Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 22, Issue 6, 2022

Chronic heart failure represents a relevant concern for public health. The endocrine system is heavily involved in the induction and progression of chronic heart failure. Among endocrine disorders, the most relevant alterations are related to the growth hormone-insulin like growth factor 1 axis, serum testosterone, dehydroepiandrosterone sulfate, triiodothyronine levels, insulin resistance, and type 2 diabetes mellitus. It is currently debated whether these changes might be simple adaptive mechanisms or, instead, they may deteriorate myocardial pump function over time. In this commentary on a recently published paper by Antonio Cittadini et al. (Eur J Prev Cardiol. 2021), we briefly presented and discussed data form the “Trattamento Ormonale nello Scompenso CArdiaco; Hormone Treatment in Heart Failure (TOSCA) Registry”. One or more hormonal deficiencies or metabolic disorders, including insulin resistance and diabetes mellitus, were more commonly diagnosed in patients with heart failure (358 patients, 75% of study group). The presence of multiple hormone deficiency identified a subset of patients at increased risk of hospitalization and death, with a graded relation between the number of deficiencies and total events. This finding suggests a possible causal role of hormone deficiencies in CHF progression. Screening of hormonal and metabolic imbalances in CHF patients would be an interesting opportunity for improving the prognosis of patients with heart failure as it would identify high-risk patients requiring an additional medical management of the underlying endocrine and metabolic disorders.

Steroidogenesis in the adrenal cortex or gonads is a complicated process modulated by various elements either at the tissue or molecular level. The substrate cholesterol is first delivered to the outer membrane of mitochondria, undergoing a series of enzymatic reactions along with the material exchange between the mitochondria and the ER (endoplasmic reticulum) and ultimately yielding various steroids, such as aldosterone, cortisol, testosterone, and estrone. Several valves are set to adjust the amount of production as per the needs, e.g., StAR (steroidogenic acute regulator) controls the traffic of cholesterol from the outer membrane to the inner membrane of mitochondria which is a rate-limiting step. Moreover, the “need” is partly reflected by trophic signals, like ACTH, LH, and downstream pathways, such as the intracellular cAMP pathway, representing the endocrinal regulation of steroid synthesis. The coordinated activities of these related factors are all associated with another crucial cellular constituent, the cytoskeleton, which plays a crucial role in cellular architecture and substrate trafficking. Though considerable studies have been performed regarding steroid synthesis, details regarding the upstream signaling pathways and mechanisms of the regulation by the cytoskeleton network still remain unclear. The metabolism and interplays of the pivotal cellular organelles with cytoskeleton are worth exploring as well. This review summarizes the research of different periods, describing the roles of specific cytoskeleton elements in steroidogenesis and related signaling pathways involved in steroid synthesis. In addition, we discuss the inner cytoskeletal network involved in steroidogenic processes, such as mitochondrial movement, organelle interactions, and cholesterol trafficking.

The first traces of man’s of poison use date back to ten thousand years ago since the last period of the Paleolithic era. Man used poison for hunting and defense. Indeed, in the second half of the 19th century, arrows made from the bones of animals characterized by particular grooves were found in some caves. In ancient Greece, the term pharmakon (άρμαΚν) had a double meaning: remedy for therapy and venom. This is the period in which humans became aware of the fact that poison cannot be defined simply as a substance capable of changing the properties of things. Poison is very frequently mentioned in the history of the Roman Empire, and its use continued through the Renaissance and even during the modern era. Poison was the protagonist in multiple political intrigues of power and is one of the most used lethal weapons over the years. Thought of as the optimal solution for a perfect murder, the poison has a long history. Its success is due to the invisible, untraceable, and often unpunished death it causes.

The fast spread of coronavirus 2019 (COVID-19) calls for immediate action to counter the associated significant loss of human life and deep economic impact. Certain patient populations like those with obesity and diabetes are at higher risk for acquiring severe COVID-19 disease and have a higher risk of COVID-19 associated mortality. In the absence of an effective and safe vaccine, the only immediate promising approach is to repurpose an existing approved drug. Several drugs have been proposed and tested as adjunctive therapy for COVID-19. Among these drugs are the glucagon-like peptide-1 (GLP-1) 2 agonists and the dipeptidylpeptidase-4 (DPP-4) inhibitors. Beyond their glucose-lowering effects, these drugs have several pleiotropic protective properties, which include cardioprotective effects, anti-inflammatory and immunomodulatory activities, antifibrotic effects, antithrombotic effects, and vascular endothelial protective properties. This narrative review discusses these protective properties and addresses their scientific plausibility for their potential use as adjunctive therapy for COVID-19 disease.

Esophageal cancer is one of the most common types of gastrointestinal malignancies that is encountered. It has a global distribution and affects males and females, and is linked to significant morbidity and mortality. The mechanisms underlying pathophysiology are multifactorial and involve the interaction of genetic and environmental factors. This review article describes the immunological and metabolic changes that occur in malignancy of the esophagus.

Lipid metabolism disorder plays a fundamental role in the pathogenesis of atherosclerosis. As the largest metabolic organ of the human body, the liver has a key role in lipid metabolism by influencing fat production, fat decomposition, and the intake and secretion of serum lipoproteins. Numerous clinical and experimental studies have indicated that the dysfunction of hepatic lipid metabolism is closely related to the onset of atherosclerosis. However, the identity and functional role of hepatic lipid metabolism responsible for these associations remain unknown. This review presented that cholesterol synthesis, cholesterol transport, and the metabolism of triglycerides, lipoproteins, and fatty acids are all associated with hepatic lipid metabolism and atherosclerosis. Moreover, the roles of gut microbiota, inflammatory response, and oxidative stress in the pathological association between hepatic lipid metabolism and atherosclerosis are also discussed. This significant evidence strongly supports that hepatic lipid metabolism disorders may increase the risk of atherosclerosis.

Progesterone receptor membrane component 1 (PGRMC1) is a trans-membrane evolutionarily conserved protein with a cytochrome b5 like heme/steroid binding domain. PGRMC1 clinical levels are strongly suggested to correlate with poor patient survival and lung cancer prognosis. PGRMC1 has been reported to possess pleiotropic functions, such as participating in cellular and membrane trafficking, steroid hormone signaling, cholesterol metabolism and steroidogenesis, glycolysis and mitochondrial energy metabolism, heme transport and homeostasis, neuronal movement and synaptic function, autophagy, anti-apoptosis, stem cell survival and the list is still expanding. PGRMC1 mediates its pleiotropic functions through its ability to interact with multiple binding partners, such as epidermal growth factor receptor (EGFR), sterol regulatory element binding protein cleavage activating protein (SCAP), insulin induced gene-1 protein (Insig-1), heme binding proteins (hepcidin, ferrochelatase and cyp450 members), plasminogen activator inhibitor 1 RNA binding protein (PAIR-BP1). In this review, we provide a comprehensive overview of PGRMC1 and its associated pleiotropic functions that are indispensable for lung cancer promotion and progression, suggesting it as a prospective therapeutic target for intervention. Notably, we have compiled and reported various preclinical studies wherein prospective agonists and antagonists had been tested against PGRMC1 expressing cancer cell lines, suggesting it as a prospective therapeutic target for cancer intervention.

Background: Preeclampsia (PE) is defined as a salient complication of late pregnancy. microRNAs (miRNAs) have emerged as critical biological regulators in PE. This study determined miR-27b-3p expression in serum of PE patients and investigated its clinical significance in PE. Methods: This study enrolled a total of 130 pregnant women, including 90 PE patients (51 mild PE and 39 severe PE) and 40 healthy controls. miR-27b-3p expression in the serum of PE patients and healthy controls was detected using RT-qPCR. The correlation among miR-27b-3p expression and 24-h urine protein, systolic blood pressure (SBP), diastolic blood pressure (DBP), serum creatinine, and fetal birth weight was analyzed using Pearson's correlation coefficient. The targeting relationship between miR-27b-3p and PPARG was verified. PPARG protein level in PE patients was detected using ELISA kits. The predictive efficiency of miR-27b-3p and PPARG in PE was analyzed using the receiver operating characteristic (ROC) curve. Results: Compared to normal pregnant women, PE pregnant women, especially severe PE patients, had higher miR-27b-3p expression. miR-27b-3p was positively correlated with 24-h urine protein, SBP, DBP, and serum creatinine but negatively correlated with fetal birth weight. PPARG was poorly expressed in PE patients and negatively correlated with miR-27b-3p. ROC curve showed that both miR-27b-3p and PPARG had good predictive efficacy on PE. Conclusion: miR-27b-3p expression in serum of pregnant women with PE was positively correlated with the severity of PE symptoms, suggesting the involvement of miR-27b-3p in PE occurrence.

Background: COVID-19 is a worldwide pandemic with high rates of morbidity and mortality, and an uncertain prognosis leading to an increased risk of infection in health providers and limited hospital care capacities. In this study, we have proposed a predictive, interpretable prognosis scoring system with the use of readily obtained clinical, radiological and laboratory characteristics to accurately predict worsening of the condition and overall survival of patients with COVID-19. Methods: This is a single-center, observational, prospective, cohort study. A total of 347 patients infected with COVID-19 presenting to the Tanta University Hospital, Egypt, were enrolled in the study, and clinical, radiological and laboratory data were analyzed. Top-ranked variables were identified and selected to be integrated into a Cox regression model, building the scoring system for accurate prediction of the prognosis of patients with COVID-19. Results: The six variables that were finally selected in the scoring system were lymphopenia, serum CRP, ferritin, D-Dimer, radiological CT lung findings and associated chronic debilitating disease. The scoring system discriminated risk groups with either mild disease or severe illness characterized by respiratory distress (and also those with hypoxia and in need for oxygen therapy or mechanical ventilation) or death. The area under the curve to estimate the discrimination performance of the scoring system was more than 90%. Conclusion: We proposed a simple and clinically useful predictive scoring model for COVID- 19 patients. However, additional independent validation will be required before the scoring model can be used commonly.

Background: Insulin Resistance (IR) is confirmed as a key feature of Nonalcoholic Fatty Liver Disease (NAFLD) in children and adolescents. Numerous studies report that adiponectin (APN) levels are inversely associated with the status of IR in adults with NAFLD. This study aimed to investigate the relationship between serum total APNand Homeostasis Model Assessment Insulin Resistance (HOMA-IR) in adolescents with NAFLD. Methods: 382 newly-diagnosed NAFLD adolescents, aged 9-16 years old, were enrolled and divided into three subgroups according to the APNtertile. Simple and multiple linear regression analyses were performed to assess the correlation between HOMA-IR and APN in boys and girls, respectively. Results: The HOMA-IR values tended to decrease in boys according to APN tertiles: 5.6(4.4-7.3) vs. 5.2(4.6-6.9) vs. 4.9(4.1-5.8) (p<0.01), and there was a significant difference in the HOMA-IR values among three APN tertile subgroups in girls (p<0.01). Univariate analysis showed that body mass index, waist circumference, weight-to-height ratio, fasting blood glucose, insulin, triglyceride, and APN were significantly associated with HOMA-IR in boys (p<0.05). In girls, body mass index, fasting blood glucose, insulin, total cholesterol, triglyceride, and APN were significantly associated with HOMA-IR (p<0.05).APN was found to be a significant determinant for HOMA-IR only in boys (β=-0.147, p<0.01). Conclusion: Our findings showed that APN was an independent and significant determinant for increased HOMA-IR in boys with NAFLD. Further studies are needed to explore the underlying mechanisms.

Background: Specific Antibody Deficiency (SAD) is a primary immunodeficiency disease (PID) characterized by the occurrence of recurrent infections and inadequate antibody response to polysaccharide new antigens. Objective: This study aims to determine the titer of specific antibodies against unconjugated 23-valent pneumococcal polysaccharide vaccine (PPSV-23), the presence of SAD, and its association with clinical and laboratory findings in Ataxia-telangiectasia (A-T) and selective immunoglobulin A deficiency (SIgAD) patients. Methods: 32 A-T patients and 43 SIgAD patients were included in this cross-sectional study. Samples of the patients were obtained before and three weeks after vaccination with PPSV-23. Specific immunoglobulin G (IgG) directed towards pneumococcal capsular antigen and specific antibodies against whole pneumococcal antigens was measured. Results: Comparison of the response to vaccination revealed that 81.3% of A-T patients and 18.6% of the SIgAD patients had an inadequate response to PPSV-23 (p<0.001). The prevalence of recurrent infection (p=0.034) and pneumonia (p=0.003) in SIgAD patients was significantly higher in non-responders than responders. Likewise, the number of marginal zone B cells (p=0.037), transitional B cells (p=0.019), plasmablasts (p=0.019), CD8+ naïve T cells (p=0.036), and percentage of CD8+ T cells (p=0.047), switched memory B cells (SMB) (p=0.026) and immunoglobulin M (IgM) memory B cells (p=0.022) in SIgAD patients were significantly lower in non-responder group than responder group. In contrast, the percentage of CD4 T+ cells in A-T patients was lower in the non-responder group than responders (p=0.035). Conclusion: SAD is more frequent in A-T patients than SIgAD patients. The role of SMB and T cells should not be underestimated in SAD.

Background: Diagnostic imaging techniques, including magnetic resonance imaging (MRI) should be performed on all patients with incidentalomas. However, limited number of studies on whether the quantitative measurements (signal intensity index, adrenal to spleen ratio) in MRI could predict the functional status of adrenal adenomas are available. Methods: Between 2015-2020, 404 patients (265 females, 139 males) with adrenal mass who were referred to the university hospital for further investigation were included. After detailed diagnostic hormonal evaluation, all patients were examined with the MRI 1.5 T device (Signa, GE Medical Systems; Milwaukee, USA). The signal intensities of the adrenal lesions on T2W images were qualitatively evaluated and noted as homogenous or heterogeneous in comparison with the liver signal intensity (SI). A chemical-shift SI index and chemical shift adrenal-to-spleen SI ratio were also calculated. Results: While 331(81.9%) of the patients had nonfunctional adrenal mass, the rest (n=73, 18.1%) were patients with functional (autonomous cortisol secretion-ACS, Cushing syndrome-CS, pheochromocytoma, primary hyperaldosteronism-PA) adrenal masses. In phase vs. phase values of patients with NFAI, Pheo(n=17), ACS (n=30), CS (n=11), and PA (n=15) were 474.04±126.7 vs. 226.6±132.4, 495.3±182.8 vs. 282.17±189.1, 445.2±134.8 vs. 203.3±76.2, 506.8±126.5 vs. 212.2±73.6 and 496.2±147.5 vs. 246.6±102.1, respectively. Mean signal intensity index (SII) and adrenal to spleen ratio (ASR) of all groups (NFAI, Pheo, ACS, CS, PA) were 52.0±24.8 and 0.51, 44.9±22.5 and 0.55, 49.5±24.5 and 0.53, 56.2±16.4 and 0.43, 47.6±25.1 and 0.54, respectively. Based on the currently accepted measurements in the case of ASR and SII, all lesions were similar and observed as fat rich adenomas (p*= 0.552, p** = 0.45). Conclusion: The quantitative assessment (SII, ASR) of intracellular lipids in an incidentally discovered adrenal tumor could only help distinguish adrenal masses in the case of adenomas or non-adenomas. As an initial diagnostic evaluation, clinical and laboratory assessment to distinguish hormone secretion should be done for all patients with adrenal incidentalomas.

Background: Gaucher Disease (GD) is a rare autosomal recessive inherited disease caused by the deficiency of glucocerebrosidase and characterized by a broad spectrum of clinical manifestations, including hepatosplenomegaly, bone infiltration, and cytopenia. Moreover, it is even involved in the central nervous system. GD is classified into three phenotypes on the ground of neurologic involvement: type 1 (GD1), the commonly adult-onset, non-neuropathic variant; type 2 (GD2), the acute neuropathic form; and type 3 (GD3), the severe chronic neuro-visceral form. Recently, several studies have shown a promising outcome of ambroxol chaperone therapy for the treatment of GD, but its therapeutic role in GD1-associated liver cirrhosis and portal hypertension was not verified. Case Presentation: A 36-year-old male patient was admitted for esophageal varices lasting for one year with a 34-year history of liver and spleen enlargement. The patient was diagnosed with GD1 with cirrhosis and portal hypertension based on the identification of Gaucher cells and advanced fibrosis in the liver biopsy tissue and two known pathogenic mutations on the glucocerebrosidase (GBA) gene. The patient received 660 mg/d of ambroxol for up to two years. At his six-month follow- up, the patient exhibited a remarkable increase in GBA activity (+35.5%) and decrease in liver stiffness (-19.5%) and portal vein diameter (-41.2%) as examined by ultrasound elastography and computer tomography, respectively. At two-year follow-up, the liver stiffness was further reduced (-55.5%) in comparison with untreated patients. Conclusion: This case report suggests that long-term treatment with high dose ambroxol may play a role in the reduction of hepatic fibrosis in GD1.