Prostaglandins

BackgroundThe function of diverse ruminal microbes is tightly linked to rumen development and host physiology. The system of ruminal microbes is an excellent model to clarify the fundamental ecological relationships among complex nutrient-microbiome-host interactions. Here, neonatal lambs are introduced to different dietary regimes to investigate the influences of early-life crosstalk between nutrients and microbiome on rumen development.ResultsWe find starchy corn-soybean starter-fed lambs exhibit the thickest ruminal epithelia and fiber-rich alfalfa hay-fed lambs have the thickest rumen muscle. Metabolome and metagenome data reveal that indole-3-carboxaldehyde (3-IAld) and prostaglandin D2 (PGD2) are the top characteristic ruminal metabolites associated with ruminal epithelial and muscular development, which depend on the enhanced ruminal microbial synthesis potential of 3-IAld and PGD2. Moreover, microbial culture experiment first demonstrates that Bifidobacterium pseudolongum is able to convert tryptophan into 3-IAld and Candida albicans is a key producer for PGD2. Transcriptome sequencing of the ruminal epithelia and smooth muscle shows that ruminal epithelial and muscular development is accompanied by Wnt and Ca2+ signaling pathway activation. Primary cell cultures further confirm that 3-IAld promotes ruminal epithelial cell proliferation depending on AhR-wnt/β-catenin signaling pathway and PGD2 accelerates ruminal smooth muscle cell proliferation via Ca2+ signaling pathway. Furthermore, we find that 3-IAld and PGD2 infusion promote ruminal epithelial and musculature development in lambs.ConclusionsThis study demonstrates that early-life ruminal microbiome-derived 3-IAld and PGD2 are effective promoters of rumen development, which enhances our understanding of nutrient-microbiome-host interactions in early life.

Prostate cancer presents as an immunologically "cold" malignancy, characterized by a lack of response to immunotherapy in the majority of patients. The dysfunction of prostate tumor metabolism is recognized as a critical factor in immune evasion, resulting in reduced effectiveness of immunotherapeutic interventions. Despite this awareness, the precise molecular mechanisms underpinning metabolic dysregulation in prostate cancer and its intricate relationship with immune evasion remain incompletely elucidated. In this study, we introduce the multi-drug resistance protein ABCC4/MRP4 as a key player prominently expressed in prostate cancer, exerting a pivotal role in suppressing the activity of intratumoral CD8+ T cells. Depletion of ABCC4 in prostate cancer cells halts the release of prostaglandin E2 (PGE2), a molecule that diminishes the population of CD8+ T cells and curtails their cytotoxic capabilities. Conversely, constraining the activation of PGE2 signaling in CD8+ T cells effectively improved the efficacy of prostate cancer treatment with PD-1 blockade. During this process, downregulation of the JAK1-STAT3 pathway and depolarization of mitochondria emerge as crucial factors contributing to T cell anergy. Collectively, our research identifies the ABCC4-PGE2 axis as a promising target for reversing dysfunction within tumor-infiltrating lymphocytes (TILs) and augmenting the suboptimal responsiveness to immunotherapy in prostate cancer.

The lack of knowledge about the mechanism of hyperoxia-induced intestinal injury has attracted considerable attention, due to the potential for this condition to cause neonatal complications. This study aimed to explore the relationship between hyperoxia-induced oxidative damage and ferroptosis in intestinal tissue and investigate the mechanism by which hyperoxia regulates inflammation through ferroptosis. The study systematically evaluated the effects of hyperoxia on oxidative stress, mitochondrial damage, ferroptosis, and inflammation of intestinal epithelial cells both in vitro and in vivo. The results showed that ferroptosis was involved in intestinal oxidative damage caused by hyperoxia and was regulated by Nrf2. Moreover, hyperoxia-induced oxidative damage regulated inflammation through ferroptosis by upregulating the COX-2/PGE2/EP2 signaling pathway. These findings have important implications for future clinical prevention and therapeutic approaches to neonatal organ injury caused by hyperoxia treatment.

BackgroundAmong patients with early pregnancy loss (EPL) without medication complications or need for urgent surgical evacuation, treatment should largely be guided by patient preference. However, evidence describing medication management for EPL in the emergency department (ED) setting is limited. We examine the occurrence of medication management of EPL with misoprostol in an urban Texas ED, describe associated clinical outcomes, and identify patient and clinical factors associated with offering this treatment.MethodsThis was a retrospective study of patients with confirmed EPL at a single urban academic ED in Texas from November 1, 2022, to May 31, 2024. Data were collected via relevant EHR review. Eligible patients were identified via ICD-10 codes and reviewed using a structured abstraction tool. We identified patients who received expectant or medication management with misoprostol and reported clinical outcomes using descriptive statistics. An exploratory multivariable logistic regression was used to identify characteristics predictive of patients being offered misoprostol.ResultsDuring the study period, 181 patients met our inclusion criteria. Most patients (n = 154; 85.1%) received expectant management. Misoprostol was offered to 44 patients (24%); 27 patients (15.0%) received the medication, all of whom had an OB consult. Seven-day return ED visits were low in both the expectant (n = 18; 11.5%) and medication (n = 2; 7.4%) management groups. Of the 18 patients managed expectantly with a 7-day return ED visit, six received misoprostol during the second visit. OB consultation strongly predicted patients being offered misoprostol (aOR 15.1; 95% CI 4.8-47.61).ConclusionMedication management was rarely provided to ED patients with confirmed EPL; OB was consulted for all patients who received misoprostol. Return ED visits were rare among patients managed expectantly and with misoprostol. Several patients received misoprostol during a return ED visit, which may suggest a missed opportunity for medication treatment of EPL during initial ED presentation.