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Blood Aug 2022
Topics: Dinoprostone; Immunosuppressive Agents; Lung; Neutrophils
PubMed: 36006676
DOI: 10.1182/blood.2022017345 -
International Journal of Biological... 2019Endometriosis (EMS) is the most common gynecological disease in women of reproductive age, and it is associated with chronic pelvic pain, dyspareunia and infertility. As... (Review)
Review
Endometriosis (EMS) is the most common gynecological disease in women of reproductive age, and it is associated with chronic pelvic pain, dyspareunia and infertility. As a consequence of genetic, immune and environmental factors, endometriotic lesions have high cyclooxygenase (COX)-2 and COX-2-derived prostaglandin E (PGE) biosynthesis compared with the normal endometrium. The transcription of the PTGS2 gene for COX-2 is associated with multiple intracellular signals, which converge to cause the activation of mitogen-activated protein kinases (MAPKs). COX-2 expression can be regulated by several factors, such as estrogen, hypoxia, proinflammatory cytokines, environmental pollutants, metabolites and metabolic enzymes, and platelets. High concentrations of COX-2 lead to high cell proliferation, a low level of apoptosis, high invasion, angiogenesis, EMS-related pain and infertility. COX-2-derived PGE performs a crucial function in EMS development by binding to EP2 and EP4 receptors. These basic findings have contributed to COX-2-targeted treatment in EMS, including COX-2 inhibitors, hormone drugs and glycyrrhizin. In this review, we summarize the most recent basic research in detail and provide a short summary of COX-2-targeted treatment.
Topics: Animals; Cyclooxygenase 2; Dinoprostone; Endometriosis; Estrogens; Female; Humans; Pain
PubMed: 31853218
DOI: 10.7150/ijbs.35128 -
Frontiers in Immunology 2021Macrophage polarization is mainly steered by metabolic reprogramming in the tissue microenvironment, thus leading to distinct outcomes of various diseases. However, the...
Macrophage polarization is mainly steered by metabolic reprogramming in the tissue microenvironment, thus leading to distinct outcomes of various diseases. However, the role of lipid metabolism in the regulation of macrophage alternative activation is incompletely understood. Using human THP-1 and mouse bone marrow derived macrophage polarization models, we revealed a pivotal role for arachidonic acid metabolism in determining the phenotype of M2 macrophages. We demonstrated that macrophage M2 polarization was inhibited by arachidonic acid, but inversely facilitated by its derived metabolite prostaglandin E2 (PGE2). Furthermore, PPARγ bridges these two seemingly unrelated processes modulating oxidative phosphorylation (OXPHOS). Through inhibiting PPARγ, PGE2 enhanced OXPHOS, resulting in the alternative activation of macrophages, which was counterweighted by the activation of PPARγ. This connection between PGE2 biosynthesis and macrophage M2 polarization also existed in human and mouse esophageal squamous cell carcinoma. Our results highlight the critical role of arachidonic acid and metabolic PGE2 as immune regulators in modulating tissue homeostasis and pathological process.
Topics: Animals; Arachidonic Acid; Carcinoma, Squamous Cell; Cell Differentiation; Dinoprostone; Esophageal Neoplasms; Homeostasis; Humans; Inflammation; Lipid Metabolism; Macrophage Activation; Macrophages; Mice; Oxidative Phosphorylation; PPAR gamma; Signal Transduction; THP-1 Cells; Th2 Cells
PubMed: 34149684
DOI: 10.3389/fimmu.2021.618501 -
Journal of Sports Science & Medicine Dec 2022Dysmenorrhea with high prevalence has been categorized as primary dysmenorrhea (PD) and secondary dysmenorrhea due to differences in pathogenesis. A significant number... (Randomized Controlled Trial)
Randomized Controlled Trial
The Sprint-Interval Exercise Using a Spinning Bike Improves Physical Fitness and Ameliorates Primary Dysmenorrhea Symptoms Through Hormone and Inflammation Modulations: A Randomized Controlled Trial.
Dysmenorrhea with high prevalence has been categorized as primary dysmenorrhea (PD) and secondary dysmenorrhea due to differences in pathogenesis. A significant number of reproductive females suffering from monthly menstruation have to deal with negative impacts on their quality of life, work/study productivity, activities, and social relationships. In addition to medical treatment, exercise has been recognized as a complementary and alternative strategy for disease prevention, alleviation, and rehabilitation. This study aimed to investigate the potential effects of exercise on the severity of primary dysmenorrhea, physiological modulation, and physical fitness. Participants consisted of university students who were enrolled in the study and divided into a non-PD (Control) and a PD group based on recruiting criteria, the latter being randomly assigned to either an untreated dysmenorrhea group or a dysmenorrhea group that underwent 10 weeks of high intensity interval training (HIIT) exercise (Dysmen and DysmenHIIT, respectively). The DysmenHIIT group used spinning bikes and the training intensity was validated by heart rate monitors and BORG rating of perceived exertion. Forms containing participant information (premenstrual symptoms, menstrual distress, and a Short Form McGill Pain Questionnaire) as well as physical fitness, biochemical variables, hormone and prostaglandin (PGE2 and PGF2α) levels were assessed before and after the exercise intervention. After intervention, premenstrual symptoms (anger, anxiety, depression, activity level, fatigue, etc.), menstrual distress symptoms (cramps, aches, swelling, etc.), and pain severity were shown to be significantly mitigated, possibly through hormone (estradiol, prolactin, progesterone, and cortisol) modulation. Furthermore, high-sensitivity C-reactive protein (HsCRP), PGE2 and PGF2α levels were also down-regulated, resulting in the amelioration of uterine contraction and inflammation. Participants' physical fitness, including cardiovascular endurance and explosive force, was significantly improved after HIIT. The 10-week HIIT spinning bike exercise used in this study could be employed as a potential and complementary treatment for PD symptoms alleviation and considered as part of an educational health plan for promoting women's health. However, the effects of HIIT utilizing different exercise methods and accounting for different age populations and secondary PD warrant further investigation.
Topics: Humans; Female; Dysmenorrhea; Bicycling; Quality of Life; Dinoprost; Dinoprostone; Physical Fitness; Hormones; Inflammation
PubMed: 36523895
DOI: 10.52082/jssm.2022.595 -
Journal of Biomedical Science Aug 2023Excess polymorphonuclear neutrophil (PMN) recruitment or excessive neutrophil extracellular trap (NET) formation can lead to the development of multiple organ...
BACKGROUND
Excess polymorphonuclear neutrophil (PMN) recruitment or excessive neutrophil extracellular trap (NET) formation can lead to the development of multiple organ dysfunction during sepsis. M2 macrophage-derived exosomes (M2-Exos) have exhibited anti-inflammatory activities in some inflammatory diseases to mediate organ functional protection, but their role in treating sepsis-related acute lung injury (ALI) remains unclear. In this study, we sought to investigate whether M2-Exos could prevent potentially deleterious inflammatory effects during sepsis-related ALI by modulating abnormal PMN behaviours.
METHODS
C57BL/6 wild-type mice were subjected to a caecal ligation and puncture (CLP) mouse model to mimic sepsis in vivo, and M2-Exos were administered intraperitoneally 1 h after CLP. H&E staining, immunofluorescence and immunohistochemistry were conducted to investigate lung tissue injury, PMN infiltration and NET formation in the lung. We further demonstrated the role of M2-Exos on PMN function and explored the potential mechanisms through an in vitro coculture experiment using PMNs isolated from both healthy volunteers and septic patients.
RESULTS
Here, we report that M2-Exos inhibited PMN migration and NET formation, alleviated lung injury and reduced mortality in a sepsis mouse model. In vitro, M2-Exos significantly decreased PMN migration and NET formation capacity, leading to lipid mediator class switching from proinflammatory leukotriene B4 (LTB4) to anti-inflammatory lipoxin A4 (LXA4) by upregulating 15-lipoxygenase (15-LO) expression in PMNs. Treatment with LXA4 receptor antagonist attenuated the effect of M2-Exos on PMNs and lung injury. Mechanistically, prostaglandin E2 (PGE2) enriched in M2-Exos was necessary to increase 15-LO expression in PMNs by functioning on the EP4 receptor, upregulate LXA4 production to downregulate chemokine (C-X-C motif) receptor 2 (CXCR2) and reactive oxygen species (ROS) expressions, and finally inhibit PMN function.
CONCLUSIONS
Our findings reveal a previously unknown role of M2-Exos in regulating PMN migration and NET formation through lipid mediator class switching, thus highlighting the potential application of M2-Exos in controlling PMN-mediated tissue injury in patients with sepsis.
Topics: Mice; Animals; Dinoprostone; Neutrophils; Neutrophil Infiltration; Extracellular Traps; Lung Injury; Immunoglobulin Class Switching; Mice, Inbred C57BL; Sepsis; Macrophages; Platelet Activating Factor
PubMed: 37533081
DOI: 10.1186/s12929-023-00957-9 -
Cellular and Molecular Life Sciences :... May 2022The pathogenesis of liver fibrosis in nonalcoholic fatty liver disease (NAFLD) remains unclear and the effective treatments have not been explored yet. The activation of...
The pathogenesis of liver fibrosis in nonalcoholic fatty liver disease (NAFLD) remains unclear and the effective treatments have not been explored yet. The activation of hepatic stellate cells (HSCs) is considered as the most critical factor in the progression of liver fibrosis and cirrhosis. Autophagy has recently been identified as a new mechanism to regulate HSC activation. Here, we found that liver macrophages were polarized toward type 2 (M2) during the progression of nonalcoholic steatohepatitis (NASH) and liver fibrosis in both patients and NAFLD mice. Using the methionine-choline-deficient (MCD) diet NAFLD murine model and the in vitro cell culture system, we identified that the M2 macrophages promoted HSC autophagy by secreting prostaglandin E2 (PGE2) and binding its receptor EP4 on the surface of HSCs, which consequently enhanced HSC activation, extracellular matrix deposition, and liver fibrosis. Mechanistically, PGE2/EP4 signals enhanced HSC autophagy through the Erk pathway. A specific PGE2/EP4 antagonist E7046 significantly inhibited M2 macrophage-mediated HSC autophagy and improved liver fibrosis and histopathology in NAFLD mice. Our study provides novel mechanistic insights into the regulation of HSC activation and liver fibrosis. Our findings suggest that the PGE2/EP4 pathway is a promising therapeutic target to prevent NASH progression into cirrhosis.
Topics: Animals; Autophagy; Benzoates; Dinoprostone; Fibrosis; Hepatic Stellate Cells; Humans; Liver; Liver Cirrhosis; Macrophages; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Pyrazoles
PubMed: 35588334
DOI: 10.1007/s00018-022-04319-w -
The EMBO Journal Aug 2022Brown adipose tissue (BAT) functions as a thermogenic organ and is negatively associated with cardiometabolic diseases. N -methyladenosine (m A) modulation regulates the...
Brown adipose tissue (BAT) functions as a thermogenic organ and is negatively associated with cardiometabolic diseases. N -methyladenosine (m A) modulation regulates the fate of stem cells. Here, we show that the prostaglandin E (PGE )-E-prostanoid receptor 3 (EP3) axis was activated during mouse interscapular BAT development. Disruption of EP3 impaired the browning process during adipocyte differentiation from pre-adipocytes. Brown adipocyte-specific depletion of EP3 compromised interscapular BAT formation and aggravated high-fat diet-induced obesity and insulin resistance in vivo. Mechanistically, activation of EP3 stabilized the Zfp410 mRNA via WTAP-mediated m A modification, while knockdown of Zfp410 abolished the EP3-induced enhancement of brown adipogenesis. EP3 prevented ubiquitin-mediated degradation of WTAP by eliminating PKA-mediated ERK1/2 inhibition during brown adipocyte differentiation. Ablation of WTAP in brown adipocytes abrogated the protective effect of EP3 overexpression in high-fat diet-fed mice. Inhibition of EP3 also retarded human embryonic stem cell differentiation into mature brown adipocytes by reducing the WTAP levels. Thus, a conserved PGE -EP3 axis promotes BAT development by stabilizing WTAP/Zfp410 signaling in a PKA/ERK1/2-dependent manner.
Topics: Adipocytes, Brown; Adipose Tissue, Brown; Animals; Cell Cycle Proteins; Dinoprostone; Humans; Methyltransferases; Mice; RNA; RNA Splicing Factors; Receptors, Prostaglandin E, EP3 Subtype; Thermogenesis
PubMed: 35781818
DOI: 10.15252/embj.2021110439 -
EBioMedicine Jul 2019Defective clearance of apoptotic cells (ACs) has been suggested to be involved in the pathogenesis of systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs)...
BACKGROUND
Defective clearance of apoptotic cells (ACs) has been suggested to be involved in the pathogenesis of systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) exhibit promising therapeutic effects on SLE, but whether MSCs phagocytose ACs and contributes to the underlying mechanism in the treatment of SLE remain unknown.
METHODS
Human umbilical cord (UC) MSCs were co-cultured with ACs, and the engulfment of ACs by MSCs was either detected by flow cytometry or observed under confocal laser scanning microscope. Peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) were cultured in MSC conditioned medium (MCM) or MSC exposed to ACs (AC-MSC) conditioned medium (ACMCM), and then CD4 T cell proliferation was detected. Soluble factors including prostaglandin (PG)E2 in the supernatants of MSCs and AC-MSCs, as well as in the mouse peritoneal lavage fluids (PLF) were determined by enzyme-linked immunosorbent assay (ELISA). Cyclooxygenase (COX)2 inhibitors and siRNA transfection were utilized to determine the function of COX2/PGE2 in AC-MSC-mediated immunosuppression. PGE2 metabolites (PGEM) in the plasma of SLE patients were measured before and 24 h after MSC transplantation respectively.
FINDINGS
Human UC MSCs possessed the ability to engulf ACs. AC-MSCs increased MSC-mediated suppression of CD4 T cell proliferation compared to MSCs alone. Mechanistically, ACs stimulated MSCs to express COX2 and consequently produced PGE2 that inhibited T cell responses. NF-κB signalling pathway mediated the activation of COX2/PGE2 in AC-MSCs. Importantly, in patients with SLE, the plasma PGEM levels increased significantly in those with reduced apoptotic mononuclear cells in peripheral blood after MSC transplantation.
INTERPRETATION
Clearance of ACs by MSCs contributes to immunosuppressive function via increasing PGE2 production. These findings reveal a previously unrecognized role of MSC-mediated phagocytosis of ACs in MSC-based immunotherapy. FUND: This study was supported by grants from the Chinese Major International (Regional) Joint Research Project (No. 81720108020), the Jiangsu Province Major Research and Development Program (No. BE2015602) and the Jiangsu Province 333 Talent Grant (BRA2016001). WJ. Chen was supported by the Intramural Research Program of NIH, NIDCR.
Topics: Adolescent; Adult; Aged; Animals; Apoptosis; CD4-Positive T-Lymphocytes; Cell Proliferation; Culture Media, Conditioned; Dinoprostone; Flow Cytometry; Humans; Immune Tolerance; Immunosuppression Therapy; Lupus Erythematosus, Systemic; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Middle Aged; Phagocytosis; Signal Transduction; Umbilical Cord; Young Adult
PubMed: 31248835
DOI: 10.1016/j.ebiom.2019.06.016 -
International Journal of Cosmetic... Jun 2022Skin ageing is a multifactorial process involving formation of reactive oxygen species, consecutive inflammation with reduced epidermal and dermal cell viability and...
OBJECTIVE
Skin ageing is a multifactorial process involving formation of reactive oxygen species, consecutive inflammation with reduced epidermal and dermal cell viability and resulting damage to the extracellular matrix. Effective dermocosmetic treatment modalities should ideally address these hallmarks in a holistic approach. Here, we determined the corresponding activity profile of bakuchiol, a plant-derived meroterpene, in an array of in vitro, ex vivo and in vivo studies and compared it to retinol, currently considered as gold standard in topical antiageing cosmetics.
METHODS
The antioxidative capacity and power of bakuchiol and retinol were analysed by measuring 2,2'-diphenyl-1-picrylhydrazyl (DPPH) reduction via its absorption decay and electron spin resonance spectroscopy, respectively. Effects on prostaglandin E2 (PGE2), macrophage migration inhibitory factor (MIF), fibroblast growth factor 7 (FGF7), collagen type I and VII (COL1A1, COL7A1), fibronectin (FN) levels as well as the metabolization of water-soluble tetrazolium 1 (WST-1) were determined in human dermal fibroblasts. Epidermal regeneration was assessed utilizing an in vitro wound healing model. FN protein levels were analysed ex vivo after treatment with a formulation containing bakuchiol, retinol or vehicle using suction blister fluid. Skin condition improvement was determined in vivo in a split-face comparison study after application of bakuchiol or vehicle.
RESULTS
In contrast to retinol, bakuchiol demonstrated high antioxidative efficacy. Levels of PGE2 and MIF were significantly decreased by both bakuchiol and retinol. Bakuchiol but not retinol significantly increased FGF7 protein levels. WST-1 metabolization levels were significantly augmented by bakuchiol and retinol. Bakuchiol and retinol application led to a significant augmentation of COL1A1, COL7A1 and FN protein levels. Wounds supplemented with bakuchiol but not retinol displayed a significant increase in epidermis regeneration. Clinically, areas treated with a bakuchiol-containing formulation showed a statistically significant increase in FN protein values after a 4-week application compared to untreated areas and areas treated with vehicle.
CONCLUSION
These data provide evidence for the multidirectional efficacy of bakuchiol against cellular hallmarks of skin ageing. Its activity profile shares some common features with retinol but demonstrates several hitherto unknown biopositive effects in our studies, namely stimulation of the critical extracellular matrix component FN, and accelerated epidermal regeneration and wound healing.
Topics: Collagen; Collagen Type VII; Dinoprostone; Humans; Phenols; Skin; Skin Aging; Vitamin A
PubMed: 35514037
DOI: 10.1111/ics.12784 -
Journal of Extracellular Vesicles Jun 2023Although inflammation is a vital defence response to infection, if left uncontrolled, it can lead to pathology. Macrophages are critical players both in driving the...
Although inflammation is a vital defence response to infection, if left uncontrolled, it can lead to pathology. Macrophages are critical players both in driving the inflammatory response and in the subsequent events required for restoring tissue homeostasis. Extracellular vesicles (EVs) are membrane-enclosed structures released by cells that mediate intercellular communication and are present in all biological fluids, including blood. Herein, we show that extracellular vesicles from plasma (pEVs) play a relevant role in the control of inflammation by counteracting PAMP-induced macrophage activation. Indeed, pEV-treatment of macrophages simultaneously with or prior to PAMP exposure reduced the secretion of pro-inflammatory IL-6 and TNF-α and increased IL-10 response. This anti-inflammatory activity was associated with the promotion of tissue-repair functions in macrophages, characterized by augmented efferocytosis and pro-angiogenic capacity, and increased expression of VEGFa, CD300e, RGS2 and CD93, genes involved in cell growth and tissue remodelling. We also show that simultaneous stimulation of macrophages with a PAMP and pEVs promoted COX2 expression and CREB phosphorylation as well as the accumulation of higher concentrations of PGE2 in cell culture supernatants. Remarkably, the anti-inflammatory activity of pEVs was abolished if cells were treated with a pharmacological inhibitor of COX2, indicating that pEV-mediated induction of COX2 is critical for the pEV-mediated inhibition of inflammation. Finally, we show that pEVs added to monocytes prior to their M-CSF-induced differentiation to macrophages increased efferocytosis and diminished pro-inflammatory cytokine responses to PAMP stimulation. In conclusion, our results suggest that pEVs are endogenous homeostatic modulators of macrophages, activating the PGE2/CREB pathway, decreasing the production of inflammatory cytokines and promoting tissue repair functions.
Topics: Humans; Extracellular Vesicles; Dinoprostone; Cyclooxygenase 2; Macrophages; Cytokines; Inflammation
PubMed: 37272889
DOI: 10.1002/jev2.12331