Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 22, Issue 10, 2022

Hyperhomocysteinemia is an independent risk factor for atherosclerosis, even in early childhood. A mutation in genes that code homocysteine metabolism enzymes or deficiency of specific vitamin cofactors may cause hyperhomocysteinemia. Vitamin B complex has been correlated with serum homocysteine levels. Any abnormality in its metabolism or nutritional deficiency may lead to hyperhomocysteinemia. Both vitamin B complex and homocysteine levels are partly genetically determined. Specifically, the most studied polymorphism is 677T-C in exon 5 of the 5,10- methylenetetrahydrofolate reductase (MTHFR) gene, which plays an important role in folate’s metabolism. This polymorphism has been shown to be correlated with hypertension and cardiovascular disease. Polymorphisms in methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L) gene have also been correlated with increased risk for coronary artery disease. Other common serious polymorphisms regard the area with high linkage disequilibrium, including the neuroblastoma breakpoint family, NBPF3 gene, and ~ 12-50 kb upstream of the tissue nonspecific alkaline phosphatase gene. Finally, the polymorphisms which have been mostly associated with vitamin B12 concentration are the rs11254363 polymorphism at intron 52 of the intrinsic factor vitamin B12 receptor of the CUBN and the rs526934 polymorphism at intron 8 of transcobalamin I. To sum up, several polymorphisms have already been associated with vitamin B complexes and therefore homocysteine level, highlighting the complex nature of vitamin B genetics.

Background: Thyroid hormones play a vital role in regulating our body’s metabolism. Two important thyroid hormones released from the thyroid gland are tri-iodothyronine (T3) and tetra-iodothyronine (T4). Thyroid-stimulating hormone and thyroid regulating hormone control the T3 and T4 levels in our body. Increased TSH levels indicate hypothyroidism and decreased TSH levels indicate hyperthyroidism. Iodine is a crucial nutrient for the synthesis of thyroid hormones and is mostly obtained from our diet. Other essential nutrients for the thyroid hormones formation include selenium, iron, vitamin D, vitamin B12, etc. Dietary changes in these nutrients can result in alterations in thyroid function and structure. Although normally, the hormonal diseases cannot be cured, but we can improve their signs and symptoms using suitable dietary supplements. Objective: The aim of the study was to thoroughly analyze the various benefits and risks associated with the use of dietary supplements for the prevention and treatment of various thyroid disorders, like hypothyroidism, as seen in Hashimoto’s thyroiditis; hyperthyroidism, as seen in Graves’ disease; sick euthyroidism and subclinical hypothyroidism. Methods: Literature was searched using the search terms “dietary supplements+thyroid diseases” on Pubmed, Google Scholar, Scopus, Cochrane Library, and other search engines, and data were collected from 1967 to November, 2021, including research inputs from the authors. The literature was thoroughly searched, and deep knowledge was acquired on this topic, which was then sequentially organized and summarized using suitable tables and figures. Conclusion: After analyzing various studies on this topic, we arrived at the conclusion that although there are various claimed and observed health benefits of dietary supplements in the prevention and treatment of various thyroid disorders, still several studies have shown too many risks to be associated with the use of dietary supplements, and people using these products should be aware of these risks in order to use them very judiciously for the improvement of their thyroid status.

Diabetes mellitus is a metabolic disease caused by a combination of genetic and environmental factors. The importance of the inflammatory response occurring in the pancreas and adipose tissue in the occurrence and progression of diabetes has been gradually accepted. Excess blood glucose and free fatty acids produce large amounts of inflammatory cytokines and chemokines through oxidative stress and endoplasmic reticulum stress. There is sufficient evidence that proinflammatory mediators, such as interleukin (IL)-1β, IL-6, macrophage chemotactic protein-1, and tumor necrosis factor-α, are engaged in insulin resistance in peripheral adipose tissue and the apoptosis of pancreatic β-cells. IL-36, IL-37, and IL-38, as new members of the IL-1 family, play an indispensable role in the regulation of immune system homeostasis and are involved in the pathogenesis of inflammatory and autoimmune diseases. Recently, the abnormal expression of IL-36, IL-37, and IL-38 in diabetes has been reported. In this review, we discuss the emerging functions, potential mechanisms, and future research directions on the role of IL-36, IL-37, and IL-38 in diabetes mellitus and its complications.

N6-methyladenosine (m6A) is a prevalent modification of RNA in eukaryotes, bacteria, and viruses. It is highly conserved and can affect the structure, localization, and biology functions of RNA. In recent years, multiple m6A methylation sites have been identified in the viral RNA genome and transcripts of DNA viruses. This modification occurs commonly during the primary infection and is dynamically regulated by a methyltransferase (writers), demethylase (eraser) and m6A-binding proteins (readers) within the host cells. The abnormal m6A modification not only affects the replication of pathogenic viruses and host immune response but also contributes to the pathogenesis of virus-induced cancers. In this review, we highlight recent advances on the mechanism of m6A modification on viral replication, host immune response and carcinogenesis to provide a novel insight for epigenetic prevention of viral infection and virus-driven carcinogenesis.

Familial hypercholesterolemia (FH) as a high-frequency genetic disorder is diagnosed based on family and/or patient’s history of coronary heart disease (CHD) or some other atherosclerotic diseases, LDL-C levels, and/or clinical signs such as tendinous xanthoma, arcus cornealis before age 45 years as well as a functional mutation in the LDLR, apoB or PCSK9 gene. Its clinical features are detectable since early childhood. Early diagnosis and timely treatment increase life expectancy in most patients with FH. Current FH therapies decrease the level of lowdensity lipoprotein up to ≥50% from baseline with diet, pharmacotherapeutic treatment, lipid apheresis, and liver transplantation. The cornerstone of medical therapy is the use of more potent statins in higher doses, to which often ezetimibe has to be added, but some FH patients do not achieve the target LDL-C with this therapy Therefore, besides these and the most recent but already established therapeutic approaches including PCSK9 inhibitors, inclisiran, and bempedoic acid, new therapies are on the horizon such as gene therapy, CRISPR/Cas9 strategy, etc. This paper focuses on cellular and molecular potential strategies for the treatment of FH.

Background: We investigated the relationship between respiratory function measured by spirometry analysis and anthropometric variables (skeletal and fat mass) and nutritional status in the institutionalized elderly, particularly at high-risk for adverse outcomes after respiratory infections and malnutrition. Design: This is a multicenter cross-sectional study with a quantitative approach conducted among older people institutionalized living in nursing homes. Methods: Respiratory function was assessed by measuring the forced vital capacity, forced expiratory volume in the first second, the ratio between FEV1 and FVC (FEV1/FVC), and peak expiratory flow in percentage by means of spirometric analysis (values of the forced expiratory volume measured during the first second of the forced breath (FEV1) and forced vital capacity (FVC)). Nutritional assessment and anthropometry analyses were performed to evaluate under or over nutrition/weight. Results: There was a significant (p<0.05) and positive correlation between FEV1 and skeletal muscle mass index, whereas fat mass index correlated significantly (p<0.01) with the FEV1/FVC index. FEV1/FVC values were both significantly (p<0.05) associated with high body mass index and triglyceride levels in the blood. The prevalence of individuals with ventilator restrictive pattern (FEV1/FVC>70% with FEV1 and FVC<80%) was 27.6% and 12 individuals (21.1%) received daily bronchodilators as part of the pharmacological treatment for respiratory disorders. Logistic regression was performed to identify predictors of restrictive respiratory patterns. The following variables were included in the model: age group, female gender, Charlson comorbidity index, body-mass index (BMI), fat mass index, skeletal muscle mass index, total cholesterol, and triglycerides concentration. The model was statistically significant (p < 0.05; R2 = 0.39), correctly classifying 70.0% of cases, with a sensitivity of 89.3% and a specificity of 50.0%. Area under curve was 0.71 (IC95% 0.54-0.88; p=0.023).The highest OR for the restrictive respiratory pattern was for BMI (OR=5.09) and triglycerides concentration in blood (>150 mg/dl) (OR=5.59). Conclusion: The relationship between a restrictive pattern of respiratory function and fat mass deserves future investigation to manage these parameters as a possible modifiable factor of altered respiratory function in overweight institutionalized older individuals.

Background: Lymphoproliferative disorders include a heterogeneous list of conditions that commonly involve dysregulation of lymphocyte proliferation resulting in lymphadenopathy and bone marrow infiltration. These disorders have various presentations, most notably autoimmune manifestations, organomegaly, lymphadenopathy, dysgammaglobulinemia, and increased risk of chronic infections. Case Presentation: A young boy presented with symptoms overlapping different lymphoproliferative disorders, including episodes of chronic respiratory tract infections, dysgammaglobulinemia, lymphadenopathy-associated with splenomegaly as well as skin rashes. Genetic studies revealed multiple heterozygous variants, including a novel mutation in the NFΚB1 gene. Conclusion: This novel mutation can reveal new aspects in the pathogenesis of lymphoproliferative disorders and propose new treatments for them.

Background: Bile acid synthesis disorders are rare congenital diseases that can lead to cirrhosis and end-stage liver disease if left untreated. Cholic acid administration is the only treatment that can prevent patients from fatal outcomes. Since 2013 in Europe, there has been just one formulation of cholic acid: Orphacol®. It is difficult to administer to infant patients because of its formulation (capsules) and the need for dose titration depending on the patient’s weight. Case Presentation: Two sisters affected by 3-β-hydroxy-Δ-5-C27-steroid dehydrogenase deficiency showed soon after birth failure to thrive, cholestasis, and fat-soluble vitamin deficiency. Both biochemical findings and liver biopsies confirmed cholestasis and initial liver damage. Patients were treated for eight years with a liquid formulation of a cholic acid galenic compound, and then they started to be treated with capsules of the registered drug. Clinical conditions and biochemical findings were checked periodically during both therapies. Conclusion: Clinical and laboratory data showed no differences between the cholic acid galenic compound and the registered drug in terms of efficacy and safety. Furthermore, the galenic compound showed benefits of more manageable dose titration, easier intake due to its liquid formulation, and lower costs than commercial cholic acid capsules.

Background: Prader-Willi syndrome is the most frequent genetic cause of obesity and is often complicated by glucose metabolism alterations. Conventional therapies prescribed for type 2 diabetes frequently failed to achieve adequate glycemic control in patients with Prader-Willi syndrome. Beneficial effects of glucagon like peptide-1 receptor agonists exenatide and liraglutide have been reported for the management of type 2 diabetes in Prader-Willi syndrome, but no data are currently available in this population on the use of semaglutide. Case Presentation: We report for the first time the use of semaglutide 1 mg per week in a 33-yearold man with Prader-Will syndrome complicated by poorly controlled diabetes and severe obesity. After 12 months of semaglutide treatment, we observed an important reduction in glycated hemoglobin levels (11.1% to 7.2%) and body weight (99.5 kg to 94.3 kg), with a notable decrease in fat mass and insulin requirements. Interestingly, our patient had already tried liraglutide therapy in adjunction to metformin and insulin therapy, reporting no substantial efficacy. Conclusion: The beneficial effects of semaglutide on glycemic control and weight reduction provide a promising treatment for diabetes and obesity in Prader-Willi syndrome, even where other glucagons like peptide-1 receptor agonists have failed. Further studies are required to confirm the efficacy and safety of semaglutide in patients with Prader-Willi syndrome.