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The cornea protects the interior of the eye from external agents such as bacteria, viruses, and debris. Synthetic glucocorticoids are widely prescribed in the treatment of ocular infections and disorders. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR); however, the molecular and physiological functions of GR signaling in the cornea are poorly understood. This study found that treatment of mice with glucocorticoid eye drops led to a profound regulation of the corneal transcriptome. These glucocorticoid-regulated genes were associated with multiple biological functions, including the immune response. To understand the direct role of GR signaling in the cornea, mice with conditional knockout of GRs in the corneal epithelium were generated. Mice lacking corneal GRs exhibited microphthalmia, loss of pupils, a deformed and opaque lens, and mislocalization of key structural proteins within the corneal epithelial layers. Global transcriptomic approaches revealed that loss of GR signaling in the cornea also resulted in the dysregulation of a large cohort of genes strongly associated with an enhanced inflammatory response. Finally, corneal GR signaling was required for preventing neovascularization of blood and lymphatic vessels and thereby immune cell infiltration of the cornea. These results reveal that corneal GR signaling plays a critical role in ocular development and in maintaining the homeostasis of the eye., Competing Interests: Disclosure Statement None declared., (Published by Elsevier Inc.)

Objective: The impact of the COVID-19 pandemic goes beyond morbidity and mortality from that disease. Increases in maternal mortality have also been described but have not been extensively studied to date. This study aimed to examine changes in maternal mortality and identify correlates and predictors of excess maternal mortality in Colombia during the pandemic., Setting: Analysis of data from the national epidemiological surveillance databases of Colombia (Sivigila)., Participants: Deaths among 6342 Colombian pregnant women who experienced complications associated with pregnancy, childbirth or the perperium during 2008-2020 were included in this study. For inequalities analysis, a subsample of 1055 women from this group who died in 2019 or 2020 years were analysed., Methods: We collected data from the national surveillance system (Sivigila) on maternal mortality. Analysis was carried out in two stages, starting with a time series modelling using the Box-Jenkins approach. Data from Sivigila for 2008-2019 were used to establish a baseline of expected mortality levels. Both simple and complex inequality metrics, with the maternal mortality ratios (MMRs), were then calculated using the Multidimensional Poverty Index as a socioeconomic proxy., Results: Maternal deaths in 2020 were 12.6% (95% CI -21.4% to 95.7%) higher than expected. These excess deaths were statistically significant in elevation for the months of July (97.4%, 95% CI 35.1% to 250.0%) and August (87.8%, 95% CI 30.5% to 220.8%). The MMR was nearly three times higher in the poorest municipalities compared with the most affluent communities in 2020., Conclusions: The COVID-19 pandemic had considerable impact on maternal health, not only by leading to increased deaths, but also by increasing social health inequity. Barriers to access and usage of essential health services are a challenge to achieving health-related Sustainable Development Goals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/ NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GRβ) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GR iKO ) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker.

Context: Despite the importance of cultural beliefs in clinical practice, few systematic reviews have investigated how these beliefs influence food practices in pregnant women., Objective: To explore the role of cultural beliefs in eating patterns and food practices among pregnant women, highlighting food recommendations, food taboos and restrictions, and their association with health., Data Sources: A systematic review was conducted using the following electronic databases: PubMed, Scopus, CINAHL, PsycINFO, and Web of Science from May 2014 to May 2019., Data Extraction: Articles were included if the studies included pregnant women, analyzed how cultural beliefs may influence eating patterns, were peer-reviewed articles with original data, published in the last 5 years, and in English or Spanish language. Quality assessment was also performed., Data Analysis: A total of 544 articles were identified in the search and 24 were included in the final analysis (17 using qualitative design, 6 using quantitative design, and 1 with a mixed-design). These studies were predominantly from the African continent (n = 15). Our findings showed that culture is a key factor related to "taboos" and food restrictions, which are transmitted by the family or members of community, having a strong religious or spiritual influence. All these restrictions are related to the fear of unfavorable pregnancy outcomes such as the risk of abortion, dystocia, and congenital macrosomia, or are used to avoid child problems such as cutaneous and respiratory disorders., Conclusions: Findings from this study indicate cultural beliefs are strongly associated with food patterns and eating habits in pregnant women. Administrators and health professionals should be aware of these beliefs to minimize problems in the perinatal period., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Our immune system has evolved as a complex network of cells and tissues tasked with maintaining host homeostasis. This is evident during the inflammatory responses elicited during a microbial infection or traumatic tissue damage. These responses seek to eliminate foreign material or restore tissue integrity. Even during periods without explicit disturbances, the immune system plays prominent roles in tissue homeostasis. Perhaps one of the most studied cells in this regard is the macrophage. Tissue-resident macrophages are a heterogenous group of sensory cells that respond to a variety of environmental cues and are essential for organ function. Endogenously produced glucocorticoid hormones connect external environmental stress signals with the function of many cell types, producing profound changes in immune cells, including macrophages. Here, we review the current literature which demonstrates specific effects of glucocorticoids in several organ systems. We propose that tissue-resident macrophages, through glucocorticoid signaling, may play an underappreciated role as regulators of organ homeostasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Diaz-Jimenez, Kolb and Cidlowski.)

Glucocorticoids promote CXCR4 expression by T cells, monocytes, macrophages, and eosinophils, but it is not known if glucocorticoids regulate CXCR4 in B cells. Considering the important contributions of CXCR4 to B cell development and function, we investigated the glucocorticoid/CXCR4 axis in mice. We demonstrate that glucocorticoids upregulate CXCR4 mRNA and protein in mouse B cells. Using a novel strain of mice lacking glucocorticoid receptors (GRs) specifically in B cells, we show that reduced CXCR4 expression associated with GR deficiency results in impaired homing of mature B cells to bone marrow, whereas migration to other lymphoid tissues is independent of B cell GRs. The exchange of mature B cells between blood and bone marrow is sensitive to small, physiologic changes in glucocorticoid activity, as evidenced by the lack of circadian rhythmicity in GR-deficient B cell counts normally associated with diurnal patterns of glucocorticoid secretion. B cell GRKO mice mounted normal humoral responses to immunizations with T-dependent and T-independent (Type 1) Ags, but Ab responses to a multivalent T-independent (Type 2) Ag were impaired, a surprise finding considering the immunosuppressive properties commonly attributed to glucocorticoids. We propose that endogenous glucocorticoids regulate a dynamic mode of B cell migration specialized for rapid exchange between bone marrow and blood, perhaps as a means to optimize humoral immunity during diurnal periods of activity.

Glucocorticoids are potent endogenous anti-inflammatory molecules, and their cognate receptor, glucocorticoid receptor (GR), is expressed in nearly all immune cells. Macrophages are heterogeneous immune cells having a central role in both tissue homeostasis and inflammation and also play a role in the pathogenesis of some inflammatory diseases. Paradoxically, glucocorticoids have only a limited efficacy in controlling the resolution of these macrophage-related diseases. Here, we report that the transcriptomes of monocyte-like THP-1 cells and macrophage-like THP-1 cells (THP1-MΦ) have largely conserved gene expression patterns. In contrast, the differentiation to THP1-MΦ significantly altered the sensitivity of gene transcription to glucocorticoids. Among glucocorticoid-regulated genes, we identified the exopeptidase dipeptidyl peptidase-4 ( DPP4 ) as a critical glucocorticoid-responsive gene in THP1-MΦ. We found that GR directly induces DPP4 gene expression by binding to two glucocorticoid-responsive elements (GREs) within the DPP4 promoter. Additionally, we show that glucocorticoid-induced DPP4 expression is blocked by the GR antagonist RU-486 and by GR siRNA transfection and that DPP4 enzyme activity is reduced by DPP4 inhibitors. Of note, glucocorticoids highly stimulated macrophage mobility; unexpectedly, DPP4 mediated the glucocorticoid-induced macrophage migration, and siRNA-mediated knockdowns of GR and DPP4 blocked dexamethasone-induced THP1-MΦ migration. Moreover, glucocorticoid-induced DPP4 activation was also observed in proinflammatory M1-polarized murine macrophages, as well as peritoneal macrophages, and was associated with increased macrophage migration. Our results indicate that glucocorticoids directly up-regulate DPP4 expression and thereby induce migration in macrophages, potentially explaining why glucocorticoid therapy is less effective in controlling macrophage-dominated inflammatory disorders.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by mucosa damage associated with an uncontrolled inflammatory response. This immunological impairment leads to altered inflammatory mediators such as IL-33, which is shown to increase in the mucosa of active UC (aUC) patients. MicroRNAs present a distorted feature in inflamed colonic mucosa and are potential IL-33 regulating candidates in UC. Therefore, we studied the microRNA and mRNA profiles in inflamed colonic samples of UC patients, evaluating the effect of a microRNA (selected by in silico analysis and its expression in UC patients), on IL-33 under inflammatory conditions. We found that inflamed mucosa ( n = 8) showed increased expression of 40 microRNAs and 2,120 mRNAs, while 49 microRNAs and 1,734 mRNAs were decreased, as determined by microarrays. In particular, IL-33 mRNA showed a 3.8-fold increase and eight members of a microRNA family (miR-378), which targets IL-33 mRNA in the 3'UTR, were decreased (-3.9 to -3.0 times). We selected three members of the miR-378 family (miR-378a-3p, miR-422a, and miR-378c) according to background information and interaction energy analysis, for further correlation analyses with IL-33 expression through qPCR and ELISA, respectively. We determined that aUC ( n = 24) showed high IL-33 levels, and decreased expression of miR-378a-3p and miR-422a compared to inactive UC ( n = 10) and controls ( n = 6). Moreover, both microRNAs were inversely correlated with IL-33 expression, while miR-378c does not show a significant difference. To evaluate the effect of TNFα on the studied microRNAs, aUC patients with anti-TNF therapy were compared to aUC receiving other treatments. The levels of miR-378a-3p and miR-378c were higher in aUC patients with anti-TNF. Based on these findings, we selected miR-378a-3p to exploring the molecular mechanism involved by in vitro assays, showing that over-expression of miR-378a-3p decreased the levels of an IL-33 target sequence β-gal-reporter gene in HEK293 cells. Stable miR-378a-3p over-expression/inhibition inversely modulated IL-33 content and altered viability of HT-29 cells. Additionally, in an inflammatory context, TNFα decreased miR-378a-3p levels in HT-29 cells enhancing IL-33 expression. Together, our results propose a regulatory mechanism of IL-33 expression exerted by miR-378a-3p in an inflammatory environment, contributing to the understanding of UC pathogenesis., (Copyright © 2019 Dubois-Camacho, Diaz-Jimenez, De la Fuente, Quera, Simian, Martínez, Landskron, Olivares-Morales, Cidlowski, Xu, Gao, Xie, Chnaiderman, Soto-Rifo, González, Calixto and Hermoso.)