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Scientific Reports Mar 2024Abdominal aortic aneurysm (AAA) is a deadly, permanent ballooning of the aortic artery. Pharmacological and genetic studies have pointed to multiple proteins, including...
Abdominal aortic aneurysm (AAA) is a deadly, permanent ballooning of the aortic artery. Pharmacological and genetic studies have pointed to multiple proteins, including microsomal prostaglandin E synthase-1 (mPGES-1), as potentially promising targets. However, it remains unknown whether administration of an mPGES-1 inhibitor can effectively attenuate AAA progression in animal models. There are still no FDA-approved pharmacological treatments for AAA. Current research stresses the importance of both anti-inflammatory drug targets and rigor of translatability. Notably, mPGES-1 is an inducible enzyme responsible for overproduction of prostaglandin E (PGE)-a well-known principal pro-inflammatory prostanoid. Here we demonstrate for the first time that a highly selective mPGES-1 inhibitor (UK4b) can completely block further growth of AAA in the ApoE-/- angiotensin (Ang)II mouse model. Our findings show promise for the use of a mPGES-1 inhibitor like UK4b as interventional treatment of AAA and its potential translation into the clinical setting.
Topics: Animals; Mice; Angiotensin II; Aorta; Aortic Aneurysm, Abdominal; Dinoprostone; Disease Models, Animal; Prostaglandin-E Synthases; Prostaglandins
PubMed: 38521811
DOI: 10.1038/s41598-024-57437-9 -
Nagoya Journal of Medical Science Feb 2024Prostaglandin E1 intracavernous injection test is an established method for diagnosing erectile dysfunction. However, the evaluation is non-objective and often...
Prostaglandin E1 intracavernous injection test is an established method for diagnosing erectile dysfunction. However, the evaluation is non-objective and often influenced by the evaluator's subjectivity. Herein, we measured and objectively evaluated shear wave elastography results of the corpus cavernosum before and after injection in 16 patients who underwent prostaglandin E1 testing. The response score of prostaglandin E1 tests were "1" in 2 cases, "2" in 2 cases, and "3" in 12 cases. The average transmission velocity before the injection and at the time of maximum erection after the injection were 2.21 m/s and 1.57 m/s, respectively. Transmission velocity decreased during erection in 14 of 16 cases (87.5%). The overall rate of change in transmission velocity due to injection was -26.7% and was significantly different between the poor (responses 1 and 2: -16.1%) and good erection (response 3: -30.2%) groups. To the best of our knowledge, this is the first attempt to evaluate erectile phenomenon using percutaneous ultrasonic elastography in Japan. Rate of change in shear wave transmission velocity due to prostaglandin E1 injection in the corpus cavernosum penis was associated with the degree of erection. Therefore, the rate of change in shear wave transmission velocity in the corpus cavernosum penis could be used as an objective index of erectile phenomenon. Percutaneous ultrasonic elastography is a non-invasive and useful test method for diagnosing erectile dysfunction, determining the therapeutic effect, and predicting prognosis.
Topics: Male; Humans; Erectile Dysfunction; Alprostadil; Elasticity Imaging Techniques; Penile Erection; Penis
PubMed: 38505715
DOI: 10.18999/nagjms.86.1.104 -
Zhongguo Xiu Fu Chong Jian Wai Ke Za... Mar 2024To explore the molecular mechanism of miR-515-5p in inhibiting chondrocyte apoptosis and alleviating inflammatory response in osteoarthritis (OA).
[miR-515-5p targeting Toll-like receptor 4 regulates myeloid differentiation primary response gene 88/nuclear factor-kappa B pathway to inhibit apoptosis and inflammatory response of osteoarthritis chondrocytes].
OBJECTIVE
To explore the molecular mechanism of miR-515-5p in inhibiting chondrocyte apoptosis and alleviating inflammatory response in osteoarthritis (OA).
METHODS
Human cartilage cell line C28/I2 was cultured and treated with 10 ng/mL interleukin 1β (IL-1β) for 24 hours to construct an OA model. C28/I2 cells were transfected with miR mimics, mimics negative control (NC), over expression (oe)-NC, and oe-Toll-like receptor 4 (TLR4), respectively, and then treated with 10 ng/mL IL-1β for 24 hours to establish OA model. Cell proliferation capacity was detected by cell counting kit 8 and 5-Ethynyl-2'-deoxyuridine, cell apoptosis and cell cycle were detected by flow cytometry, and B-cell lymphoma 2 protion (Bcl-2), Bcl-2-associated X protein (Bax), cleaved-Caspase-3, TLR4, myeloid differentiation primary response gene 88 (MyD88), p65 and phosphorylated p65 (p-p65) protein expression levels were detected by Western blot. Real-time fluorescence quantitative PCR was used to detect mRNA expression levels of miR-515-5p and TLR4, and ELISA was used to detect pro-inflammatory factor prostaglandin E2 (PGE2), tumor necrosis factor α (TNF -α), and IL-6 levels in cell supernatant. The potential binding sites between miR-515-5p and TLR4 were predicted by BiBiServ2 database, and the targeting relationship between miR-515-5p and TLR4 was verified by dual luciferase reporting assay.
RESULTS
After the treatment of C28/I2 cells with IL-1β, the expressions of miR-515-5p and Bcl-2 protein and the proliferation ability of C28/I2 cells significantly reduced. The expression levels of Bax and cleaved-Caspase-3 protein, the levels of pro-inflammatory factors (PGE2, TNF-α, IL-6) in the supernatant of C28/I2 cells, and the apoptosis of C28/I2 cells significantly increased. In addition, the proportion of the cells at S phase and G phase decreased significantly, and the proportion of cells at G phase increased significantly, suggesting that the cell cycle was blocked after IL-1β treatment. After transfection with miR mimics, the expression level of miR-515-5p in the cells significantly up-regulated, partially reversing the apoptosis of OA chondrocytes induced by IL-1β, and alleviating the cycle arrest and inflammatory response of OA chondrocytes. After treating C28/I2 cells with IL-1β, the mRNA and protein levels of TLR4 significantly increased. Overexpression of miR-515-5p targeted inhibition of TLR4 expression and blocked activation of MyD88/nuclear factor κB (NF-κB) pathway. Overexpression of TLR4 could partially reverse the effect of miR mimics on IL-1β-induced apoptosis and inflammation of OA chondrocytes.
CONCLUSION
miR-515-5p negatively regulates the expression of TLR4, inhibits the activation of MyD88/NF-κB pathway and apoptosis of OA chondrocytes, and effectively alleviates the inflammatory response of the cells.
Topics: Humans; Adaptor Proteins, Signal Transducing; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Chondrocytes; Dinoprostone; Interleukin-1beta; Interleukin-6; MicroRNAs; Myeloid Differentiation Factor 88; NF-kappa B; Osteoarthritis; RNA, Messenger; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 38500425
DOI: 10.7507/1002-1892.202312091 -
Cells Mar 2024NAD boosting via nicotinamide riboside (NR) confers anti-inflammatory effects. However, its underlying mechanisms and therapeutic potential remain incompletely defined....
NAD boosting via nicotinamide riboside (NR) confers anti-inflammatory effects. However, its underlying mechanisms and therapeutic potential remain incompletely defined. Here, we showed that NR increased the expression of CC-chemokine receptor 7 (CCR7) in human M1 macrophages by flow cytometric analysis of cell surface receptors. Consequently, chemokine ligand 19 (CCL19, ligand for CCR7)-induced macrophage migration was enhanced following NR administration. Metabolomics analysis revealed that prostaglandin E2 (PGE2) was increased by NR in human monocytes and in human serum following in vivo NR supplementation. Furthermore, NR-mediated upregulation of macrophage migration through CCL19/CCR7 was dependent on PGE2 synthesis. We also demonstrated that NR upregulated PGE2 synthesis through SIRT3-dependent post-transcriptional regulation of cyclooxygenase 2 (COX-2). The NR/SIRT3/migration axis was further validated using the scratch-test model where NR and SIRT3 promoted more robust migration across a uniformly disrupted macrophage monolayer. Thus, NR-mediated metabolic regulation of macrophage migration and wound healing may have therapeutic potential for the topical management of chronic wound healing.
Topics: Humans; Dinoprostone; Sirtuin 3; Ligands; Receptors, CCR7; Macrophages; Niacinamide; Pyridinium Compounds
PubMed: 38474420
DOI: 10.3390/cells13050455 -
Prostaglandins, Leukotrienes, and... Feb 2024Prostaglandin E2 (PGE2) signals differently through 4 receptor subtypes (EP1-EP4) to elicit diverse physiologic/pathologic effects. We previously reported that PGE2 via...
Prostaglandin E2 (PGE2) signals differently through 4 receptor subtypes (EP1-EP4) to elicit diverse physiologic/pathologic effects. We previously reported that PGE2 via its EP3 receptor reduces cardiac contractility and male mice with cardiomyocyte-specific deletion of the EP4 receptor (EP4 KO) develop dilated cardiomyopathy. The aim of this study was to identify pathways responsible for this phenotype. We performed ingenuity pathway analysis (IPA) and found that genes differentiating WT mice and EP4 KO mice were significantly overrepresented in mitochondrial (adj. p value = 6.28 × 10) and oxidative phosphorylation (adj. p value = 1.58 × 10) pathways. Electron microscopy from the EP4 KO hearts show substantial mitochondrial disarray and disordered cristae. Not surprisingly, isolated adult mouse cardiomyocytes (AVM) from these mice have reduced ATP levels compared to their WT littermates and reduced expression of key genes involved in the electron transport chain (ETC) in older mice. Moreover, treatment of AVM from C57Bl/6 mice with PGE2 or the EP3 agonist sulprostone resulted in changes of various genes involved in the ETC, measured by the Mitochondrial Energy Metabolism RT-profiler assay. Lastly, the EP4 KO mice have reduced expression of superoxide dismuatse-2 (SOD2), whereas treatment of AVM with PGE2 or sulprostone increase superoxide production, suggesting increased oxidative stress levels in these EP4 KO mice. Altogether the current study supports the premise that PGE2 acting via its EP4 receptor is protective, while signaling through its other receptors, likely EP3, is deleterious.
Topics: Animals; Myocytes, Cardiac; Dinoprostone; Mice; Receptors, Prostaglandin E, EP4 Subtype; Mice, Knockout; Male; Mice, Inbred C57BL; Mitochondria, Heart; Oxidative Phosphorylation; Mitochondria
PubMed: 38471265
DOI: 10.1016/j.plefa.2024.102614 -
Sheng Li Xue Bao : [Acta Physiologica... Feb 2024Prostaglandin E (PGE2) is an important lipid molecule derived from arachidonic acid, which regulates a variety of physiological and pathological activities. Based on the... (Review)
Review
Prostaglandin E (PGE2) is an important lipid molecule derived from arachidonic acid, which regulates a variety of physiological and pathological activities. Based on the inhibition of inflammatory PGE production, non-steroidal anti-inflammatory drugs (NSAIDs) are considered as the most commonly used drugs to treat inflammatory diseases and to relieve fever and pain symptoms. PGE mediates its functions via four different G protein-coupled receptors, named EP1-EP4. Though the limited distribution and low PGE affinity of EP1, it plays important roles in the maintenance of many physiological functions and homeostasis. Moreover, EP1 is widely involved in the inflammatory response, pain perception and multisystem pathological function regulation. In this review, we will briefly summarize the recent advances on the physiological and pathophysiological function of EP1 and its targeted drugs development.
Topics: Humans; Arachidonic Acid; Dinoprostone; Homeostasis; Pain
PubMed: 38444136
DOI: No ID Found -
Journal of Translational Medicine Mar 2024Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous...
BACKGROUND
Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity.
METHODS
Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens.
RESULTS
While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient.
CONCLUSIONS
This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.
Topics: Humans; Melanoma; Immune Checkpoint Inhibitors; Cyclooxygenase 2; Dinoprostone; Blood Group Antigens; Cyclooxygenase 2 Inhibitors; Inflammation; Receptors, Antigen, T-Cell
PubMed: 38443917
DOI: 10.1186/s12967-024-04973-7 -
Bone Research Mar 2024Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment. However, it is unclear whether the signals of bone...
Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment. However, it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the brain. In this study, we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone prostaglandin E2 (PGE2) concentration in response to mechanical loading. Bone PGE2 levels are in proportion to their weight bearing. When weight bearing changes in the tail-suspension mice, the PGE2 concentrations in bones change in line with their weight bearing changes. Deletion of cyclooxygenase-2 (COX2) in the osteoblast lineage cells or knockout of receptor 4 (EP4) in sensory nerve blunts bone formation in response to mechanical loading. Moreover, knockout of TrkA in sensory nerve also significantly reduces mechanical load-induced bone formation. Moreover, mechanical loading induces cAMP-response element binding protein (CREB) phosphorylation in the hypothalamic arcuate nucleus (ARC) to inhibit sympathetic tyrosine hydroxylase (TH) expression in the paraventricular nucleus (PVN) for osteogenesis. Finally, we show that elevated PGE2 is associated with ankle osteoarthritis (AOA) and pain. Together, our data demonstrate that in response to mechanical loading, skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis, while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.
Topics: Animals; Mice; Dinoprostone; Ankle; Interoception; Brain; Pain; Osteoarthritis
PubMed: 38443372
DOI: 10.1038/s41413-024-00316-w -
The Journal of Biological Chemistry Apr 2024Regulators of G protein signaling (RGS) proteins constrain G protein-coupled receptor (GPCR)-mediated and other responses throughout the body primarily, but not...
Regulators of G protein signaling (RGS) proteins constrain G protein-coupled receptor (GPCR)-mediated and other responses throughout the body primarily, but not exclusively, through their GTPase-activating protein activity. Asthma is a highly prevalent condition characterized by airway hyper-responsiveness (AHR) to environmental stimuli resulting in part from amplified GPCR-mediated airway smooth muscle contraction. Rgs2 or Rgs5 gene deletion in mice enhances AHR and airway smooth muscle contraction, whereas RGS4 KO mice unexpectedly have decreased AHR because of increased production of the bronchodilator prostaglandin E2 (PGE2) by lung epithelial cells. Here, we found that knockin mice harboring Rgs4 alleles encoding a point mutation (N128A) that sharply curtails RGS4 GTPase-activating protein activity had increased AHR, reduced airway PGE2 levels, and augmented GPCR-induced bronchoconstriction compared with either RGS4 KO mice or WT controls. RGS4 interacted with the p85α subunit of PI3K and inhibited PI3K-dependent PGE2 secretion elicited by transforming growth factor beta in airway epithelial cells. Together, these findings suggest that RGS4 affects asthma severity in part by regulating the airway inflammatory milieu in a G protein-independent manner.
Topics: Animals; Humans; Mice; Asthma; Bronchoconstriction; Dinoprostone; Epithelial Cells; GTPase-Activating Proteins; Mice, Knockout; Phosphatidylinositol 3-Kinases; Respiratory Hypersensitivity; RGS Proteins; Cell Line
PubMed: 38432633
DOI: 10.1016/j.jbc.2024.107127 -
Kidney International Jul 2024Despite the recent advances in our understanding of the role of lipids, metabolites, and related enzymes in mediating kidney injury, there is limited integrated...
Despite the recent advances in our understanding of the role of lipids, metabolites, and related enzymes in mediating kidney injury, there is limited integrated multi-omics data identifying potential metabolic pathways driving impaired kidney function. The limited availability of kidney biopsies from living donors with acute kidney injury has remained a major constraint. Here, we validated the use of deceased transplant donor kidneys as a good model to study acute kidney injury in humans and characterized these kidneys using imaging and multi-omics approaches. We noted consistent changes in kidney injury and inflammatory markers in donors with reduced kidney function. Neighborhood and correlation analyses of imaging mass cytometry data showed that subsets of kidney cells (proximal tubular cells and fibroblasts) are associated with the expression profile of kidney immune cells, potentially linking these cells to kidney inflammation. Integrated transcriptomic and metabolomic analysis of human kidneys showed that kidney arachidonic acid metabolism and seven other metabolic pathways were upregulated following diminished kidney function. To validate the arachidonic acid pathway in impaired kidney function we demonstrated increased levels of cytosolic phospholipase A2 protein and related lipid mediators (prostaglandin E2) in the injured kidneys. Further, inhibition of cytosolic phospholipase A2 reduced injury and inflammation in human kidney proximal tubular epithelial cells in vitro. Thus, our study identified cell types and metabolic pathways that may be critical for controlling inflammation associated with impaired kidney function in humans.
Topics: Humans; Phenotype; Acute Kidney Injury; Male; Middle Aged; Metabolomics; Female; Kidney Transplantation; Adult; Image Cytometry; Kidney; Phospholipases A2; Arachidonic Acid; Kidney Tubules, Proximal; Transcriptome; Dinoprostone; Fibroblasts; Gene Expression Profiling; Epithelial Cells; Biopsy; Multiomics
PubMed: 38431215
DOI: 10.1016/j.kint.2024.01.041