Mechanisms of Abnormal Lipid Metabolism in the Pathogenesis of Disease.

Lipid metabolism is a critical component in preserving homeostasis and health, and lipids are significant chemicals involved in energy metabolism in living things. With the growing interest in lipid metabolism in recent years, an increasing number of studies have demonstrated the close relationship between abnormalities in lipid metabolism and the development of numerous human diseases, including cancer, cardiovascular, neurological, and endocrine system diseases. Thus, understanding how aberrant lipid metabolism contributes to the development of related diseases and how it works offers a theoretical foundation for treating and preventing related human diseases as well as new avenues for the targeted treatment of related diseases. Therefore, we discuss the processes of aberrant lipid metabolism in various human diseases in this review, including diseases of the cardiovascular system, neurodegenerative diseases, endocrine system diseases (such as obesity and type 2 diabetes mellitus), and other diseases including cancer.

Metabolic-associated fatty liver disease and the role of hormones in its aetiopathogenesis.

Metabolic-associated fatty liver disease (MAFLD) is a newly coined term that links the presence of liver steatosis (characterised by the accumulation of lipids in at least 5% of liver cells) with a condition of overall systemic metabolic dysfunction. MAFLD impacts 24-36% of the global population. As per the official guidelines, a diagnosis of MAFLD can be made when hepatosteatosis is accompanied by type 2 diabetes mellitus, overweight, obesity, or at least 2 other specific metabolic abnormalities (increased waist circumference, hypertension, dyslipidaemia, prediabetes, elevated C-reactive protein level, or increased homeostasis model assessment of insulin resistance: HOMA-IR). MAFLD is a heterogeneous illness associated with multiple diseases that impact various organs, particularly endocrine organs. Endocrinopathies can significantly influence the progression and severity of MAFLD. This paper provides a brief overview of the existing research on the connection between liver steatosis and the functioning of endocrine organs. The authors also propose dividing endocrine diseases into those having a possible, strong, and clear relationship with hepatosteatosis (for the purpose of preliminary recommendations regarding the need for monitoring the possible progression of MAFLD in these groups of patients).

Endocrine, auxological and metabolic profile in children and adolescents with Down syndrome: from infancy to the first steps into adult life.

Down syndrome (DS) is the most common chromosomal disorder worldwide. Along with intellectual disability, endocrine disorders represent a remarkable share of the morbidities experienced by children, adolescents and young adults with DS. Auxological parameters are plotted on syndrome-specific charts, as growth rates are reduced compared to healthy age- and gender-matched peers. Furthermore, children with DS are at increased risk for thyroid dysfunctions, diabetes mellitus, osteopenia and obesity compared to general population. Additionally, male individuals with DS often show infertility, while women tend to experience menopause at an overall younger age than healthy controls. Given the recent outstanding improvements in the care of severe DS-related comorbidities, infant mortality has dramatically decreased, with a current average life expectancy exceeding 60 years. Accordingly, the awareness of the specificities of DS in this field is pivotal to timely detect endocrine dysfunctions and to undertake a prompt dedicated treatment. Notably, best practices for the screening and monitoring of pediatric endocrine disorders in DS are still controversial. In addition, specific guidelines for the management of metabolic issues along the challenging period of transitioning from pediatric to adult health care are lacking. By performing a review of published literature, we highlighted the issues specifically involving children and adolescent with DS, aiming at providing clinicians with a detailed up-to-date overview of the endocrine, metabolic and auxological disorders in this selected population, with an additional focus on the management of patients in the critical phase of the transitioning from childhood to adult care.

New insights into the vitamin D/PTH axis in endocrine-driven metabolic bone diseases.

BACKGROUND: Endocrine regulation of bone metabolisms is the focus of the "Skeletal Endocrinology" series of meetings. AIMS: To report on the outcome of the discussion on the role of vitamin D/PTH axis in endocrine osteopathies held during the 10th Skeletal Endocrinology Meeting which took place in Stresa (Italy) in March 2023. OUTCOMES: Vitamin D/PTH axis has relevant influence on several outcomes in the general population and in patients affected by endocrinopathies such as hypoparathyroidism and secreting pituitary adenomas. CONCLUSIONS: Assessing the status of the vitamin D/PTH axis and using vitamin D and PTH as therapeutic agents is mandatory in several endocrine-related bone metabolic conditions.

Endocrine involvement in hepatic glycogen storage diseases: pathophysiology and implications for care.

Hepatic glycogen storage diseases constitute a group of disorders due to defects in the enzymes and transporters involved in glycogen breakdown and synthesis in the liver. Although hypoglycemia and hepatomegaly are the primary manifestations of (most of) hepatic GSDs, involvement of the endocrine system has been reported at multiple levels in individuals with hepatic GSDs. While some endocrine abnormalities (e.g., hypothalamic­pituitary axis dysfunction in GSD I) can be direct consequence of the genetic defect itself, others (e.g., osteopenia in GSD Ib, insulin-resistance in GSD I and GSD III) may be triggered by the (dietary/medical) treatment. Being aware of the endocrine abnormalities occurring in hepatic GSDs is essential (1) to provide optimized medical care to this group of individuals and (2) to drive research aiming at understanding the disease pathophysiology. In this review, a thorough description of the endocrine manifestations in individuals with hepatic GSDs is presented, including pathophysiological and clinical implications.

Identification of hsa_circRNA_100632 as a novel molecular biomarker for fulminant type 1 diabetes.

Objective: Circular RNAs (circRNAs) are associated with diabetes, but their role in fulminant type 1 diabetes (FT1D) is unclear. Thus, we characterized the role of circRNAs in FT1D. Research design and methods: CircRNA expression profiles were detected in peripheral blood mononuclear cells (PBMCs) of five FT1D patients and five controls using a circRNA microarray. An independent cohort comprised of 40 FT1D cases, 75 type 1 diabetes (T1D) cases, and 115 controls was used to verify the circRNAs using quantitative real-time polymerase chain reaction (qRT-PCR). Spearman's correlation analysis and receiver operating characteristic (ROC) curve analysis were performed to determine the clinical diagnostic capability of circRNAs. Bioinformatics was used to identify potential biological functions and circRNA-miRNA-mRNA interactions. Results: There were 13 upregulated and 13 downregulated circRNAs in PBMCs of patients with FT1D. Five circRNAs were further verified in a second cohort. Hsa_circRNA_100632 was significantly upregulated in the FT1D and T1D groups. Hsa_circRNA_100632 was differentiated between patients with FT1D and controls [area under the curve (AUC) 0.846; 95% CI 0.776-0.916; P<0.0001] as well as between patients with FT1D and patients with T1D (AUC 0.726; 95% CI 0.633-0.820; P<0.0001). Bioinformatics analysis showed that hsa_circRNA_100632 may be involved in 47 circRNA-miRNA-mRNA signaling pathways associated with diabetes. Conclusions: CircRNAs were aberrantly expressed in PBMCs of patients with FT1D, and hsa_circRNA_100632 may be a diagnostic marker of FT1D.

Novel Role of the SIRT1 in Endocrine and Metabolic Diseases.

Silent information regulator 1 (SIRT1), a highly conserved NAD+-dependent deacetylase, is a cellular regulator that has received extensive attention in recent years and regarded as a sensor of cellular energy and metabolism. The accumulated evidence suggests that SIRT1 is involved in the development of endocrine and metabolic diseases. In a variety of organisms, SIRT1 regulates gene expression through the deacetylation of histone, transcription factors, and lysine residues of other modified proteins including several metabolic and endocrine signal transcription factors, thereby enhancing the therapeutic effects of endocrine and metabolic diseases. These evidences indicate that targeting SIRT1 has promising applications in the treatment of endocrine and metabolic diseases. This review focuses on the role of SIRT1 in endocrine and metabolic diseases. First, we describe the background and structure of SIRT1. Then, we outline the role of SIRT1 in endocrine and metabolic diseases such as hyperuricemia, diabetes, hypertension, hyperlipidemia, osteoporosis, and polycystic ovarian syndrome. Subsequently, the SIRT1 agonists and inhibitors in the above diseases are summarized and future research directions are proposed. Overall, the information presents here may highlight the potential of SIRT1 as a future biomarker and therapeutic target for endocrine and metabolic diseases.

Pediatric endocrinopathies related to COVID-19: an update.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the seventh coronavirus to be linked to human disease. The SARS-CoV-2 virus may have several pathophysiologic interactions with endocrine systems, resulting in disruptions in glucose metabolism, hypothalamus and pituitary function, adrenal function, and mineral metabolism. An increasing amount of evidence demonstrates both the influence of underlying endocrine abnormalities on the outcome of COVID-19 and the effect of the SARS-CoV-2 virus on endocrine systems. However, a systematic examination of the link to pediatric endocrine diseases has been missing. DATA SOURCES: The purpose of this review is to discuss the impact of SARS-CoV-2 infection on endocrine systems and to summarize the available knowledge on COVID-19 consequences in children with underlying endocrine abnormalities. For this purpose, a literature search was conducted in EMBASE, and data that were discussed about the effects of COVID-19 on endocrine systems were used in the current study. RESULTS: Treatment suggestions were provided for endocrinopathies associated with SARS-CoV-2 infection. CONCLUSIONS: With the global outbreak of COVID-19, it is critical for pediatric endocrinologists to understand how SARS-CoV-2 interacts with the endocrine system and the therapeutic concerns for children with underlying problems who develop COVID-19. While children and adults share certain risk factors for SARS-CoV-2 infection sequelae, it is becoming obvious that pediatric responses are different and that adult study results cannot be generalized. While pediatric research gives some insight, it also shows the need for more study in this area.

Targeting trafficking as a therapeutic avenue for misfolded GPCRs leading to endocrine diseases.

G protein-coupled receptors (GPCRs) are plasma membrane proteins associated with an array of functions. Mutations in these receptors lead to a number of genetic diseases, including diseases involving the endocrine system. A particular subset of loss-of-function mutant GPCRs are misfolded receptors unable to traffic to their site of function (i.e. the cell surface plasma membrane). Endocrine disorders in humans caused by GPCR misfolding include, among others, hypo- and hyper-gonadotropic hypogonadism, morbid obesity, familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, X-linked nephrogenic diabetes insipidus, congenital hypothyroidism, and familial glucocorticoid resistance. Several in vitro and in vivo experimental approaches have been employed to restore function of some misfolded GPCRs linked to endocrine disfunction. The most promising approach is by employing pharmacological chaperones or pharmacoperones, which assist abnormally and incompletely folded proteins to refold correctly and adopt a more stable configuration to pass the scrutiny of the cell's quality control system, thereby correcting misrouting. This review covers the most important aspects that regulate folding and traffic of newly synthesized proteins, as well as the experimental approaches targeted to overcome protein misfolding, with special focus on GPCRs involved in endocrine diseases.

Per- and poly-fluoroalkyl substances (PFAS) and female reproductive outcomes: PFAS elimination, endocrine-mediated effects, and disease.

Per- and poly-fluoroalkyl substances (PFAS) are widespread environmental contaminants frequently detected in drinking water supplies worldwide that have been linked to a variety of adverse reproductive health outcomes in women. Compared to men, reproductive health effects in women are generally understudied while global trends in female reproduction rates are declining. Many factors may contribute to the observed decline in female reproduction, one of which is environmental contaminant exposure. PFAS have been used in home, food storage, personal care and industrial products for decades. Despite the phase-out of some legacy PFAS due to their environmental persistence and adverse health effects, alternative, short-chain and legacy PFAS mixtures will continue to pollute water and air and adversely influence women's health. Studies have shown that both long- and short-chain PFAS disrupt normal reproductive function in women through altering hormone secretion, menstrual cyclicity, and fertility. Here, we summarize the role of a variety of PFAS and PFAS mixtures in female reproductive tract dysfunction and disease. Since these chemicals may affect reproductive tissues directly or indirectly through endocrine disruption, the role of PFAS in breast, thyroid, and hypothalamic-pituitary-gonadal axis function are also discussed as the interplay between these tissues may be critical in understanding the long-term reproductive health effects of PFAS in women. A major research gap is the need for mechanism of action data - the targets for PFAS in the female reproductive and endocrine systems are not evident, but the effects are many. Given the global decline in female fecundity and the ability of PFAS to negatively impact female reproductive health, further studies are needed to examine effects on endocrine target tissues involved in the onset of reproductive disorders of women.

Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects.

Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function.

Role of Hydrogen Sulfide in the Endocrine System.

Hydrogen sulfide (H2S), as one of the three known gaseous signal transduction molecules in organisms, has attracted a surging amount of attention. H2S is involved in a variety of physiological and pathological processes in the body, such as dilating blood vessels (regulating blood pressure), protecting tissue from ischemia-reperfusion injury, anti-inflammation, carcinogenesis, or inhibition of cancer, as well as acting on the hypothalamus and pancreas to regulate hormonal metabolism. The change of H2S concentration is related to a variety of endocrine disorders, and the change of hormone concentration also affects the synthesis of H2S. Understanding the effect of biosynthesis and the concentration of H2S on the endocrine system is useful to develop drugs for the treatment of hypertension, diabetes, and other diseases.

Biallelic splicing variants in the nucleolar 60S assembly factor RBM28 cause the ribosomopathy ANE syndrome.

Alopecia, neurologic defects, and endocrinopathy (ANE) syndrome is a rare ribosomopathy known to be caused by a p.(Leu351Pro) variant in the essential, conserved, nucleolar large ribosomal subunit (60S) assembly factor RBM28. We report the second family of ANE syndrome to date and a female pediatric ANE syndrome patient. The patient presented with alopecia, craniofacial malformations, hypoplastic pituitary, and hair and skin abnormalities. Unlike the previously reported patients with the p.(Leu351Pro) RBM28 variant, this ANE syndrome patient possesses biallelic precursor messenger RNA (pre-mRNA) splicing variants at the 5' splice sites of exon 5 (ΔE5) and exon 8 (ΔE8) of RBM28 (NM_018077.2:c.[541+1_541+2delinsA]; [946G > T]). In silico analyses and minigene splicing experiments in cells indicate that each splice variant specifically causes skipping of its respective mutant exon. Because the ΔE5 variant results in an in-frame 31 amino acid deletion (p.(Asp150_Lys180del)) in RBM28 while the ΔE8 variant leads to a premature stop codon in exon 9, we predicted that the ΔE5 variant would produce partially functional RBM28 but the ΔE8 variant would not produce functional protein. Using a yeast model, we demonstrate that the ΔE5 variant does indeed lead to reduced overall growth and large subunit ribosomal RNA (rRNA) production and pre-rRNA processing. In contrast, the ΔE8 variant is comparably null, implying that the partially functional ΔE5 RBM28 protein enables survival but precludes correct development. This discovery further defines the underlying molecular pathology of ANE syndrome to include genetic variants that cause aberrant splicing in RBM28 pre-mRNA and highlights the centrality of nucleolar processes in human genetic disease.

Mitochondrial Fission Protein 1: Emerging Roles in Organellar Form and Function in Health and Disease.

Mitochondrial fission protein 1 (Fis1) was identified in yeast as being essential for mitochondrial division or fission and subsequently determined to mediate human mitochondrial and peroxisomal fission. Yet, its exact functions in humans, especially in regard to mitochondrial fission, remains an enigma as genetic deletion of Fis1 elongates mitochondria in some cell types, but not others. Fis1 has also been identified as an important component of apoptotic and mitophagic pathways suggesting the protein may have multiple, essential roles. This review presents current perspectives on the emerging functions of Fis1 and their implications in human health and diseases, with an emphasis on Fis1's role in both endocrine and neurological disorders.

Optoacoustic imaging in endocrinology and metabolism.

Imaging is an essential tool in research, diagnostics and the management of endocrine disorders. Ultrasonography, nuclear medicine techniques, MRI, CT and optical methods are already used for applications in endocrinology. Optoacoustic imaging, also termed photoacoustic imaging, is emerging as a method for visualizing endocrine physiology and disease at different scales of detail: microscopic, mesoscopic and macroscopic. Optoacoustic contrast arises from endogenous light absorbers, such as oxygenated and deoxygenated haemoglobin, lipids and water, or exogenous contrast agents, and reveals tissue vasculature, perfusion, oxygenation, metabolic activity and inflammation. The development of high-performance optoacoustic scanners for use in humans has given rise to a variety of clinical investigations, which complement the use of the technology in preclinical research. Here, we review key progress with optoacoustic imaging technology as it relates to applications in endocrinology; for example, to visualize thyroid morphology and function, and the microvasculature in diabetes mellitus or adipose tissue metabolism, with particular focus on multispectral optoacoustic tomography and raster-scan optoacoustic mesoscopy. We explain the merits of optoacoustic microscopy and focus on mid-infrared optoacoustic microscopy, which enables label-free imaging of metabolites in cells and tissues. We showcase current optoacoustic applications within endocrinology and discuss the potential of these technologies to advance research and clinical practice.

H19 in Endocrine System Tumours.

Long non-coding RNAs (lncRNAs) are over 200 nucleotides long recently discovered RNA molecules that are not involved in the translation process. Accumulating evidence shows that H19 lncRNA is an important regulator of gene expression and its altered expression contributes to carcinogenesis. The aim of this review was to reveal current knowledge about H19 lncRNA and its impact on tumours of the endocrine system. We present findings about H19 altered regulation and its association with tumorigenesis, cancer progression and differentiation, and its potential use in diagnostics, prognostics and therapy. The mechanism and molecular pathways involved in these processes are discussed.