Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 22, Issue 8, 2022

Obesity is a growing pandemic. Endocrine-disrupting chemicals are widespread in the environment. In this perspective, the authors examine the issue related to the exposure to several chemicals with endocrine-disrupting properties as promoting factors to obesity. Data show that Phthalates, Bisphenol compounds, Persistent Organic Pollutants (POPs), solvents, and personal care products can modify metabolic properties in a dose-response and sex-specific manner. Phthalates and bisphenol compounds increase body mass index, waist circumference, waist to height ratio, and the sum of skinfold thicknesses in women and not in men. Low-dose exposure to Persistent Organic Pollutants is strongly associated with increased body mass index in men and decreased this parameter in women. The mechanism through which these compounds act on anthropometric parameters is not entirely understood. Several studies suggest a possible interference in gonadotropin secretion and the thyroid axis. These inspire a decrease in both total and free testosterone levels in men and FT3 and FT4 levels in women, particularly after a pregnancy. The impact of endocrine disruptor chemicals on adipose tissue inflammation and future cardio-metabolic disorders remains to be elucidated. Therefore, studies involving both healthy and obese individuals are needed to unambiguously confirm results from in vitro and animal models.

Non-alcoholic fatty liver disease (NAFLD) is marked by the excessive intrusion of triglycerides into hepatocytes without any role of alcohol consumption. Various risk factors have been attributed to this disease pathogenesis, including metabolic disorders, immune response, and even an intricate relationship between the two. The role of insulin resistance (IR) in NAFLD has long been known; however, the molecular basis of disease progression under this metabolic backdrop is still being investigated. Similarly, the periodontitis-mediated immune response is another major factor involved in NAFLD manifestation, which has generated huge interest. The prevalence of pathogenic bacteria elicits a strong immune response, which according to the studies shows a strong correlation with NAFLD state. Such pre-existing conditions have a strong probability of explaining the disease onset. Additionally, increasing reports on inflammatory response and its links to insulin resistance have further increased the scope of understanding NAFLD. Through this review, we aim to elaborate on these factors explaining their role in the disease progression.

Background: Type 1 diabetes (T1D) is a chronic autoimmune disease affecting people globally. Usually developed during childhood, T1D is characterized by the destruction of pancreatic β-cells due to immune cell attack and the establishment of an inflammatory process. Objective: The study aimed to investigate the effects of vitamin D through its nuclear receptor and the ω-3 polyunsaturated fatty acids (PUFAs) through their lipid derivatives in T1D modulation. Both components exert anti-inflammatory activity and act directly on cells of the immune system, attenuating the destruction of insulin-producing cells. Furthermore, they lead to a better glycemic level, reducing the need for insulin and a normal immune state, such as C-peptide maintenance. Methods: Presently, our review highlights the significant studies that evaluated the supplementation of vitamin D and ω-3 PUFAs in humans and animal models in the modulation of T1D. Conclusion: The data collected suggests that supplementation can provide potential benefits, mainly when done early in the diagnosis, since it reduces the need for insulin and the risk of complications generated by the disease.

Background: Growing pieces of evidence demonstrate a close relationship between type 2 diabetes (T2D) and neurodegenerative disorders such as Alzheimer’s disease. The similarity of physiological and pathological processes occurring in pancreatic β-cells and neurons over the course of these pathologies allows raising the question of the practicability of studying neuroprotective substances for their potential antidiabetic activity. Objective: This review analyzes studies of antidiabetic and cytoprotective action on pancreatic β- cells of the neuroprotective compounds that can attenuate the oxidative stress and enhance the expression of neurotrophins: low-molecular-weight NGF mimetic compound GK-2, selective anxiolytic afobazole, antidepressants lithium chloride, and lithium carbonate on the rat streptozotocin model of T2D. Results: It was found that all the above-listed neuroprotective substances have a pronounced antidiabetic activity. The decrease in the β-cells number, the average area of the pancreatic islets, as well as the violation of their morphological structure caused by the streptozotocin was significantly weakened by the therapy with the investigated neuroprotective substances. The extent of these morphological changes clearly correlates with the antihyperglycemic effect of these compounds. Conclusion: The presented data indicate that the neuroprotective substances attenuating the damaging effect of oxidative stress and neurotrophins deficit cannot only protect neurons but also exert their cytoprotective effect towards pancreatic β-cells. These data may provide a theoretical basis for the further study of neuroprotective drugs as potential therapeutic options for T2D prevention and treatment.

COVID-19, a pandemic caused by SARS-CoV-2, has been spread all over the world and is responsible for serious fatalities. SARS-CoV-2 belongs to the family of β-coronavirus that affects pulmonary gas exchange and triggers cytokines storm. Vigorous inflammation, hyper-coagulation, a decrease in the lymphocytic count, and an increase in the neutrophilic count are observed in the second week after the onset of the disease. Fever, dry cough, sneezing, shortness of breath, and respiratory distress are the symptoms of COVID-19. The use of sanitizers, social distancing, vaccination, wearing gloves and face masks, and other preventative measures are all important in preventing coronavirus outbreaks. People with weak immunity are more susceptible to coronavirus. Various natural immunity boosters are known for their immune boosting properties; among them are vitamin C, D, and B complex, medicinal mushrooms, plant-based stuff, and minerals play important roles by increasing the beneficial flora of the human body. All these natural immunity boosters improve the innate and adaptive immune response against coronavirus. Hence, we conclude that the use of natural immunity boosters prevents the attack of coronavirus and makes a person stronger against the suspected attack of COVID-19 and/or other viral diseases.

Background: Systemic lupus erythematosus (SLE) is known to be associated with an increased risk of cardiovascular diseases (CVD). SLE patients suffer from CVD 3.5 times more often than healthy people. Cytokine-mediated inflammation is actively involved in the development of cardiovascular pathology. Objective: Here, we analyzed serum levels of nine cytokines of steroids-treated SLE patients depending on the presence of concomitant CVD. Methods: The levels of interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-10, IL-21, tumor necrosis factor α (TNFα), B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL) were analyzed using multiplex immunoassay. Results: In the total group of SLE patients (n=29), the concentrations of IL-6 and IL-10 were higher, and the APRIL level decreased compared to healthy donors (n=39, p<0.05). The same changes were observed in the group of patients without CVD (n=15); the levels of IL-6 and IL- 10 were found to be increased, and the level of APRIL was lower than in healthy individuals (p<0.05). In the group of SLE patients with CVD (n=14), the concentrations of IL-4, IL-6, IL- 10, and TNFα were found to be increased (p<0.05). Interestingly, the levels of TNFα and BAFF in SLE patients with CVD were higher than in patients without cardiovascular pathology. Thus, TNFα and BAFF levels were significantly altered in SLE with concomitant CVD compared to SLE without CVD. Conclusion: These findings suggest that cytokine profiles in SLE with concomitant CVD and SLE without CVD are different, which should be considered in further research with large samples.

Objective: Cortex Mori Radicis (CMR) has been reported to possess antipyretic, anticonvulsant, anti-allergic, anti-inflammatory, and anti-diabetic effects. In this study, we aimed to investigate the effect of CMR on streptozotocin (STZ)-induced diabetic renal injury in mice and explore the underlying mechanism. Methods: Mice were gavaged with different doses of CMR for continuous 7 days. Then, STZ (50 mg/kg) was applied to induce renal injury associated with type 1 diabetes. Firstly, blood glucose levels and metabolic parameters were evaluated, including weight, food intake, and excrement. HE and PAS staining were performed to examine renal histological changes. Renal inflammation, fibrosis, and oxidative stress were assayed by real-time PCR and ELISA, separately. Additionally, podocyte- related markers, such as nephrin and wilms' tumor-1 (WT-1), were detected by immunohistochemical staining and Western blot separately. Lastly, expression of transient receptor potential canonical channel 6 (TRPC6) and activation of MAPK signaling pathways were assayed. Results: CMR pretreatment significantly lowered the blood glucose levels, suppressed renal inflammation, fibrosis, and oxidative stress, and relieved renal pathological injury, accompanying the inhibition of nephrin and WT-1 expression in STZ-induced diabetic mice. Moreover, CMR decreased the expression of TRPC6 and suppressed the phosphorylation of ERK, but not P38 MAPK and JNK. Notably, the application of hyperforin, a specific activator of TRPC6, significantly abrogated the hypoglycemic effect of CMR and reversed the suppression of CMR on TRPC6 expression and ERK activation in the diabetic mice. Conclusion: Our findings indicated that CMR attenuated early renal injury in STZ-induced diabetic mice by inhibiting ERK signaling via regulation of TRPC6, suggesting that CMR can be considered as a promising candidate for the management of diabetes-related renal complications.

Background: Sexual disorders are the most common clinical manifestations of hypogonadism. Functional hypogonadism is the most frequent form, and clomiphene citrate (CC) has been recently introduced as a possible off-label therapeutic option for these patients. Objectives: This study aimed to evaluate the effects of CC on the overall sexual function in dysmetabolic obese men with low testosterone (T) levels. Methods: This was a sub-study of a randomized, double-blind, cross-over, placebo-controlled trial that included twenty-four obese or overweight subjects with impaired glucose tolerance or type 2 diabetes and confirmed low total T (≤10.4 nmol/l) levels. Subjects were treated with CC or placebo (Plac) for 12 weeks, with an interval wash-out period of 6 weeks between treatments. All subjects were on metformin 2gr/day and a low-calorie diet. The between-treatment difference in the overall sexual function was assessed by IIEF-15 and a qADAM questionnaire. Results: IIEF-15 and qADAM questionnaire data were available for 18 individuals. In unadjusted analyses, CC was associated with lower IIEF-15 total, erectile function, and intercourse satisfaction domain scores than Plac. After adjustments for multiple variables, CC was associated with a higher IIEF-15 sexual desire domain score (+0.9 ± 0.8; p<.001) despite a lower qADAM score (-2.1 ± 0.9; p=.008) with respect to Plac. No differences were found for the other domains between groups. Discussion: The clinical significance of the absolute changes in IIEF-15 and qADAM scores during CC versus Plac is limited. However, CC has a reliable effect on sexual desire and is also as safe as Plac. According to the sample size, duration of follow-up, and inclusion criteria defined for the main study, further studies are therefore needed to assess the long-term efficacy of CC. Conclusion: Compared to Plac, CC was found to be associated with a neutral effect on overall sexual function.

Background: Chromosome Xp21 deletion syndrome is a rare X-linked recessive defect that occurs as a result of multiple gene deletions, including Glycerol kinase (GK) and its neighboring genes, dystrophin, which causes Duchenne muscular dystrophy (DMD), and NR0B1, which causes congenital adrenal hypoplasia (CAHhttps://www.omim.org/entry/300200). Patients usually present with glycerol kinase deficiency, congenital adrenal hypoplasia, Duchenne muscular dystrophy, hyperglycerolemia, and glyceroluria, associated with DMD and/or CAH, growth failure, myopathy, osteoporosis, mental retardation, and psychomotor retardation. Case Presentation: Herein, we report a 3-year- old boy from Iraq who had bloody diarrhea, food intolerance and abdominal cramp, adrenal insufficiency, recurrent fevers, tuberculosis (TB) infection, cervical abscess, oral thrush, cervical and mediastinal lymphadenopathies, developmental delay, and undescended testis. His parents are non-consanguine and had no family history of diseases. Next generation sequencing demonstrated a hemizygote deletion in chromosome X. Conclusion: Loss of a large part of the X-chromosome most likely can explain the clinical findings of this patient. Contiguous gene deletion syndrome in Xp21 should be considered after diagnosing adrenal insufficiency to treat metabolic complications efficiently.

Background: Schimke immuno-osseous dysplasia (SIOD) is a very rare autosomal recessive genetic disease caused by mutations in the SMARCAL1 gene. It is characterized by spondyloepiphyseal dysplasia, T-cell immunodeficiency, hypercromic nevi, hypercholestero-lemia, and steroid-resistant nephrotic syndrome with progressive renal failure to end-stage kidney disease. Case Presentation: We report two cases of SIOD in sisters, diagnosed after the debut of nephrotic syndrome. Both had a personal history of short stature, acetabular hip dysplasia, and hypercholesterolemia. The first case, a 6-year-old girl, presented peripheral refractory edema, severe arterial hypertension, and progressive decrease of the glomerular filtration rate. Steroid-resistance of nephrotic syndrome was confirmed, treated with tacrolimus without response. Renal function worsened over the following 4 months, so haemodialysis was started. Her sister, a 5-year-old girl, had the steroid-resistant nephrotic syndrome and normal blood pressure and renal function under enalapril treatment. In view of the suspicion of SIOD, genetic studies were carried out, revealing the same mutation in homozygosis. Conclusion: SIOD has a variable expression with multi-systemic involvement with a short life expectancy. Early diagnosis is important, which can encourage the early start of treatment and anticipation of complications that may be life-threatening.

Background: We report the case of a 43-year-old Chinese male with Tophaceous gout who had been living in Italy for some years. Case Presentation: Previous treatments with allopurinol had induced Steven Johnson syndrome, dictating a switch to febuxostat 80 mg daily. After two years of treatment with febuxostat, he developed a diffuse maculopapular rash with severe itching. Rheumatologists stopped febuxostat; however, gout worsened over the following years despite treatment with kalnicitrate and colchicine. Therefore, an allergy consultation was called for. A slow desensitization protocol with febuxostat was started, with a low oral dosage scheme to be increased up to 80 mg/day. Febuxostat was prepared in a solid formulation by the consultation pharmacist as pills instead of the more frequently used liquid suspension. Conclusion: The patient is currently receiving febuxostat 80 mg, and he has shown no side effects as of now, while his gout has improved. This is the first reported example and he has shown no side effect till now, while his gout improved of a successful desensitization protocol using a solid preparation of diluted febuxostat given as pills.