UNASSIGNED: The combined effects of metformin and epigallocatechin-3-gallate (EGCG) on cortisol, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), and blood glucose levels have not been investigated. This study evaluated the effectiveness of combining EGCG with metformin in regulating those levels in a rat model of diet-induced diabetes and obesity.
UNASSIGNED: Thirty diabetic and obese rats on a high-fat diet were treated daily for 28 days with EGCG (100 mg/kg of body weight/day), metformin (200 mg/kg of body weight/day), or both. Control groups comprised lean rats, untreated obese diabetic rats, and metformin-only-treated rats. Blood samples were collected to measure cortisol and fasting blood glucose (FBG) levels and liver tissue samples were examined for 11β-HSD1 levels.
UNASSIGNED: Rats receiving combination therapy had significantly reduced cortisol levels (from 36.70±15.13 to 31.25±7.10 ng/mL) compared with the untreated obese diabetic rats but not the rats receiving monotherapy. Rats receiving combination therapy and EGCG monotherapy had significantly lower 11β-HSD1 levels compared with the untreated obese diabetic rats (92.68±10.82 and 93.74±18.11 ng/L vs. 120.66±14.00 ng/L). Combination therapy and metformin monotherapy significantly reduced FBG levels (440.83±133.3 to 140.50±7.36 mg/dL and 480.67±86.32 to 214.17±102.78 mg/dL, respectively) by approximately 68.1% and 55.4% compared with rats receiving EGCG monotherapy and untreated obese diabetic rats.
UNASSIGNED: Combining EGCG with metformin exhibited synergistic effects compared with monotherapy for managing diabetes, leading to improved outcomes in reduction of baseline cortisol levels along with reduction in 11β-HSD1 and blood glucose levels.

Trachoma, caused by Chlamydia trachomatis, is the most common infectious blindness in the world and is present in indigenous Mayan from Chiapas (Mexico). Inflammatory genes are activated when suffering from trachoma, thus some polymorphisms could increase the susceptibility to develop irreversible blindness. This study aimed to evaluate the genetic risk of developing late-stage trachoma in Mayan ethnic groups. In a case-control study (n = 51 vs n = 102, respectively), the following single-nucleotide polymorphisms (SNPs) in genes related to inflammation were analysed: HSD11B1 (rs11807619), HSD11B1 (rs932335), ABCG2 (rs2231142), SLCO1B1 (rs4149056), IL-10 (rs1800890), TNF (rs1800629), MMP2 (rs243865) and ACE. Three SNPs were associated with late-stage trachoma risk: (i) the T allele of rs11807619, (ii) the C allele of rs932335, which are linked to the HSD11B1 gene (OR = 22.5-27.3), particularly in men when adjusts for gender (OR = 16-16.7); and (iii) D allele of rs4340 in the ACE gene (OR = 5.2-5.3). In fact, significant linkage disequilibrium demonstrated association between ACE gene and HSD11B1 SNPs (r = 0.17-0.179; P = 0.0048-0.0073). Two SNPs HSD11B1 gene (P = 0.013 vs 0.0039) and HSD11B1-ACE haplotypes showed association with late-stage trachoma in Mayan ethnic groups.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver-related morbidity and mortality. Though high fructose intake is acknowledged as a metabolic hazard, its role in the etiology of MASLD requires further clarification. Here, we demonstrated that high dietary fructose drives MASLD development and promotes MASLD progression in mice, and identified Usp2 as a fructose-responsive gene in the liver. Elevated USP2 levels were detected in the hepatocytes of MASLD mice; a similar increase was observed following fructose exposure in primary hepatocytes and mouse AML12 cells. Notably, hepatocytes overexpressing USP2 presented with exaggerated lipid accumulation and metabolic inflammation when exposed to fructose. Conversely, USP2 knockdown mitigated these fructose-induced changes. Furthermore, USP2 was found to activate the C/EBPα/11β-HSD1 signaling, which further impacted the equilibrium of cortisol and cortisone in the circulation of mice. Collectively, our findings revealed the role of dietary fructose in MASLD pathogenesis and identified the USP2-mediated C/EBPα/ 11β-HSD1 signaling as a potential target for the management of MASLD.

BACKGROUND: In inflammatory diseases such as rheumatoid arthritis (RA), steroid metabolism is a central component mediating the actions of immuno-modulatory glucocorticoids and sex steroids. However, the regulation and function of cellular steroid metabolism within key leukocyte populations such as macrophages remain poorly defined. In this study, the inflammatory regulation of global steroid metabolism was assessed in RA macrophages.
METHODS: Bulk RNA-seq data from RA synovial macrophages was used to assess transcripts encoding key enzymes in steroid metabolism and signalling. Changes in metabolism were assessed in synovial fluids, correlated to measures of disease activity and functionally validated in primary macrophage cultures.
RESULTS: RNA-seq revealed a unique pattern of differentially expressed genes, including changes in genes encoding the enzymes 11β-HSD1, SRD5A1, AKR1C2 and AKR1C3. These correlated with disease activity, favouring increased glucocorticoid and androgen levels. Synovial fluid 11β-HSD1 activity correlated with local inflammatory mediators (TNFα, IL-6, IL-17), whilst 11β-HSD1, SRD5A1 and AKR1C3 activity correlated with systemic measures of disease and patient pain (ESR, DAS28 ESR, global disease activity). Changes in enzyme activity were evident in inflammatory activated macrophages in vitro and revealed a novel androgen activating role for 11β-HSD1. Together, increased glucocorticoids and androgens were able to suppress inflammation in macrophages and fibroblast-like-synoviocytes.
CONCLUSIONS: This study underscores the significant increase in androgen and glucocorticoid activation within inflammatory polarized macrophages of the synovium, contributing to local suppression of inflammation. The diminished profile of inactive steroid precursors in postmenopausal women may contribute to disturbances in this process, leading to increased disease incidence and severity.

UNASSIGNED: Blood biomarkers are proposed as a diagnostic alternative to amyloid PET or cerebrospinal fluid (CSF) analyses for the diagnosis of Alzheimer\'s disease (AD). Relatively little is known of the natural history of patients identified by different blood biomarkers.
UNASSIGNED: To identify patients with elevated plasma phosphorylated tau (pTau)181 from a prior Phase 2a trial, and explore the natural histories of their clinical progression, and potential efficacy of Xanamem, a selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in these patients.
UNASSIGNED: A prespecified, double-blind analysis was conducted in 72 participants with clinically diagnosed AD and available plasma samples from baseline and Week 12 of the \"XanADu\" Phase 2a trial of Xanamem versus placebo. The analysis prespecified plasma pTau181 > median to identify patients more likely to have AD (\"H\", > 6.74 pg/mL, n = 34). Cohen\'s d (d) of≥0.2 defined potential clinical significance.
UNASSIGNED: In the placebo group, H patients showed greater clinical progression compared to L patients (pTau181≤median) on ADCOMS (d = 0.55, p < 0.001), CDR-SB (d = 0.63, p < 0.001), MMSE (d = 0.52, p = 0.12), and ADAS-Cog14 (d = 0.53, p = 0.19). In H patients, a potentially clinically meaningful Xanamem treatment effect compared to placebo was seen in the CDR-SB (LS mean difference 0.6 units, d = 0.41, p = 0.09) and Neuropsychological Test Battery (NTB; LS mean difference 1.8 units, d = 0.26, p = 0.48) but not ADCOMS or ADAS-Cog14.
UNASSIGNED: This trial demonstrates that elevated plasma pTau181 identifies participants more likely to have progressive AD and is a suitable method for enrichment in AD clinical trials. Xanamem treatment showed evidence of potential clinically meaningful benefits.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans. It increases in diverse conditions, including ageing, obesity, osteoporosis, glucocorticoid therapy, and notably, during caloric restriction (CR). BMAT potentially influences skeletal, metabolic, and immune functions, but the mechanisms of BMAT expansion remain poorly understood. Our hypothesis is that, during CR, excessive glucocorticoid activity drives BMAT expansion. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid activity by catalysing intracellular regeneration of active glucocorticoids from inert 11-keto forms. Mice lacking 11β-HSD1 resist metabolic dysregulation and bone loss during exogenous glucocorticoid excess; thus, we hypothesised that 11β-HSD1 knockout mice would also resist excessive glucocorticoid action during CR, thereby restrining BMAT expansion and bone loss. To test this, we first confirmed that 11β-HSD1 is expressed in mouse and human bone marrow. We then investigated the effects of CR in male and female control and 11β-HSD1 knockout mice from 9 to 15 weeks of age. CR increased Hsd11b1 mRNA in adipose tissue and bone marrow. Deletion of Hsd11b1 did not alter bone or BMAT characteristics in mice fed a control diet and had little effect on tibial bone microarchitecture during CR. Notably, Hsd11b1 deletion attenuated the CR-induced increases in BMAT and prevented increases in bone marrow corticosterone in males but not females. This was not associated with suppression of glucocorticoid target genes in bone marrow. Instead, knockout males had increased progesterone in plasma and bone marrow. Together, our findings show that knockout of 11β-HSD1 prevents CR-induced BMAT expansion in a sex-specific manner and highlights progesterone as a potential new regulator of bone marrow adiposity.

The similarity of the clinical picture of metabolic syndrome and hypercortisolemia supports the hypothesis that obesity may be associated with impaired expression of genes related to cortisol action and metabolism in adipose tissue. The expression of genes encoding the glucocorticoid receptor alpha (GR), cortisol metabolizing enzymes (HSD11B1, HSD11B2, H6PDH), and adipokines, as well as selected microRNAs, was measured by real-time PCR in adipose tissue from 75 patients with obesity, 19 patients following metabolic surgery, and 25 normal-weight subjects. Cortisol levels were analyzed by LC-MS/MS in 30 pairs of tissues. The mRNA levels of all genes studied were significantly (p < 0.05) decreased in the visceral adipose tissue (VAT) of patients with obesity and normalized by weight loss. In the subcutaneous adipose tissue (SAT), GR and HSD11B2 were affected by this phenomenon. Negative correlations were observed between the mRNA levels of the investigated genes and selected miRNAs (hsa-miR-142-3p, hsa-miR-561, and hsa-miR-579). However, the observed changes did not translate into differences in tissue cortisol concentrations, although levels of this hormone in the SAT of patients with obesity correlated negatively with mRNA levels for adiponectin. In conclusion, although the expression of genes related to cortisol action and metabolism in adipose tissue is altered in obesity and miRNAs may be involved in this process, these changes do not affect tissue cortisol concentrations.

Long-term β-adrenoceptor (β-AR) stimulation is a pathological mechanism associated with cardiovascular diseases resulting in endothelial and perivascular adipose tissue (PVAT) dysfunction. In this study, we aimed to identify whether β-adrenergic signaling has a direct effect on PVAT. Thoracic aorta PVAT was obtained from male Wistar rats and cultured ex vivo with the β-AR agonist isoproterenol (Iso; 1 µM) or vehicle for 24 hours. Conditioned culture medium (CCM) from Iso-treated PVAT induced a marked increase in aorta contractile response, induced oxidative stress, and reduced nitric oxide production in PVAT compared to vehicle. In addition, Iso-treated PVAT and PVAT-derived differentiated adipocytes exhibited higher corticosterone release and protein expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme responsible for de novo synthesis of corticosterone. Macrophages exposed to Iso also exhibited increased corticosterone release in response to β-AR stimulation. Incubation of Iso-treated PVAT and PVAT-derived differentiated adipocytes with β3-AR antagonist restored aorta contractile function modulated by Iso-CCM and normalized 11β-HSD1 protein expression. These results show that β3-AR signaling leads to upregulation of 11β-HSD1 in PVAT, thus increasing corticosterone release and contributing to impair the anticontractile function of this tissue.

BI 187004, a selective small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β-HSD1 inhibition (50%) was detected in a very low-dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose-dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target-mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high-affinity and low-capacity target 11β-HSD1. The non-intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small-molecule compound. Among the various models explored, the best model was a two-compartment TMDD model with three transit absorption components. The final model provides insights into 11β-HSD1 binding-related parameters for BI 187004, including the total amount of 11β-HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM-1h-1), and the first-order dissociation rate constant (estimated to be 0.11 h-1). Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004\'s future clinical trials.

Excess cortisol is associated with more severe cognitive decline, Alzheimer\'s disease, and related dementia phenotypes. The intracellular enzyme 11β-HSD1 regenerates active cortisol from inactive cortisone. In this current issue, high regional brain occupancy of Xanamemtrademark, determined by [11C]TARACT PET imaging of 11β-HSD1, in cognitively normal individuals and mild cognitive impartment/Alzheimer\'s disease (AD) patients is presented. In the future, comprehensive kinetic modeling using arterial sampling for occupancy studies, and whole-body PET imaging of 11β-HSD1 enzyme levels, in combination with stable isotope studies of cortisol metabolism, can provide broad insight into enzyme levels and activity in AD and other relevant diseases.