Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 23, Issue 3, 2023

Many therapies have been developed against COVID-19 since it first appeared in December 2019. Antivirals, antimalarials, cephalosporins, colchicine, anticoagulants, and corticosteroids, among others, have been evaluated as protecting agents against antibacterial complications due to their anti-inflammatory and immunomodulatory effects against thrombosis and cell death caused by infection with SARS-CoV-2. Nevertheless, the overall balance in their application has not been found to be satisfactory. On the other hand, developing and applying several vaccines against this virus have marked an important watershed in preventive and prophylactic medicine in the new millennium. However, given the regular efficacy reported of some of them, the still scarce affordability, and the emergency of new strains for which no drug has been evaluated, the search for new pharmacological therapy alternatives still represents an essential component in the clinical management of COVID-19, and the rapid identification of drugs with potential antiviral and/or immunomodulatory properties is needed. In the present review, a potential therapeutic effect of metformin and other antidiabetic therapies for the management of COVID-19 are proposed and discussed from the viewpoint of their in vitro and in vivo immunomodulatory effects. Given that acute inflammation is an important component of COVID-19, antidiabetic therapies could be promising alternatives in its management and reducing the disease's severity. In order to understand how metformin and other antidiabetic therapies could work in the context of COVID-19, here we review the possible mechanisms of action through a detailed description of cellular and molecular events.

Background: Phytochemicals belonging to the class of flavonoids have been used in medicine for the treatment of different kinds of human health complications. Flavonoids have beneficial health aspects in medicine mainly due to their anti-microbial, anti-diabetic, anti-inflammatory, anticancer, and anti-carcinogenic activities. They have been scientifically investigated for their health benefit and pharmacological activities in medicine. Engeletin is a pure flavanonol class phytocompound present in the skin of white grapes and white wine. Engeletin has numerous pharmacological activities in medicine. Methods: In order to know the beneficial health aspects of engeletin in medicine, scientific data on engeletin have been collected from different literature sources and analyzed in the present work. The present work summarized the important findings of engeletin with respect to its medicinal uses, pharmacological activities, and analytical aspects in medicine. All the scientific data were collected from PubMed, Google, Scopus, Science Direct and Google Scholar and analyzed in the present work. Results: Scientific data analysis of research works revealed the biological importance and therapeutic benefit of engeletin in medicine. Engeletin has attracted scientific attention mainly due to its antiinflammatory and anti-tumor potential. Engeletin could inhibit the occurrence of cervical cancer and delay the development of liver damage and lung cancer in mice. Engeletin was found to inhibit lipopolysaccharides- induced endometritis in mice by inhibiting the inflammatory response. Pharmacological data analysis revealed the therapeutic importance of engeletin against acute lung injury, inflammatory diseases, liver injury, pulmonary fibrogenesis, Alzheimer’s disease, endometritis, cervical carcinogenesis, lung cancer, and osteoarthritis. Analytical data signified the importance of modern analytical tools for separating, isolating, and identifying engeletin. Conclusion: Scientific data analysis revealed the biological importance and therapeutic benefit of engeletin in medicine and other allied health sectors.

The ubiquity of the obesity condition in the United States, Europe and other regions with developed economies will associate to a significant adverse impact on public health. Numerous data indicate that social, behavioral, neuroendocrine, and metabolic factors may encourage compulsive eating behaviors thus increasing the risk of obesity. Several pathological conditions overlap with excess weight. Among the most common, there are binge eating disorder (BED) and food addiction (FA), which share several neurobiological and behavioral aspects with substance addictions. BED has many features in common with addictive behavior, such as loss of control and the need to frequently repeat the dysfunctional pattern despite negative consequences. The food addiction hypothesis assumes that exposure to highly palatable foods alters the reward circuits of the brain, resulting in a behavioral phenotype similar to substance addiction and facilitating dysfunctional eating behaviors, such as binge eating crises. In this review, over 100 publications, researched on MEDLINE from 2000 until march 2021, were included since they evaluate neuroendocrine changes, emotional homeostatic factors and the reward circuit, associating them with exposure to highly palatable foods, loss of control, the way we eat, the increase in impulsiveness and the inability to change eating behavior despite the negative consequences related to overweight and obesity. Finally, understanding the underlying neurobiological circuits of compulsive eating behaviors and food addiction could result in a great therapeutic potential for patients suffering from ailments nutrition and obesity.

Objective: This study aimed to identify the potential biomarkers in DN. Methods: DN datasets GSE30528 and GSE47183 were downloaded from the Gene Expression Omnibus database. Immune cell infiltration was analyzed using CIBERSORT. Weighted gene co-expression network analysis (WGCNA) was performed to obtain the module genes specific to DN. The relevant genes were identified intersecting the module genes and differentially expressed genes (DEGs). The core genes were identified using the MCC algorithm in Cytoscape software. ROC and Pearson analyses alongside gene set enrichment analysis (GSEA) were performed to identify the key gene for the core genes. Finally, we performed the Spearman to analyze the correlation between key gene and glomerular filtration rate (GFR), serum creatinine (Scr), age and sex in DN. Results: CIBERSORT analysis revealed the immune cell infiltration in the DN renal tissue and Venn identified 12 relevant genes. Among these, 5 core genes, namely TYROBP, C1QA, C1QB, CD163 and MS4A6A, were identified. Pearson analyses revealed that immune cell infiltration and expression of core genes are related. The key genes with high diagnostic values for DN were identified to be CD163 via ROC analyses. After Spearman correlation analysis, the expression level of CD163 was correlated with GFR (r =0.27), a difference that nearly reached statistical significance (P =0.058). However, there was no correlation between the level of CD163 and age (r =-0.24, P =0.09), sex (r =-0.11, P=0.32) and Scr (r=0.15, P=0.4). Conclusion: We found that CD163 in macrophages may be a potential biomarker in predicting and treating DN.

Background: Evidence shows that a low-grade inflammation sustains type 2 diabetes (T2D). Pancreatic macrophages release cytokines and chemokines that play a fundamental role in the pathophysiology of islet damage and destruction of beta-cells.

Methods: The authors discuss the main mechanism by which resident (pancreatic) and circulating macrophages regulate beta-cell development and survival in several scenarios, including T2D, type 1 diabetes mellitus, obesity, and insulin resistance. Data are mostly related to in vitro and animal studies.

Results: Lastly, an overview of the role of the Mediterranean diet components (i.e., polyphenols, polyunsaturated fatty acids, prebiotics, probiotics, and vitamins) will be illustrated as potential agents for reducing inflammation and oxidative stress in patients with T2D when used along with antihyperglycemic treatments.

Background: The adipose tissue influences by an extensive crosstalk at the local and systemic level the energy balance, including storage, mobilization, and utilization at both central and peripheral sites in response to specific external stimuli or metabolic changes. The balance between energy intake and expenditure is a delicate equilibrium among multifactorial aspects ranging from genetic to environmental influences.

Aim: The evidence from several recently published papers dealing with the topic of the beneficial health effects of micronutrient and plant bioactive compounds on obesity and/or comorbidities has been reported in this paper.

Methodology: MEDLINE database (PubMed database; National Library of Medicine, Bethesda, MD and Google Scholar) was searched by combining the terms of specific micronutrients and/or plant bioactive compounds associated with obesity and related comorbidities. All English language manuscripts published between 2005 and 2021 in the MEDLINE database were searched, selected, and reviewed here.

Conclusion: People do not consume single food or ingredients but global composite diets; thus, the evaluation of mechanisms of action, efficacy and safety of vitamins and mineral and natural bioactive compounds is still a challenge in research on nutrition and food supplements.

Background: The healing of cutaneous wounds requires better strategies, which remain a challenge. Previous reports indicated that the therapeutic function of mesenchymal stem cells is mediated by exosomes. This work demonstrated the regenerative effects of engineered BMSCsderived Exosomal miR-542-3p in skin wound mouse models.

Methods: Bone marrow mesenchymal stem cells (BMSCs) -derived exosomes (BMSCs-Exos) were isolated by ultracentrifugation and identified by Transmission Electron Microscope (TEM) and Nanoparticle Tracking Analysis (NTA). BMSCs-Exo was loaded with miRNA-542-3p by electroporation. We explored the effects of miRNA-542-3p-Exo on the proliferation and migration of Human Skin Fibroblasts (HSFs)/Human dermal microvascular endothelial cells (HMECs). In addition, The angiogenesis of HMECs was detected by Tube formation assay in vitro. The effects of miRNA-542-3p-Exo in the skin wound mouse model were detected by H staining, Masson staining, and immunofluorescence analysis. We assessed the effect of miRNA-542-3p-Exo on collagen deposition, new blood vessel formation, and wound remodeling in a skin wound mouse model.

Results: MiRNA-542-3p-Exos could be internalized by HSFs/HMECs and enhance the proliferation, migration, and angiogenesis of HSFs/HMECs in vitro and in vivo. The protein expression of collagen1/3 was significantly increased after miRNA-542-3p-Exo treatment in HSFs. In addition, the local injection of miRNA-542-3p-Exo promoted cellular proliferation, collagen deposition, neovascularization, and accelerated wound closure.

Conclusion: This study suggested that miRNA-542-3p-Exo can stimulate HSFs/HMECs function. The treatment of miRNA-542-3p-Exo in the skin wound mouse model significantly promotes wound repair. The therapeutic potential of miRNA-542-3p-Exo may be a future therapeutic strategy for cutaneous wound healing.

Background: Oral aphthosis is one of the major manifestations of Behçet’s disease (BD), a chronic, multisystemic vasculitis. BD etio-pathogenicity related to oral health lack. Objective: This study investigated the possible relationships between poor oral hygiene, oral activity, disease severity and saliva’s Interleukin (IL)-32, IL-6, IL-10 and nitric oxide (NO) levels in Behçet’s patients to determine their role in disease prognosis and their potential therapeutic interest. Methods: Fifty-six patients with BD (22 orally active; 34 orally inactive) and 31 healthy subjects have been included in our study. Salivary levels of IL-32, IL-6, and IL-10 were measured using ELISA, while NO levels were assessed by modified Griess’s method. Oral health status and disease severity scores were recorded for each participant. Kruskal-Wallis test and Spearman’s test were performed for statistical analyses. Results: We observed that the tested molecules were increased in BD patients compared to healthy controls (p<0.05). Moreover, only IL-32 levels were associated with oral activity in patients (p<0.05). Interestingly, the disease severity score was noted to be correlated positively and significantly with both IL-32 saliva levels (p<0.01) and plaque index (p<0.05) in BD patients. Furthermore, IL-32 levels were correlated with plaque index (p<0.0001). Conclusion: Our results suggest that IL-32, IL- 6, IL-10 and NO were increased in saliva during BD. Our study indicated that IL-32 was associated with the genesis of oral ulcers in response to dental plaque. Ultimately, salivary IL-32 may serve as a prognostic biomarker and a possible therapeutic target for managing Behçet’s disease severity.

Background and Aims: Dietary habits, food, and nutrition-associated oral dysbiosis lead to the formation of microbial biofilm, which affects the overall health of an individual by promoting systemic diseases like cardiovascular disease, immunological disorders, and diabetes. Today's diets contain a variety of fermentable carbohydrates, including highly processed starch and novel synthetic carbohydrates such as oligofructose, sucralose, and glucose polymers. These constitute risk factors in the initiation and progression of oral dysbiosis. Oral, lung and gut microbiomes are interlinked with each other via direct and indirect ways. It is unknown whether or not lactobacilli and Lactobacillus phages are able to rescue dysbiotic effects by decreasing the uptake into the cells of excess simple sugars and their derivatives present within the digestive tract. Materials and Methods: Using transwell cell culture plate inserts, six groups of in vitro co-cultured TR146 and HepG2 cells, grown in DMEM medium either with or without sucrose (10 % v/v), were treated with 1) PBS, 2) Fructilactobacillus sanfranciscensis (F.s) H2A, 3) F.s H2A and sucrose, 4) F.s H2A plus sucrose plus phage EV3 lysate, 5) F.s H2A plus sucrose plus phage EV3 supernatant, and 6) F.s H2A plus sucrose plus phage EV3 particles. The pH of the culture medium (indicating lactic acid production) and key oral biomarkers, including cytokines (IL-1β and IL-6), inflammatory chemokines (e.g., CXCL8 and CCL2), and homeostatic chemokines (e.g., CXCL4 and CCL18) were measured. Results: Excess sucrose significantly enhanced inflammatory signal molecules (e.g., IL-1β, IL-6, and CCL2) secretion, concomitant with the enhancement of intracellular triglycerides in co-cultured HepG2 cells. Co-culture with F.s H2A decreased the sucrose-induced release of inflammatory signal molecules from co-cultured cells, these effects being abolished by F.s phage EV3. Conclusion: This study shows that Lactobacillus phages apparently influence the interplay between food components, oral microbiota, and the oral cellular milieu, at least in part by affecting the microbial uptake of excess free simple sugars from the oral milieu. To confirm the biological consequences of these effects on human oral microbiota and health, further studies are warranted, incorporating ex vivo studies of human dental plaque biofilms and host biomarkers, such as cytohistological, molecular, or biochemical measurements.

Background: Neuroinflammation and cytokines play critical roles in neuropathic pain and axon degeneration/regeneration. Cytokines of transforming growth factor-β superfamily have implications in pain and injured nerve repair processing. However, the transcriptional profiles of the transforming growth factor-β superfamily members in dorsal root ganglia under neuropathic pain and axon degeneration/regeneration conditions remain elusive. Objective: We aimed to plot the transcriptional profiles of transforming growth factor-β superfamily components in lumbar dorsal root ganglia of sciatic nerve-axotomized rats and to further verify the profiles by testing the analgesic effect of activin C, a representative cytokine, on neuropathic pain. Methods: Adult male rats were axotomized in sciatic nerves, and lumbar dorsal root ganglia were isolated for total RNA extraction or section. A custom microarray was developed and employed to plot the gene expression profiles of transforming growth factor-β superfamily components. Realtime RT-PCR was used to confirm changes in the expression of activin/inhibin family genes, and then in situ hybridization was performed to determine the cellular locations of inhibin α, activin βC, BMP-5 and GDF-9 mRNAs. The rat spared nerve injury model was performed, and a pain test was employed to determine the effect of activin C on neuropathic pain. Results: The expression of transforming growth factor-β superfamily cytokines and their signaling, including some receptors and signaling adaptors, were robustly upregulated. Activin βC subunit mRNAs were expressed in the small-diameter dorsal root ganglion neurons and upregulated after axotomy. Single intrathecal injection of activin C inhibited neuropathic pain in spared nerve injury model. Conclusion: This is the first report to investigate the transcriptional profiles of members of transforming growth factor-β superfamily in axotomized dorsal root ganglia. The distinct cytokine profiles observed here might provide clues toward further study of the role of transforming growth factor-β superfamily in the pathogenesis of neuropathic pain and axon degeneration/regeneration after peripheral nerve injury.

Aim: This study aimed to assess the role of Tight junction proteins (TJPs) and claudins in smokers with and without COPD compared to healthy individuals. Background: Chronic obstructive pulmonary disease (COPD) is a complex chronic respiratory disease, including various inflammatory mediators. The prime etiological element in the development of COPD is cigarette smoking. The lung airway epithelium comprises beneficial immunological barriers to draw in insults, such as environmental particulates, cigarette smoke, etc. Tight junctions (TJ) connected by transmembrane proteins determine epithelial permeability. Cigarette smoke is indicated to defect TJ integrity. The possible involvement of the airway epithelium in the pathogenesis of COPD has recently become apparent; however, its detailed mechanisms remain elusive. The integrity of airway epithelium is crucial for airway homeostasis; defective airway barrier activity contributes to COPD. Objective: In the present study, the objective was to investigate mRNA expression levels of TJP’s like TJP-1, TJP-2, TJP-3, Tight junction-associated proteins-1, claudin-1, claudin-3, claudin-4, claudin-7, claudin-10, claudin-15, claudin-19, and claudin-25 from blood samples of smokers with COPD and compared them with smokers without COPD and healthy individuals. Methods: The mRNA expressions were evaluated by the quantitative PCR method. Results: The gene expressions of these TJPs were significantly down-regulated, specifically in COPD patients with a history of smoking (Smokers with COPD). Besides, FEV% was also established for these patients. Similarly, smokers with COPD showed a significant increase in the expression levels of transcription factors, like ZEB-1, ZEB-2, PDGFA, and HDGF, compared to COPD patients without a history of smoking (smokers without COPD) and the healthy subjects. Conclusion: In conclusion, cigarette smoke disrupts TJ of the human airway epithelium, and the transcriptional factors counteract this smoke-induced COPD. Thus, TJPs may serve as protective elements for airway epithelial homeostasis during COPD.

Background: The prevalence of erectile dysfunction (ED) rises with the number and severity of chronic diseases. Aims: This cross-sectional study assessed the frequency and severity of ED in patients with multiple chronic conditions. Methods: The 5-item International Index of Erectile Function questionnaire (IIEF-5) was used to diagnose and classify ED. The Charlson Comorbidity Index (CCI) was used to assess the burden of chronic comorbidity. The primary outcome was to assess the ED frequency according to CCI severity. The secondary outcomes included the assessment of the correlation between 1) IIEF-5 and total testosterone (TT), 2) CCI and TT, and 3) IIEF-5 and CCI. Lastly, the CCI and modified CCI (mCCI) performances were compared with each other. Results: The overall frequency of ED increased along with the CCI score severity: 45% for CCI=0; 95% for CCI=1; 91% for CCI=2; 99% for CCI≥3 (p<.0001). CCI correlated negatively with TT levels and IIEF-5 score (r=-0.34 and -0.44; p<.0001). Compared to the CCI, a novel proposed mCCI performs well. Discussion: The frequency and severity of ED are relevant in outpatients with sexual complaints and those with chronic comorbidities. Despite limitations, mCCI may be considered a reliable tool to assess the overall burden of multiple chronic conditions in patients with comorbidities. Conclusion: ED is a reliable proxy of overall male health. Further studies are needed to confirm this potential application.

Background: A considerable number of COVID-19 vaccines became available following the outbreak. Yet, various inflammatory and autoimmune complications have been reported following vaccination. We aimed to report the case of a type 1 diabetic patient converting from Hashimoto’s thyroiditis to Graves’ disease after the fourth dose of COVID-19 vaccine, thought to trigger an autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). Case Presentation: A thirty-one-year-old female patient with type 1 diabetes and Hashimoto’s thyroiditis applied to our clinic with complaints of palpitations, anxiety, and weight loss one month after the fourth dose of COVID-19 vaccine (2 doses of CoronaVac + 2 doses of Pfizer/BioNTech). She was receiving levothyroxine 50 mcg/day. When her thyroid function tests showed thyrotoxicosis, we initially considered thyroxine-related exogenous thyrotoxicosis. However, we considered Graves’ disease upon persisting thyrotoxicosis despite thyroxine withdrawal, positive serum TSH receptor antibody titers, and other imaging findings. Therefore, various autoimmune and inflammatory events have been reported after the COVID-19 vaccination. Adjuvants in vaccines can trigger autoimmune events, which lead to ASIA syndrome. COVID-19 vaccines may cause increased TSH receptor antibody levels or change the balance in the activity of blocking and stimulating antibodies, which may cause a conversion from Hashimoto’s to Graves’ disease. Conclusion: This was the first case report where the patient experienced a conversion from Hashimoto’s to Graves’ disease after COVID-19 vaccination, which may ultimately be related to ASIA syndrome. Yet, more data is needed to elucidate such a relationship, and patients should closely be checked regularly after four doses of vaccination.

Background: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder. ICF1 is caused by bi-allelic mutations in the gene encoding deoxyribonucleic acid methyltransferase-3B (DNMT3B). Herein, we report a novel homozygous DNMT3B mutation in a patient with ICF1. Case Presentation: An eight-month-old Iranian Caucasian infant of consanguineous 1st-degree cousins presented to our clinic for evaluation of neutropenia. Physical examination was unremarkable except for low-set ears and a systolic cardiac murmur. He had a history of recurrent respiratory infections and oral thrush. Moreover, a collateral artery between the bronchial and pulmonary arteries was observed on the angiogram, mimicking a patent ductus arteriosus on the echocardiogram. Growth percentiles were normal; however, he had a neurodevelopmental delay. Family history was significant for a sibling who deceased at nine months of age after recurrent respiratory infections. Laboratory evaluation revealed a normal white blood cell count with neutropenia and normal bone marrow studies. He had hypogammaglobinemia with normal flow cytometric studies and was treated with prophylactic trimethoprim-sulfamethoxazole and itraconazole. After that, he was re-admitted three times due to recurrent episodes of pneumonia and an episode of pseudomonas aeruginosa meningitis. Currently, he is five years old and doing well on monthly intravenous immunoglobulin. Due to recurrent infections, hypogammaglobulinemia, and neutropenia, as well as a family history of consanguinity and a sibling who deceased during infancy, a primary immune deficiency was suspected. Genetic studies utilizing whole-exome sequencing demonstrated a homozygous missense mutation in DNMT3B (LRG_56t1:c.2008C>T; p.Arg670Trp) in the patient studied. The mutation has not been previously reported. Conclusion: We describe a novel homozygous DNMT3B mutation in an Iranian boy with ICF1. It is associated with recurrent infections, hypogammaglobinemia, neutropenia, mild facial anomalies, and a bronchopulmonary collateral artery.