 of 144) were obese whereas 59% of patients without vitamin D deficiency were obese (69 of 117) (p=0.003). Waist circumference was different between subjects with deficiency or normal 25 (OH) D levels (p=0.016). Conclusion: This study clearly shows that vitamin D deficiency is significantly associated to AT in overweight and obese subjects and confirms that obesity is associated to lower vitamin D circulating levels. We suggest that screening for AT should be suggested in all obese subjects with vitamin D deficiency and that vitamin D deficiency should be researched in all obese subjects with AT.

Background: Cytochrome P450 2C9 (CYP450 2C9) has an important role in metabolic processes. Mutations in CYP450 2C9 genes may affect the catalytic activity of this enzyme. The aim of the present study is to assess the genetic polymorphisms of Cytochrome P450 (2C9) enzyme in Turkmen and Fars ethnic groups with type 2 diabetes compared with controls. Methods: A total of 336 Turkmen and 336 Fars type 2 diabetic patients and 336 healthy Turkmen and Fars individuals were included in this study. Genomic DNA was extracted from whole blood samples and then the CYP2C9 genotyping was done using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism technique. Results: The CYP2C9*1, CYP2C9*2 and CYP2C9*3 allele frequencies in type 2 diabetic patients were 85.27%, 11.68%, and 3.05%, and in control were 87.13%, 8.56%, and 4.31%, respectively. We found significant differences between allele distribution of 2C9 in type 2 diabetic patients and controls. CYP2C9*2 and CYP2C9*3 allele frequency was significantly different in Turkmen and Fars type 2 diabetic compared to two ethnic controls. The CYP2C9*1/*1 and CYP2C9*1/*2 genotypes frequencies in type 2 diabetic Turkmen showed significant differences compared to Turkmen control. There were significant differences in the genotype frequency of CYP2C9*1/*1, CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, and CYP2C9*2/*3 between type 2 diabetic Fars and Fars controls. Two diabetic ethnic groups showed statistically significant differences in frequencies of CYP2C9*2/*2 and CYP2C9*2/*3 genotypes. Conclusion: Our study suggests that diabetic patients with mutant CYP2C9 polymorphism may show different antidiabetic drug metabolism compared to the wild-type allele. In this regard, determination of CYP2C9 alleles and genotypes can be a useful tool for the treatment of diabetic patients with antidiabetic drugs because it may assist physicians' to determine optimal dosage and efficiency of drugs metabolized by this polymorphic enzyme.

Background: The association of bullous pemphigoid (BP) and neurologic disease (ND) has been proven. Objective: To investigate the presence of specific markers for the association between BP and ND. Method: A total of 47 patients with PB, at the onset of the disease, were retrospectively recruited from January 2015 to October 2017 in a single center (Dermatology Unit, University of Bari “Aldo Moro”, Bari, Italy). Results: We have found an association between BP, ND and specific serologic profile characterized by higher levels of anti-BP180 and anti-BP230 (t(45)=2.319, p=0.025 and t(45)= 2.486, p=0.017, respectively), as compared to BP patients without ND. Furthermore, the univariate analysis revealed a significant association between ND and anti-BP230 positivity (P= 0.043). In detail, we observed a 4-time increased risk to have ND in BP patients showing anti-BP230 positivity. Conclusion: BP230 (BPAG1) is a member of the plakine family that links hemidemosomes to keratin filaments, being expressed at neuronal level. Thus, we hypothesized that alterations induced in ND could lead to the impairment of the “immune privilege”, thus provoking the exposition of BP230 neuronal isoform.

Background and Objective: Thyroid-associated ophthalmopathy (TAO) is the most common extrathyroidal manifestation of Graves disease, occasionally severe and refractory to treatment, mainly in long-term disease. In these cases, one of the most important infiltrating cytokines in the orbital tissue is interleukin-6 (IL-6). Methods: This is a case report, the methodology consisted of the application of tocilizumab in a patient with graves disease and the patient's follow-up. Results: We present the case of a 54-year-old male with TAO who responded adequately to treatment with tocilizumab, an antibody directed against the IL-6 receptor. Conclusion: Tocilizumab could be an optional treatment in patients with TAO.