Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 23, Issue 2, 2023

Background: Due to the COVID-19 pandemic, current epidemiological conditions may exacerbate the risk of new-onset, recurrence and relapse of eating disorders. This perspective aims to better analyse the phenomenon. Results: Some data suggest that new-onset and recurrence/relapse of eating disorders are increasing due to the pandemic. Government restrictions, self-confinement, social isolation, restriction to healthcare facilities access, delayed access to diagnosis and cure, fear of contagion, distress and difficulties related to the telemedicine approach contribute to this burden. The Immune system dysfunction usually observed in undernourishment (e.g., anorexia nervosa) could delay the diagnosis of respiratory infections, including COVID-19, and predispose to possible bacterial superinfections. Conversely, patients with binge eating, obesity or metabolic syndrome are susceptible to high-grade systemic inflammation and poor prognosis once the infection has occurred. Discussion: More detailed data combining research on eating disorders and COVID-19 are required despite some evidence. Many data show that telemedicine has beneficial aspects, but its impact on long-term mental health is still poorly understood. Short- and long-term consequences of COVID-19 in patients with eating disorders are unknown, but they will likely become more apparent over time. Conclusion: Working on emotion regulating strategies in a post-pandemic world, when people have inadequate control over the background of negative emotions, could be a future treatment strategy. Long-term studies with a larger sample size are essential to assess the long-term consequences of the blockade on patients and their healthcare providers and identify useful strategies to improve clinical management.

Trace metals can be divided into two subgroups considering their pathophysiological effects: the first consists of microelements essential for life (arsenic, cobalt, chromium, copper, fluorine, iron, iodine, manganese, molybdenum, nickel, selenium, silicon, tin, vanadium and zinc), implicated in important metabolic processes; the second includes toxic microelements, such as cadmium (Cd), mercury (Hg), chromium (Cr), and lead (Pb) for living organisms, even at low concentrations. These metals contribute to serious consequences for human health, including male infertility. Studies performed in several in vitro and in vivo models revealed that environmental exposure to toxic pollutants, as heavy metals, negatively affects human male fertility. Stem cells, due to their ability to self-renew and differentiate in several cell types, have been proposed as a useful tool in assisted reproductive technology, permitting the spermatogenesis recovery in patients with irreversible infertility. Considering the effects of heavy metals on male fertility and, from a demographic point of view, the decreased fertility ratio, further strategies are required to maintain a sustainable turn-over of 2 children for woman. We discuss here the findings on the biological effects of heavy metal pollution in the male fertility and underline the related socioeconomic impact on population demography.

Aims: The present study aimed to provide summarized data related to the phytocompouds improving glucose uptake in the diabetic state. Background: Glucose uptake in peripheral tissues such as skeletal muscle and adipose tissue is considered as an important step in the regulation of glucose homeostasis. Reducing high blood glucose levels in diabetic patients via targeting peripheral glucose uptake is a promising strategy to develop new antidiabetic medications derived from natural products. Objective: The current review focused on antidiabetic natural phytocompounds acting on glucose uptake in adipocytes and skeletal muscles to highlight their phytochemistry, the mechanistic pathway involved, toxicity, and clinical assessment. Methods: A systematic search was conducted in the scientific database with specific keywords on natural phytocompounds demonstrated to possess glucose uptake stimulating activity in vitro or ex vivo during the last decade. Results: In total, 195 pure molecules and 7 mixtures of inseparable molecules isolated from the plants kingdom, in addition to 16 biomolecules derived from non-herbal sources, possess a potent glucose uptake stimulating capacity in adipocytes and/or skeletal muscles in adipocytes and/or skeletal muscles in vitro or ex vivo. Molecular studies revealed that these plant-derived molecules induced glucose uptake via increasing GLUT-4 expression and/or translocation through insulin signaling pathway, AMPK pathway, PTP1B activity inhibition or acting as partial PPARγ agonists. These phytocompounds were isolated from 91 plants, belonging to 57 families and triterpenoids are the most sous-class of secondary metabolites showing this activity. Among all the phytocompounds listed in the current review, only 14 biomolecules have shown an interesting activity against diabetes and its complications in clinical studies. Conclusion: Epicatechin, catechin, epigallocatechin 3-gallate, quercetin, quercetin 3-glucoside, berberine, rutin, linoleic acid, oleanolic acid, oleic acid, chlorogenic acid, gallic acid, hesperidin, and corosolic acid are promising phytocompounds that showed great activity against diabetes and diabetes complications in vitro and in vivo. However, for the others phytocompounds further experimental studies followed by clinical trials are needed. Finally, foods rich in these compounds cited in this review present a healthy diet for diabetic patients.

Background: Late-Onset Hypogonadism (LOH) is defined as a clinical and biochemical syndrome associated with advancing age. It is characterized by specific symptoms and less specific manifestations due to deficiency of serum testosterone (T) levels. Objective: This review aims to summarize the evidence related to LOH definition, diagnostic approach, and treatment to answer a clinical question: “Is Testosterone the fountain of youth for aging men?” Methodology: MEDLINE/PubMed and institutional websites were searched for original papers, guidelines, and position statements published in the last ten years. Results: Observational and randomized controlled studies on T replacement therapy in older men have been reported. Discussion and Conclusion: Despite some heterogeneities regarding diagnostic definition, therapeutic target, and testosterone prescription, all guidelines agreed that male hypogonadism should be diagnosed and managed in aged men as in adulthood. However, trials assessing the efficacy of T therapy conducted for male rejuvenating are lacking; thus, T prescription for this purpose is not recommended.

The objective of the review led to the pursuit of adopting dipeptidyl peptidase-4 inhibitors (DPP4i) as a novel pharmacotherapy in diabetes mellitus (DM) and cardiorenal syndrome (CRS). The CRS is defined as the co-existence of myocardial ischemia with renal failure. At present, the commercially available drugs enhance insulin secretion or action. However, most of the drugs are associated with adverse effects, such as weight gain or hypoglycemia. As a result, newer therapies with better safety and efficacy profiles are being explored. The DPP4 protease enzyme is involved in cardiovascular and renal diseases in association with over-expressed cytokines. The novel characteristic of DPP4i is to control the elevated blood glucose levels in response to nutrient ingestion without causing hypoglycemia. Also, DPP4i are indirectly involved in reducing myocardial ischemia by promoting cardioprotective peptides. They protect the glucagon-like peptide 1 (GLP-1) from the deteriorating effect of the DPP4 enzyme. The GLP-1 receptors (GLP-1R) are abundantly expressed in renal and cardiovascular tissue. The overexpression of GLP-1R will confer protection of the heart and kidney during CRS. DPP4i were found to significantly clear plasma glucose by the simultaneously activating natural thrombolytic system and increasing insulin levels. They can be used in the early stages of the disease, including pre-diabetes or obesity combined with impaired incretin response, while the combination of DPP4i with metformin or thiazolidinediones as insulin sensitizers offers an additional improvement in the treatment of DM. With its positive attributes in a host of associated parameters of interest, DPP4i are studied extensively in the present review.

Objective: Hyperandrogenic skin disorders, such as hirsutism, acne and alopecia, affect approximately 10-20% of women of reproductive age, reducing quality of life and causing psychological impairment. Spironolactone is a commonly used antiandrogen, especially in women who are not sexually active or have contraindications to hormonal contraceptives. The aim of this study was to evaluate the effects of spironolactone, especially after its withdrawal, in patients with hyperandrogenic skin disorders. Methods: Retrospective analysis of 63 women with hyperandrogenic skin symptoms due to polycystic ovary syndrome (PCOS), treated with spironolactone for at least 6 months as first-line treatment. Results: After a mean time of treatment of 25.7 months, all patients reported a significant improvement in hyperandrogenic skin disorders; only 5 patients were dissatisfied and required the addition of an oral contraceptive. The therapy was well tolerated and the most frequent side-effect was intermestrual bleeding in 68.2% of cases, affecting mainly classic PCOS phenotype. Thirthyeight patients showed prolonged effects 33.7 months after spironolactone withdrawal, whereas 20 relapsed 17.5 months after discontinuation. No significant difference in clinical and biochemical parameters was observed between these two groups both at baseline and after spironolactone treatment. Ovulatory PCOS patients were treated for a shorter time and reported earlier relapse than classic PCOS patients. Conclusion: Spironolactone is an effective and safe treatment for hyperandrogenic skin disorders, showing long-lasting effects even several months after its discontinuation.

Background: Clopidogrel activity is influenced by cytochrome P450 (CYP450). CYP2C19 polymorphisms vary by ethnicity and region. Objective: The aim of the study is to assess the effect of genetic polymorphisms in CYP2C19*2 and *3 and clinical and demographic factors on major adverse cardiovascular events (MACE) in Kazak patients following percutaneous coronary intervention (PCI). Methods: 397 patients with PCI treated with clopidogrel and aspirin for at least 12 months were enrolled and outcomes within 1 year were recorded. Approximately 2 ml of peripheral venous blood samples were used for genotype detection. Multivariable logistic regression analyses were performed to identify factors associated with MACE. Results: 95 patients (23.9%) suffered MACE during the period. Logistic regression analysis revealed CYP2C19*2 carriers (odds ratio [OR]: 2.431, 95% [confidence interval] CI: 1.136- 5.275, P = 0.027) and poor metabolizers (OR: 2.128, 95% CI: 0.899-4.82, P = 0.043) to be significantly associated with MACE. Conclusion: The CYP2C19*2 allele variants and poor metabolizers were found to be associated with MACE in a clopidogrel-treated Kazak population with acute coronary syndrome following PCI.

Background: Kidney disease is common in patients with heart failure (HF). The Donadio equation combines plasma creatinine and bioimpedance vector analysis (BIVA) to estimate creatinine clearance. This study aimed to compare the Donadio formula to the Cockcroft-Gault (CG), Modification of Diet in Renal Disease Study (MDRD-4), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in patients with HF. Methods: We analysed data from 900 patients (mean age: 76 ± 10 years) with HF. All of them underwent clinical, laboratory, BIVA, and echocardiographic evaluations. Results: Donadio equation overestimated eGFR as compared to CG and CKD-EPI formulas (+6.8 and +12 mL/min/1.73 m2, respectively) while computing similar results to MDRD-4 (overestimation: +0.1 mL/min/1.73 m2). According to the different formulas, the prevalence of renal insufficiency (eGFR< 30 ml/min/1.73 m2) in relation to the different formulas was as follows: 24% with Donadio, 21% with CG, 13% with MDRD-4, and 23% with CKD-EPI formulas. All the equations demonstrated a high precision rate (r>0.8 for all). There was a “good” agreement between the Donadio and CG/MDRD-4 formulas and “fair” with the CDK-EPI formula. The Donadio equation showed a high accuracy in predicting severe renal dysfunction (eGFR< 30 mL/min/1.73 m2) in patients with HF (AUC > 0.9), showing comparable performances to CG. Conclusion: The Donadio formula provided an estimation of GFR comparable to MDRD-4 in HF patients, independently from acute or chronic HF conditions. The use of BIVA in HF patients may be adopted both for HF management and for evaluating kidney function.

Background: Mitochondrial morphology reversibly changes between fission and fusion. As these changes (mitochondrial dynamics) reflect the cellular condition, they are one of the simplest indicators of cell state and predictors of cell fate. However, it is currently difficult to classify them using a simple and objective method. Objective: The present study aimed to evaluate mitochondrial morphology using Deep Learning (DL) technique. Methods: Mitochondrial images stained by MitoTracker were acquired from HeLa and MC3T3-E1 cells using fluorescent microscopy and visually classified into four groups based on fission or fusion. The intra- and inter-rater reliabilities for visual classification were excellent [(ICC(1,3), 0.961 for rater 1; and 0.981 for rater 2) and ICC(1,3), respectively]. The images were divided into test and train images, and a 50-layer ResNet CNN architecture (ResNet-50) using MATLAB software was used to train the images. The datasets were trained five times based on five-fold cross-validation. Result: The mean of the overall accuracy for classifying mitochondrial morphology was 0.73±0.10 in HeLa. For the classification of mixed images containing two types of cell lines, the overall accuracy using mixed images of both cell lines for training was higher (0.74±0.01) than that using different cell lines for training. Conclusion: We developed a classifier to categorize mitochondrial morphology using DL.

Background: Hematotoxicity is an underexplored endpoint of toxicity in most of the chemical exposures. An adverse effect on the hematological system arising out of xenobiotic exposure causes impaired hemostasis and coagulation leading to disease. BPA and acetaminophen are widely used synthetic chemicals worldwide and both are known and have numerous toxic effects. Since both can be simultaneously exposed to humans over a period of time, we hypothesized that their exposure can cause hematotoxicity, which may be ameliorated by melatonin. Objective: In the current study, we aimed to find the effect of single and co-treatment of bisphenol A and acetaminophen on the RBC and coagulation factors in rats, and amelioration of impairment by melatonin. Methods: Oxidative stress in red blood cells, bleeding time, blood clotting time, prothrombin time, partial thromboplastin time, and fibrinogen levels were assessed as indicators of hematotoxicity with single and co-exposure to bisphenol A and acetaminophen in rats. The effect of melatonin as a hemato-protective agent was assessed in the co-exposure. Results: An increase in RBC oxidative stress and decrease in bleeding time, blood clotting time, prothrombin time, and partial thromboplastin time along with an increase in fibrinogen levels were observed with bisphenol A and acetaminophen treatment, which were further aggravated with cotreatment of the two. Melatonin treatment, however, was seen to decrease the increase in oxidative stress and ameliorate the impairment in coagulation factors. Conclusion: Bisphenol A and acetaminophen cause an increase in the oxidative stress in the red blood cells, and cause a shift toward pro-coagulation, which is alleviated by treatment with melatonin.

Background: Gaucher disease is a common lysosomal storage disease caused by the deficiency of the β-glucosidase enzyme, leading to sphingolipid accumulation in the reticuloendothelial system in Gaucher cells. Clinical findings are quite variable and some patients may remain asymptomatic lifelong. However, even when patients have mild symptoms, there is a significant increase in their quality of life with enzyme replacement therapy. We aimed to reveal the relationship between a rare mutation in the Glucosylceramidase Beta (GBA) gene and clinical signs and symptoms. Another aim of the study was to show the effect of enzyme replacement therapy on the quality of life, even in patients with mild symptoms. Case Presentation: Here, we report a 46-year-old male diagnosed with Gaucher disease based on splenic Gaucheromas incidentally discovered in a cardiac computerized tomography scan. In GBA gene analysis, the extremely rare R87W mutation was detected in a homozygous state. In retrospect, the patient had nonspecific symptoms such as fatigue and bone pain for a long time, which were substantially ameliorated by enzyme replacement therapy. Conclusion: In patients with adult-onset Gaucher disease, the symptoms may be mild, causing significant diagnostic delay. Gaucher disease may be included in the differential diagnosis of abdominal malignancies. Early diagnosis and treatment can improve quality of life and prevent unnecessary procedures.

Background: Congenital disorder of glycosylation caused by mutation of the DOLK(DOLK-CDG) is a group of rare autosomal recessive diseases with an early-onset age and poor prognosis. DOLK-CDG can cause the dysfunction of multiple systems and organs such as the heart, skin, nerves, and bones. Case Presentation: We report a child with DOLK-CDG diagnosed and treated in the Affiliated Hospital of Qingdao University. The child was born with neonatal asphyxia, Ichthyoid rash, and congenital heart disease. His fingers of both the hands looked like lotus roots, and the palm and foot were covered by a white membrane. He was hospitalized with a severe infection at 4 months after birth. Physical examination showed that he was complicated with development delay and hypotonia. He experienced convulsions 1 hour after admission and died of multiple organ failure 2 hours after admission. Blood samples were taken for genetic testing before the child died. The results showed that there was a novel compound heterozygous mutation in DOLK, c.1268C>G (P.P423R) and c.1581_1583del (P.527_528del). Conclusion: This mutation is new and not included in the human gene mutation library. The discovery of the novel mutation broadened the mutation spectrum of DOLK. At the same time, we sorted out the DOLK-CDG gene mutation sites and related clinical manifestations reported by August 2021 through a literature review.

Background: The response against adjuvants in vaccines is presented as autoimmune/inflammatory syndrome (ASIA). In this case report, we presented both SAT and Graves’ disease in a patient as ASIA following the BNT162b2 mRNA COVID-19 vaccination. Case Presentation: A 31-year-old woman was admitted to the endocrinology outpatient clinic with the complaint of neck pain following the second dose of the BNT162B2 SARS-CoV-2 (Pfizer/BioNTech) vaccine. On physical examination, her thyroid gland was tender on palpation. Her thyroid function tests were compatible with hyperthyroidism, and inflammatory markers were high. In the thyroid ultrasonography (US) examination, we observed bilateral diffuse hypoechoic areas in the thyroid gland and increased vascularity in some parts of the thyroid. Anti-thyroid stimulating hormone receptor antibodies (TRAB) were positive. Overall, we considered concurrent subacute thyroiditis (SAT) and Graves’ disease. Conclusion: The present study may be the first report to evaluate SAT and Graves’ disease as ASIA following mRNA COVID-19 vaccination. Clinicians should be aware of possible vaccine-related complications.

Savant syndrome is a rare and unusual condition that occurs in the presence of severe developmental disabilities, disorders, and injuries. The syndrome can be congenital from birth to childhood or acquired as a result of a brain injury or damage to the central nervous system. There are several findings that indicate that savant syndrome usually occurs with significant brain metabolism alterations resulting in critical brain network changes. These types of changes in the brain are usually explained by the “tyranny of the left hemisphere” theory, which indicates the inhibition of the left hemisphere to allow the right hemisphere to develop savant abilities. Another way to temporarily simulate these types of changes in the brain can be through different neuromodulation techniques such as transcranial magnetic stimulation and transcranial direct current stimulation. Such neuromodulation techniques might help us discover the “hidden talent” potential through modulating the brain network metabolism. We herein discussed the types of savant syndrome along with its relation to specific neurometabolic network alterations. Furthermore, we provide a perspective on how newly developed neuromodulation and cognitive rehabilitation techniques can help simulate savant syndrome in healthy individuals through modulating the brain network activity.