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Lipids in Health and Disease Jul 2023Studies have shown that the lipid metabolism mediator leukotriene and prostaglandins are associated with the pathogenesis of allergic rhinitis (AR). The aim of this...
BACKGROUND
Studies have shown that the lipid metabolism mediator leukotriene and prostaglandins are associated with the pathogenesis of allergic rhinitis (AR). The aim of this study was to identify key lipid metabolism-related genes (LMRGs) related to the diagnosis and treatment of AR.
MATERIALS AND METHODS
AR-related expression datasets (GSE75011, GSE46171) were downloaded through the Gene Expression Omnibus (GEO) database. First, weighted gene co-expression network analysis (WGCNA) was used to get AR-related genes (ARRGs). Next, between control and AR groups in GSE75011, differentially expressed genes (DEGs) were screened, and DEGs were intersected with LMRGs to obtain lipid metabolism-related differentially expressed genes (LMR DEGs). Protein-protein interaction (PPI) networks were constructed for these LMR DEGs. Hub genes were then identified through stress, radiality, closeness and edge percolated component (EPC) analysis and intersected with the ARRGs to obtain candidate genes. Biomarkers with diagnostic value were screened via receiver operating characteristic (ROC) curves. Differential immune cells screened between control and AR groups were then assessed for correlation with the diagnostic genes, and clinical correlation analysis and enrichment analysis were performed. Finally, real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was made on blood samples from control and AR patients to validate these identified diagnostic genes.
RESULTS
73 LMR DEGs were obtained, which were involved in biological processes such as metabolism of lipids and lipid biosynthetic processes. 66 ARRGs and 22 hub genes were intersected to obtain four candidate genes. Three diagnostic genes (LPCAT1, SGPP1, SMARCD3) with diagnostic value were screened according to the AUC > 0.7, with markedly variant between control and AR groups. In addition, two immune cells, regulatory T cells (Treg) and T follicular helper cells (TFH), were marked variations between control and AR groups, and SMARCD3 was significantly associated with TFH. Moreover, SMARCD3 was relevant to immune-related pathways, and correlated significantly with clinical characteristics (age and sex). Finally, RT-qPCR results indicated that changes in the expression of LPCAT1 and SMARCD3 between control and AR groups were consistent with the GSE75011 and GSE46171.
CONCLUSION
LPCAT1, SGPP1 and SMARCD3 might be used as biomarkers for AR.
Topics: Humans; Lipid Metabolism; Lipogenesis; Acyltransferases; Databases, Factual; Gene Expression Profiling
PubMed: 37480069
DOI: 10.1186/s12944-023-01825-z -
British Journal of Cancer Mar 2024Many urothelial bladder carcinoma (UBC) patients don't respond to immune checkpoint blockade (ICB) therapy, possibly due to tumor-associated neutrophils (TANs)... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Many urothelial bladder carcinoma (UBC) patients don't respond to immune checkpoint blockade (ICB) therapy, possibly due to tumor-associated neutrophils (TANs) suppressing lymphocyte immune response.
METHODS
We conducted a meta-analysis on the predictive value of neutrophil-lymphocyte ratio (NLR) in ICB response and investigated TANs' role in UBC. We used RNA-sequencing, HALO spatial analysis, single-cell RNA-sequencing, and flow cytometry to study the impacts of TANs and prostaglandin E2 (PGE2) on IDO1 expression. Animal experiments evaluated celecoxib's efficacy in targeting PGE2 synthesis.
RESULTS
Our analysis showed that higher TAN infiltration predicted worse outcomes in UBC patients receiving ICB therapy. Our research revealed that TANs promote IDO1 expression in cancer cells, resulting in immunosuppression. We also found that PGE2 synthesized by COX-2 in neutrophils played a key role in upregulating IDO1 in cancer cells. Animal experiments showed that targeting PGE2 synthesis in neutrophils with celecoxib enhanced the efficacy of ICB treatment.
CONCLUSIONS
TAN-secreted PGE2 upregulates IDO1, dampening T cell function in UBC. Celecoxib targeting of PGE2 synthesis represents a promising approach to enhance ICB efficacy in UBC.
Topics: Animals; Humans; Dinoprostone; Celecoxib; Neutrophils; Cyclooxygenase 2; Urinary Bladder; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; CD8-Positive T-Lymphocytes; RNA
PubMed: 38233491
DOI: 10.1038/s41416-023-02552-z -
Journal of Ethnopharmacology Dec 2023Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used clinically to treat inflammatory diseases clinically. However, the adverse effects of NSAIDs cannot be...
ETHNOPHARMACOLOGICAL RELEVANCE
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used clinically to treat inflammatory diseases clinically. However, the adverse effects of NSAIDs cannot be ignored. Therefore, it is critical for us to find alternative anti-inflammatory drugs that can reduce adverse reactions to herbal medicine, such as Iris tectorum Maxim., which has therapeutic effects and can treat inflammatory diseases and liver-related diseases.
AIM OF THE STUDY
This study aimed to isolate active compounds from I. tectorum and investigate their anti-inflammatory effects and action mechanisms.
MATERIALS AND METHODS
Fourteen compounds were isolated from I. tectorum using silica gel column chromatography, Sephadex LH-20, ODS and high performance liquid chromatography, and their structures were identified by examining physicochemical properties, ultraviolet spectroscopy, infrared spectroscopy, mass spectrometry, and nuclear magnetic resonance spectroscopy. Classical inflammatory cell models were established using lipopolysaccharide (LPS)-stimulated RAW264.7 cells and rat primary peritoneal macrophages to examine the effect of these compounds. To examine the action mechanisms, the nitric oxide (NO) levels were measured by Griess reagent and the levels of inflammatory cytokines in the supernatant were measured by ELISA; The expressions of major proteins in prostaglandin E (PGE) synthesis and the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways were examined by Western blotting, and the mRNA expression levels were measured by quantitative real-time polymerase chain reaction; and the nuclear translocation of p65 was examined by high content imaging. Molecular docking was used to predict the binding of active compound to target protein.
RESULTS
Our findings revealed that Iristectorigenin C (IT24) significantly inhibited the levels of NO and PGE without affecting cyclooxygenase (COX)-1/COX-2 expression in LPS-induced RAW264.7 cells and rat peritoneal macrophages. Furthermore, IT24 was shown to decrease the expression of microsomal prostaglandin synthetase-1 (mPGES-1) in LPS-induced rat peritoneal macrophages. IT24 did not suppress the phosphorylation and nuclear translocation of proteins in the NF-κB pathway, but it inhibited the phosphorylation of p38/JNK in LPS-stimulated RAW264.7 cells. Additionally, molecular docking analysis indicated that IT24 may directly bind to the mPGES-1 protein.
CONCLUSION
IT24 might inhibit mPGES-1 and the p38/JNK pathway to exert its anti-inflammatory effects and could be also developed as an inhibitor of mPGES-1 to prevent and treat mPGES-1-related diseases, such as inflammatory diseases, and holds promise for further research and drug development.
Topics: Rats; Animals; MAP Kinase Signaling System; Lipopolysaccharides; NF-kappa B; Molecular Docking Simulation; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Macrophages, Peritoneal; Cyclooxygenase 2; Nitric Oxide; Nitric Oxide Synthase Type II
PubMed: 37301305
DOI: 10.1016/j.jep.2023.116706 -
Metabolites Nov 2023Mild-to-moderate pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD). It is characterized by narrowing and thickening of... (Review)
Review
Mild-to-moderate pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD). It is characterized by narrowing and thickening of the pulmonary arteries, resulting in increased pulmonary vascular resistance (PVR) and ultimately leading to right ventricular dysfunction. Pulmonary vascular remodeling in COPD is the main reason for the increase of pulmonary artery pressure (PAP). The pathogenesis of PH in COPD is complex and multifactorial, involving chronic inflammation, hypoxia, and oxidative stress. To date, prostacyclin and its analogues are widely used to prevent PH progression in clinical. These drugs have potent anti-proliferative, anti-inflammatory, and stimulating endothelial regeneration properties, bringing therapeutic benefits to the slowing, stabilization, and even some reversal of vascular remodeling. As another well-known and extensively researched prostaglandins, prostaglandin E2 (PGE2) and its downstream signaling have been found to play an important role in various biological processes. Emerging evidence has revealed that PGE2 and its receptors (i.e., EP1-4) are involved in the regulation of pulmonary vascular homeostasis and remodeling. This review focuses on the research progress of the PGE2 signaling pathway in PH and discusses the possibility of treating PH based on the PGE2 signaling pathway.
PubMed: 37999248
DOI: 10.3390/metabo13111152 -
Journal of Ethnopharmacology Jan 2024Ding-kun-dan (DKD), as one of well-known traditional Chinese medicine (TCM), is considered as an effective prescription to regulate menstruation, benefit Qi and nourish... (Randomized Controlled Trial)
Randomized Controlled Trial
ETHNOPHARMACOLOGICAL RELEVANCE
Ding-kun-dan (DKD), as one of well-known traditional Chinese medicine (TCM), is considered as an effective prescription to regulate menstruation, benefit Qi and nourish the blood. Previous studies had showed that DKD could improve sex hormone levels, insulin resistance, metabolism abnormalities and regulate immunity in animal models with polycystic ovary syndrome or endometriosis, however, little study conducted to reveal its clinical efficacy in Primary Dysmenorrhea (PD).
AIM OF THE STUDY
To compare the effect of Ding-kun-dan (DKD) with Marvelon on relief of symptoms and change of serum pain-related factors in patients with primary dysmenorrhea.
MATERIALS AND METHOD
136 patients with primary dysmenorrhea were randomly assigned to the DKD group (n = 73, take one tablet per day from 5th day of the menstrual cycle for 10 days every 28 days) and the Marvelon group (n = 63, take one tablet per day from 5th day of the menstrual cycle for 21 days every 28 days), the therapeutic effects were analyzed through evaluating the change of VAS scores, CMSS scores and the level of PGF, PGE, PGF/PGE and NO during the 12 weeks intervention.
RESULTS
Both DKD and Marvelon could effectively relief pain and other associated symptoms at each visit (Baseline, 4 week, 8 week and 12 week). Although Marvelon was significantly superior to DKD in reducing VAS scores, the total CMSS, CMSS severity and duration scores at each posttreatment follow-up (P < 0.01), VAS scores in the DKD group decreased significantly over time while scores in the COC group only dropped rapidly after the first two months of treatment. Efficacy gap between two interventions continuously narrowed over time and the efficacy of DKD became non-inferior at the 12 week compared to that of Marvelon (the difference between groups, - 0.78%; 95% confidence interval (CI), -13.67%-12.75%; non-inferiority margin, 15%). DKD group had better efficacy on mild pain compared to that of the COC group with no statistical difference (75% VS 61.9%, P > 0.05). DKD and Marvelon could effectively reduce PGF, PGE and higher PGF/PGE in patients with PD. There was no statistical difference in the level of PGF, PGE, PGF/PGE and NO between DKD and Marvelon group at each follow-up. No serious adverse effect was observed.
CONCLUSION
Ding-kun-dan is another available, effective and safe method for patients with primary dysmenorrhea to choose, especially for those who are suffered from mild pain and/or contraindicated to hormonal agents.
Topics: Female; Humans; Desogestrel; Dinoprostone; Double-Blind Method; Dysmenorrhea; Endometriosis; Medicine, Chinese Traditional; Prospective Studies
PubMed: 37517569
DOI: 10.1016/j.jep.2023.116975 -
International Journal of Molecular... Nov 2023Gintonin, newly extracted from ginseng, is a glycoprotein that acts as an exogenous lysophosphatidic acid (LPA) receptor ligand. This study aimed to demonstrate the in...
Gintonin, newly extracted from ginseng, is a glycoprotein that acts as an exogenous lysophosphatidic acid (LPA) receptor ligand. This study aimed to demonstrate the in vivo preventive effects of gintonin on gastric damage. ICR mice were randomly assigned to five groups: a normal group (received saline, 0.1 mL/10 g, p.o.); a control group (administered 0.3 M HCl/ethanol, 0.1 mL/10 g, p.o.) or indomethacin (30 mg/kg, p.o.); gintonin at two different doses (50 mg/kg or 100 mg/kg, p.o.) with either 0.3 M HCl/ethanol or indomethacin; and a positive control (Ranitidine, 40 mg/kg, p.o.). After gastric ulcer induction, the gastric tissue was examined to calculate the ulcer index. The expression of gastric damage markers, such as tumor necrosis factor (TNF)-α, cyclooxygenase 2 (COX-2), and LPA2 and LPA5 receptors, were measured by Western blotting. Interleukin-6 (IL-6) and prostaglandin E2 (PGE2) levels were measured by enzyme-linked immunosorbent assay. The platelet endothelial cell adhesion molecule (PECAM-1), Evans blue, and occludin levels in gastric tissues were measured using immunofluorescence analysis. Both HCl/ethanol- and indomethacin-induced gastric ulcers showed increased TNF-α, IL-6, Evans blue permeation, and PECAM-1, and decreased COX-2, PGE2, occludin, and LPA5 receptor expression levels. However, oral administration of gintonin alleviated the gastric ulcer index induced by HCl/ethanol and indomethacin in a dose-dependent manner. Gintonin suppressed TNF-α and IL-6 expression, but increased COX-2 expression and PGE2 levels in mouse gastric tissues. Gintonin intake also increased LPA5 receptor expression in mouse gastric tissues. These results indicate that gintonin can play a role in gastric protection against gastric damage induced by HCl/ethanol or indomethacin.
Topics: Mice; Animals; Indomethacin; Stomach Ulcer; Platelet Endothelial Cell Adhesion Molecule-1; Cyclooxygenase 2; Tumor Necrosis Factor-alpha; Ethanol; Interleukin-6; Dinoprostone; Evans Blue; Occludin; Mice, Inbred ICR; Gastric Mucosa
PubMed: 38069044
DOI: 10.3390/ijms242316721 -
Inflammopharmacology Dec 2023Acetylsalicylic acid (ASA), also known as aspirin, was discovered in 1897 as an acetylated form of salicylate. It has been widely used for its anti-inflammatory and... (Review)
Review
Acetylsalicylic acid (ASA), also known as aspirin, was discovered in 1897 as an acetylated form of salicylate. It has been widely used for its anti-inflammatory and antiplatelet effects. It is commonly used for its cardiovascular benefits and is prescribed as secondary prophylaxis after a heart attack. Furthermore, low-dose, long-term ASA is used to reduce the risk of heart attack and stroke in individuals without prior cardiovascular disease. Acetylsalicylic acid acts as a non-selective inhibitor of cyclooxygenase (COX), which inhibits the synthesis of prostaglandins and prevents pro-inflammatory cytokines. Findings suggest that targeting cytokines and growth factors could be a potential therapeutic strategy for reducing neuroinflammation and slowing down the progression of dementia. Additionally, prostaglandins contribute to synaptic plasticity and can act as retrograde messengers in synapses. Research has implicated COX-1, one of the isoforms of the enzyme, in neuroinflammation and neurodegenerative disorders. The inhibition of COX-1 might potentially prevent impairments in working memory and reduce neuroinflammation caused by beta-amyloid proteins in some conditions, such as Alzheimer's disease (AD). Cyclooxygenase-2, an inducible form of the enzyme, is expressed in cortical and hippocampal neurons and is associated with long-term synaptic plasticity. The inhibition or knockout of COX-2 has been shown to decrease long-term potentiation, a process involved in memory formation. Studies have also demonstrated that the administration of COX-2 inhibitors impairs cognitive function and memory acquisition and recall in animal models. There remains a debate regarding the effects of aspirin on dementia and cognitive decline. Although some studies suggest a possible protective effect of non-steroidal anti-inflammatory drugs, including aspirin, against the development of AD, others have shown inconsistent evidence. This review provides an overview of the effects of ASA or its active metabolite salicylate on learning, memory, and synaptic plasticity.
Topics: Animals; Humans; Aspirin; Neuroinflammatory Diseases; Alzheimer Disease; Memory Disorders; Anti-Inflammatory Agents; Prostaglandins; Cyclooxygenase 2; Myocardial Infarction; Cytokines
PubMed: 37924473
DOI: 10.1007/s10787-023-01347-1 -
Signal Transduction and Targeted Therapy Sep 2023
Topics: Receptors, Prostaglandin; Glucose; Cardiomegaly
PubMed: 37669930
DOI: 10.1038/s41392-023-01541-1 -
Veterinary Research Communications Sep 2023Bovine in vitro endometrial models that resemble tissue function in vivo are needed to study infertility, long-term uterine alterations induced by pathogens and impact...
Bovine in vitro endometrial models that resemble tissue function in vivo are needed to study infertility, long-term uterine alterations induced by pathogens and impact of endocrine disruptor chemicals on reproductive function and other reproductive system complications that cause high economic losses in livestock species. The present study aimed to generate an innovative, reproducible, and functional 3D scaffold-based model of the bovine endometrium structurally robust for long term-culture. We developed a multicellular model containing both endometrial epithelial and stromal cells. Epithelial cells organized to form a luminal-like epithelial layer on the surface of the scaffold. Stromal cells produced their own extracellular matrix forming a stable subepithelial compartment that physiologically resembles the normal endometrium. Both cell types released prostaglandin E and prostaglandin F following a treatment with oxytocin and arachidonic acid. Additionally signal pathways mediating oxytocin and arachidonic acid stimulation of prostaglandin synthesis were analyzed by real time PCR (RT-PCR). Oxytocin receptor (OXTR), prostaglandin E receptor 2 (EP2), prostaglandin E receptor 4 (EP4), prostaglandin F receptor (PTGFR), prostaglandin E synthase (PTGES), PGF-synthase (PGFS) and prostaglandin-endoperoxide synthase 2 (COX-2) expression was detected in both control and treatment groups, however, only significant changes in abundance of OXTR mRNA transcripts were found. The results obtained by this study are a step forward in bovine in vitro culture technology. This 3D scaffold-based model provides a platform to study regulatory mechanisms involved in endometrial physiology and can set the basis for a broader tool for designing and testing novel therapeutic strategies for recurrent uterine pathologies.
Topics: Female; Animals; Cattle; Oxytocin; Arachidonic Acid; Endometrium; Dinoprostone; Prostaglandin-E Synthases
PubMed: 37154859
DOI: 10.1007/s11259-023-10130-0 -
Cell Communication and Signaling : CCS Aug 2023Extracellular vesicles (EVs) are membrane-coated nanoparticles secreted by almost all cell types in living organisms. EVs, as paracrine mediators, are involved in...
BACKGROUND
Extracellular vesicles (EVs) are membrane-coated nanoparticles secreted by almost all cell types in living organisms. EVs, as paracrine mediators, are involved in intercellular communication, immune response, and several reproductive events, including the maintenance of pregnancy. Using a domestic animal model (Sus scrofa) with an epitheliochorial, superficial type of placentation, we focused on EV biogenesis pathway at the embryo-maternal interface, when the embryonic signaling occurs for maternal recognition and the maintenance of pregnancy.
RESULTS
Transmission electron microscopy was used during early pregnancy to visualize EVs and apocrine and/or merocrine pathways of secretion. Immunofluorescent staining localized proteins responsible for EV biogenesis and cell polarization at the embryo-maternal interface. The expression profiles of genes involved in biogenesis and the secretion of EVs pointed to the possible modulation of endometrial expression by embryonic signals. Further in vitro studies showed that factors of embryonic origin can regulate the expression of the ESCRT-II complex and EV trafficking within endometrial luminal epithelial cells. Moreover, miRNA-mediated rapid negative regulation of gene expression was abolished by delivered embryonic signals.
CONCLUSIONS
Our findings demonstrated that embryonic signals are potent modulators of ESCRT-dependent EV-mediated secretory activity of the endometrium during the critical stages of early pregnancy. Video Abstract.
Topics: Animals; Female; Pregnancy; Biological Transport; Cell Communication; Endosomes; Extracellular Vesicles; Endosomal Sorting Complexes Required for Transport
PubMed: 37596609
DOI: 10.1186/s12964-023-01221-1