Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 19, Issue 8, 2019

Background: The effects of exercise on the innate/inflammatory immune responses are crucially mediated by catecholamines and adrenoreceptors; and mediations in both stimulatory and anti-inflammatory responses have been attributed to them. Obesity and metabolic syndrome are included among low-grade chronic inflammatory pathologies; particularly because patients have a dysregulation of the inflammatory and stress responses, which can lead to high levels of inflammatory cytokines that induce insulin resistance, contributing to the onset or exacerbation of type 2 diabetes. Macrophages play a crucial role in this obesity-induced inflammation. Although most of the antiinflammatory effects of catecholamines are mediated by β adrenergic receptors (particularly β2), it is not known whether in altered homeostatic conditions, such as obesity and during exercise, innate/ inflammatory responses of macrophages to β2 adrenergic stimulation are similar to those in cells of healthy organisms at baseline. Objective: This review aims to emphasize that there could be possible different responses to β2 adrenergic stimulation in obesity, and exercise in this condition. Methods: A revision of the literature based on the hypothesis that obesity affects β2 adrenergic regulation of macrophage-mediated innate/inflammatory responses, as well as the effect of exercise in this context. Conclusion: The inflammatory responses mediated by β2 adrenoreceptors are different in obese individuals with altered inflammatory states at baseline compared to healthy individuals, and exercise can also interfere with these responses. Nevertheless, it is clearly necessary to develop more studies that contribute to widening the knowledge of the neuroimmune regulation process in obesity, particularly in this context.

Objective: This narrative review gives an overview on the essential role of adequate nutrition to an optimally functioning immune defence. Micronutrients act as regulators of the immune response, with the focus of this review on the immunomodulatory effects of the trace elements iron, zinc and selenium, and the vitamins A, D, E, C, B6 and B12 and folic acid. Results: Iron deficiency especially impairs the Th1 cell-borne cellular immunity. T lymphocytes are also most affected by a deficiency of zinc, needed for their maturation and the balance between the different T cell subpopulations and acting as a redox signal in the regulation of many enzymes. Selenium is also involved in redox reactions as the glutathione peroxidases and other redox enzymes are selenoproteins. Selenium status has shown special effects on cellular immunity and resistance to viral infections. Vitamin A in the form of retinoic acid induces a humoral Th2 cell response via antigen-presenting cells and is involved in maintaining intestinal immune defence and tolerance through its nuclear receptor RAR and via kinase signalling cascades. Immune tolerance is particularly promoted by vitamin D acting through dendritic cells to stimulate the differentiation of regulatory T cells. Vitamin E has antiinflammatory effects and stimulates naïve T cells especially in the elderly. Besides its antioxidative properties, vitamin C has effects on cell signalling and epigenetic regulation. The B vitamins are required for cytotoxic cellular immunity and modulate T cell responses. Conclusion: A diverse diet and regular exposure to sunlight are the best sources for a balanced nutrient supply to maintain an optimal immune defence.

Background and Objective: An overview of the history of endocrinology indicates that definitions of some initially developed concepts, including the term ‘hormone’ have been changed over time. This review provides a historical overview of current definitions of ‘hormone’ and the criteria of a true hormone. In addition, a brief history of hormone-related concepts and their transformation over time are discussed. Results: Classically, a hormone is a chemical substance secreted into the bloodstream and acts on distant tissues, usually in a regulatory fashion. Several newly discovered bioregulators and chemical signaling molecules are far from the classical definition of a true hormone and could not fulfill many relevant criteria. Major developments in the field of endocrinology accompanied by the complex terminology, currently used to describe hormonal actions of chemical messengers, underscore the need of the revision of such classical concepts. Conclusion: Complex terminology currently used to describe different hormonal actions of chemical messengers, suggests that it is time to conceptualize the term hormone and revise its classical definition.

Objective: Schistosomiasis is a debilitating disease that affects 200 million people worldwide. Schistosoma haematobium and Schistosoma mansoni are the major causative agents of this disease. Cancer-association and infertility-association in Schistosoma haematobium infection have already been described and it is known that the parasite produces a catechol-estrogen molecule that induces a hormonal imbalance in the host. Methods: In order to better understand the relation of hormonal imbalance in experimental Schistosoma mansoni infection, we investigated a serum panel of steroid hormones in Schistosoma mansoni infected hamsters. Results: We found a decrease in the serum levels of Estradiol (E2), Testosterone and Progesterone in infected females and an increase of Testosterone and a decrease in Progesterone in infected males in comparison with controls. Conclusion: These results indicate that S. mansoni alters the levels of steroid hormones in infected males and females and it will increase the repertoire of data about the host-parasite molecular interplay and its relation with the endocrine system.

Background and Objective: Spasticity (most common disability in upper motor neuron syndrome or UMNS) caused an inability of patients’ to perform daily activities and a decrease inquality of life. One of the promising methods nowadays, but still not widely used in everyday practice, for spasticity reduction is extracorporeal shock wave. The aim of this study was to evaluate the objective clinical effects of combined treatment botulinum toxin type A and radial Extracorporeal Shock Wave Therapy in spasticity post stroke. Methods: We considered 30 subjects (14 female and 16 male) with post stroke spasticity of Biceps Brachii, Superficial Flexor Digitorum, Gastrocnemius Medialis and Lateralis and we divided patients into two groups (group A received botulinum toxin injection and physiotherapy while group B received botulinum toxin injection, rESWT and physiotherapy). Assessments were performed before treatment (t0), after 1 (t1), 2 (t2) e 3 (t3) months using Modified Ahworth Scale, Visual Analogical Scale for pain and MyotonPro® device (to assessed myometric evaluation of muscles tone and stiffness). Results: Visual Analogical Scale, Modified Ahworth Scale, muscles tone and stiffness statistically decreased until t3 in the group A and in the group B, but the differences between the two groups were significant at the t1 only. Conclusion: Radial Extracorporeal Shock Wave Therapy could be an effective physical treatment aimed at the reduction of upper and lower limbs spasticity and could lead to the improvement of trophic conditions of the spastic muscles in post-stroke.

Background: Increased parathyroid hormone (PTH) level is associated with coronary artery disease, hypertension and left ventricular hypertrophy which are all predisposing factors for the ischemic cerebrovascular event (ICVE). Carotid intima-media thickness (CIMT) and aortic distensibility are the two early, subclinical predictors of atherosclerosis. The relation of PTH with CIMT and aortic distensibility in patients with ICVE has not been previously studied. Objective: Our aim was to study the relationship of PTH levels with aortic distensibility and CIMT in patients with ICVE. Methods: Sixty-four ICVE patients and 50 control group were enrolled in the study. PTH levels, aortic distensibility and CIMT were measured in all individuals. Results: PTH levels were significantly higher in ICVE patients than in the controls (60.1±21.6 vs. 52.3±6.2 pg/ml) (p=0. 008). PTH levels were found to be inversely correlated with aortic distensibility (r= -0. 420, p=0.001) and positively correlated with CIMT (r:0, 285, p=0,002). Conclusion: The present study shows that PTH levels are increased in patients with acute ischemic cerebrovascular event compared to the control group. It also demonstrates that PTH levels are inversely related to aortic distensibility of ascending aorta and positively associated with CIMT.

Objective: The aim of this study was to examine pancreatic pathology and the prophylactic effects of pregabalin in lipopolysaccharide (LPS) induced sepsis model in aged rats. Methods: Twenty-four female, one-year-old, Wistar Albino rats were assigned to three groups; Group I (control), Group II (study group: 5mg/kg LPS intraperitoneal, single dose) and Group III(treatment group: 5mg/kg LPS+30 mg/kg oral pregabalin one hour before LPS). Animals were sacrificed by exsanguination 6 hours after LPS administration. Blood and pancreatic tissue samples were collected for biochemical, pathological, and immunohistochemical analyses. Results: LPS caused increases in serum amylase and lipase level but led to a reduction in glucose levels. Following histopathological analysis, numerous neutrophil leucocyte infiltrations were observed in vessels and pancreatic tissues. Increased caspase-3 expression was observed in both the endocrine and exocrine pancreas in the LPS group. Similarly, IL-6, caspase-3 (Cas-3), inducible nitric oxide synthase (iNOS), granulocyte colony-stimulating factor (G-CSF) and serum amyloid-A (SAA) expressions were increased by LPS. Pregabalin improved biochemical, histopathological, and immunohistochemical findings. Conclusion: This study showed that LPS causes pathological findings in the pancreas, but pregabalin has ameliorative effects in aged rats with sepsis. Cas-3, IL-6, iNOS, G-CSF, and SAA all play pivotal roles in the pathogenesis of LPS-induced pancreatic damage.

Objective: Traditionally prepared infusions and decoctions are commonly used in the management of diabetes mellitus, in southern Nigeria; one of such is the aqueous extract of the sclerotia of Pleurotus tuberregium (“usu” milk). In this study, the effects of the extract on the body weights, tissue/ organ weights, fasting blood glucose, blood/plasma lipid profiles and atherogenic indices were investigated in normal and alloxan-induced diabetic rabbits. Methods: Diabetes mellitus was induced by the injection of alloxan (120 mg/kg body weight) via the marginal ear vein. The extract was administered orally at 100, 200 and 300 mg/kg to normal and diabetic rabbits; while metformin was administered at 50 mg/kg. The crude extract was analyzed by gas chromatography, coupled to flame ionization detector. Results: Thirty-one known flavonoids were detected, consisting mainly of isoquercetin (28.5%), luteolin (24.3%), quercetin (18.8%) and kaempferol (11.3%). Sitosterol (82.0%) and stigmasterol (12.5%) were the most abundant of the seven phytosterols detected. Compared to the diabetic control, the treatment significantly (p<0.05) lowered the weights of the kidney and liver, as well as the levels of blood glucose and triglyceride, plasma VLDL, LDL and non-HDL cholesterol, atherogenic index of plasma, cardiac risk ratio, atherogenic coefficient and Castelli’s risk index II. It, however, significantly (p<0.05) increased plasma HDL cholesterol, without significantly affecting blood total cholesterol levels. Conclusion: This study showed that the extract was hypoglycemic, and improved lipid profile and atherogenic indices, thus highlighting its cardioprotective potential, thereby supporting its use in the management of diabetes mellitus.

Background: Diabetic nephropathy is a common worldwide multifactorial disease where involvement of genetic factors is well etablished. The aim of this study was to investigate the HLA genes implication in the development of type 1 diabetic nephropathy. Methods: We performed a case- control study where one hundred and fifty subjects were examined. Patients were divided in two groups; with and without type 1 diabetic nephropathy. HLA typing was performed using Polymerase Chain Reaction- Sequence Specific Oligonucleotide (PCR- SSO) method. HLA association to clinical phenotype and HLA haplotype analysis was also investigated. Results: HLA B*51 is increased in patients without type 1 diabetic nephropathy (7.14% vs. 0 %, P <0.05, OR= 0), however no other studied alleles seem to have any effect (all P>0.05). Haplotype analysis also does not reveal any significant association, however, A*02-B*18-DRB1*03-DQA1*05- DQB1*03 haplotype shows a tendency to be associated with the development of diabetic nephropathy (P = 0.05). Conclusion: These results suggest a protective effect of HLA B*51 allele from type 1 diabetic nephropathy. However, further studies are required in order to clarify its potential implication as a protective marker.

Objective: The purpose of the study is to evaluate whether low-dose exposure to benzene, an environmental pollutant to which male and female traffic policemen are daily exposed to could cause alterations in plasma luteinizing hormone (LH) levels. Methods: From an initial sample of 1594 workers, we only selected 95 workers of whom study we knew the values of late-shift benzene and LH hormone. All subjects underwent biological monitoring (final blood benzene evaluation) and luteinizing hormone dosing. Excluding subjects with the main confounding factors, the final sample included 76 workers. The normal distribution of the variables was evaluated using the Kolmogorov - Smirnov test, followed by the logarithmic transformation of the LH and benzene values. The comparison among means was performed by using the t-test for the independent samples. The ANOVA test was performed for variables with more than 2 modes (ages and seniority) and Pearson correlation index between variables in the total sample and after subdivision as to sex, job, sports activity and smoking. The results were considered significant when p values were less than 0.05. Results / Conclusion: The study did not show a correlation between benzene levels and LH plasma levels in outdoor workers.

Background: We aimed to assess Vitamin D levels in patients with Type 1 Diabetes (T1D) and to investigate the correlation between vitamin D and metabolic imbalance. Material and Methods: For our study, we selected thirty-one patients with T1D without complications and fifty-seven healthy controls. Diabetic patients were diagnosed using the criteria of the World Health Organization/American Diabetes Association. Vitamin D, Parathyroid Hormone (PTH), insulin and C peptide assay were performed using chimilunescence. Glucose level, lipid profile, glycated haemoglobin (HbA1c) and ionogram were also analysed. Results: Vitamin D, HbA1c and Gly levels were found to be significant in T1D patients than in controls (P<0.5). However, for PTH, no significant difference was observed (P > 0. 05) and the results show a non-significant difference of total cholesterol potassium, sodium, phosphor and calcium concentration averages. Conclusion: Our results indicate that the deficiency of VD is associated with an increased risk of T1DM in Algerian population.

Background: Mesenchymal stem cells (MSCs) are highly preferred in clinical therapy for repair and regeneration of diseased tissues for their multipotent properties. Conventionally, MSCs have been cultured in media supplemented with animal derived serum, however, it is ideal to expand MSCs in media containing supplements of human origin for clinical therapy. Currently, a number of human derived products are being studied as an alternative to animal sources. Amongst these, platelet lysate (PL) has gained interest in the culture of MSCs without affecting their phenotypic property. Objective: In this study, we used various concentration of PL (2.5, 5, 7.5 & 10%) in the growth medium of MSCs to identify the least concentration of PL that could be an effective alternative to animal products. Methods: MSCs were isolated from Wharton’s Jelly by using explant method and expanded in various concentration of PL supplemented medium against the standard FBS containing medium. WJ-MSCs were characterised as per the minimal criteria proposed by International Society for Cell therapy (ISCT), Proliferation study by BrdU assay, gene expression study by qRT-PCR, sterility test for bacteria, Mycoplasma by PCR and endotoxin detection by LAL assay. Results: Whartons jelly derived MSCs (WJ-MSCs) cultured using standard medium supplemented with various concentration of PL exhibited enhanced proliferation and differentiation potential, unaltered immunophenotypic property and genetic stability when compared with the commercial medium containing 10% FBS. Conclusion: The least concentration of PL for an ideal expansion of MSCs was found to be 2.5% and was comparable to FBS.

Background: Inflammation may occur in Type2 diabetes mellitus. sPLA2 is among the factors that contribute to the activation of pathways involved in inflammation. Several agents affect serum sPLA2 level, one of which is genetic diversity. Objective: The current study was performed to determine whether there is a relationship between sPLA2 gene (−763C > G) polymorphism and circulating sPLA2 level in patients with Type 2 diabetes. Methods: DNA was extracted from blood samples and used for the amplification of sPLA2 gene using ARMS-PCR. Results: A statistical analysis using SPSS (version 16) revealed a significant correlation between −763C > G sPLA2 gene polymorphisms and the disease incidence in patients with T2DM. Among the three possible genotypes (GG, CC, and CG), CG genotype was found to have a higher frequency(53%) in T2DM patients. GG and CC genotypes frequencies were 20 and 27%, respectively. In healthy individuals, the frequencies of CC, GG, and GC genotypes were 77, 9.8% and 13.2%, respectively). Patients with genotype GG had the highest level of sPLA2. We showed that C>G polymorphism at position– 763 is associated with a high level of sPLA2 in both T2DM patients and healthy individuals. The average of sPLA2 circulating level was (170.48± 84.90), (106.62 ± 74.31), in patients and normal individuals, respectively. Conclusion: Our findings show that sPLA2 serum level is significantly higher in patients with T2DM disease than that in healthy individuals.

Background: Tamoxifen (TAM) is a frequently used hormonal prodrug for patients with breast cancer that needs to be activated by cytochrome P450 2D6 (CYP2D6) into Zusammen-endoxifen (Z-END). Objective: The purpose of the study was to determine the association between CYP2D6*10 (c.100C>T) genotype and attainment of the plasma steady-state Z-END minimal threshold concentration (MTC) in Indonesian women with breast cancer. Methods: A cross-sectional study was performed in 125 ambulatory patients with breast cancer consuming TAM at 20 mg/day for at least 4 months. The frequency distribution of CYP2D6*10 (c.100C>T) genotypes (C/C: wild type; C/T: heterozygous mutant; T/T: homozygous mutant) was detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), the results of which were subsequently confirmed by sequencing. The genotypes were categorized into plasma Z- END concentrations of <5.9 ng/mL and ≥5.9 ng/mL, which were measured using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Results: Percentages of C/C, CT, and T/T genotypes were 22.4%, 29.6%, and 48.8%, respectively. Median (25-75%) Z-END concentrations in C/C, C/T, and T/T genotypes were 9.58 (0.7-6.0), 9.86 (0.7-26.6), and 3.76 (0.9-26.6) ng/mL, respectively. Statistical analysis showed a significant difference in median Z-END concentration between patients with T/T genotype and those with C/C or C/T genotypes (p<0.001). There was a significant association between CYP2D6*10 (c.100C>T) genotypes and attainment of plasma steady-state Z-END MTC (p<0.001). Conclusion: There was a significant association between CYP2D6*10 (c.100C>T) and attainment of plasma steady-state Z-END MTC in Indonesian breast cancer patients receiving TAM at a dose of 20 mg/day.

Background: Atorvastatin (ATV) inhibits the conversion of 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) to mevalonate formation and promotes lowering of the LDL cholesterol fraction. However, ATV exhibits pleiotropic metabolic actions beyond cholesterol-lowering properties. Objective: We aimed to evaluate the effect of ATV on oxidizing species generation and cytokine secretion in Peripheral Blood Mononuclear Cells (PBMNC) of Type 2 Diabetes Mellitus (T2DM) patients in comparison to healthy control. Methods: Both NADPH-oxidase-dependent and mitochondrial ROS generation were assessed by chemoluminescence luminol-dependent assay and fluorometric experiment, using Dichlorofluorescein Assay (DCFH-DA), respectively. IL-1β and IL-6 were quantified by classical ELISA. Results: ATV inhibited NADPH-oxidase dependent ROS generation, but showed no effect on mitochondrial ROS generation and activated IL-1β and IL-6 secretions in PBMNC from control and T2DM patients. ROS generation and cytokine secretion in the presence of an inhibitor of Protein Kinase Cβ (iPKCβ) and ATV led to similar results. The secretion of IL-1β, PDB-induced in the presence of iPKCβ, but not ATV, was increased. ATV and iPKCβ exacerbated PDB-induced IL-6 secretion. LPS activated the secretion of IL-1β and IL-6 which was potentiated by ATV. Conclusion: ATV inhibited ROS generation and activated IL-1 β/IL-6 secretion in PBMNC of diabetes patients. Its effect was not affected by the hyperglymemia.

Background: Genetic variants in pre-microRNA genes or the 3'UTR of miRNA target genes could influence miRNA-mediated regulation of gene expression and thus contribute to the susceptibility and prognosis of human diseases. Several studies have investigated the association of genetic variants in the seed region of miRNAs with cardiometabolic phenotypes .Therefore the aim of study was to investigate the potential association of miR-4513 rs2168518 C>T gene variability with the risk of developing CAD and its association with different cardiometabolic phenotypes in an Indian cohort to stratify CAD burden in the general population. Methods: The study was conducted on 100 clinically confirmed CAD patients and 100 healthy individuals. Genotyping of MicroR-4513 rs2168518C>T gene variability was performed using Amplification refractory mutation system PCR method. Results: A significant difference was observed in the genotype distribution among CAD cases and healthy controls. The frequencies of three genotypes CC, CT, TT in CAD patient and healthy controls were 5%, 77%, 18%, and 28%, 45% and 27% respectively. A multivariate analysis showed that miR- 4513 rs2168518 polymorphism is associated with an increased susceptibility to CAD in codominant inheritance model for variant CC vs. CT OR 9.58 CI (3.45-26.57), RR 2.3(1.75-3.02), P=0.001. Results also indicate a potential dominant effect of miR-4513 rs2168518 C/T polymorphism on susceptibility of CAD in dominant inheritance model for variant CC vs. (CT+TT) OR 7.38 (2.71-20.07), RR 1.96 (1.56-2.46), P=0.001. In allelic comparison, T allele weakly increased risk of CAD compared to C allele (OR=1.50, 95% CI (1.09-2.26) RR 1.15 (0.94-1.39) P=0.044. Conclusion: It is concluded that CT genotype and T allele of microR-4513 rs2168518 is strongly associated with increased susceptibility to CAD. Furthers studies with larger sample sizes are necessary to confirm this result.

Objective: Current treatment options for Allergic Rhinitis (AR) may have their own limitations and side effects. This study aimed to investigate the effects of Ma-al-Shaeer (MS), a novel natural formulation based on Hordeum vulgare, in the treatment of AR compared with Fexofenadine (FX). Methods: A total of 77 patients with AR were divided into two groups: MS group (n=38) and FX group (n=39). The first group received 15 g of dried MS powder, and the second group received 60 mg of FX twice daily for 14 days. At baseline (week zero) and after the 14-day treatment period (week two), both groups were evaluated for sneezing, rhinorrhea, nasal congestion, nasal itching, post nasal drip, eye, throat, or ear symptoms, headache, cough, mental function, quality of life scores, blood eosinophil count and total IgE levels. Rhinitis control assessment tests were conducted at week zero and again at one week after cessation of treatment (week three) in both groups. Results: All symptoms of AR except cough were significantly reduced in both groups; for nasal congestion, post nasal drip, and headache, the MS treatment was found to be superior. Rhinitis control was significantly increased after treatment in both groups (p value < 0.001). Both drugs significantly reduced total IgE levels. There was no significant change in eosinophil count in either group. Conclusion: MS formulation based on H. vulgare may be an effective treatment for AR. Further studies are needed to confirm the effect of MS as an alternative treatment in AR.

Objectives: In the postmenopausal period, most women suffer vasomotor symptoms (VMS). It is well-known that VMS can worsen the quality of life. Diet seems to play a relevant role in the development of VMS, but the effect of diet on VMS is mainly limited to observational studies, and analyses of nutritional supplements. The aim of this study was thus to determine the efficacy of a lactoovo- vegetarian (LOVe) diet rich in omega-3 fatty acids vs. a lacto-ovo-vegetarian diet rich in EVO (extra-virgin olive oil) in reducing VMS frequency in postmenopausal women. Methods: A two-arms (lacto-ovo-vegetarian diet with EVO vs. lacto-ovo-vegetarian diet rich in omega-3) randomized-controlled trial with a follow-up period of 16 weeks. We considered as primary outcome the change in the Kupperman index (follow-up vs. baseline evaluation, reported as delta, D) and in its subscales. Secondary outcomes included changes in common anthropometric and biohumoral measurements. Results: Among 54 women randomly assigned to a study group, 40 (mean age 55.1±5.4 years) completed the study and complied with their assigned diet. Women randomized to the omega-3 group (n=18) showed significant improvements, compared to the EVO group (n=22), in Kupperman index (Δ=-11.4±9.8 vs. -5.9±8.2; p=0.045), hot flashes (Δ=-3.3±3.4 vs. -1.3±2.6; p=0.04), and a marginally significant improvement in nervousness (Δ=-1.7±1.7 vs. -0.8±1.5; p=0.07). No significant differences were observed for the secondary outcomes. No relevant side effects were reported. Conclusion: After 16 weeks, a lacto-ovo-vegetarian diet rich in omega-3 reduced VMS frequency in postmenopausal women more than the lacto-ovo-vegetarian diet rich in EVO.