Revealing the Biochemical Regulations of L-PGDS in Hepatic Insulin-Resistance using HepG2 cells.

Deslorelin influences canine epididymal gene expression of the androgen receptor and prostaglandin metabolism.

Introduction: Prostaglandin D2 (PGD2) is elevated in the bald scalp of men with androgenetic alopecia (AGA) and inhibits hair growth. Cetirizine, an H1-antihistamine, reduces PGD2 production and has anti-inflammatory effects, making it a potential therapeutic candidate. Methods: Ten men aged 18–60 years with Norwood–Hamilton grade III vertex to V AGA applied 1 ml of 1% cetirizine in propylene glycol/butylene glycol daily for 16 weeks. Exclusion criteria included recent use of minoxidil, finasteride, or other antiandrogenic therapies. Hair counts in a 1 cm² tattoo-marked vertex area and blinded photographic assessments were evaluated at baseline and week 16. Results: Nine participants completed the study. Mean hair count increased from 139.6 (SE 13.9) to 163.4 (SE 15.5), a statistically significant change (p = 0.009). Blinded global photographs showed a +2 improvement in one patient, +1 in two, and no change in six. Trichoscopic counts improved in all patients. No adverse events occurred. Conclusion: Despite limitations, this report provides additional real-world data supporting cetirizine as a potential therapy in AGA. Larger randomized controlled studies with longer follow-up are needed to establish efficacy, durability, and mechanism of action.

β-alanine has been shown to significantly improve nitrogen utilization efficiency in beef cattle, but its impact on growth performance remains unclear. This study involved 36 healthy 18-month-old Simmental crossbred bulls with similar weights (627 ± 41 kg). The cattle were divided into two groups, with each group comprising six replicates of three animals. While the control group received the basal diet, the treatment group was administered an additional 96 g/d/cattle rumen-protected β-alanine (RP-β-Ala). The study was conducted over a 35-day period, which included an initial 7 days for adaptation. At the end of the trial, body weight was recorded, and samples were collected. Results show that RP-β-Ala enhanced average daily gain (p = 0.065) and crude protein (CP) digestibility (p = 0.065) and reduced gain-to-feed ratio (p = 0.078). Analysis of rumen microbiota revealed that RP-β-Ala positively modulated the rumen microbiota by enriching beneficial genera such as Prevotella, Treponema, and Selenomonas. This enrichment increased volatile fatty acid production and nitrogen utilization efficiency, as evidenced by elevated ruminal ammonia-N and microbial CP levels, along with decreased serum urea nitrogen. Metabolomics identified key alterations in arachidonic acid metabolism, specifically the upregulation of metabolites 14,15-DiHETrE and prostaglandin D2, and enhanced antioxidative capability indicated by increased serum total antioxidant capacity (T-AOC). Concurrently, RP-β-Ala reduced serum TNF-α levels. This reduction was achieved by suppressing harmful bacteria like Thermoactinomyces and Saccharopolyspora, along with inhibiting their polyamine synthesis, specifically spermine and spermidine. Collectively, these effects alleviated oxidative stress and inflammation. These findings demonstrate that RP-β-Ala enhances beef cattle growth through improved energy supply and antioxidant capacity.

Understanding the metabolic pathways and kinetics of prostaglandins is essential for elucidating their biological functions and therapeutic potential. Prostaglandin D2 (PGD2), a somnogen in the brain, undergoes nonenzymatic conversion into J-series prostaglandins, including 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). PGD2 is possibly transported by lipocalin-type prostaglandin D synthase (L-PGDS), which may also influence its metabolism. However, the kinetics of PGD2 metabolism, particularly in the context of the PGD2-L-PGDS complex, remains poorly understood. In this study, we investigated the effects of L-PGDS on the dehydration reaction of PGD2 in an aqueous buffer using real-time NMR spectroscopy, complemented by UV-visible absorption spectroscopy. In the absence of L-PGDS, 15d-PGJ2 was formed over several tens of hours via the transient accumulation of prostaglandin J2 and 15-deoxy-Δ12,14-prostaglandin D2 as intermediates. In contrast, the PGD2-L-PGDS complex converted to a L-PGDS-15d-PGJ2 complex, without exhibiting detectable reaction intermediates or byproducts, at a time scale of 3 h. We also determined the crystal structure of the L-PGDS-15d-PGJ2 complex, demonstrating that the covalent bond is formed between Cys65 of L-PGDS and the carbon atom at the C9 position of 15d-PGJ2. These results, combined with the fact that L-PGDS is present in excess relative to PGD2 and 15d-PGJ2 in the arachnoid membrane, suggest that most PGD2 exists in the L-PGDS-bound form and that 15d-PGJ2 generated through dehydration is rapidly and effectively sequestered by L-PGDS. Thus, L-PGDS may function as a scavenger for 15d-PGJ2, mitigating its potential deleterious effects in the arachnoid membrane. This real-time NMR-based approach provides a useful platform for studying the metabolism behavior of other prostaglandins under physiologically relevant conditions.

Alopecia is a multifactorial disorder in which immune, endocrine, metabolic, and microbial systems converge within the follicular microenvironment. In alopecia areata (AA), loss of immune privilege, together with interferon-γ- and interleukin-15-driven activation of the JAK/STAT cascade, promotes cytotoxic infiltration, whereas selective inhibitors, including baricitinib, ritlecitinib, and durvalumab, restore immune balance and permit anagen reentry. In androgenetic alopecia (AGA), excess dihydrotestosterone and androgen receptor signaling increase DKK1 and prostaglandin D2, suppress Wnt and β-catenin activity, and drive follicular miniaturization. Combination approaches utilizing low-dose oral minoxidil, platelet-rich plasma, exosome formulations, and low-level light therapy enhance vascularization, improve mitochondrial function, and reactivate metabolism, collectively supporting sustained regrowth. Elucidation of intracellular axes such as JAK/STAT, Wnt/BMP, AMPK/mTOR, and mitochondrial redox regulation provides a mechanistic basis for rational, multimodal intervention. Advances in stem cell organoids, biomaterial scaffolds, and exosome-based therapeutics extend treatment from suppression toward structural follicle reconstruction. Recognition of microbiome and mitochondria crosstalk underscores the need to maintain microbial homeostasis and redox stability for durable regeneration. This review synthesizes molecular and preclinical advances in AA and AGA, outlining intersecting signaling networks and regenerative interfaces that define a framework for precision and sustained follicular regeneration.

Uncovering novel endocannabinoidome-gut microbiome-brain axis-based therapeutic targets in a Fragile X Syndrome mouse model.

The adenosine A2A receptor (A2AR) is a Class A G protein-coupled receptor (GPCR) that regulates inflammation, glucose metabolism, and energy homeostasis in metabolically active tissues. While the effects of small-molecule ligands and protein interactions with A2AR have been extensively studied, the regulatory influence of endogenous metabolites remains unexplored. To address this gap, we employed the Mass spectrometry Integrated with equilibrium Dialysis for the discovery of Allostery Systematically (MIDAS) platform to screen a library of human metabolites for interactions with A2AR. This approach identified 180 metabolites that interact with A2AR, including allosteric and orthosteric modulators. We characterized the mechanisms of three metabolites previously unreported to interact with A2AR: prostaglandin D2, an allosteric antagonist that fully inhibits receptor signaling, and two orthosteric agonists, S-adenosyl-L-homocysteine and 2'-deoxyadenosine, that fully activate A2AR. Overall, these findings highlight the potential of the MIDAS platform to uncover previously unrecognized metabolite-GPCR interactions for research and therapeutic applications.

IgE-activated human lung mast cells preferentially release prostaglandin D2, thromboxane A2, and cysteinyl-leukotrienes.

Reduced aldehyde dehydrogenase 2 in respiratory tract associates with dysregulated alcohol metabolism and respiratory reactions in aspirin-exacerbated respiratory disease.

Lipocalin-type prostaglandin D₂ synthase (L-PGDS) deficiency disrupts heme catabolism and iron homeostasis in mice.

ABSTRACTObjectiveCordyceps sinensis (CS) is a fungus that parasitizes the larvae and corpses of Batmadaceae insects. CS is used as a traditional Chinese medicine and has shown promising clinical efficacy in the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to identify potential targets of CS in the treatment of COPD and to analyse the related biological processes and signalling pathways.MethodsThrough the use of network pharmacological tools, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, as well as corroborating data from Gene Expression Omnibus (GEO) and the literature, potential targets for CS treatment of COPD were identified and analysed.ResultsThese results suggest that CS alleviates COPD symptoms with key biomarkers such as interleukins (ILs), tumour necrosis factor (TNF), and reactive oxygen species (ROS). The primary active constituents of CS comprise Cordycepin, d‐mannitol, Ergosterol, Cordyceps polysaccharides, and others. During the pathogenesis of COPD, CS exerts modulates effects on various proteins and signalling pathways, influencing gene expression patterns such as poly ADP‐ribose polymerase 1 (PARP1), phosphodiesterase 4A (PDE4A), phosphodiesterase 4B (PDE4B), phosphodiesterase 4C (PDE4C), phosphodiesterase 4D (PDE4D), prostaglandin D2 receptor 2 (PTGDR2), heme oxygenase 1 (HMOX1), and matrix metallopeptidase 1 (MMP1).ConclusionCS alleviates COPD symptoms by suppressing inflammation, apoptosis, and oxidative stress, suggesting novel therapeutic strategies.

Dietary eicosapentaenoic and docosahexaenoic acids reduce oxylipins that provide early mediators of colonic inflammation induced by chemotherapy.

Severe Coronavirus disease 2019 (COVID-19) is associated with abnormal innate and adaptive immune responses, as well as systemic alterations, including a shift in lipid network. A case–control study was conducted to describe the systemic lipidomic profile in COVID-19 according to disease severity. Selected polyunsaturated fatty acids (PUFAs), oxylipins, and endocannabinoids were analysed using a targeted liquid chromatography coupled to mass spectrometry in tandem method. Multivariate receiver operating characteristic curve-based model evaluation was performed to define a lipidomic signature for the disease. A total of 135 hospitalized COVID-19 patients, of whom 85 had severe form, and 134 healthy individuals were included. Patients exhibited increased levels of free PUFAs, proinflammatory and pro-resolving oxylipins, and endocannabinoids compared to controls. A combination of five lipid mediators, i.e., prostaglandin D2, prostaglandin E2, thromboxane B2, lipoxin B4, and 2-archidonylglycerol, discriminates patients from control individuals with excellent accuracy [AUC, 0.977 (0.950–0.995)]. The severe form is characterized by an imbalance between proinflammatory and pro-resolving oxylipins and increased endocannabinoids. COVID-19 is associated with a lipid storm that conditions disease severity. Targeting lipid mediators-related metabolic and signalling pathways could be an interesting therapeutic option in severe forms.

Background/Objectives: Endothelial dysfunction plays a central role in the development of cardiovascular diseases. β-Casomorphin-7 (BCM-7), a biologically active peptide generated during the digestion of A1 β-casein, is presumed to contribute to this process; however, its direct effects on endothelial cells have not been previously investigated. Here, we aimed to assess whether BCM-7 treatment induces endothelial cell dysfunction through inflammatory cytokines and reactive oxygen species (ROS). Methods: In our study, we analyzed the effects of BCM-7 (5 µg/mL) in combination with lipopolysaccharide (LPS, 100 ng/mL) on human umbilical vein endothelial cells (HUVECs/TERT2). The cell viability, apoptosis, necrosis, and intracellular reactive oxygen species were measured. Furthermore, proinflammatory cytokines and enzymes involved in the regulation of inflammation were assessed with quantitative real-time PCR. The gene and protein expression of enzymes that regulate inflammation and vascular function, thus maintaining endothelial homeostasis were assessed. Results: BCM-7 enhanced intracellular ROS production p ≤ 0.001, increased the expression of interleukin-6 (IL-6) and interleukin-8 (IL-8) p ≤ 0.001, and was more effective when used in combination with LPS p ≤ 0.001. It decreased the expression of cyclooxygenase-1 (COX-1) p ≤ 0.05, during 4 h of exposure, whereas it increased the expression of cyclooxygenase-2 (COX-2) p ≤ 0.001, lipoxygenase-5 (LOX-5) p ≤ 0.01, and nitric oxide synthase 3 (NOS3) p ≤ 0.001; prostaglandin D2 synthase (PTGDS) (p ≤ 0.05), expression was also increased after short treatment. Conclusions: Our results suggest that BCM-7 may contribute to the development of endothelial dysfunction, especially in the presence of LPS, by enhancing oxidative stress and inflammatory response.

The Bruton tyrosine kinase inhibitor acalabrutinib aborts ongoing acute food-induced anaphylactic reactions in humanized mice.

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating complex disease with an elusive etiology, lacking objective diagnostic biomarkers. This study leverages advanced Automated Machine Learning (AutoML) to analyze plasma metabolomic and lipidomic profiles for the purpose of ME/CFS detection. Methods: We utilized a publicly available dataset comprising 888 metabolic features from 106 ME/CFS patients and 91 matched controls. Three AutoML frameworks—TPOT, Auto-Sklearn, and H2O AutoML—were benchmarked under identical time constraints. Univariate ROC and PLS-DA analyses with cross-validation, permutation testing, and VIP-based feature selection were applied to standardized, log-transformed omics data to identify significant discriminatory metabolites/lipids and assess their intercorrelations. Results: TPOT significantly outperformed its counterparts, achieving an area under the curve (AUC) of 92.1%, accuracy of 87.3%, sensitivity of 85.8%, and specificity of 89.0%. The PLS-DA model revealed a moderate but statistically significant discrimination between ME/CFS and controls. Explainable artificial intelligence (XAI) via SHAP analysis of the optimal TPOT model identified key metabolites implicating dysregulated pathways in mitochondrial energy metabolism (succinic acid, pyruvic acid, leucine), chronic inflammation (prostaglandin D2, 11,12-EET), gut–brain axis communication (glycocholic acid), and cell membrane integrity (pc(35:2)a). Conclusions: Our results demonstrate that TPOT-derived models not only provide a highly accurate and robust diagnostic tool but also yield biologically interpretable insights into the pathophysiology of ME/CFS, highlighting its potential for clinical decision support and elucidating novel therapeutic targets.

The risk of developing melanoma increases with age. Although immune checkpoint blockade (ICB) therapy has shown considerable success, a significant portion of melanoma patients either fail to respond to ICB or eventually develop resistance. This leads to the urgent need for exploring novel treatments. Phospholipase A2 group IID (PLA2G2D) is an inducible enzyme found in myeloid cells, especially in aging dendritic cells (DCs), that exert an immunosuppressive effect by producing anti- or proinflammatory small lipid molecules, including prostaglandin D2 (PGD2). An aging-related increase of PLA2G2D-PGD2 expression makes this signaling a promising target for treating aging-associated diseases. The overexpression of hematopoietic PGD2 synthase identified in both human and mouse melanoma tissue further highlights the potential of PLA2G2D-PGD2-targeting therapy. In this study, we show that the absence of PLA2G2D or the PGD2 receptor, PTGDR, restricts primary tumor growth and lung metastasis of subcutaneously implanted melanoma, as demonstrated using middle-aged Pla2g2d-/- and Ptgdr-/- mice. These therapeutic benefits are linked to increased tumor infiltration of activated γδ T cells, which can be amplified in B16F10-bearing wild-type mice through the adoptive transfer of Ptgdr-/- DCs. These tumor-restraining effects were also confirmed in DC-specific PTGDR-deficient (zDCcrePtgdrfloxp) mice. Mechanistically, the enhanced production of IL-1β by Ptgdr-/- DCs contributes to the activation and accumulation of γδ T cells in tumor tissue. In summary, our findings highlight the effectiveness of targeting the PLA2G2D-PGD2/PTGDR axis to reprogram aging dendritic cells, thereby inhibiting melanoma progression and presenting a promising therapeutic target, particularly for elderly patients.

The microsporidian Enterocytozoon hepatopenaei (EHP) is a highly contagious pathogen that causes severe growth retardation in penaeid shrimp. EHP infection damages the hepatopancreatic tubules, causes hematopoietic infiltration, and recruits granulocytes and inflammatory cells to the shrimp stomach and intestine. In this study, we investigated whether EHP infection induced the eicosanoid biosynthesis pathway in the gastrointestinal tract of the Pacific white shrimp Litopenaeus vannamei. Shrimp hepatopancreases, stomachs, and intestines were collected on days 0, 7, and 21 of the EHP cohabitation experiment for analysis. On day 7, the levels of cyclooxygenase (COX) and prostaglandin F synthase (PGFS) enzymes, which catalyze the production of prostaglandins, were elevated in the hepatopancreas of EHP-infected shrimp. The stomach of EHP-infected shrimp also contained higher levels of 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-hydroxyeicosapentaenoic acid (12-HEPE) than the control shrimp. Nevertheless, the most significant impact of EHP infection on day 7 was observed in shrimp intestines, in which the levels of prostaglandin F2α (PGF2α), 8-HETE, and four isomers of HEPEs were higher in the EHP-infected shrimp than in the control shrimp. As the EHP infection progressed to day 21, the upregulation of COX and PGFS persisted in the EHP-infected hepatopancreas, leading to increasing levels of PGF2α and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). The upregulation of prostaglandins was in contrast with the decreasing levels of HETEs and HEPEs in the hepatopancreas of EHP-infected shrimp. Meanwhile, the stomach of EHP-infected shrimp contained higher levels of prostaglandin D2, PGF2α, 15d-PGJ2, and most of the hydroxy fatty acids than the control shrimp. The levels of eicosanoid precursors, namely arachidonic acid and eicosapentaenoic acid, were upregulated in the shrimp gastrointestinal tract collected on days 7 and 21, suggesting that substrate availability contributes to the increasing levels of eicosanoids after EHP infection. Our study provides the first comprehensive analysis of the eicosanoid biosynthesis pathway in response to EHP infection. Moreover, the results indicate that eicosanoids are part of the host-pathogen interactions in crustaceans.

The prostaglandin D2 receptor 1 (DP1), a member of the prostanoid G protein-coupled receptor (GPCR) family, plays critical roles in allergic responses, sleep regulation, immune modulation, and vasodilation. Here, we present five high-resolution cryo-electron microscopy (cryo-EM) structures of the human DP1 receptor, including an apo structure, two inactive state structures bound to two different inverse agonists developed by ONO Pharmaceutical, and two active state structures in complex with the Gs protein and bound to the endogenous agonist PGD2 and its selective derivative BW245C. Structural analysis, complemented by molecular dynamics simulations and site-directed mutagenesis, reveals key residues involved in ligand recognition and suggests a distinct activation mechanism for DP1, which lacks most of the conserved class A GPCR motifs. Notably, the unique residue K76 within the conserved sodium pocket acts as a major activation switch, while amphiphilic helix 8 adopts an unconventional orientation essential for receptor function. These findings offer valuable insights into the structure and function of prostanoid receptors and may facilitate the development of therapeutics targeting DP1.