Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 21, Issue 4, 2021

Intellectual disability (ID), previously called mental retardation, is the most common neurodevelopmental disorder characterized by life-long intellectual and adaptive functioning impairments that have an impact on individuals, families, and society. Its prevalence is estimated to 3% of the general population and its etiology is still insufficiently understood. Besides the involvement of genetic and environmental factors, immunological dysfunctions have been also suggested to contribute to the pathophysiology of ID. Over the years, immune biomarkers related to ID have gained significant attention and researchers have begun to look at possible cytokine profiles in individuals suffered from this disorder. In fact, in addition to playing crucial physiological roles in the majority of normal neurodevelopmental processes, cytokines exert an important role in neuroinflammation under pathological conditions, and interactions between the immune system and central nervous system have long been under investigation. Cytokine levels imbalance has been reported associated with some behavioral characteristics and the onset of some syndromic forms of ID. In this review, we will focus on immunological biomarkers, especially the cytokine profiles that have been identified in people with ID. Thus, data reported and discussed in the present paper may provide additional information to start further studies and to plan strategies for early identification and managing of ID.

Inadequate serum selenium levels may delay the growth and physiological changes in bone metabolism. In humans, reduced serum selenium concentrations are associated with both increased bone turnover and reduced bone mineral density. Moreover, a reduced nutritional intake of selenium may lead to an increased risk of bone disease. Therefore, selenium is an essential nutrient playing a role in bone health, probably due to specific selenium-proteins. Some selenium-proteins have an antioxidation enzymatic activity and participate in maintaining the redox cellular balance, regulating inflammation and proliferation/differentiation of bone cells too. At least nine selenium-proteins are known to be expressed by fetal osteoblasts and appear to protect bone cells from oxidative stress at bone microenvironment. Mutations of selenium-proteins and reduced circulating levels of selenium are known to be associated with skeletal diseases such as the Kashin-Beck osteoarthropathy and postmenopausal osteoporosis. In addition, the intake of selenium appears to be inversely related to the risk of hip fragility fractures. Recent data suggest that an altered selenium state may affect bone mass even in males and selenium-proteins and selenium concentrations were positively associated with the bone mass at femoral, total and trochanteric sites. However, selenium, but not selenium-proteins, seems to be associated with femoral neck bone mass after adjustment for many bone fracture risk factors. The present review summarizes the findings of observational and interventional studies, which have been designed for investigating the relationship between selenium and bone metabolism.

COVID-19 cases have been reported as a global threat and several studies are being conducted using various modelling techniques to evaluate patterns of disease dispersion in the upcoming weeks. Here we propose a simple statistical model that could be used to predict the epidemiological extent of community spread of COVID-19 from the explicit data based on optimal ARIMA model estimators. Raw data was retrieved on confirmed cases of COVID-19 from Johns Hopkins University (https://github.com/CSSEGISandData/COVID-19) and the Auto-Regressive Integrated Moving Average (ARIMA) model was fitted based on cumulative daily figures of confirmed cases aggregated globally for ten major countries to predict their incidence trend. Statistical analysis was completed by using R 3.5.3 software. The optimal ARIMA model having the lowest Akaike information criterion (AIC) value for US (0,2,0); Spain (1,2,0); France (0,2,1); Germany (3,2,2); Iran (1,2,1); China (0,2,1); Russia (3,2,1); India (2,2,2); Australia (1,2,0) and South Africa (0,2,2) imparted the nowcasting of trends for the upcoming weeks. These parameters are (p, d, q) where p refers to the number of autoregressive terms, d refers to the number of times the series has to be differenced before it becomes stationary, and q refers to the number of moving average terms. Results obtained from the ARIMA model showed a significant decrease in cases in Australia; a stable case for China and rising cases have been observed in other countries. This study predicted the possible proliferate of COVID-19, although spreading significantly depends upon the various control and measurement policy taken by each country.

Inborn errors of metabolism (IEM) are a heterogeneous group of rare genetic disorders that are generally transmitted as autosomal or X-linked recessive disorders. These defects arise due to mutations associated with specific gene(s), especially the ones associated with key metabolic enzymes. These enzymes or their product(s) are involved in various metabolic pathways, leading to the accumulation of intermediary metabolite(s), reflecting their toxic effects upon mutations. The diagnosis of these metabolic disorders is based on the biochemical analysis of the clinical manifestations produced and their molecular mechanism. Therefore, it is imperative to devise diagnostic tests with high sensitivity and specificity for early detection of IEM. Recent advances in biochemical and polymerase chain reaction-based genetic analysis along with pedigree and prenatal diagnosis can be life-saving in nature. The latest development in exome sequencing for rapid diagnosis and enzyme replacement therapy would facilitate the successful treatment of these metabolic disorders in the future. However, the longterm clinical implications of these genetic manipulations is still a matter of debate among intellectuals and requires further research.

Rheumatoid arthritis is a chronic inflammatory autoimmune disease characterized by the failure of spontaneous resolution of inflammation with lifetime perseverance, becoming one of the major causes of disability in millions of people. It is mainly characterized by progressive erosion of cartilage in response to the formation of pannus leading to chronic polyarthritis and joint distortion. Early diagnosis and advances in molecular biology undoubtedly revolutionized therapeutic interventions in the past decade for better disease management. Despite favorable prospects, many patients still fail to respond to the current therapies urging a burning need to develop newer and safer medications. Herbal plants have been utilized since the ancient era and provided the base for massive bioactive compounds with flaunting therapeutic potential, many being advanced to drugs that are consumed worldwide for treating countless ailments. Scientific studies showed the involvement of several cellular mechanisms like oxidative stress suppression, downregulated synthesis of proinflammatory cytokines namely interleukins (IL-1, IL-6), TNF-α, NF-ΚB, demoted metalloproteinases induced cartilage destruction and augmentation of free radical scavenging and antioxidant activity in the treatment of rheumatoid arthritis. A plethora of active phytoconstituents like flavonoids, saponins, terpenes, alkaloids, lactones, etc, have been isolated from herbal plants with proven curative actions. The present review enlists some of the herbal drugs that can be used to amend the effects of rheumatoid arthritis and impart symptomatic relief to patients.

New pieces of evidence suggest that combining basal insulin with glucagone-like peptide 1 receptor agonists (GLP-1RA) in patients with type 2 diabetes could promptly ameliorate glucose control and prevent both hypoglycemic events and unnecessary weight gain compared to more intensive insulin regimens. To review the efficacy/effectiveness and safety of fixed-ratio combinations of basal insulin and GLP- 1RA (FRCs). Authors searched PubMed/MEDLINE, ClinicalTrials.gov, Cochrane Library, and Google Scholar for freely available original articles, randomized clinical trials (RCTs), clinical reviews, and meta-analysis written in English until January 2020. FRCs provide significative reductions in HbA1c levels in both insulin-naïve (-1.4% to -2%) and insulin- experienced (-1.5% to -2%) type 2 diabetic patients with moderate glucose impairment. More patients achieved the recommended glycemic targets on FRCs compared to those on mono-therapy with basal insulin or GLP-1RAs. The intensification with FRCs results in better glycemic control compared to basal insulin at fasting as well as during the postprandial state. The frequency of hypoglycemia is similar or lower in patients treated with FRCs than in those on basal insulin alone at a similar dose. Weight trend can be variable, ranging from -2.7 to +2 Kg for iDegLira and -0.7 to -1.3 Kg for iGlar- Lixi. However, a lower weight gain is obtained with iDegLira compared to iDeg (-2.2 to -2.5 Kg), iGlar (-1.7 to -3.2 Kg), and basal-bolus (-3.6 Kg) as well as with iGlarLixi compared to iGlar (-1.4 Kg). FRCs should be considered to safely improve the metabolic control in type 2 diabetic patients with moderate glycemic impairment while on oral medications, basal oral regimen or GLP-1RAs. However, a few but significative pieces of evidence suggest that FRCs could be a safe and effective treatment instead of a low dose basal-bolus intensification for patients with mild or moderate glucose impairment in order to reduce the risk of hypoglycemia and unnecessary weight gain, and for simplifying treatment regimen as well.

Predominantly antibody deficiencies (PADs) are a heterogeneous group of primary immunodeficiency disorders (PIDs), consisting of recurrent infections, autoimmunity, inflammation, and other immune complications. In the recent years, several immunological and genetic defects have been recognized in PADs. Currently, 45 distinct PAD disorders with 40 different genetic defects have been identified based on the 2019 IUIS classification. Genetic analysis is helpful for diagnosing PIDs; however, genetic studies are expensive, time-consuming, and unavailable everywhere. Flow cytometry is a highly sensitive tool for evaluating the immune system and diagnosing PADs. In addition to cell populations and subpopulations assay, flow cytometry can measure cell surface, intracellular and intranuclear proteins, biological changes associated with specific immune defects, and certain functional immune abnormalities. These capabilities help in rapid diagnostic and prognostic assessment as well as in evaluating the pathogenesis of PADs. For the first time, this review particularly provides an overview of the application of flow cytometry for diagnosis, immunophenotyping, and determining the pathogenesis of PADs.

Background: Immunodeficiency, centromeric instability and facial dysmorphism (ICF) syndrome is a rare autosomal recessive immune disorder presenting with hypogammaglobulinemia, developmental delay, and facial anomalies. The ICF type 1, type 2, type 3 and type 4 are characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS gene, respectively. This study aimed to present a comprehensive description of the clinical, immunologic and genetic features of patients with ICF syndrome. Methods: PubMed, Web of Science, and Scopus were searched systemically to find eligible studies. Results: Forty-eight studies with 118 ICF patients who met the inclusion criteria were included in our study. Among these patients, 60% reported with ICF-1, 30% with ICF-2, 4% with ICF-3, and 6% with ICF-4. The four most common symptoms reported in patients with ICF syndrome were: delay in motor development, low birth weight, chronic infections, and diarrhea. Intellectual disability and preterm birth among patients with ICF-2 and failure to thrive, sepsis and fungal infections among patients with ICF-1 were also more frequent. Moreover, the median levels of all three immunoglobulins (IgA, IgG, IgM) were markedly reduced within four types of ICF syndrome. Conclusion: The frequency of diagnosed patients with ICF syndrome has increased. Early diagnosis of ICF is important since immunoglobulin supplementation or allogeneic stem cell transplantation can improve the disease-free survival rate.

Background: Recent clinical trial studies have reported that L-carnitine supplementation can reduce the mortality rate in patients with sepsis, but there are no definitive results in this context. The current systematic review and meta-analysis aimed to evaluate the effect of L-carnitine supplementation on 28-day and one-year mortality in septic patients. Methods: A systematic search conducted on Pubmed, Scopus and Cochrane Library databases up to June 2019 without any language restriction. The publications were reviewed based on the Cochrane handbook and preferred reporting items for systematic reviews and meta-analyses (PRISMA). To compare the effects of L-carnitine with placebo, Risk Ratio (RR) with 95% confidence intervals (CI) were pooled according to the random effects model. Results: Across five enrolled clinical trials, we found that L-carnitine supplementation reduce one-year mortality in septic patients with SOFA> 12 (RR: 0.68; 95% CI: 0.49 to 0.96; P= 0.03) but had no significant effect on reducing 28-day mortality ((RR: 0.93; 95% CI: 0.68 to 1.28; P= 0.65) compared to placebo. Finally, we observed that based on current trials, L-carnitine supplementation may not have clinically a significant effect on mortality rate. Conclusion: L-carnitine patients with higher SOFA score can reduce the mortality rate. However, the number of trials, study duration and using a dosage of L-carnitine are limited in this context and further large prospective trials are required to clarify the effect of L-carnitine on mortality rate in septic patients.

Introduction: Yersinia enterocolitica infection is reportedly associated with the development of autoimmune thyroid diseases (AITD). However, evidence that such infection can lead to AITD is controversial. Thus, this study was aimed to investigate the associations of Y. enterocolitica infection with AITD. Methods: A meta-analysis was performed using PubMed, Web of Science, Embase and Cochrane library to identify relevant studies. The odds ratios (OR) and associated 95% confidence intervals [CI] were obtained. Data were analyzed by STATA 13.0 (Stata Corporation, College Station, TX, USA). Results: Of 215 articles identified, 8 studies with a total of 1490 participants met the criteria and were included in the meta-analysis. There was a significant association between Y. enterocolitica positivity and AITD (OR: 4.31 [CI 95%: 1.81–10.07], P-value: 0.00). According to the subgroup analysis, Y. enterocolitica infection statistically increased the risk of Graves' disease (GD) (OR: 6.12, [CI 95%: 3.71-10.10], P-value: 0.00). Likewise, the pooled OR of association between Y. enterocolitica positivity and hashimoto’s thyroiditis (HT) was 2.84 (CI 95%: 0.71-11.25, P-value: 0.1). Conclusion: The current studies suggest that Y. enterocolitica may be associated with the development of AITD. Further study is needed to explore the underlying mechanisms.

Background: The therapeutic effect of Cola nitida hot infusion against diabetes hepatic injury was investigated in livers of diabetic rats. Cola nitida was infused in boiling water and concentrated. Methods: The concentrated infusion was administered to T2D rats at low and high doses (150 and 300 mg/kg body weight (bw), respectively). The normal group (positive control) and another diabetic group (negative control) were administered distilled water, while metformin served as the standard drug. A toxic group that consists of normal rats administered a high dose of C. nitida. After 6 weeks, the rats were sacrificed, and their livers were collected. They were assayed for oxidative stress markers, myeloperoxidase, acetylcholinesterase and ATPase activities. Hepatic lipid metabolites were profiled with GC-MS and their metabolic pathways were analyzed using the MetaboAnalyst 4.0 online server. Results: Treatment with C. nitida caused a significant elevation of glutathione level and SOD activity, while concomitantly inhibiting lipid peroxidation, myeloperoxidase, acetylcholinesterase and ATPase activities in hepatic tissues of the rats. Treatment with C. nitida also caused significant depletion of diabetes-generated lipid metabolites, with concomitant generation of fatty esters and steroids as well as inactivation of diabetes-activated pathways. Conclusion: These data demonstrate the therapeutic effect of C. nitida against diabetic hepatotoxicity in diabetic rats.

Aim: This study aims to add to previous analyses and describe the trends in MSA research from three decades, 1988 to 2018, through assessing the medical literature. Additionally, a collaboration network was analyzed to determine the most common process in development of MSA research. Methods: This research was a descriptive survey with a scientometric approach. The data for the present study were collected from the Web of Science (WoS) and search strategy based on Medical Subject Heading (MeSH) term. In this research, the data analysis was performed based on collaboration network and theme analysis. Results and Conclusion: In this study, 6530 articles were retrieved from 1988 to 2018 divided in three different periods. These articles were drafted by 39,184 authors, 3,865 organizations, 80 countries, and 832 journals. Further, 287 articles with more than 100 citations were found. The global citation score (GCS) was 250,834 times and the average citations per article was 3,841 times. The MSA research field demonstrated a diagram for a chronological period to assess the most relevant themes. Each diagram depended on the sum of documents linked to each research topic. Scientometric analysis of the field of MSA can be regarded as a roadmap for future research and policymaking in this important area.

Aim: The study was conducted to assess the antidiabetic and antihyperlipidemic effects of Lippia citriodora. Background: Lippia citriodora Kunth (Verbenaceae) is a medicinal plant with many traditional uses. Objective: The goal of this study was to investigate the antidiabetic activity of aqueous extract of Lippia citriodora and its capacity to improve the lipid profile in diabetic rats. Methods: Normal and diabetic rats were treated orally for 15 days by the leaves aqueous extract of Lippia citriodora (LCLAE) (100 mg/kg). The whole glucose utilization and liver architecture were also evaluated. The in vitro antioxidant activity of LCLAE was also assessed. Results: LCLAE lowered blood glucose and lipid levels in all groups. Moreover, LCLAE ameliorated the liver structure and exhibited antioxidant activity. Conclusion: In conclusion, this study demonstrates the hypoglycemic and antihyperlipidemic effects of LCLAE in rats.

Background and Objective: APOE has an important role in lipids metabolism, and in the variability in low density lipoprotein (LDL) response to statins treatment between individuals. In this study, we aim to investigate the association between APOE polymorphism and response to statins in Jordanian hyperlipidemic patients at the diabetic clinic of Jordan University Hospital. Methods: One hundred and fifty two Jordanian Hyperlipidemic patients (52 males and 100 females) aged between 35-75 years were enrolled in this study. This study was approved by the Institutional Review Board (IRB) of Jordan University Hospital. The genotypes of the patients were identified by polymerase chain reaction followed by restriction fragment length polymorphism assay method (PCRRFLP). Results and Conclusion: The study showed that there is an association between APOE polymorphism and response to statin therapy. Patients who were APOE ε4 carriers had lower response to statins compared to ε3 and ε2 carriers (p=0.002). In addition, we found that there was no significant association between APOE polymorphism and LDL baseline (p=0.214). No significant differences were found in APOE genotypes distribution between males and females (p=0.06). No significant association was found between age and APOE genotypes (p=0.347). A genotype screening test for dyslipidemic Jordanian patients is recommended to choose the appropriate treatment decisions, dosage, and to recognize the potential side effects of statin therapy.

Background & Objective: Nanoparticles are used in cosmetic and dermatologic products, due to better skin penetration properties. Incorporation of natural products exhibiting medicinal properties in nano-preparations could significantly improve the efficacy of these products and improve the quality of life without the side effects of synthetic formulations. Methods: We here report the green synthesis of Copper Oxide nanoparticles, using Cucumber extract, and their detailed bio-physical and bio-chemical characterization. Results: These Copper Oxide-Cucumber nanoparticles exhibit significant anti-bacterial and anti-fungal properties, Ultra Violet-radiation protection ability and reactive-oxygen species inhibition properties. Importantly, these nanoparticles do not exhibit significant cellular toxicity and, when incorporated in skin cream, exhibit skin rejuvenating properties. Conclusion: Our findings have implications for nanoparticle-based cosmetics and dermatologic applications.

Background: Thyroid peroxidase (TPO) gene mutation leads to a change in enzyme built structure resulting in the anti-TPO autoantibodies production that may cause thyroid destruction. Aim: To evaluate the association of three single nucleotide polymorphisms (SNPs) of the TPO gene and anti-TPO levels in Egyptian patients with autoimmune hypothyroidism and correlate them with the disease severity. Methods: Two hundred patients with newly discovered autoimmune hypothyroidism were included in the study (100 with subclinical hypothyroidism and 100 of them with overt hypothyroidism) and 100 healthy individuals as a control group were genotyped by PCR-REFLP. Results: The TT genotype of rs2071400 C/T and the T allele were significantly more frequent in patients with subclinical hypothyroidism and overt hypothyroidism than in the control group. But there were no significant differences in the TT genotype and T allele between subclinical and overt hypothyroidism patients. As regards TPO rs732609 A/C polymorphism, the CC genotype of rs732609 A/C and the C allele were significantly increased in patients with subclinical hypothyroidism and overt hypothyroidism than in controls. There was a significant difference in the CC genotype and C allele between subclinical and overt hypothyroidism patients. Concerning TPO rs1126797 C/T polymorphism, there were no significant differences of genotype or allele frequencies between patients groups and control group. Conclusion: We found an association of rs2071400 C/T and rs732609A/C polymorphisms with autoimmune hypothyroidism and correlated anti-TPO levels with different genotypes in hypothyroid patients. Also, we found an association of rs732609A/C polymorphism with the disease severity.

Aim: The purpose of this research was to investigate the effect of chrysin on one of the natural antioxidants on aging progression in an animal model. Background: Oxidative stress and inflammation increase in hepatic tissue during aging, leading to liver dysfunction. Objective: The current research was conducted to show the effect of chrysin on the activities of antioxidant enzyme (catalase, glutathione peroxidase, and superoxide dismutase), serum nitric oxide (NO), and lipid peroxidation as well as inflammatory cytokines (TNF-α, IL-6, and IL-1β) of aging rats. Methods: Male Wistar rats of different ages, 2, 10, and 20 months, were randomly divided into six groups as follows (n=8, per each group): young control rats (C2), young CH-treated rats (CH2), middle- aged control rats (C10), middle-aged CH-treated group (CH10), aged control group (C20), and aged CH-treated group (CH20). Chrysin (20 mg/kg) was administered intraperitoneally once a day for 30 days. Result: Present findings indicated that chrysin treatment ameliorated the increased liver levels of lipid peroxidation, TNF-α, and IL-1β as well as serum levels of NO. Conclusion: The findings suggest that chrysin could be effective against the progression of ageinduced damage by modulation of oxidant-antioxidant system and inflammatory response.

Background: The incidence of thyroid cancer is increasing rapidly and there is an urgent need to explore novel therapeutic targets for thyroid cancer. MiR-140 has been reported to affect the progression of various cancers, which makes it possible to play a role in thyroid cancer. This study aimed to investigate the expression and role of miR-140 in thyroid cancer. Methods: The expression of miR-140 was investigated by reverse transcription-quantitative polymerase chain reaction (qRT-PCR) in thyroid cancer tissues and cell lines. The prognostic value of miR- 140 in thyroid cancer was evaluated by Kaplan-Meier survival and Cox regression. Moreover, the effects of miR-140 on cell proliferation, migration, and invasion of thyroid cancer were investigated by CCK-8 and Transwell assay. Results: MiR-140 was downregulated in thyroid cancer tissues and cells, which correlated with TNM stage and lymph node metastasis of patients. Patients with low miR-140 expression had a shorter survival time compared with that in patients with high miR-140 expression. Furthermore, miR-140 acts as an independent factor for the prognosis of thyroid cancer. Overexpression of miR-140 inhibited cell proliferation, migration, and invasion of thyroid cancer. Conclusion: MiR-140 can serve as a potential prognostic factor for patients with thyroid cancer and suppress the progression of thyroid cancer, which provides new insight for the therapeutic target for thyroid cancer.

Introduction: Hyperglycemia is associated with an elevated level of reactive nitrogen species (RNS) that leads to nitrosative stress and exacerbates the progression of diabetic complications. Methods: Present study was aimed to evaluate the therapeutic effects of essential oils (EOs) on increased serum levels of nitric oxide (NO) in diabetogenic rats. Diabetogenic rats were treated with EOs separately and/or in combination at the dose of 100 mg/kg, orally for one month. Blood sampling was done at the 1^st, 15^th and 30^th day of the treatment period to investigate the effect of treatment on biomarkers of diabetic complications. Results: In diabetogenic rats, serum levels of NO, malondialdehyde (MDA) and pro-inflammatory cytokines were significantly increased when compared with that of the control group. Whereas, diabetogenic rats treated with EOs decreased serum levels of NO, MDA and pro-inflammatory cytokines up to a significant extent when compared with that diabetogenic rats treated with the standard antidiabetic drug. Moreover, EOs also increased insulin sensitivity in peripheral tissues and insulin secretion from β-cells of pancreatic islets more efficiently when compared with that of diabetogenic rats. Additionally, it was also found that EOs improved lipid profile and normal functions of kidney and liver as compared to that of diabetogenic rats. Conclusion: Findings of this study indicate that EOs may reduce pro-inflammatory cytokine levels by modulating the expression of NO. EOs may also ameliorate the nitrosative stress and maintain glucose homeostasis that are major culprits of diabetic complications.

Background: Sarcoidosis and Sjögren's syndrome (SS) are chronic multi-system inflammatory diseases of unknown origin that most commonly attack the salivary glands. Both of the diseases have vague and non-specific symptoms, causing difficulties for the clinicians to distinguish between the two diseases. Main diagnostic criteria of SS exclude sarcoidosis. However, a co-existence of both diseases should be noted. Here, a case of co-existing sarcoidosis and Sjögren's syndrome is reported, complicated with severe hypercalcemia and renal failure, in addition to a literature review. Case Presentation: A 71-year-old man visited our hospital complaining of daily progressive oral dryness, thirst, and blurred vision with a feeling of dry eyes for a one-year duration. His physical examination showed enlargement of both sides of cervical and supraclavicular lymph nodes. Lung auscultation showed decreased breath sounds with bibasilar inspiratory crackles. However, initial laboratory results revealed severe hypercalcemia with moderate hypercalciuria and renal failure. The final diagnosis was co-existing SS and sarcoidosis according to clinical, radiological, and laboratory data. The patient received oral prednisone therapy for 18 months. After a follow-up of years, the serum calcium concentration, renal function, and chest CT scan remained normal after prednisone treatment stopped for more than 18 months. Conclusion: In the literature, calcium metabolic disorder and renal involvement have not been reported among patients with Sarcoidosis and Sjögren's syndrome, suggesting that calcium metabolic disorder may be underestimated. Serum and urine calcium concentration should be measured in addition to routine laboratory tests.