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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 -
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 -
The Journal of Clinical Investigation Jul 2020The sensory nerve was recently identified as being involved in regulation of bone mass accrual. We previously discovered that prostaglandin E2 (PGE2) secreted by...
The sensory nerve was recently identified as being involved in regulation of bone mass accrual. We previously discovered that prostaglandin E2 (PGE2) secreted by osteoblasts could activate sensory nerve EP4 receptor to promote bone formation by inhibiting sympathetic activity. However, the fundamental units of bone formation are active osteoblasts, which originate from mesenchymal stromal/stem cells (MSCs). Here, we found that after sensory denervation, knockout of the EP4 receptor in sensory nerves, or knockout of COX-2 in osteoblasts, could significantly promote adipogenesis and inhibit osteogenesis in adult mice. Furthermore, injection of SW033291 (a small molecule that locally increases the PGE2 level) or propranolol (a beta blocker) significantly promoted osteogenesis and inhibited adipogenesis. This effect of SW033291, but not propranolol, was abolished in conditional EP4-KO mice under normal conditions or in the bone repair process. We conclude that the PGE2/EP4 sensory nerve axis could regulate MSC differentiation in bone marrow of adult mice.
Topics: Adipogenesis; Animals; Cyclooxygenase 2; Dinoprostone; Gene Knockout Techniques; Mesenchymal Stem Cells; Mice; Mice, Knockout; Osteoblasts; Osteogenesis; Receptors, Prostaglandin E, EP4 Subtype; Sensory Receptor Cells
PubMed: 32191640
DOI: 10.1172/JCI131554 -
Nature Communications Mar 2023Dectin-1 (gene Clec7a), a receptor for β-glucans, plays important roles in the host defense against fungi and immune homeostasis of the intestine. Although this...
Blocking Dectin-1 prevents colorectal tumorigenesis by suppressing prostaglandin E2 production in myeloid-derived suppressor cells and enhancing IL-22 binding protein expression.
Dectin-1 (gene Clec7a), a receptor for β-glucans, plays important roles in the host defense against fungi and immune homeostasis of the intestine. Although this molecule is also suggested to be involved in the regulation of tumorigenesis, the role in intestinal tumor development remains to be elucidated. In this study, we find that azoxymethane-dextran-sodium-sulfate-induced and Apc-induced intestinal tumorigenesis are suppressed in Clec7a mice independently from commensal microbiota. Dectin-1 is preferentially expressed on myeloid-derived suppressor cells (MDSCs). In the Clec7a mouse colon, the proportion of MDSCs and MDSC-derived prostaglandin E (PGE) levels are reduced, while the expression of IL-22 binding protein (IL-22BP; gene Il22ra2) is upregulated. Dectin-1 signaling induces PGE-synthesizing enzymes and PGE suppresses Il22ra2 expression in vitro and in vivo. Administration of short chain β-glucan laminarin, an antagonist of Dectin-1, suppresses the development of mouse colorectal tumors. Furthermore, in patients with colorectal cancer (CRC), the expression of CLEC7A is also observed in MDSCs and correlated with the death rate and tumor severity. Dectin-1 signaling upregulates PGE-synthesizing enzyme expression and PGE suppresses IL22RA2 expression in human CRC-infiltrating cells. These observations indicate a role of the Dectin-1-PGE-IL-22BP axis in regulating intestinal tumorigenesis, suggesting Dectin-1 as a potential target for CRC therapy.
Topics: Animals; Humans; Mice; Carcinogenesis; Cell Transformation, Neoplastic; Colorectal Neoplasms; Dinoprostone; Lectins, C-Type; Myeloid-Derived Suppressor Cells; Interleukin-22
PubMed: 36932082
DOI: 10.1038/s41467-023-37229-x -
Journal of Cellular Physiology Jun 2022Prostaglandin (PG) signaling regulates a wide variety of physiological and pathological processes, including body temperature, cardiovascular homeostasis, reproduction,... (Review)
Review
Prostaglandin (PG) signaling regulates a wide variety of physiological and pathological processes, including body temperature, cardiovascular homeostasis, reproduction, and inflammation. Recent studies have revealed that PGs play pivotal roles in embryo development, ciliogenesis, and organ formation. Prostaglandin E2 (PGE2) and its receptor EP4 modulate ciliogenesis by increasing the anterograde intraflagellar transport. Many G-protein-coupled receptors (GPCRs) including EP4 are localized in cilia for modulating cAMP signaling under various conditions. During development, PGE2 signaling regulates embryogenesis, hepatocyte differentiation, hematopoiesis, and kidney formation. Prostaglandins are also essential for skeletal muscle repair. This review outlines recent advances in understanding the functions and mechanisms of prostaglandin signaling in ciliogenesis, embryo development, and organ formation.
Topics: Cilia; Dinoprostone; Embryonic Development; Prostaglandins; Signal Transduction
PubMed: 34927727
DOI: 10.1002/jcp.30659 -
Archives of Gynecology and Obstetrics Jun 2020Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (COXibs) inhibit the progression of endometrial cancer, ovarian cancer and cervical cancer.... (Review)
Review
PURPOSE
Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (COXibs) inhibit the progression of endometrial cancer, ovarian cancer and cervical cancer. However, concerning the adverse effects of NSAIDs and COXibs, it is still urgent and necessary to explore novel and specific anti-inflammation targets for potential chemoprevention. The signaling of cyclooxygenase 2-prostaglandin E-prostaglandin E receptors (COX-2-PGE-EPs) is the central inflammatory pathway involved in the gynecological carcinogenesis.
METHODS
Literature searches were performed to the function of COX-2-PGE-EPs in gynecological malignancies.
RESULTS
This review provides an overview of the current knowledge of COX-2-PGE-EPs signaling in endometrial cancer, ovarian cancer and cervical cancer. Many studies demonstrated the upregulated expression of the whole signaling pathway in gynecological malignancies and some focused on the function of COX-2 and cAMP-linked EP2/EP4 and EP3 signaling pathway in gynecological cancer. By contrast, roles of EP1 and the exact pathological mechanisms have not been completely clarified. The studies concerning EP receptors in gynecological cancers highlight the potential advantage of combining COX enzyme inhibitors with EP receptor antagonists as therapeutic agents in gynecological cancers.
CONCLUSION
EPs represent promising anti-inflammation biomarkers for gynecological cancer and may be novel treatment targets in the near future.
Topics: Cyclooxygenase 2; Dinoprostone; Female; Genital Neoplasms, Female; Humans
PubMed: 32363546
DOI: 10.1007/s00404-020-05559-6 -
Placenta Jan 2021Prostaglandin E2 (PGE2) and F2α (PGF2α) are the two most prominent prostanoids in parturition. They are involved in cervical ripening, membrane rupture, myometrial... (Review)
Review
Prostaglandin E2 (PGE2) and F2α (PGF2α) are the two most prominent prostanoids in parturition. They are involved in cervical ripening, membrane rupture, myometrial contraction and inflammation in gestational tissues. Because multiple receptor subtypes for PGE2 and PGF2α exist, coupled with diverse signaling pathways, the effects of PGE2 and PGF2α depend largely on the spatial and temporal expression of these receptors in intrauterine tissues. It appears that PGE2 and PGF2α play different roles in parturition. PGE2 is probably more important for labor onset, while PGF2α may play a more important role in labor accomplishment, which may be attributed to the differential effects of PGE2 and PGF2α in gestational tissues. PGE2 is more powerful than PGF2α in the induction of cervical ripening. In terms of myometrial contraction, PGE2 produces a biphasic effect with an initial contraction and a following relaxation, while PGF2α consistently stimulates myometrial contraction. In the fetal membranes, both PGE2 and PGF2α appear to be involved in the process of membrane rupture. In addition, PGE2 and PGF2α may also participate in the inflammatory process of intrauterine tissues at parturition by stimulating not only neutrophil influx and cytokine production but also cyclooxygenase-2 expression thereby intensifying their own production. This review summarizes the differential roles of PGE2 and PGF2α in parturition with respect to their production and expression of receptor subtypes in gestational tissues. Dissecting the specific mechanisms underlying the effects of PGE2 and PGF2α in parturition may assist in developing specific therapeutic targets for preterm and post-term birth.
Topics: Dinoprost; Dinoprostone; Female; Humans; Labor, Obstetric; Myometrium; Parturition; Pregnancy; Uterine Contraction
PubMed: 33429118
DOI: 10.1016/j.placenta.2020.12.012 -
Immunity Jun 2023Type 1 conventional dendritic cells (cDC1s) are critical for CD8 T cell-mediated tumor control. In this issue of Immunity, Bayerl et al. expose a mechanism leading to...
Type 1 conventional dendritic cells (cDC1s) are critical for CD8 T cell-mediated tumor control. In this issue of Immunity, Bayerl et al. expose a mechanism leading to cancer progression where prostaglandin E induces dysfunctional cDC1s, which cannot coordinate CD8 T cell migration and expansion.
Topics: Humans; Dinoprostone; Neoplasms; CD8-Positive T-Lymphocytes; Cell Movement; Dendritic Cells
PubMed: 37315532
DOI: 10.1016/j.immuni.2023.05.015