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Frontiers in Immunology 2023Imiquimod (IMQ) is a topical agent that induces local inflammation the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in... (Randomized Controlled Trial)
Randomized Controlled Trial
Imiquimod (IMQ) is a topical agent that induces local inflammation the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model. This randomized, double-blind, placebo-controlled study was conducted in 24 healthy volunteers. Oral prednisolone (0.25 mg/kg/dose) or placebo (1:1) was administered twice daily for 6 consecutive days. Two days after treatment initiation with prednisolone or placebo, 5 mg imiquimod (IMQ) once daily for two following days was applied under occlusion on the tape-stripped skin of the back for 48 h in healthy volunteers. Non-invasive (imaging and biophysical) and invasive (skin punch biopsies and blister induction) assessments were performed, as well as IMQ stimulation of whole blood. Prednisolone reduced blood perfusion and skin erythema following 48 h of IMQ application (95% CI [-26.4%, -4.3%], p = 0.0111 and 95% CI [-7.96, -2.13], p = 0.0016). Oral prednisolone suppressed the IMQ-elevated total cell count (95% CI [-79.7%, -16.3%], p = 0.0165), NK and dendritic cells (95% CI [-68.7%, -5.2%], p = 0.0333, 95% CI [-76.9%, -13.9%], p = 0.0184), and classical monocytes (95% CI [-76.7%, -26.6%], p = 0.0043) in blister fluid. Notably, TNF, IL-6, IL-8, and Mx-A responses in blister exudate were also reduced by prednisolone compared to placebo. Oral prednisolone suppresses IMQ-induced skin inflammation, which underlines the value of this cutaneous challenge model in clinical pharmacology studies of novel anti-inflammatory compounds. In these studies, prednisolone can be used as a benchmark.
Topics: Humans; Imiquimod; Blister; Healthy Volunteers; Dermatitis; Prednisolone; Inflammation; Anti-Inflammatory Agents
PubMed: 37545524
DOI: 10.3389/fimmu.2023.1197650 -
Molecules (Basel, Switzerland) Aug 2023A new skincare application scenario for dark tea, a unique and post-fermented tea popular in the health food industry, was developed in this paper. The effects of dark...
A new skincare application scenario for dark tea, a unique and post-fermented tea popular in the health food industry, was developed in this paper. The effects of dark tea polysaccharide (DTP) on stress-induced skin problems and its mechanism of action were investigated by modeling cortisone-induced stress injury in human HaCaT keratinocytes and SZ95 sebaceous gland cells. The results showed a reduced cortisol conversion induced by cortisone under the action of DTP with a concentration of 200 μg/mL, probably by inhibiting the expression of the HSD11B1 enzyme. DTP was also able to suppress the cortisone-induced elevation of lipid levels in SZ95 sebocytes at this concentration. In addition, the composition and structure of DTP were verified by ultrafiltration, ultraviolet-visible spectrophotometry (UV-VIS), high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) and infrared spectroscopy. In brief, DTP has a unique and significant stress-relieving effect, which provides new ideas for the development of new ingredients for the skin care industry.
Topics: Humans; Cortisone; Epithelial Cells; Keratinocytes; Polysaccharides; Tea
PubMed: 37630380
DOI: 10.3390/molecules28166128 -
Cell Reports Aug 2023Immune responses differ between females and males, although such sex-based variance is incompletely understood. Observing that bacteremia of the opportunistic pathogen...
Immune responses differ between females and males, although such sex-based variance is incompletely understood. Observing that bacteremia of the opportunistic pathogen Burkholderia gladioli caused many more deaths of female than male mice bearing genetic deficiencies in adaptive immunity, we determined that this was associated with sex bias in the innate immune memory response called trained immunity. Female attenuation of trained immunity varies with estrous cycle stage and correlates with serum progesterone, a hormone that decreases glycolytic capacity and recall cytokine secretion induced by antigen non-specific stimuli. Progesterone receptor antagonism rescues female trained immune responses and survival from controlled B. gladioli infection to magnitudes similar to those of males. These data demonstrate progesterone-dependent sex bias in trained immunity where attenuation of female responses is associated with survival outcomes from opportunistic infection.
Topics: Female; Male; Animals; Mice; Progesterone; Sexism; Trained Immunity; Opportunistic Infections; Adaptive Immunity
PubMed: 37590139
DOI: 10.1016/j.celrep.2023.113007 -
International Journal of Molecular... Aug 2023Biliary obstruction diseases are often complicated by an impaired intestinal barrier, which aggravates liver injury. Treatment of the intestinal barrier is often...
Biliary obstruction diseases are often complicated by an impaired intestinal barrier, which aggravates liver injury. Treatment of the intestinal barrier is often neglected. To investigate the mechanism by which intestinal bile acid deficiency mediates intestinal barrier dysfunction after biliary obstruction and identify a potential therapeutic modality, we mainly used a bile duct ligation (BDL) mouse model to simulate biliary obstruction and determine the important role of the bile acid receptor FXR in maintaining intestinal barrier function and stemness. Through RNA-seq analysis of BDL and sham mouse crypts and qRT-PCR performed on intestinal epithelial-specific knockout () and wild-type mouse crypts, we found that FXR might maintain intestinal stemness by regulating CYP11A1 expression. Given the key role of CYP11A1 during glucocorticoid production, we also found that FXR activation could promote intestinal corticosterone (CORT) synthesis by ELISA. Intestinal organoid culture showed that an FXR agonist or corticosterone increased crypt formation and organoid growth. Further animal experiments showed that corticosterone gavage treatment could maintain intestinal barrier function and stemness, decrease LPS translocation, and attenuate liver injury in BDL mice. Our study hopefully provides a new theoretical basis for the prevention of intestinal complications and alleviation of liver injury after biliary obstruction.
Topics: Animals; Mice; Bile Acids and Salts; Cholestasis; Cholesterol Side-Chain Cleavage Enzyme; Corticosterone; Intestines
PubMed: 37686300
DOI: 10.3390/ijms241713494 -
Food Chemistry Oct 2023Human milk (HM) is a complex biological system that contains a wide range of bioactive components including oestrogens and progesterone. Whilst maternal oestrogens and... (Review)
Review
Human milk (HM) is a complex biological system that contains a wide range of bioactive components including oestrogens and progesterone. Whilst maternal oestrogens and progesterone concentrations drop rapidly after birth, they remain detectable in HM across lactation. Phytoestrogens and mycoestrogens, which are produced by plants and fungi, are also present in HM and can interact with oestrogen receptors to interfere with normal hormone functions. Despite the potential impact of HM oestrogens and progesterone on the infant, limited research has addressed their impact on the growth and health of breastfed infants. Furthermore, it is important to comprehensively understand the factors that contribute to these hormone levels in HM, in order to establish effective intervention strategies. In this review, we have summarized the concentrations of naturally occurring oestrogens and progesterone in HM from both endogenous and exogenous sources and discussed both maternal factors impacting HM levels and relationships with infant growth.
Topics: Infant; Female; Humans; Milk, Human; Progesterone; Infant Health; Breast Feeding; Lactation; Estrogens
PubMed: 37209436
DOI: 10.1016/j.foodchem.2023.136375 -
The Journal of Endocrinology Sep 202311β-Hydroxysteroid dehydrogenase 1 (11βHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of...
11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of active glucocorticoids in tissues including brain, liver and adipose tissue (coupled to hexose-6-phosphate dehydrogenase, H6PDH). 11βHSD1 activity in individual tissues is thought to contribute significantly to glucocorticoid levels at those sites, but its local contribution vs glucocorticoid delivery via the circulation is unknown. Here, we hypothesised that hepatic 11βHSD1 would contribute significantly to the circulating pool. This was studied in mice with Cre-mediated disruption of Hsd11b1 in liver (Alac-Cre) vs adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2H3]-cortisol (d3F) from [9,12,12-2H3]-cortisone (d3E), measuring 11βHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2H4]-cortisol (d4F) in male mice. Concentrations of steroids in plasma and amounts in liver, adipose tissue and brain were measured using mass spectrometry interfaced with matrix-assisted laser desorption ionisation or liquid chromatography. Amounts of d3F were higher in liver, compared with brain and adipose tissue. Rates of appearance of d3F were ~6-fold slower in H6pdh-/- mice, showing the importance for whole-body 11βHSD1 reductase activity. Disruption of liver 11βHSD1 reduced the amounts of d3F in liver (by ~36%), without changes elsewhere. In contrast disruption of 11βHSD1 in adipose tissue reduced rates of appearance of circulating d3F (by ~67%) and also reduced regenerated of d3F in liver and brain (both by ~30%). Thus, the contribution of hepatic 11βHSD1 to circulating glucocorticoid levels and amounts in other tissues is less than that of adipose tissue.
Topics: Male; Mice; Animals; Glucocorticoids; Hydrocortisone; Cortisone; Adipose Tissue; Steroids; 11-beta-Hydroxysteroid Dehydrogenase Type 1
PubMed: 37343234
DOI: 10.1530/JOE-23-0034 -
Neuroscience and Biobehavioral Reviews Jun 2024Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis.... (Review)
Review
Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity. Microglia and astrocytes play an important role in neuroinflammation, and their production of inflammatory mediators can be both activated and inhibited by steroid-PAMs and GABA. What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease.
Topics: Pregnanolone; Humans; Animals; Neuroinflammatory Diseases; Microglia; Astrocytes; GABA-A Receptor Antagonists
PubMed: 38608826
DOI: 10.1016/j.neubiorev.2024.105668 -
Drug Design, Development and Therapy 2023Allopregnanolone is a kind of neuroactive steroid or neurosteroid in the central nervous system that acts as an endogenenous GABA receptor positive modulator. However,... (Review)
Review
BACKGROUND
Allopregnanolone is a kind of neuroactive steroid or neurosteroid in the central nervous system that acts as an endogenenous GABA receptor positive modulator. However, at present, no comprehensive bibliometric analysis regarding allopregnanolone research is available. In our study, we intend to analyze the research trends and hot spots related to allopregnanolone in the past 20 years.
METHODS
We searched for allopregnanolone related articles and reviews between 2004 and 2023 from the Web of Science Core Collection database. Then, the bibliometric analysis was conducted using VOSviewer, CiteSpace, Microsoft Excel 2019, as well as the online bibliometric analysis platform (http://bibliometric.com/).
RESULTS
A total of 1841 eligible publications were identified. The number of annual publications and citations was generally on the rise. Among countries, the United States ranked first in overall publications, citations, international cooperation, and the number of research institutions. The University of North Carolina was the most active institution, conducting numerous preclinical and clinical work that focusing on allopregnanolone treatment for diverse psychiatric or neurologic disorders. As for authors, Dr. Frye CA, Morrow AL, and Pinna G were identified as the top three prolific scholars due to their great publications and citations. Based on the publication clusters and citation bursts analysis, the keyword co-occurrence network, the strongest citation bursts, and co-cited references analysis, the hot spots in recent years included "depression", "postpartum depression", "GABA receptor", and so on.
CONCLUSION
Allopregnanolone is still a popular area of research, and the United States leads the way in this area. Dr. Frye CA, Morrow AL, Pinna G, and their teams contributed greatly to the mechanism study and translation study of allopregnanolone. The use of allopregnanolone for the treatment of psychiatric or neurologic disorders, especially postpartum depression, is the current hot spot. However, the underlying mechanisms of anti-depression are still not clear, deserving more in-depth research.
Topics: Female; Humans; Pregnanolone; Bibliometrics; Central Nervous System; Databases, Factual; Depression, Postpartum; Nervous System Diseases
PubMed: 38024537
DOI: 10.2147/DDDT.S434364 -
General and Comparative Endocrinology Aug 2024Fecal samples are a non-invasive and relatively accessible matrix for investigating physiological processes in resident killer whale (Orcinus orca) populations. The high... (Review)
Review
Fecal samples are a non-invasive and relatively accessible matrix for investigating physiological processes in resident killer whale (Orcinus orca) populations. The high lipid content of the diet (primarily salmonids) leads to lower density fecal material and slower dispersion, facilitating sample collection. As fecal discharge is relatively infrequent and the volume of sample is variable, maximizing analytical options is an important consideration. Here we present an extraction methodology to measure hormones and lipid content from the same fecal aliquot. Lipid extractions are commonly conducted using chloroform and methanol from Folch or Bligh and Dyer (B&D), while alcohol is the primary solvent for hormone extraction. We evaluated the possibility of using the methanol layer from lipid extractions to assess fecal steroid hormone levels. Folch and B&D methanol residues were assayed form metabolites of progesterone (PMs) and corticosterone (GCs), and results were compared to aliquots extracted in 70 % ethanol. Hormone concentrations measured in the methanol layer from Folch and B&D extractions were 55 % to 79 % lower than concentrations in 70 % ethanol. We developed mathematical corrections, using linear regression models fitted to Folch or B&D methanol vs 70 % ethanol hormone concentrations (p < 0.01). Fecal concentrations of PMs and GCs from methanol extractions were biologically validated and are significantly higher in confirmed pregnant females compared to non-pregnant individuals (p < 0.05). This study demonstrates that lipid extraction protocols may be used for the analysis of multiple biomarkers, maximizing the use of small-volume samples.
Topics: Animals; Feces; Whale, Killer; Corticosterone; Progesterone; Female; Lipids
PubMed: 38705419
DOI: 10.1016/j.ygcen.2024.114544 -
Journal of Cellular and Molecular... Dec 2023Steroid-induced femoral head necrosis (SIFHN) is a serious clinical complication that is caused by prolonged or excessive use of glucocorticoids (GCs). Osteoblast...
Steroid-induced femoral head necrosis (SIFHN) is a serious clinical complication that is caused by prolonged or excessive use of glucocorticoids (GCs). Osteoblast apoptosis and osteogenic differentiation dysfunction caused by GC-induced oxidative stress and mitochondrial impairment are strongly implicated in SIFHN. Apocynin (APO) is a kind of acetophenone extracted from an herb. In recent years, APO has received much attention for its antiapoptotic and antioxidant properties. This study aimed to investigate whether APO could protect against SIFHN and explore the mechanism. In our study, low-dose APO had no toxic effects on osteoblasts and restored dexamethasone (Dex)-treated osteoblasts by improving survival, inhibiting OS and restoring mitochondrial dysfunction. Mechanistically, APO alleviated Dex-induced osteoblast injury by activating the Nrf2 pathway, and the use of ML385 to block Nrf2 significantly eliminated the protective effect of APO. In addition, APO could reduce the formation of empty lacunae, restore bone mass and promote the expression of Nrf2 in SIFHN rats. In conclusion, APO protects osteoblasts from Dex-induced oxidative stress and mitochondrial dysfunction through activation of the Nrf2 pathway and may be a beneficial drug for the treatment of SIFHN.
Topics: Rats; Animals; Dexamethasone; NF-E2-Related Factor 2; Osteogenesis; Glucocorticoids; Oxidative Stress; Acetophenones; Apoptosis; Osteoblasts; Mitochondrial Diseases
PubMed: 37749949
DOI: 10.1111/jcmm.17974