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Clinical Oral Investigations May 2024Mechano-sensitive odontoblast cells, which sense mechanical loading and various stresses in the tooth structure, synthesize early signaling molecules such as... (Comparative Study)
Comparative Study
The importance of mechanosensitive cell mediated prostaglandin and nitric oxide synthesis in the pathogenesis of apical periodontitis: comparative with chronic periodontitis.
OBJECTIVES
Mechano-sensitive odontoblast cells, which sense mechanical loading and various stresses in the tooth structure, synthesize early signaling molecules such as prostaglandin E2 (PGE2) and nitric oxide (NO) as an adaptive response. It is thought that these synthesized molecules can be used for the diagnosis and treatment of periodontal and periapical diseases. The aim of this study was to investigate the relationship between the severity of apical periodontitis (AP) and chronic periodontitis (CP) and serum (s) TNF-α, IL-10, PGE2 and NO levels, as well as PGE2 and NO levels in gingival crevicular fluid (GCF) samples.
MATERIALS & METHODS
A total of 185 subjects were divided into three categories: AP group (n = 85), CP group (n = 50) and healthy control group (n = 50). The AP group was divided into 3 subgroups according to abscess scoring (AS-PAI 1, 2 and 3) based on the periapical index. The CP group was divided into 4 subgroups according to the periodontitis staging system (PSS1, 2,3 and 4). After recording the demographic and clinical characteristics of all participants, serum (s) and gingival crevicular fluid (GCF) samples were taken. TNF-α, IL-10, PGE2 and NO levels were measured in these samples.
RESULTS
Unlike serum measurements (sTNF-α, sIL-10, sNO and sPGE2), GCF-NO and GCF-PGE levels of the AP group were significantly higher than the control group in relation to abscess formation (54.4 ± 56.3 vs. 22.5 ± 12.6 µmol/mL, p < 0.001 and 100 ± 98 vs. 41 ± 28 ng/L, p < 0.001, respectively). Confirming this, the GCF-NO and GCF-PGE levels of the AS-PAI 1 group, in which abscesses have not yet formed, were found to be lower than those in AS-PAI 2 and 3, which are characterized by abscess formation [(16.7(3.7-117.8), 32.9(11.8-212.8) and 36.9(4.3-251.6) µmol/mL, p = 0,0131; 46.0(31.4-120.0), 69.6(40.3-424.2) and 74.4(32.1-471.0) ng/L, p = 0,0020, respectively]. Consistent with the increase in PSS, the levels of sTNF [29.8 (8.2-105.5) vs. 16.7(6.3-37.9) pg/mL, p < 0.001], sIL-10 [542(106-1326) vs. 190(69-411) pg/mL, p < 0.001], sNO [182.1(36.3-437) vs. 57.0(15.9-196) µmol/mL, p < 0.001], sPGE2 [344(82-1298) vs. 100(35-1178) ng/L, p < 0.001], GCF-NO [58.9 ± 33.6 vs. 22.5 ± 12.6 ng/L, p < 0.001] and GCF-PGE2 [ 99(37-365) vs. 30(13-119), p < 0.001] in the CP group were higher than the control group. Comparison ROC analysis revealed that the GCF-PGE2 test had the best diagnostic value for both AP and CP (sensitivity: 94.1 and 88.0; specificity: 64.0 and 78.0, respectively; p < 0.001).
CONCLUSIONS
GCF-PE2 and GCF-NO have high diagnostic value in the determination of AP and CP, and can be selected as targets to guide treatment. In addition, the measurements of PGE2 and NO in GCF can be used as an important predictor of pulpal necrosis leading to abscess in patients with AP.
CLINICAL RELEVANCE
In this article, it is reported that syntheses of early signaling molecules such as PGE2 and NO can be used for the diagnosis and treatment target of periapical and periodontal infections.
Topics: Humans; Periapical Periodontitis; Male; Female; Chronic Periodontitis; Nitric Oxide; Gingival Crevicular Fluid; Adult; Dinoprostone; Interleukin-10; Tumor Necrosis Factor-alpha; Middle Aged; Enzyme-Linked Immunosorbent Assay; Case-Control Studies
PubMed: 38795217
DOI: 10.1007/s00784-024-05721-3 -
Marine Drugs May 2024Utilizing plant-based resources, particularly their by-products, aligns with sustainability principles and circular bioeconomy, contributing to environmental...
Utilizing plant-based resources, particularly their by-products, aligns with sustainability principles and circular bioeconomy, contributing to environmental preservation. The therapeutic potential of plant extracts is garnering increasing interest, and this study aimed to demonstrate promising outcomes from an extract obtained from an underutilized plant waste. , an invasive macroalga found in the Orbetello Lagoon, thrives in eutrophic conditions, forming persistent mats covering approximately 400 hectares since 2005. The biomass of undergoes mechanical harvesting and is treated as waste, requiring significant human efforts and economic resources-A critical concern for municipalities. Despite posing challenges to local ecosystems, the study identified as a natural source of bioactive metabolites. Phytochemical characterization revealed lipids, amino acids, and other compounds with potential anti-inflammatory activity in extract. In vitro assays with LPS-stimulated RAW 264.7 and TNF-α/IFN-γ-stimulated HaCaT cells showed the extract inhibited reactive oxygen species (ROS), nitric oxide (NO), and prostaglandin E2 (PGE2) productions, and reduced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions via NF-κB nuclear translocation, in RAW 264.7 cells. It also reduced chemokines (TARC/CCL17, RANTES/CCL5, MCP-1/CCL2, and IL-8) and the cytokine IL-1β production in HaCaT cells, suggesting potential as a therapeutic candidate for chronic diseases like atopic dermatitis. Finally, in silico studies indicated palmitic acid as a significant contributor to the observed effect. This research not only uncovered the untapped potential of but also laid the foundation for its integration into the circular bioeconomy, promoting sustainable practices, and innovative applications across various industries.
Topics: Animals; Anti-Inflammatory Agents; Mice; RAW 264.7 Cells; Humans; Phytochemicals; Plant Extracts; HaCaT Cells; Nitric Oxide; Reactive Oxygen Species; Cyclooxygenase 2; Nitric Oxide Synthase Type II; NF-kappa B; Dinoprostone; Chlorophyta; Seaweed
PubMed: 38786617
DOI: 10.3390/md22050226 -
Nature Communications May 2024Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of...
Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4/CD44/CD62L and CD4/CD44/CD62L/CD27 T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injury.
Topics: Animals; Pneumonia, Pneumococcal; Disease Models, Animal; Mice; Dinoprostone; Mice, Inbred C57BL; Streptococcus pneumoniae; Receptors, Prostaglandin E, EP4 Subtype; Macrophages; Lung; Macrophages, Alveolar; Integrin alpha Chains; Female; Antigens, CD; T-Lymphocytes
PubMed: 38773113
DOI: 10.1038/s41467-024-48138-y -
Zhongguo Fei Ai Za Zhi = Chinese... Apr 2024Tumor microenvironment (TME) is one of the important factors in tumorigenesis and progression, in which tumor-associated macrophages (TAMs) play an important role in...
BACKGROUND
Tumor microenvironment (TME) is one of the important factors in tumorigenesis and progression, in which tumor-associated macrophages (TAMs) play an important role in non-small cell lung cancer (NSCLC) progression. However, the mechanism of TAMs in NSCLC progression remains unclear, so this study aimed to investigate the role of TAMs in NSCLC progression and to find potential therapeutic targets.
METHODS
Gene Expression Profiling Interactive Analysis (GEPIA) database was used to analyze the expression of prostaglandin E2 receptor 4 (EP4) mRNA in NSCLC and normal lung tissues; the protein expression levels of cyclooxygenase-2 (COX-2), EP4, cluster of differentiation 86 (CD86), CD163 and CD31 were detected by immunohistochemistry (IHC) in 120 NSCLC tissues and 24 paracancerous tissues specimens. The nude mouse lung adenocarcinoma cell A549 and macrophage RAW264.7 co-transplanted tumor model was established. And the samples were collected by gavage with EP4 inhibitor E7046, and then stained with hematoxylin-eosin (HE), IHC, and immunofluorescence (IF), and then detected by Western blot for the epithelial mesenchymal transformation (EMT) of the tumor tissues of the nude mice in each group. Western blot was used to detect the expressions of EMT related protiens in each group of nude mice; full-length transcriptome sequencing was used to screen the key genes causing liver metastasis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed.
RESULTS
EP4 mRNA expression level in NSCLC tissues was generally lower than that in normal lung tissues (P<0.05); COX-2, EP4, CD163, CD31 proteins were differentially expressed in NSCLC tissues and adjacent tissues, and differences were observed in many clinicopathological parameters of NSCLC patients; RAW264.7 shortened the latency period of tumorigenesis of A549 and promoted the proliferation of tumors and liver metastasis of tumors, and E7046 could reduce tumor cell proliferation activity, tumor tissue vascular density and M2-type macrophage infiltration in nude mice; IF staining showed that macrophages were mainly distributed around the metastatic foci of tumors; Western blot results showed that compared with A549 alone transplantation group, the relative expression of E-cadherin protein in tumor tissues of mice in A549 and RAW264.7 co-transplantation group was significantly decreased, and the difference was statistically significant (P<0.05), while the relative expression of N-cadherin protein was up-regulated, but the difference was not statistically significant (P>0.05); the main pathways enriched in the differential genes of the full-length transcriptome were the PI3K-AKT and MAPK signaling pathways.
CONCLUSIONS
During NSCLC development, the COX-2/PGE2/EP4 axis may promote tumor progression by inducing macrophage functional activation, and EP4 may be a potential new target for tumor immunotherapy. This study provides new perspectives and ideas for in-depth exploration of the mechanisms of NSCLC development, as well as a theoretical basis for the development of new therapeutic strategies for NSCLC.
Topics: Receptors, Prostaglandin E, EP4 Subtype; Humans; Cyclooxygenase 2; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Animals; Dinoprostone; Mice; Macrophages; Macrophage Activation; Male; Female; A549 Cells; RAW 264.7 Cells
PubMed: 38769827
DOI: 10.3779/j.issn.1009-3419.2024.101.05 -
PloS One 2024[This corrects the article DOI: 10.1371/journal.pone.0227245.].
[This corrects the article DOI: 10.1371/journal.pone.0227245.].
PubMed: 38768081
DOI: 10.1371/journal.pone.0304233 -
Frontiers in Immunology 2024The parasitic helminth is a potent inducer of type 2 immune responses by stimulating dendritic cells (DCs) to prime T helper 2 (Th2) responses. We previously found that...
The parasitic helminth is a potent inducer of type 2 immune responses by stimulating dendritic cells (DCs) to prime T helper 2 (Th2) responses. We previously found that soluble egg antigens (SEA) promote the synthesis of Prostaglandin E (PGE2) by DCs through ERK-dependent signaling via Dectin-1 and Dectin-2 that subsequently induces OX40L expression, licensing them for Th2 priming, yet the ligands present in SEA involved in driving this response and whether specific targeting of PGE2 synthesis by DCs could affect Th2 polarization are unknown. We here show that the ability of SEA to bind Dectin-2 and drive ERK phosphorylation, PGE2 synthesis, OX40L expression, and Th2 polarization is impaired upon cleavage of high-mannose glycans by Endoglycosidase H treatment. This identifies high-mannose glycans present on glycoproteins in SEA as important drivers of this signaling axis. Moreover, we find that OX40L expression and Th2 induction are abrogated when microsomal prostaglandin E synthase-1 (mPGES) is selectively inhibited, but not when a general COX-1/2 inhibitor is used. This shows that the synthesis of PGE2 is vital for the Th2 priming function of SEA-stimulated DCs as well as points to the potential existence of other COX-dependent lipid mediators that antagonize PGE2-driven Th2 polarization. Lastly, specific PGE2 inhibition following immunization with eggs dampened the egg-specific Th cell response. In summary, our findings provide new insights in the molecular mechanisms underpinning Th2 induction by and identify druggable targets for potential control of helminth driven-Th2 responses.
Topics: Animals; Schistosoma mansoni; Dinoprostone; Th2 Cells; Lectins, C-Type; Mannose; Mice; Polysaccharides; Antigens, Helminth; Dendritic Cells; Schistosomiasis mansoni; Ovum; Mice, Inbred C57BL; OX40 Ligand
PubMed: 38742105
DOI: 10.3389/fimmu.2024.1372927 -
PloS One 2024
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lignans; beta Catenin; Lung Neoplasms; Biphenyl Compounds; Cell Movement; Dinoprostone; Signal Transduction; Cell Line, Tumor; Allyl Compounds; Phenols
PubMed: 38739616
DOI: 10.1371/journal.pone.0303600 -
Nature May 2024Expansion of antigen-experienced CD8 T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer....
Expansion of antigen-experienced CD8 T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer. Interleukin-2 (IL-2) acts as a key regulator of CD8 cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE), a known negative regulator of immune response in the tumour microenvironment, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8 TILs via the PGE receptors EP2 and EP4. Mechanistically, PGE inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ chain, resulting in defective assembly of IL-2Rβ-IL2Rγ membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
Topics: Humans; Dinoprostone; Mitochondria; Lymphocytes, Tumor-Infiltrating; Signal Transduction; Interleukin-2; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Interleukin Receptor Common gamma Subunit; CD8-Positive T-Lymphocytes; Interleukin-2 Receptor beta Subunit; Tumor Microenvironment; Cell Proliferation; Animals; Mice; Down-Regulation; Neoplasms
PubMed: 38658764
DOI: 10.1038/s41586-024-07352-w -
Nature May 2024Cancer-specific TCF1 stem-like CD8 T cells can drive protective anticancer immunity through expansion and effector cell differentiation; however, this response is...
Cancer-specific TCF1 stem-like CD8 T cells can drive protective anticancer immunity through expansion and effector cell differentiation; however, this response is dysfunctional in tumours. Current cancer immunotherapies can promote anticancer responses through TCF1 stem-like CD8 T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1CD8 T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE) restricts the proliferative expansion and effector differentiation of TCF1CD8 T cells within tumours, which promotes cancer immune escape. PGE does not affect the priming of TCF1CD8 T cells in draining lymph nodes. PGE acts through EP and EP (EP/EP) receptor signalling in CD8 T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1 tumour-infiltrating CD8 T lymphocytes (TILs). Ablation of EP/EP signalling in cancer-specific CD8 T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE-mediated inhibition of TCF1 TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1 TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE-EP/EP axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.
Topics: Animals; Female; Humans; Male; Mice; CD8-Positive T-Lymphocytes; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Dinoprostone; Disease Models, Animal; Hepatocyte Nuclear Factor 1-alpha; Interleukin-2; Lymph Nodes; Lymphocytes, Tumor-Infiltrating; Mice, Inbred C57BL; Neoplasms; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; Stem Cells; Tumor Escape
PubMed: 38658748
DOI: 10.1038/s41586-024-07254-x -
Sheng Li Xue Bao : [Acta Physiologica... Apr 2024Chronic liver disease (CLD) is a major global health burden in terms of growing morbidity and mortality. Although many conditions can cause CLD, leading to cirrhosis and... (Review)
Review
Chronic liver disease (CLD) is a major global health burden in terms of growing morbidity and mortality. Although many conditions can cause CLD, leading to cirrhosis and hepatocellular carcinoma (HCC), viral hepatitis, drug-induced liver injury (DILI), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most common culprits. Prostaglandin E (PGE), produced in the liver, is an important lipid mediator derived from the ω-6 polyunsaturated fatty acid, arachidonic acid, and plays a critical role in hepatic homeostasis. The physiological effects of PGE are mediated through four classes of E-type prostaglandin (EP) receptors, namely EP1, EP2, EP3 and EP4. In recent years, an increasing number of studies has been done to clarify the effects of PGE and EP receptors in regulating liver function and the pathogenesis of CLD to create a new potential clinical impact. In this review, we overview the biosynthesis and regulation of PGE and discuss the role of its synthesizing enzymes and receptors in the maintenance of normal liver function and the development and progress of CLD. We also discuss the potential of the PGE-EP receptors system in treating CLD with various etiologies.
Topics: Humans; Dinoprostone; Receptors, Prostaglandin E; Liver Diseases; Chronic Disease; Animals; Liver; Liver Diseases, Alcoholic; Non-alcoholic Fatty Liver Disease
PubMed: 38658381
DOI: No ID Found