Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 20, Issue 1, 2020

Background: Balanced sporting activity should be considered a resource in the treatment of eating disorders (ED), in particular of the BED and in obesity and, if conducted and guided by expert preparers and rehabilitators, in some forms of anorexia and in bulimia. Objective: To assess the role of excessive physical activity, predominantly interfering with daily activities by ultimately resulting in greater energy consumption leading to weight loss, and study the diagnostic criteria of bulimia and anorexia nervosa. Methods: A number of literature studies also report the presence of ED among athletes. A 2004 study reported that the prevalence of eating disorders in sports would be 13.5% compared to 4.5% of the control subjects. Results: In general, nutrition is used as a tool for improving performance not only of athletes but also of technicians and coaches. But in the presence of factors of vulnerability towards ED, the tendency to manipulate the weight can result in an eating disorder or the so-called athletic anorexia or the RED-S. Conclusion: It is important to emphasize that not only do professional athletes suffer from it, but also good-looking amateurs and laypersons.

Objective: The Renin-Angiotensin-Aldosterone System (RAAS) plays a major role in the regulation of cardiovascular functions, water and electrolytic balance, and hormonal responses. We perform a review of the literature, aiming at providing the current concepts regarding the angiotensin interaction with the immune system in the brain and the related implications for cardiovascular and neuroendocrine responses. Methods: Appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined. Results: Angiotensin II (ANG II), beside stimulating aldosterone, vasopressin and CRH-ACTH release, sodium and water retention, thirst, and sympathetic nerve activity, exerts its effects on the immune system via the Angiotensin Type 1 Receptor (AT 1R) that is located in the brain, pituitary, adrenal gland, and kidney. Several actions are triggered by the binding of circulating ANG II to AT 1R into the circumventricular organs that lack the Blood-Brain-Barrier (BBB). Furthermore, the BBB becomes permeable during chronic hypertension thereby ANG II may also access brain nuclei controlling cardiovascular functions. Subfornical organ, organum vasculosum lamina terminalis, area postrema, paraventricular nucleus, septal nuclei, amygdala, nucleus of the solitary tract and retroventral lateral medulla oblongata are the brain structures that mediate the actions of ANG II since they are provided with a high concentration of AT 1R. ANG II induces also T-lymphocyte activation and vascular infiltration of leukocytes and, moreover, oxidative stress stimulating inflammatory responses via inhibition of endothelial progenitor cells and stimulation of inflammatory and microglial cells facilitating the development of hypertension. Conclusion: Besides the well-known mechanisms by which RAAS activation can lead to the development of hypertension, the interactions between ANG II and the immune system at the brain level can play a significant role.

Objective: The need of today’s research is to develop successful and reliable diabetic animal models for understanding the disease susceptibility and pathogenesis. Enormous success of animal models had already been acclaimed for identifying key genetic and environmental factors like Idd loci and effects of microorganisms including the gut microbiota. Furthermore, animal models had also helped in identifying many therapeutic targets and strategies for immune-intervention. In spite of a quite success, we have acknowledged that many of the discovered immunotherapies are working on animals and did not have a significant impact on human. Number of animal models were developed in the past to accelerate drug discovery pipeline. However, due to poor initial screening and assessment on inequivalent animal models, the percentage of drug candidates who succeeded during clinical trials was very low. Therefore, it is essential to bridge this gap between pre-clinical research and clinical trial by validating the existing animal models for consistency. Results and Conclusion: In this review, we have discussed and evaluated the significance of animal models on behalf of published data on PUBMED. Amongst the most popular diabetic animal models, we have selected six animal models (e.g. BioBreeding rat, “LEW IDDM rat”, “Nonobese Diabetic (NOD) mouse”, “STZ RAT”, “LEPR Mouse” and “Zucker Diabetic Fatty (ZDF) rat” and ranked them as per their published literature on PUBMED. Moreover, the vision and brief imagination for developing an advanced and robust diabetic model of 21st century was discussed with the theme of one miceone human concept including organs-on-chips.

Objective: Thyroid Hormones (TH) are essential for normal growth, development and continued optimal function of most of the body organs including the eye. TH signaling plays a central role in the regulation of retinal development and maturation. Deficiency in TH during fetal and early postnatal development impairs growth of the eye and proliferation of all retinal cell types. The present article reviews the most important topics of the different derangements in thyroid function and structure and its relation with eye diseases. Methods: A literature search strategy was conducted for all English-language literature. Results: From a clinical practice viewpoint, it should be mentioned that both hypothyroidism and hyperthyroidism are accompanied by ocular diseases i.e. thyroid-associated ophthalmopathy, diabetic retinopathy and age-related macular degeneration. Although the orbit and globe are not common sites for metastatic thyroid cancers, orbital metastasis may be the primary clinical manifestation of thyroid carcinoma. Finally, some medications as amiodarone may be accompanied by both thyroid dysfunction and adverse ocular events. Conclusion: Thyroid disorders and eye diseases are interrelated through several mechanisms thus, awareness of this relation has a great impact on early diagnosis and treatment.

Background: Bone is an important tissue and its normal function requires tight coordination of transcriptional networks and signaling pathways, and many of these networks/ pathways are dysregulated in pathological conditions affecting cartilage and bones. Long non-coding RNA (lncRNA) refers to a class of RNAs with a length of more than 200 nucleotides, lack of protein-coding potential, and exhibiting a wide range of biological functions. Although studies on lcnRNAs are still in their infancy, they have emerged as critical players in bone biology and bone diseases. The functions and exact mechanism of bone-related lncRNAs have not been fully classified yet. Objective: The objective of this article is to summarize the current literature on lncRNAs on the basis of their role in bone biology and diseases, focusing on their emerging molecular mechanism, pathological implications and therapeutic potential. Discussion: A number of lncRNAs have been identified and shown to play important roles in multiple bone cells and bone disease. The function and mechanism of bone-related lncRNA remain to be elucidated. Conclusion: At present, majority of knowledge is limited to cellular levels and less is known on how lncRNAs could potentially control the development and homeostasis of bone. In the present review, we highlight some lncRNAs in the field of bone biology and bone disease. We also delineate some lncRNAs that might have deep impacts on understanding bone diseases and providing new therapeutic strategies to treat these diseases.

Background: Deltamethrin (DLM) is a type 2 pyrethroid insecticide used in agriculture and home to control pests. However, emerging reports have indicated the immunotoxicity of DLM. Objective: Thus, in the current investigation, we have checked the immune-protective role of quercetin in DLM-induced immunotoxicity by using in silico and in vitro techniques. Results: In silico results have shown good interaction of quercetin towards immune cell receptors (T & B cell receptors). The findings of in vitro studies indicated the decrease in oxidative stress which is elevated by DLM in concentration & time-dependent manner. The increased caspases-3 activity was decreased by treatment of quercetin. The apoptosis induced by DLM in thymus and spleen was suppressed only at higher concentration (50μg/ml) of quercetin. Finally, the phenotypic changes due to DLM were restored by quercetin. Conclusion: Quercetin has strong binding affinity towards CD4, CD8 and CD28, CD45 receptors and protects the thymocytes and splenocytes against DLM-induced apoptotic signaling pathways.

Aims: Oxidative stress is increased during the acute phases of bipolar disorder (BD). Our aim here was to analyze oxidative stress biomarkers in patients with BD during euthymia and their siblings. Method: A cross-sectional study was performed in euthymic patients with BD-I (n=48), unaffected siblings (n=23) and genetically unrelated healthy controls (n=21). Protein carbonyl content (PCC), total antioxidant capacity (TRAP), lipid peroxidation (TBARS) and uric acid were measured as biomarkers of oxidative stress in blood. Results: The antioxidant capacity (TRAP) was lower (p<0.001) in patients with BD compared to their siblings and controls, whereas no differences were observed in PCC, TBARS or uric acid. In patients, the concentrations of TRAP and TBARS were positively associated with the dose of valproic acid (p<0.05 and p<0.001, respectively). The concentrations of these biomarkers were not significantly associated with any of socio-demographic and clinical variables. Conclusion: A selective reduction in antioxidant capacity is present in BD during euthymia state, whereas other markers of oxidative stress are unaltered during euthymia. Siblings did not show any alterations in oxidative stress biomarkers. Oxidative stress might represent a state-dependent marker in BD. The association between treatment with valproic acid and oxidative stress markers in euthymia deserves further studies.

Background: The current study aimed at exploring the cytokine profile in the tears of patients with Graves’ ophthalmopathy (GO). Methods: Tears were sampled from the eyes of 7 patients with active GO and 7 healthy volunteers using filter paper. Then the levels of up to 34 cytokines in the tears of each subject were detected using high-throughput protein microarray technology in line with the introduction. Results: The results of cytokine protein microarray screening showed that 10 proteins, namely, CD40, CD40 Ligand, GITR, IL-12p70, IL-1 beta, IL-2, IL-21, IL-6, MIP-3 alpha and TRANCE, were overexpressed (with fold change >1.20) and 3 proteins, namely, GM-CSF, IL-1 sRI and IL-13 were downregulated (with fold change < 0.83) in GO patients. In addition, the protein levels of CD40 and CD40 ligand (CD40L) were significantly different between GO patients and healthy controls (P=0.028 and 0.011, respectively). Further Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of differently expressed proteins showed that these proteins were involved in biological functions including biological processes (positive regulation of cytokine production, JAK-STAT cascade and leukocyte proliferation), molecular functions (cytokine and growth factor receptors binding and cytokine activity), and other important pathways (cytokine-cytokine receptor interaction, JAK-STAT signaling pathway, IL-17 signaling pathway, NF-kappa B signaling pathway, Th17 cell differentiation, and intestinal immune network for IgA production), all of which might be involved in the pathology of GO. Conclusion: Our cytokine protein microarray analysis indicated that several proteins were differentially expressed in GO patients, which provides potential targets for GO prevention.

Objective: Risk stratification and prompt treatment are essential for the management of acute coronary syndromes (ACS) and prediction of future prognosis. Subclinical vascular inflammation and novel biomarkers play an important role in the clinical evaluation of ACS patients. Methods: We enrolled patients who were admitted to emergency service with unstable angina or non- ST segment elevated ACS (NSTE-ACS) in the study population. Coronary artery disease (CAD) complexity was determined via evaluation of angiographical views and peripheral venous blood samples were collected to measure highly sensitive C-reactive protein (hs-CRP) and soluble form of Lectin-like OxLDL receptor-1 (sLOX-1) levels. Results: A total of 40 patients were enrolled in the study population, mean age was 65.1±13.8 years and male gender percentage was 52.5%. Twenty-nine of patients had NSTE-ACS and 11 patients had unstable angina presentation. The modified Gensini scores were higher for patients with elevated hs- CRP and sLOX-1 levels. Conclusion: Vascular inflammation displays the onset of ACS and it is related to more complex CAD in these patients. An increase in sLOX-1 expression is closely related to anatomical complexity of CAD in ACS.

Introduction: The goal of treatment of chronic hepatitis C (HCV) is viral eradication. However, obtaining histological regression is even more important, because it will reduce the overall morbidity and mortality related to cirrhosis. Introduction of direct-acting antivirals (DAAs) in HCV improves rates of sustained virologic response (SVR). However, fibrosis regression has not been extensively assessed. The aim of this study was to detect the factors affecting fibrosis regression in chronic HCV patients treated with interferon containing regimens versus interferon-free DAA regimens. Methods: This prospective observational cohort study was conducted at the Tropical Medicine and Infectious Diseases Department, Tanta University, Egypt, between October 2015 and December 2017. Transient elastography (FibroScan®) examination was performed before therapy, at SVR12, 6 months and 1 year after completing therapy for cured patients. Results: Reduction in fibrosis was reported in; 46.7% and 49.3% of patients with moderate fibrosis, and 89% and 78.7% of patients with advanced fibrosis after one year of interferon containing and interferon free DAAs regimens respectively. Using multiple regression analysis; it was found that BMI, degrees of hepatic stiffness and steatosis were related to regression of hepatic fibrosis after therapy. Conclusion: DAAs with or without interferon resulted in a significant reduction of liver fibrosis. BMI, steatosis and liver stiffness were independent factors for fibrosis regression in chronic HCV patients treated with DAAs. Further studies are needed to explore the mechanism by which steatosis affects HCV related fibrosis regression after treatment with DAAs.

Background & Aims: Chronic liver disease is characterized by complex hemostatic disorders because the liver is the site where most of the coagulation factors and their inhibitors are synthesized. The aim of this study was the evaluation of protein C and antithrombin III in different stages of chronic hepatitis B and C and to determine their possible role as markers of liver cell damage in different clinical stages. Methods: The study included 60 subjects who were subdivided into 4 groups: (Group I): 15 patients diagnosed as chronic viral hepatitis B or C, (Group II): 15 patients with compensated liver cirrhosis, (Group III): 15 patients with decompensated liver cirrhosis, and (Group IV) (control group): 15 healthy individuals. History taking, clinical examination and abdominal ultrasonography were made for all subjects. Investigations were done in the form of liver function tests (ALT, AST, ALP, serum bilirubin, and serum albumin), PT, PTT, CBC. Plasma levels of Antithrombin III & protein C were estimated by automated Stago compact coagulation analyzer. Results: In all patient groups, the mean value of Protein C showed significant decrease when compared to control group, mean value of antithrombin III showed a significant decrease in compensated and decompensated subjects when compared to chronic hepatitis and control groups. Antithrombin III and protein C showed a significant negative correlation with (ALT, AST, PT, PTT, INR). However, this correlation was positive with Albumin. Conclusion: Antithrombin III and protein C are natural anticoagulants and can be considered as markers of different stages of chronic liver disease. This is supported further by the comparison between the levels of these parameters and clinical stages of liver disease. Protein C is more sensitive than ATIII as a marker of hepatocellular damage.

Objective: Hashimoto’s thyroiditis (HT) is an autoimmune disorder caused by the interaction between genes and environmental triggers. HT is the most common endocrine disorder, as well as the most common cause of hypothyroidism. Autoimmunity plays a crucial role in the pathogenesis of HT and recent studies suggest that Toll-like receptor (TLR) signals lead to increased inflammatory response. The aim of our study is to investigate whether TLR-2 and TLR-4 levels and gene polymorphisms contribute to the damaged immune response leading to HT. Methods: Using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, single-nucleotide polymorphisms (SNPs) of TLR2 gene Arg677Trp, Arg753Gln, 196-174 del and TLR4 gene Asp299Gly, Thr399Ile were studied in 100 patients with HT and 100 healthy controls. Also, we investigated serum levels of TLR-2 and TLR-4 in the immunopathogenesis of HT. TLR-2 and TLR-4 serum levels were found to be significantly higher in HT patients than the control group. However, no statistical significance was found between patient and control groups in terms of genotype frequencies and allele frequency distribution of TLR2 gene Arg677Trp, Arg753Gln, 196-174 del and TLR4 gene Asp299Gly, Thr399Ile polymorphisms. Result: TLR2 gene Arg677Trp, Arg753Gln, 196-174 del and TLR4 gene Asp299Gly, Thr399Ile polymorphism do not appear to have a role in the development of HT disease. However, in our study, serum levels of TLR-2 and TLR-4 were found to be higher in HT patients than control groups. Conclusion: These findings suggest that TLR-2 and TLR-4 play an important role in the immunopathologic mechanism of disease by causing an increase in proinflammatory response.

Background and Objective: The present paper aims to study the inhibition of Candida albicans growth as candidiasis treatment, using seeds of Lepidium sativum as source. Methods: In vitro assays were carried out on the antifungal activity of three kinds of extracts from L. sativum seeds against four strains of C. albicans, then testing the same phytochemicals on the inhibition of Lipase (LCR). A new in silico study was achieved using molecular docking, with Autodock vina program, to find binding affinity of two important and major lepidine alkaloids (lepidine E and B) towards the four enzymes secreted by C. albicans as target drugs, responsible of vitality and virulence of this yeast cells: Lipase, Serine/threonine phosphatase, Phosphomannose isomerase and Sterol 14-alpha demethylase (CYP51). Results: The results of the microdillution assay show that the hexanic and alkaloidal extracts have an antifungal activity with MICs: 2.25 mg/ml and 4.5mg/ml, respectively. However, Candida rugosa lipase assay gives a remarkable IC50 values for the hexanic extract (1.42± 0.04 mg/ml) followed by 1.7± 0.1 and 2.29 ± 0.09 mg/ml of ethyl acetate and alkaloidal extracts respectively. The molecular docking confirms a significant correlation between C. albicans growth and inhibition of crucial enzymes involved in the invasion mechanism and cellular metabolisms, for the first time there were an interesting and new positive results on binding modes of lepidine E and B on the four studied enzymes. Conclusion: Through this work, we propose Lepidine B & E as potent antifungal drugs.

Background: Inflammation, oxidative stress, and adipogenesis are associated with Graves’ ophthalmopathy (GO) progression. Objective: We conducted a pilot study to investigate the effect of Enalapril on patients with mild ophthalmopathy. Method: Based on the comprehensive eye examination, 12 patients with mild ophthalmopathy were selected from referred Graves’ patients and treated with Enalapril (5 mg daily) for 6 months. Clinical and ophthalmological examination [IOP (Intraocular Pressure), vision, Margin reflex distance and exophthalmia measurement, CAS (clinical activity score) and VISA [V (vision); I (inflammation/ congestion); S (strabismus/motility restriction); and A (appearance/exposure] score assessment) was performed at the beginning, 3 months and 6 months of the study period. Quality of life was also evaluated using a standard questionnaire. Results: Mean exophthalmia at the first visit was 18.75 ± 2.39, 3 months later 18.53 ± 2.39 and 6 months later was 17.92 ± 2.31, respectively. Mean CAS was 0.71 ± 0.82 (first visit), 0.57 ± 0.54 (3 months) and 0.14 ± 0.36 (6 months), respectively. Mean Margin reflex distance was 9.09 ± 4.36 (first visit) and 9.60 ± 4.40 (6 months), respectively. There were significant differences in the case of exophthalmia (P=0.002), CAS (P=0.006), and Margin reflex distance (P=0.029) between the first visit and 6 months after treatment. The difference between the score of quality of life in patients with GO after 6 months of follow up was statistically significant (P = 0.006). Conclusion: Our results showed that Enalapril treatment could ameliorate the clinical course of GO according to the ophthalmologic examinations and subjective parameters of disease progression. However, further studies should be performed to determine the efficacy of Enalapril in Graves’ ophthalmopathy treatment.

Background: The extensive impacts of vitamin D on the immune system has gathered the attention of scholars in last years. In this regard, studies about vitamin D and incidence of asthma have showed various results. The aim of this study was to evaluate the effect of vitamin D supplements on clinical outcomes in asthmatic children with vitamin D insufficiency. Materials & Methods: This before-after interventional study was conducted on all asthmatic children who attended the Be'sat Hospital, Iran. Serum levels of 25(OH)D, asthma severity and pulmonary function tests before and after therapeutic prescription of vitamin D were evaluated. Serum levels of 25(OH)D were measured by enzyme-linked immunosorbent assay. Results: The mean age of the samples was 10.69±9.78 years and 39 subjects (57.4%) were male. The primary mean level of serum 25(OH)D (18.21±8.22, ng/mL) has significantly (p<0.05) increased after treatment (35.45±9.35, ng/mL). Also, asthma severity, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC indicators were significantly (p<0.05) increased after treatment. Conclusion: We can conclude that therapeutic prescription of vitamin D is very effective in improving the clinical status of asthmatic children.