Synovial expression of glucocorticoid receptor parallels fibroblast activation in patients with rheumatoid arthritis.

BACKGROUND: Hypocortisolemia is associated with increased expression of NR3C1 (glucocorticoid receptor, GR) in blood cells. As endogenous cortisol production is decreased in some RA patients, we tested the hypothesis that GR may be aberrantly expressed in rheumatoid synovium. METHODS: We defined the cellular pattern of NR3C1 synovial expression using human and mouse single-cell RNA-sequencing data. Bulk synovial RNA-sequencing data from early (n = 57) or established (n = 94) RA were compared to osteoarthritis (n = 22) and healthy synovium (n = 28). RESULTS: GR was expressed in all synovial cell types in both human and experimental arthritis. GR synovial expression, as well as 11ß-HSD1/11ß-HSD2 enzyme ratio, were higher in RA than healthy and osteoarthritic tissue, regardless of disease duration or treatment. Given that GR expression varied across samples, we searched for differences between RA patients with higher versus lower GR expression. Indeed, the synovial transcriptome of RA patients with high versus low GR expression (1st quartile, 30,517 ± 4876 vs. 4th quartile, 19,382 ± 2523 normalized counts) was enriched for proinflammatory gene-sets, including 'inflammatory response', 'IFN-γ response' and 'IL6/JAK/STAT3 signalling'. High synovial GR expression was also associated with increased JAK2 and PTPRK expression, denoting activation of the proinflammatory sublining fibroblasts. In contrast, low GR expression was associated with increased COMP and COL6A2 expression, denoting a resting synovial state. CONCLUSIONS: GR is overexpressed in the synovium of some RA patients in association with proinflammatory gene expression and activated sublining fibroblast status. Further studies should examine whether GR overexpression may act as a compensatory mechanism sensitizing synovial tissue to glucocorticoid action in RA.

Stress-Related Roles of Exosomes and Exosomal miRNAs in Common Neuropsychiatric Disorders.

Exosomes, natural nanovesicles that contain a cargo of biologically active molecules such as lipids, proteins, and nucleic acids, are released from cells to the extracellular environment. They then act as autocrine, paracrine, or endocrine mediators of communication between cells by delivering their cargo into recipient cells and causing downstream effects. Exosomes are greatly enriched in miRNAs, which are small non-coding RNAs that act both as cytoplasmic post-transcriptional repression agents, modulating the translation of mRNAs into proteins, as well as nuclear transcriptional gene activators. Neuronal exosomal miRNAs have important physiologic functions in the central nervous system (CNS), including cell-to-cell communication, synaptic plasticity, and neurogenesis, as well as modulating stress and inflammatory responses. Stress-induced changes in exosomal functions include effects on neurogenesis and neuroinflammation, which can lead to the appearance of various neuropsychiatric disorders such as schizophrenia, major depression, bipolar disorder, and Alzheimer's and Huntington's diseases. The current knowledge regarding the roles of exosomes in the pathophysiology of common mental disorders is discussed in this review.

Cephalometric Evaluation of Children with Short Stature of Genetic Etiology: A Review.

Introduction: A plethora of biological molecules regulate chondrogenesis in the epiphyseal growth plate. Disruptions of the quantity and function of these molecules can manifest clinically as stature abnormalities of various etiologies. Traditionally, the growth hormone/insulin-like growth factor 1 (IGF1) axis represents the etiological centre of final stature attainment. Of note, little is known about the molecular events that dominate the growth of the craniofacial complex and its correlation with somatic stature. Aim: Given the paucity of relevant data, this review discusses available information regarding potential applications of lateral cephalometric radiography as a potential clinical indicator of genetic short stature in children. Materials and Methods: A literature search was conducted in the PubMed electronic database using the keywords: cephalometric analysis and short stature; cephalometric analysis and achondroplasia; cephalometric analysis and hypochondroplasia; cephalometric analysis and skeletal abnormalities; cephalometr* and SHOX; cephalometr* and CNP; cephalometr* and ACAN; cephalometr* and CNVs; cephalometr* and IHH; cephalometr* and FGFR3; cephalometr* and Noonan syndrome; cephalometr* and "Turner syndrome"; cephalometr* and achondroplasia. Results: In individuals with genetic syndromes causing short stature, linear growth of the craniofacial complex is confined, following the pattern of somatic short stature regardless of its aetiology. The angular and linear cephalometric measurements differ from the measurements of the average normal individuals and are suggestive of a posterior placement of the jaws and a vertical growth pattern of the face. Conclusions: The greater part of the existing literature regarding cephalometric measurements in short-statured children with genetic syndromes provides qualitative data. Furthermore, cephalometric data for individuals affected with specific rare genetic conditions causing short stature should be the focus of future studies. These quantitative data are required to potentially establish cut-off values for reference for genetic testing based on craniofacial phenotypes.

Analysis of Human Milk Microbiota in Northern Greece by Comparative 16S rRNA Sequencing vs. Local Dairy Animals.

Milk is a biological fluid with a dynamic composition of micronutrients and bioactive molecules that serves as a vital nutrient source for infants. Milk composition is affected by multiple factors, including genetics, geographical location, environmental conditions, lactation phase, and maternal nutrition, and plays a key role in dictating its microbiome. This study addresses a less-explored aspect, comparing the microbial communities in human breast milk with those in mature milk from species that are used for milk consumption. Since mature animal milk is used as a supplement for both the infant (formula) and the child/adolescent, our main aim was to identify shared microbial communities in colostrum and mature human milk. Using 16S rRNA metagenomic sequencing, we focused on characterizing the milk microbiota in the Northern Greek population by identifying shared microbial communities across samples and comparing the relative abundance of prevalent genera. We analyzed ten human milk samples (from five mothers), with five collected three days postpartum (colostrum) and five collected thirty to forty days postpartum (mature milk) from corresponding mothers. To perform an interspecies comparison of human milk microbiota, we analyzed five goat and five bovine milk samples from a local dairy industry, collected fifty to seventy days after birth. Alpha diversity analysis indicated moderate diversity and stability in bovine milk, high richness in goat milk, and constrained diversity in breast milk. Beta diversity analysis revealed significant distinctions among mammalian species, emphasizing both presence/absence and abundance-based clustering. Despite noticeable differences, shared microbial components underscore fundamental aspects across all mammalian species, highlighting the presence of a core microbiota predominantly comprising the Proteobacteria, Firmicutes, and Actinobacteriota phyla. At the genus level, Acinetobacter, Gemella, and Sphingobium exhibit significant higher abundance in human milk compared to bovine and goat milk, while Pseudomonas and Atopostipes are more prevalent in animal milk. Our comparative analysis revealed differences and commonalities in the microbial communities of various mammalian milks and unraveled the existence of a common fundamental milk core microbiome. We thus revealed both species-specific and conserved microbial communities in human, bovine, and goat milk. The existence of a common core microbiome with conserved differences between colostrum and mature human milk underscores fundamental similarities in the microbiota of milk across mammalian species, which could offer valuable implications for optimizing the nutritional quality and safety of dairy products as well as supplements for infant health.

Identification of Stage-Specific microRNAs that Govern the Early Stages of Sequential Oral Oncogenesis by Strategically Bridging Human Genetics with Epigenetics and Utilizing an Animal Model.

Oral squamous cell carcinoma (OSCC) is a highly prevalent and aggressive malignancy, with mortality rates reaching 60%, mainly due to its excessive diagnostic delay. MiRNAs, a class of crucial epigenetic gene-expression regulators, have emerged as potential diagnostic biomarkers, with >200 molecules exhibiting expressional dysregulation in OSCC. We had previously established an in silico methodology for the identification of the most disease-specific molecules by bridging genetics and epigenetics. Here, we identified the stage-specific miRNAs that govern the asymptomatic early stages of oral tumorigenesis by exploiting seed-matching and the reverse interplay between miRNA levels and their target genes' expression. Incorporating gene-expression data from our group's experimental hamster model of sequential oral oncogenesis, we bioinformatically detected the miRNAs that simultaneously target/regulate >75% of the genes that are characteristically upregulated or downregulated in the consecutive stages of hyperplasia, dysplasia, and early invasion, while exhibiting the opposite expressional dysregulation in OSCC-derived tissue and/or saliva specimens. We found that all stages share the downregulation of miR-34a-5p, miR124-3p, and miR-125b-5p, while miR-1-3p is under-expressed in dysplasia and early invasion. The malignant early-invasion stage is distinguished by the downregulation of miR-147a and the overexpression of miR-155-5p, miR-423-3p, and miR-34a-5p. The identification of stage-specific miRNAs may facilitate their utilization as biomarkers for presymptomatic OSCC diagnosis.

Milk exosomes and a new way of communication between mother and child.

Extracellular vesicles are a heterogeneous group of lipid-bound vesicles released by cells into the extracellular space. EVs are an important mediator of intercellular communications and carry a wide variety of molecules that exert a biological function, such as lipids, nucleic acids, proteins, ions, and adenosine triphosphate (ATP). Extracellular vesicles are classified into microvesicles, exosomes, and apoptotic bodies depending on their biogenesis and size. Exosomes are spherical lipid-bilayer vesicles with a diameter of about 40 to 100 nm. Exosomes originate from intracellular endosomal compartments, while microvesicles originated directly from a cell's plasma membrane and apoptotic bodies originate from cells undergoing apoptosis and are released via outward blebbing and fragmentation of the plasma membrane. Specifically, exosomes have garnered great attention since they display great potential as both biomarkers and carriers of therapeutic molecules.

Exosomal Epigenetics.

Epigenetics is the study of heritable changes in gene expression that occur without changes to the underlying DNA sequence. Epigenetic modifications can include DNA methylation, histone modifications, and non-coding RNAs, among others. These modifications can influence the expression of genes by altering the way DNA is packaged and accessed by transcriptional machinery, thereby affecting cellular function and behavior. Epigenetic modifications can be influenced by a variety of factors, including environmental exposures, lifestyle factors, and aging, whilst abnormal epigenetic modifications have been implicated in a range of diseases, including cancer, neurodegenerative disorders, and cardiovascular disease. The study of epigenetics has the potential to provide new insights into the mechanisms of disease and could lead to the development of new diagnostic and therapeutic strategies. Exosomes can transfer epigenetic information to recipient cells, thereby influencing various physiological and pathological processes, and the identification of specific epigenetic modifications that are associated with a particular disease could lead to the development of targeted therapies that restore normal gene expression patterns. In recent years, the emerging role of exosomal epigenetics in human breast milk, highlighting its significance in infant nutrition and immune development. Milk exosomes are shown to carry epigenetic regulators, including miRNAs and long non-coding RNAs, which can modulate gene expression in recipient cells. These epigenetic modifications mediated by milk exosomal RNAs have implications for the development of the gastrointestinal tract, immune system, and metabolic processes in infants.

Fingerprinting Breast Milk; insights into Milk Exosomics.

Breast milk, often referred to as "liquid gold," is a complex biofluid that provides essential nutrients, immune factors, and developmental cues for newborns. Recent advancements in the field of exosome research have shed light on the critical role of exosomes in breast milk. Exosomes are nanosized vesicles that carry bioactive molecules, including proteins, lipids, nucleic acids, and miRNAs. These tiny messengers play a vital role in intercellular communication and are now being recognized as key players in infant health and development. This paper explores the emerging field of milk exosomics, emphasizing the potential of exosome fingerprinting to uncover valuable insights into the composition and function of breast milk. By deciphering the exosomal cargo, we can gain a deeper understanding of how breast milk influences neonatal health and may even pave the way for personalized nutrition strategies.

A TMEM63A Nonsense Heterozygous Variant Linked to Infantile Transient Hypomyelinating Leukodystrophy Type 19?

Infantile onset transient hypomyelination (IOTH) is a rare form of leukodystrophy that is associated with transient motor impairment and delayed central nervous system myelination. Here, we report a case of a new mutation in the transmembrane protein 63A (TMEM63A) gene identified using Whole-Exome Sequencing (WES) in an 8.5-year-old boy with clinical symptoms similar to IOTH. The patient exhibited a mild developmental delay, including hypotonia and delayed motor milestones, as well as some notable phenotypic characteristics, such as macrocephaly and macrosomia. Despite the absence of early neuroimaging, genetic testing revealed a paternally inherited variant in TMEM63A (NM_14698.3:c.220A>T;p:(Arg74*)), potentially linked to infantile transient hypomyelinating leukodystrophy type 19. Our findings in this study and the patient's favorable clinical course underscore the potential for successful myelination even with delayed initiation and may contribute to a better understanding of the genotype-phenotype correlation in IOTH, emphasizing the importance of genetic analysis in unresolved developmental delay cases and providing critical insights for accurate diagnosis, prognosis and potential therapeutic strategies in rare leukodystrophies.

SNP and Structural Study of the Notch Superfamily Provides Insights and Novel Pharmacological Targets against the CADASIL Syndrome and Neurodegenerative Diseases.

The evolutionary conserved Notch signaling pathway functions as a mediator of direct cell-cell communication between neighboring cells during development. Notch plays a crucial role in various fundamental biological processes in a wide range of tissues. Accordingly, the aberrant signaling of this pathway underlies multiple genetic pathologies such as developmental syndromes, congenital disorders, neurodegenerative diseases, and cancer. Over the last two decades, significant data have shown that the Notch signaling pathway displays a significant function in the mature brains of vertebrates and invertebrates beyond neuronal development and specification during embryonic development. Neuronal connection, synaptic plasticity, learning, and memory appear to be regulated by this pathway. Specific mutations in human Notch family proteins have been linked to several neurodegenerative diseases including Alzheimer's disease, CADASIL, and ischemic injury. Neurodegenerative diseases are incurable disorders of the central nervous system that cause the progressive degeneration and/or death of brain nerve cells, affecting both mental function and movement (ataxia). There is currently a lot of study being conducted to better understand the molecular mechanisms by which Notch plays an essential role in the mature brain. In this study, an in silico analysis of polymorphisms and mutations in human Notch family members that lead to neurodegenerative diseases was performed in order to investigate the correlations among Notch family proteins and neurodegenerative diseases. Particular emphasis was placed on the study of mutations in the Notch3 protein and the structure analysis of the mutant Notch3 protein that leads to the manifestation of the CADASIL syndrome in order to spot possible conserved mutations and interpret the effect of these mutations in the Notch3 protein structure. Conserved mutations of cysteine residues may be candidate pharmacological targets for the potential therapy of CADASIL syndrome.

Combined Brain-Heart Imaging in Takotsubo Syndrome: Towards a Holistic Patient Assessment.

Takotsubo syndrome (TTS) is a type of cardiomyopathy usually precipitated by either emotional or physical stress and potentially leading to reversible heart failure. There is emerging evidence indicating an interaction between the brain and the heart in patients with TTS. Nevertheless, these new insights are not reflected in the current clinical approach to TTS. The application of novel and existing imaging modalities for the evaluation of brain-heart interactions is an interesting approach that could potentially augment diagnostic and prognostic yield, as well as improve our pathophysiologic understanding in the context of TTS. In this opinion piece, we discuss the evidence supporting a brain-heart interaction in patients with TTS and discuss how a combined evaluation of brain-heart interactions could potentially be implemented.

Structural and Functional Insights into CRF Peptides and Their Receptors.

Corticotropin-releasing factor or hormone (CRF or CRH) and the urocortins regulate a plethora of physiological functions and are involved in many pathophysiological processes. CRF and urocortins belong to the family of CRF peptides (CRF family), which includes sauvagine, urotensin, and many synthetic peptide and non-peptide CRF analogs. Several of the CRF analogs have shown considerable therapeutic potential in the treatment of various diseases. The CRF peptide family act by interacting with two types of plasma membrane proteins, type 1 (CRF1R) and type 2 (CRF2R), which belong to subfamily B1 of the family B G-protein-coupled receptors (GPCRs). This work describes the structure of CRF peptides and their receptors and the activation mechanism of the latter, which is compared with that of other GPCRs. It also discusses recent structural information that rationalizes the selective binding of various ligands to the two CRF receptor types and the activation of receptors by different agonists.

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children.

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-ß in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-ω and/or IFN-α2.

Diurnal production of cortisol and prediction of treatment response in rheumatoid arthritis: a 6-month, real-life prospective cohort study.

OBJECTIVES: A reduced adrenal reserve-associated cortisol production relative to the enhanced needs of chronic inflammation (disproportion principle) has been observed in rheumatoid arthritis (RA). We examined the possible clinical value of diurnal cortisol measurements in active RA on treatment response prediction. METHODS: Diurnal cortisol production (measured at: 08-12:00/18:00-22:00) was assessed by electrochemiluminescence immunoassay in 28 consecutive patients with moderately/highly active RA, as well as 3 and 6 months after treatment initiation or/escalation. Twenty-eight COVID-19 patients and 28 age-matched healthy individuals (HC) served as controls. RESULTS: Saliva diurnal cortisol production in patients with RA was similar to that of HC, despite 12-fold higher serum C reactive protein (CRP) levels, and lower than COVID-19 patients (area under the curve: RA: 87.0±37.6 vs COVID-19: 146.7±14.3, p<0.001), having similarly high CRP. Moreover, a disturbed circadian cortisol rhythm at baseline was evident in 15 of 28 of patients with RA vs 4 of 28 and 20 of 28 of HC and COVID-19 patients, respectively. Treatment-induced minimal disease activity (MDA) at 6 months was achieved by 16 of 28 patients. Despite comparable demographics and clinical characteristics at baseline, non-MDA patients had lower baseline morning cortisol and higher adrenocorticotropic hormone (ACTH) levels compared with patients on MDA (cortisol: 10.9±4.0 vs 18.4±8.2 nmol/L, respectively, p=0.005 and ACTH: 4.8±3.3 vs 2.4±0.4 pmol/L, respectively, p=0.047). Baseline morning cortisol <13.9 nmol/L predicted non-MDA at 6 months (75% sensitivity, 92% specificity, p=0.006). Prospective measurements revealed that individualised diurnal cortisol production remained largely unchanged from baseline to 3 and 6 months. CONCLUSIONS: An impaired adrenal reserve is present in patients with RA. Further studies to confirm that assessment of diurnal cortisol production may be useful in guiding treatment decisions and/or predicting treatment response in RA are warranted. TRIAL REGISTRATION NUMBER: NCT05671627.

Functional MRI Techniques Suggesting that the Stress System Interacts with Three Large Scale Core Brain Networks to Help Coordinate the Adaptive Response: A Systematic Review.

OBJECTIVE: Synthesis of functional MRI (fMRI) and functional connectivity (FC) analysis data on human stress system (SS) function, as it relates to the dynamic function of the Salience (SN), Default Mode (DMN) and Central Executive (CEN) networks. METHODS: Systematic search of Medline, Scopus, Clinical Trials.gov, and Google Scholar databases of studies published prior to September 2022 resulted in 28 full-text articles included for qualitative synthesis. RESULTS: Acute stress changes the states of intra-/inter- neural network FCs and activities from those of resting, low arousal state in the SN, DMN and CEN, during which intra- and inter-network FCs and activities of all three networks are low. SS activation is positively linked to the activity of the SN and negatively to that of the DMN, while, in parallel, it is associated with an initial decrease and a subsequent increase of the intra- network FC and activity of the CEN. The FC between the DMN and the CEN increases, while those between the SN and the CEN decrease, allowing time for frontal lobe strategy input and "proper" CEN activity and task decision. SN activation is linked to sensory hypersensitivity, "impaired" memory, and a switch from serial to parallel processing, while trait mindfulness is associated with FC changes promoting CEN activity and producing a "task-ready state". CONCLUSION: SS activation is tightly connected to that of the SN, with stress hormones likely potentiating the intra-network FC of the latter, attenuating that of the DMN, and causing a biphasic suppression- to-activation response of the CEN, all adaptive changes favoring proper decisions and survival.

Inflammation in Posttraumatic Stress Disorder: Dysregulation or Recalibration?

Despite ample experimental data indicating a role of inflammatory mediators in the behavioral and neurobiological manifestations elicited by exposure to physical and psychologic stressors, causative associations between systemic low-grade inflammation and central nervous system inflammatory processes in posttraumatic stress disorder (PTSD) patients remain largely conceptual. As in other stress-related disorders, pro-inflammatory activity may play an equivocal role in PTSD pathophysiology, one that renders indiscriminate employment of anti-inflammatory agents of questionable relevance. In fact, as several pieces of preclinical and clinical research convergingly suggest, timely and targeted potentiation rather than inhibition of inflammatory responses may actually be beneficial in patients who are characterized by suppressed microglia function in the face of systemic low-grade inflammation. The deleterious impact of chronic stress-associated inflammation on the systemic level may, thus, need to be held in context with the - often not readily apparent - adaptive payoffs of low-grade inflammation at the tissue level.

Thyroid Diseases and Intestinal Microbiome.

The human microbiome plays an integral role in health. In particular, it is important for the development, differentiation, and maturation of the immune system, 70% of which resides in the intestinal mucosa. Microbiome studies conducted to date have revealed an association between disturbances in the microbiota (dysbiosis) and various pathological disorders, including changes in host immune status. Autoimmune thyroid diseases are one of the most common organ-specific autoimmune disorders, with a worldwide prevalence higher than 5%. The predominant autoimmune thyroid diseases are Hashimoto's thyroiditis and Grave's disease. Several factors, such as genetic and environmental ones, have been studied. In accordance with recent studies, it is assumed that the gut microbiome might play a significant role in triggering autoimmune diseases of the thyroid gland. However, the exact etiology has not yet been elucidated. The present review aims to describe the work carried out so far regarding the role of gut microflora in the pathogenesis of autoimmune thyroid diseases and its involvement in the appearance of benign nodules and papillary thyroid cancer. It appears that future work is needed to elucidate more precisely the mechanism for gut microbiota involvement in the development of autoimmune thyroid diseases.

Diet and metabolism are back: The oldest known Islamic medical manuscript bridges the gap from ancient to modern gout management.

Gout is a chronic disease frequently associated with lifestyle; its prevalence is increasing in Western societies, as well as in the Middle East. Apart from its partial genetic features, diet accounts for 12% of the causality of the disease, while purine-rich foods contribute decisively to its development and evaluation. The influential Persian physician of the medieval ages, Abu Bakr Muhammad Ibn Zakariya al-Razi (or by his Latin name Rhazes; 860-925 AD), wrote a short book (20 chapters) entitled 'Treatise on gout'. Rhazes adopted the Hippocratic humoralism, and suggested that the disease results from metabolic excess in the peripheral blood, presenting sex dimorphism and age-dependence. His therapeutic guidelines include a diet prescribed by a physician, the use of laxatives and emetics, counter-balancing excess or deficiency of bile or phlegm and analgesics, bloodletting, foot and steam baths, as well as salves and poultices as preventive measures. He appends differential dietary restrictions/suggestions for phlegmatic or choleric patients: Small rations and intake of good quality foods low in purine by 20% for phlegmatic and 28% for choleric patients, as well as the restriction of foods high in purine by 27% for phlegmatic and 22% for the choleric patients. Finally, the acidic to alkaloid food intake ratio suggested is 2/5 for choleric and 3/7 for phlegmatic patients. His suggested foods and drugs are vitamin C and B-rich complexes, thereby inhibiting the accumulation of tophi.

The human glucocorticoid receptor.

Glucocorticoids are members of steroid hormones that are biosynthesized in the intermediate cellular zone of the adrenal cortex (zona fasciculata) and released into the peripheral blood as final products of the hypothalamic-pituitary-adrenal (HPA) axis, as well as under the control of the circadian biologic system. These molecules regulate every physiologic function of the organism as they bind to an almost ubiquitous hormone-activated transcription factor, the glucocorticoid receptor (GR), which influences the rate of transcription of a huge number of target genes amounting to up to 20% of the mammalian genome. The evolving progress of cellular, molecular and computational-structural biology and the implication of epigenetics in every-day clinical practice have enabled us a deeper and ever-increasing understanding of how target tissues respond to natural and synthetic glucocorticoids. In this chapter, we summarize the current knowledge on the structure, expression, function and signaling of the human glucocorticoid receptor in normal and pathologic conditions.