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Ecotoxicology and Environmental Safety Jun 2024Exposure to nicotine by cigarette smoking have shown strongly defectives on the physiological function of ovaries, which in turn leads to disorders of fertility in...
Exposure to nicotine by cigarette smoking have shown strongly defectives on the physiological function of ovaries, which in turn leads to disorders of fertility in women. However, the potential molecular mechanisms remain to be elucidated. In this study, we notably found that nicotine was likely to specifically raise the expression of histone deacetylase 3 (HDAC3) to promote the apoptosis and autophagy of granulosa cells (GCs) and block follicular maturation. Moreover, prostaglandin E2 (PGE2) inhibited the apoptosis of GCs and facilitated follicular maturation, and nicotine appeared to inhibit PGE2 secretion by freezing the expression of cyclooxygenase 1 (COX1), which was the rate-limiting and essential enzyme for PGE2 synthesis. Epigenetically, the nicotine was observed to diminish the histone H3 lysine 9 acetylation (H3K9ac) level and compact the chromatin accessibility in -1776/-1499 bp region of COX1 by evoking the expression of HDAC3, with the deactivated Cas9-HDAC3/sgRNA system. Mechanistically, the COX1 protein was found to pick up and degrade the autophagy related protein beclin 1 (BECN1) to control the autophagy of GCs. These results provided a potential new molecular therapy to recover the damage of female fertility induced by nicotine from cigarette smoking.
Topics: Female; Autophagy; Animals; Nicotine; Granulosa Cells; Dinoprostone; Mice; Histone Deacetylases; Ovarian Follicle; Apoptosis; Cyclooxygenase 1
PubMed: 38653025
DOI: 10.1016/j.ecoenv.2024.116358 -
Journal of Ethnopharmacology Sep 2024Long-term chronic inflammation often leads to chronic diseases. Although Sophora flavescens has been shown to have anti-inflammatory properties, its detailed molecular...
ETHNOPHARMACOLOGICAL RELEVANCE
Long-term chronic inflammation often leads to chronic diseases. Although Sophora flavescens has been shown to have anti-inflammatory properties, its detailed molecular mechanism is still unknown.
AIM OF STUDY
This study investigated the effect of Radix Sophorae Flavescentis on the LPS-induced inflammatory response in macrophages.
MATERIALS AND METHODS
LPS was used to induce the peritoneal macrophages to simulate the inflammatory environment in vitro. Different concentrations of Radix Sophorae Flavescentis-containing (medicated) serum were used for intervention. The peritoneal macrophages were identified by using hematoxylin-eosin and immunofluorescence staining. ELISA was used to measure the TNF-α and IL-6 expression to determine the concentration of LPS. ELISA and Western blot (WB) were used to detect the PGE2 and CFHR2 expression in each group, respectively. The lentiviral vector for interference and overexpression of the CFHR2 gene was constructed, packaged, and transfected into LPS-induced macrophages. The transfection efficiency was verified by WB. Then, ELISA was used to detect the TNF-α, PGE2, and IL-6 expression. WB was used to detect the CFHR2, iNOS, COX-2, TLR2, TLR4, IFN-γ, STAT1, and p-STAT1 expression.
RESULTS
The primary isolated cells were identified as macrophages. The LPS-treated macrophages exhibited significantly higher expression of PGE2 and CFHR2, and the inflammatory factors TNF-α and IL-6, as well as iNOS, COX-2, TLR2, TLR4, IFN-γ, STAT1, and p-STAT1 expression compared with the control group (P < 0.05). The TNF-α, PGE2, and IL-6 levels, as well as CFHR2, iNOS, COX-2, TLR2, TLR4, IFN-γ, STAT1, and p-STAT1 expression were considerably lower in the LPS-induced+10% medicated-serum group, LPS-induced+20% medicated-serum group, and shCFHR interference group compared with the LPS group (P < 0.05).
CONCLUSION
Radix Sophorae Flavescentis might mediate CFHR2 expression and play an important role in inhibiting the LPS-induced pro-inflammatory response of macrophages. Radix Sophorae Flavescentis could be a potential treatment for LPS-induced related inflammatory diseases.
Topics: Animals; Lipopolysaccharides; Sophora; Anti-Inflammatory Agents; Mice; Macrophages, Peritoneal; Interleukin-6; Tumor Necrosis Factor-alpha; Dinoprostone; Plant Extracts; Inflammation; Toll-Like Receptor 2; Male; STAT1 Transcription Factor; Plant Roots; Cells, Cultured; Macrophages; Toll-Like Receptor 4; Sophora flavescens
PubMed: 38641074
DOI: 10.1016/j.jep.2024.118210 -
Archives of Toxicology Jul 20243-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in...
3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.
Topics: Animals; Reactive Oxygen Species; Zebrafish; Fluorenes; NF-kappa B; Endothelium, Vascular; Endothelial Cells; Cell Line; Cyclooxygenase 2; Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Inflammation; Dinoprostone; Dose-Response Relationship, Drug; Capillary Permeability
PubMed: 38635053
DOI: 10.1007/s00204-024-03751-0 -
International Journal of Molecular... Mar 2024Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; ) both participate in diverse pathologies including cancer progression. However, the biological...
Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; ) both participate in diverse pathologies including cancer progression. However, the biological role of the NFAT5-COX2 signaling pathway in human endometrial cancer has remained elusive. The present study explored whether NFAT5 is expressed in endometrial tumors and if NFAT5 participates in cancer progression. To gain insights into the underlying mechanisms, NFAT5 protein abundance in endometrial cancer tissue was visualized by immunohistochemistry and endometrial cancer cells (Ishikawa and HEC1a) were transfected with NFAT5 or with an empty plasmid. As a result, NFAT5 expression is more abundant in high-grade than in low-grade endometrial cancer tissue. RNA sequencing analysis of NFAT5 overexpression in Ishikawa cells upregulated 37 genes and downregulated 20 genes. Genes affected included cyclooxygenase 2 and hypoxia inducible factor 1α (). NFAT5 transfection and/or treatment with HIF-1α stabilizer exerted a strong stimulating effect on HIF-1α promoter activity as well as COX2 expression level and prostaglandin E2 receptor (PGE2) levels. Our findings suggest that activation of NFAT5-HIF-1α-COX2 axis could promote endometrial cancer progression.
Topics: Humans; Female; Cyclooxygenase 2; Gene Expression Regulation; Endometrial Neoplasms; NFATC Transcription Factors; Signal Transduction; Dinoprostone; Factor V; Transcription Factors
PubMed: 38612478
DOI: 10.3390/ijms25073666 -
European Journal of Cell Biology Jun 2024Mesenchymal stromal cells (MSCs) that are promising for cartilage tissue engineering secrete high amounts of prostaglandin E2 (PGE2), an immunoactive mediator involved...
Mesenchymal stromal cells (MSCs) that are promising for cartilage tissue engineering secrete high amounts of prostaglandin E2 (PGE2), an immunoactive mediator involved in endochondral bone development. This study aimed to identify drivers of PGE2 and its role in the inadvertent MSC misdifferentiation into hypertrophic chondrocytes. PGE2 release, which rose in the first three weeks of MSC chondrogenesis, was jointly stimulated by endogenous BMP, WNT, and hedgehog activity that supported the exogenous stimulation by TGF-β1 and insulin to overcome the PGE2 inhibition by dexamethasone. Experiments with PGE2 treatment or the inhibitor celecoxib or specific receptor antagonists demonstrated that PGE2, although driven by prohypertrophic signals, exerted broad autocrine antihypertrophic effects. This chondroprotective effect makes PGE2 not only a promising option for future combinatorial approaches to direct MSC tissue engineering approaches into chondral instead of endochondral development but could potentially have implications for the use of COX-2-selective inhibitors in osteoarthritis pain management.
Topics: Mesenchymal Stem Cells; Chondrogenesis; Dinoprostone; Humans; Cell Differentiation; Cells, Cultured; Chondrocytes
PubMed: 38608422
DOI: 10.1016/j.ejcb.2024.151412 -
Journal of Obstetrics and Gynaecology :... Dec 2024Existing treatments for primary dysmenorrhoea (PD), such as NSAIDs, impart side effects. decoction (GGD), a traditional Chinese medicine, has shown promise in treating...
BACKGROUND
Existing treatments for primary dysmenorrhoea (PD), such as NSAIDs, impart side effects. decoction (GGD), a traditional Chinese medicine, has shown promise in treating PD, but its exact mechanisms remain unclear. Here, we aimed to investigate the efficiency of GGD in alleviating PD using a rat model to understand its precise mechanism of action.
METHODS
We established a rat model of dysmenorrhoea induced by oestradiol and oxytocin. The PD rats were administered GGD or Ibuprofen (positive control) intragastrically once daily for seven consecutive days. Serum levels of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2α), β-endorphin (β-EP), thromboxane B2 (TXB2), 6-keto-prostaglandin F1α (6-keto-PGF1α) were determined using an enzyme-linked immunosorbent assay (ELISA). The expression levels of oestrogen receptor alpha (ERα) and cyclooxygenase-2 (COX-2) in uterine tissue were measured using immunohistochemical assays, and those of phosphorylated and total extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) were assessed using western blot analysis.
RESULTS
Treatment with GGD significantly reduced writhing behaviour, histopathological scores, and levels of COX-2, PGE2, and PGF2α in the serum of PD rats. Additionally, GGD increased β-EP content and inhibited ERK1/2 activation and ERα expression in uterine tissues.
CONCLUSIONS
The results of this study suggest that GGD alleviates PD in rats by suppressing the COX-2-mediated release of PGE2 and PGF2α, modulating the ERα/ERK1/2/COX-2 pathway, and increasing β-EP content. These results provide insights into the potential mechanisms of GGD in treating PD and support its further investigation as an alternative therapy for this condition.
Topics: Humans; Female; Rats; Animals; Dysmenorrhea; Cyclooxygenase 2; Estrogen Receptor alpha; Dinoprostone; Dinoprost
PubMed: 38594870
DOI: 10.1080/01443615.2024.2337691 -
Inflammopharmacology Jun 2024Based on their high antioxidant capacity and noteworthy phytochemistry, Terminalia ferdinandiana fruit and leaves have attracted considerable recent interest for their...
Based on their high antioxidant capacity and noteworthy phytochemistry, Terminalia ferdinandiana fruit and leaves have attracted considerable recent interest for their therapeutic potential. Whilst those studies have reported a variety of therapeutic properties for the fruit, the anti-inflammatory potential of T. ferdinandiana has been largely neglected and the leaves have been almost completely ignored. This study investigated the immune-modulatory and anti-inflammatory properties of T. ferdinandiana fruit and leaf extracts by evaluating their inhibition of multiple pro- and anti-inflammatory cytokines and chemokines secretion in lipopolysaccharide (LPS)-stimulated and unstimulated RAW 264.7 macrophages using multiplex bead immunoassays and ELISA assays. The methanolic extracts were particularly good immune-modulators, significantly inhibiting the secretion of all the cytokines and chemokines tested. Indeed, the methanolic extracts completely inhibited IL-10, IFN-γ, IL-1β, IL-6, MCP-1, and MIP-2a secretion, and almost completely inhibited the secretion of TNF-α. In addition, the methanolic T. ferdinandiana extracts also significantly inhibited cytosolic COX-2 levels (by 87-95%) and the synthesis of the PGE (by ~ 98%). In contrast, the methanolic extracts stimulated LTB secretion by ~ 60-90%, whilst the aqueous extracts significantly inhibited LTB secretion (by ~ 27% each). Exposure of RAW 264.7 cells to the methanolic T. ferdinandiana extracts also significantly down-regulated the cytosolic levels of NF-κB by 33-44%, indicating that the immune-modulatory and anti-inflammatory properties of the extracts may be regulated via a decrease in NF-κB transcription pathways. Taken together, these results demonstrate potent anti-inflammatory properties for the extracts and provide insights into their anti-inflammatory mechanisms.
Topics: Mice; Animals; NF-kappa B; RAW 264.7 Cells; Plant Extracts; Dinoprostone; Cytokines; Anti-Inflammatory Agents; Terminalia; Down-Regulation; Cyclooxygenase 2; Plant Leaves; Macrophages; Lipopolysaccharides; Fruit
PubMed: 38581641
DOI: 10.1007/s10787-024-01462-7 -
Scientific Reports Mar 2024Chronic rhinosinusitis (CRS) can be traditionally classified as CRSwNP [with nasal polyps (NPs)] and CRSsNP (without NPs) based on the clinical phenotypes but recently...
The cyclooxygenase-2 upregulation mediates production of PGE2 autacoid to positively regulate interleukin-6 secretion in chronic rhinosinusitis with nasal polyps and polyp-derived fibroblasts.
Chronic rhinosinusitis (CRS) can be traditionally classified as CRSwNP [with nasal polyps (NPs)] and CRSsNP (without NPs) based on the clinical phenotypes but recently suggested to be classified by the endotypes. We have identified overexpression of the cyclooxygenase-2 (COX-2) gene in NP tissues of Taiwanese CRSwNP patients. Therefore, in this study, we sought to investigate its protein expression/location/distribution in NP specimens and explore its roles in nasal polyposis. The COX-2 protein and mRNA expression was found higher in NPs than that in the control and CRSsNP patients' nasal tissues, mainly located at the epithelium and subepithelial stroma. Consistently, the CRS-related peptidoglycan (PGN) and bradykinin provoked COX-2 mRNA and protein upregulation in the human NP-derived fibroblasts and caused PGE, thromboxane A (TXA), and interleukin (IL-6) secretion in culture medium. Further analysis revealed that the PI3K/Akt activation and COX-2 induction were necessarily required for PGN-induced IL-6 production/secretion and the induced PGE, but not TXA, was speculated to affect IL-6 protein trafficking and production. Finally, the IL-6 increase observed in vitro could also be detected in NP tissues. Collectively, we demonstrated here that COX-2 protein and IL-6 are overexpressed in human NP tissues. In response to PGN challenge, the PI3K/Akt activation and COX-2-mediated PGE autacoid correlates with extracellular IL-6 protein trafficking/production in NP-derived fibroblasts, which can additionally contribute to the production of Th17-related cytokines such as IL-17 and TNF-α. This study also suggests COX-2 as a special biomarker for CRSwNP endotyping and may highlight the importance of COX-2 inhibitors in treating CRSwNP.
Topics: Humans; Chronic Disease; Cyclooxygenase 2; Dinoprostone; Fibroblasts; Interleukin-6; Nasal Polyps; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rhinitis; Rhinosinusitis; RNA, Messenger; Up-Regulation
PubMed: 38555391
DOI: 10.1038/s41598-024-58143-2 -
International Ophthalmology Mar 2024Rhegmatogenous retinal detachment is a severe vision-threatening complication that can result into proliferative vitreoretinopathy (PVR) and re-detachment of the retina...
Anti-inflammatory potential of simvastatin and amfenac in ARPE-19 cells; insights in preventing re-detachment and proliferative vitreoretinopathy after rhegmatogenous retinal detachment surgery.
PURPOSE
Rhegmatogenous retinal detachment is a severe vision-threatening complication that can result into proliferative vitreoretinopathy (PVR) and re-detachment of the retina if recovery from surgery fails. Inflammation and changes in retinal pigment epithelial (RPE) cells are important contributors to the disease. Here, we studied the effects of simvastatin and amfenac on ARPE-19 cells under inflammatory conditions.
METHODS
ARPE-19 cells were pre-treated with simvastatin and/or amfenac for 24 h after which interleukin (IL)-1α or IL-1β was added for another 24 h. After treatments, lactate dehydrogenase release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) processing, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity, prostaglandin E2 (PGE2) level, and extracellular levels of IL-6, IL-8, monocytic chemoattractant protein (MCP-1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor, as well as the production of reactive oxygen species (ROS) were determined.
RESULTS
Pre-treatment of human ARPE-19 cells with simvastatin reduced the production of IL-6, IL-8, and MCP-1 cytokines, PGE2 levels, as well as NF-κB activity upon inflammation, whereas amfenac reduced IL-8 and MCP-1 release but increased ROS production. Together, simvastatin and amfenac reduced the release of IL-6, IL-8, and MCP-1 cytokines as well as NF-κB activity but increased the VEGF release upon inflammation in ARPE-19 cells.
CONCLUSION
Our present study supports the anti-inflammatory capacity of simvastatin as pre-treatment against inflammation in human RPE cells, and the addition of amfenac complements the effect. The early modulation of local conditions in the retina can prevent inflammation induced PVR formation and subsequent retinal re-detachment.
Topics: Humans; Vitreoretinopathy, Proliferative; Retinal Detachment; NF-kappa B; Vascular Endothelial Growth Factor A; Retinal Pigment Epithelium; Simvastatin; Reactive Oxygen Species; Dinoprostone; Interleukin-6; Interleukin-8; Cytokines; Anti-Inflammatory Agents; Inflammation; Phenylacetates
PubMed: 38530532
DOI: 10.1007/s10792-024-03067-z -
Circulation. Heart Failure Apr 2024Prostaglandin E2 acts through 4 G-protein-coupled receptors (EP1-EP4). We previously reported that activation of the EP3 receptor reduces cardiac contractility, and its...
BACKGROUND
Prostaglandin E2 acts through 4 G-protein-coupled receptors (EP1-EP4). We previously reported that activation of the EP3 receptor reduces cardiac contractility, and its expression increases after a myocardial infarction (MI), mediating the reduction in cardiac function. In contrast, cardiac overexpression of the EP4 receptor in MI substantially improves cardiac function. Moreover, we recently reported that mice overexpressing EP3 have heart failure under basal conditions and worsened cardiac function after MI. Thus, the deleterious effects of the prostaglandin E2 EP receptors in the heart are mediated via its EP3 receptor. We, therefore, hypothesized that cardiomyocyte-specific knockout (CM-EP3 KO) or antagonism of the EP3 receptor protects the heart after MI.
METHODS
To test our hypothesis, we made the novel CM-EP3 KO mouse and subjected CM-EP3 KO or controls to sham or MI surgery for 2 weeks. In separate experiments, C57BL/6 mice were subjected to 2 weeks of MI and treated with either the EP3 antagonist L798 106 or vehicle starting 3 days post-MI.
RESULTS
CM-EP3 KO significantly prevented a decline in cardiac function after MI compared with WT animals and prevented an increase in hypertrophy and fibrosis. Excitingly, mice treated with L798 106 3 days after MI had significantly better cardiac function compared with vehicle-treated mice.
CONCLUSIONS
Altogether, these data suggest that EP3 may play a direct role in regulating cardiac function, and pharmaceutical targeting of the EP3 receptor may be a therapeutic option in the treatment of heart failure.
Topics: Mice; Animals; Dinoprostone; Receptors, Prostaglandin; Gene Deletion; Heart Failure; Mice, Inbred C57BL; Myocardial Infarction; Myocytes, Cardiac; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Prostaglandin E, EP3 Subtype
PubMed: 38525608
DOI: 10.1161/CIRCHEARTFAILURE.123.011089