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The EMBO Journal Aug 2021Excessive deposition of extracellular matrix, mainly collagen protein, is the hallmark of organ fibrosis. The molecular mechanisms regulating fibrotic protein...
Excessive deposition of extracellular matrix, mainly collagen protein, is the hallmark of organ fibrosis. The molecular mechanisms regulating fibrotic protein biosynthesis are unclear. Here, we find that chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a plasma membrane receptor for prostaglandin D2, is trafficked to the endoplasmic reticulum (ER) membrane in fibroblasts in a caveolin-1-dependent manner. ER-anchored CRTH2 binds the collagen mRNA recognition motif of La ribonucleoprotein domain family member 6 (LARP6) and promotes the degradation of collagen mRNA in these cells. In line, CRTH2 deficiency increases collagen biosynthesis in fibroblasts and exacerbates injury-induced organ fibrosis in mice, which can be rescued by LARP6 depletion. Administration of CRTH2 N-terminal peptide reduces collagen production by binding to LARP6. Similar to CRTH2, bumetanide binds the LARP6 mRNA recognition motif, suppresses collagen biosynthesis, and alleviates bleomycin-triggered pulmonary fibrosis in vivo. These findings reveal a novel anti-fibrotic function of CRTH2 in the ER membrane via the interaction with LARP6, which may represent a therapeutic target for fibrotic diseases.
Topics: Animals; Autoantigens; Bleomycin; Carbon Tetrachloride; Cells, Cultured; Collagen; Endoplasmic Reticulum; Fibroblasts; Intracellular Membranes; Isoproterenol; Liver; Liver Cirrhosis; Lung; Male; Mice, Transgenic; Myocardium; Protein Binding; Pulmonary Fibrosis; Receptors, Immunologic; Receptors, Prostaglandin; Ribonucleoproteins; SS-B Antigen
PubMed: 34223653
DOI: 10.15252/embj.2020107403 -
Frontiers in Oncology 2023Cyclooxygenases-2 (COX-2) and Prostaglandin E2 (PGE2), which are important in chronic inflammatory diseases, can increase tumor incidence and promote tumor growth and... (Review)
Review
Cyclooxygenases-2 (COX-2) and Prostaglandin E2 (PGE2), which are important in chronic inflammatory diseases, can increase tumor incidence and promote tumor growth and metastasis. PGE2 binds to various prostaglandin E receptors to activate specific downstream signaling pathways such as PKA pathway, β-catenin pathway, NF-κB pathway and PI3K/AKT pathway, all of which play important roles in biological and pathological behavior. Nonsteroidal anti-inflammatory drugs (NSAIDs), which play as COX-2 inhibitors, and EP antagonists are important in anti-tumor immune evasion. The COX-2-PGE2 pathway promotes tumor immune evasion by regulating myeloid-derived suppressor cells, lymphocytes (CD8 T cells, CD4 T cells and natural killer cells), and antigen presenting cells (macrophages and dendritic cells). Based on conventional treatment, the addition of COX-2 inhibitors or EP antagonists may enhance immunotherapy response in anti-tumor immune escape. However, there are still a lot of challenges in cancer immunotherapy. In this review, we focus on how the COX-2-PGE2 pathway affects tumor-associated immune cells.
PubMed: 36776289
DOI: 10.3389/fonc.2023.1099811 -
Journal of Medicinal Chemistry Jul 2023Cyclooxygenase-1 and -2 (COX1 and COX2) derived endogenous ligand prostaglandin-E (PGE) triggers several physiological and pathological conditions. It mediates signaling... (Review)
Review
Cyclooxygenase-1 and -2 (COX1 and COX2) derived endogenous ligand prostaglandin-E (PGE) triggers several physiological and pathological conditions. It mediates signaling through four G-protein coupled receptors, EP1, EP2, EP3, and EP4. Among these, EP2 is expressed throughout the body including the brain and uterus. The functional role of EP2 has been extensively studied using EP2 gene knockout mice, cellular models, and selective small molecule agonists and antagonists for this receptor. The efficacy data from in vitro and in vivo animal models indicate that EP2 receptor is a major proinflammatory mediator with deleterious functions in a variety of diseases suggesting a path forward for EP2 inhibitors as the next generation of selective anti-inflammatory and antiproliferative agents. Interestingly in certain diseases, EP2 action is beneficial; therefore, EP2 agonists seem to be clinically useful. Here, we highlight the strengths, weaknesses, opportunities, and potential threats (SWOT analysis) for targeting EP2 receptor for therapeutic development for a variety of unmet clinical needs.
Topics: Animals; Mice; Receptors, Prostaglandin E; Dinoprostone; Cyclooxygenase 2; Drug Discovery; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype
PubMed: 37458373
DOI: 10.1021/acs.jmedchem.3c00655 -
Frontiers in Cell and Developmental... 2022Hepatocellular carcinoma (HCC) is a common primary liver cancer with ∼750,000 annual incidence rates globally. PGE2, usually known as a pro-inflammatory cytokine, is... (Review)
Review
Hepatocellular carcinoma (HCC) is a common primary liver cancer with ∼750,000 annual incidence rates globally. PGE2, usually known as a pro-inflammatory cytokine, is over-expressed in various human malignancies including HCC. PGE2 binds to EP receptors in HCC cells to influence tumorigenesis or enhance tumor progression through multiple pathways such as EP1-PKC-MAPK, EP2-PKA-GSK3β, and EP4-PKA-CREB. In the progression of hepatocellular carcinoma, PGE2 can promote the proliferation and migration of liver cancer cells by affecting hepatocytes directly and the tumor microenvironment (TME) through ERK/COX-2/PGE2 signal pathway in hepatic stellate cells (HSC). For the treatment of hepatocellular carcinoma, there are drugs such as T7 peptide and EP1 antagonist ONO-8711 targeting Cox-2/PGE2 axis to inhibit tumor progression. In conclusion, PGE2 has been shown to be a traditional target with pleiotropic effects in tumorigenesis and progression of HCC that could be used to develop a new potential clinical impact. For the treatment study focusing on the COX-PGE2 axis, the exclusive usage of non-steroidal anti-inflammatory agents (NSAIDs) or COX-2-inhibitors may be replaced by a combination of selective EP antagonists and traditional anti-tumoral drugs to alleviate severe side effects and achieve better outcomes.
PubMed: 35356289
DOI: 10.3389/fcell.2022.834859 -
The Journal of Neuroscience : the... Jan 2021Clinical µ-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have...
Clinical µ-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have established an model of opioid-induced hyperalgesic priming (OIHP), in male rats, to identify nociceptor populations involved and its maintenance mechanisms. OIHP was induced by systemic administration of fentanyl and confirmed by prolongation of prostaglandin E (PGE) hyperalgesia. Intrathecal cordycepin, which reverses Type I priming, or the combination of Src and mitogen-activated protein kinase (MAPK) inhibitors, which reverses Type II priming, both partially attenuated OIHP. Parallel experiments were performed on small-diameter (<30 µm) dorsal root ganglion (DRG) neurons, cultured from fentanyl-primed rats, and rats with OIHP treated with agents that reverse Type I or Type II priming. Enhancement of the sensitizing effect of a low concentration of PGE (10 nm), another characteristic feature of priming, measured as reduction in action potential (AP) rheobase, was found in weakly isolectin B4 (IB4)-positive and IB4-negative (IB4-) neurons. In strongly IB4-positive (IB4+) neurons, only the response to a higher concentration of PGE (100 nm) was enhanced. The sensitizing effect of 10 nm PGE was attenuated in weakly IB4+ and IB4- neurons cultured from rats whose OIHP was reversed Thus, administration of fentanyl induces neuroplasticity in weakly IB4+ and IB4- nociceptors that persists and has properties of Type I and Type II priming. The mechanism underlying the enhanced sensitizing effect of 100 nm PGE in strongly IB4+ nociceptors, not attenuated by inhibitors of Type I and Type II priming, remains to be elucidated. Commonly used clinical opioid analgesics, such as fentanyl and morphine, can produce hyperalgesia and chronification of pain. To uncover the nociceptor population mediating opioid-induced hyperalgesic priming (OIHP), a model of pain chronification, and elucidate its underlying mechanism, at the cellular level, we established an model of OIHP. In dorsal root ganglion (DRG) neurons cultured from rats primed with fentanyl, robust nociceptor population-specific changes in sensitization by prostaglandin E (PGE) were observed, when compared with nociceptors from opioid naive rats. In DRG neurons cultured from rats with OIHP, enhanced PGE-induced sensitization was observed , with differences identified in non-peptidergic [strongly isolectin B4 (IB4)-positive] and peptidergic [weakly IB4-positive (IB4+) and IB4-negative (IB4-)] nociceptors.
Topics: Analgesics, Opioid; Animals; Deoxyadenosines; Dinoprostone; Fentanyl; Hyperalgesia; Lectins; Male; Mitogen-Activated Protein Kinases; Morphine; Neuronal Plasticity; Nociceptors; Pain Threshold; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; src-Family Kinases
PubMed: 33203743
DOI: 10.1523/JNEUROSCI.2160-20.2020 -
Aging Jul 2021In this study, we used bioinformatics and an cellular model of glucocorticoid-induced osteoporosis to investigate mechanisms underlying the beneficial effects of...
In this study, we used bioinformatics and an cellular model of glucocorticoid-induced osteoporosis to investigate mechanisms underlying the beneficial effects of baicalein (BN) against osteoporosis. STITCH database analysis revealed 30 BN-targeted genes, including , and . Functional enrichment analysis demonstrated that BN-targeted genes were enriched in 49 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. MIRWALK2.0 database analysis identified 110 enriched KEGG pathways related to osteoporosis. A Venn diagram demonstrated that 26 KEGG pathways were common between osteoporosis and BN-targeted genes. The top 5 common KEGG pathways were prostate cancer, bladder cancer, glioma, pathways in cancer, and melanoma. BN-targeted genes in the top 5 shared KEGG pathways were involved in PI3K-AKT, MAPK, p53, ErbB, and mTOR signaling pathways. In addition, glucocorticoid-induced osteoporosis in MC3T3-E1 cells was partially reversed by BN through inhibition of AKT, which, by upregulating FOXO1, enhanced expression of bone turnover markers (ALP, OCN, Runx2, and Col 1) and extracellular matrix mineralization. These findings demonstrate that BN suppresses osteoporosis via an AKT/FOXO1 signaling pathway.
Topics: 3T3 Cells; Animals; Bone Density Conservation Agents; Bone and Bones; Calcification, Physiologic; Cyclin D1; Databases, Factual; Extracellular Matrix; Flavanones; Forkhead Box Protein O1; Glucocorticoids; Humans; Mice; Osteoporosis; PTEN Phosphohydrolase; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 34198266
DOI: 10.18632/aging.203227 -
Life Science Alliance Sep 2022We investigated the relevance of the prostaglandin D2 pathway in Alzheimer's disease, because prostaglandin D2 is a major prostaglandin in the brain. Thus, its...
We investigated the relevance of the prostaglandin D2 pathway in Alzheimer's disease, because prostaglandin D2 is a major prostaglandin in the brain. Thus, its contribution to Alzheimer's disease merits attention, given the known impact of the prostaglandin E2 pathway in Alzheimer's disease. We used the TgF344-AD transgenic rat model because it exhibits age-dependent and progressive Alzheimer's disease pathology. Prostaglandin D2 levels in hippocampi of TgF344-AD and wild-type littermates were significantly higher than prostaglandin E2. Prostaglandin D2 signals through DP1 and DP2 receptors. Microglial DP1 receptors were more abundant and neuronal DP2 receptors were fewer in TgF344-AD than in wild-type rats. Expression of the major brain prostaglandin D2 synthase (lipocalin-type PGDS) was the highest among 33 genes involved in the prostaglandin D2 and prostaglandin E2 pathways. We treated a subset of rats (wild-type and TgF344-AD males) with timapiprant, a potent highly selective DP2 antagonist in development for allergic inflammation treatment. Timapiprant significantly mitigated Alzheimer's disease pathology and cognitive deficits in TgF344-AD males. Thus, selective DP2 antagonists have potential as therapeutics to treat Alzheimer's disease.
Topics: Alzheimer Disease; Animals; Dinoprostone; Disease Models, Animal; Lipopolysaccharide Receptors; Male; Prostaglandin D2; Prostaglandins; Rats; Rats, Transgenic; Receptors, Immunologic; Receptors, Prostaglandin
PubMed: 36167438
DOI: 10.26508/lsa.202201555 -
The Journal of Neuroscience : the... Aug 2020We evaluated the mechanism by which high-molecular-weight hyaluronan (HMWH) attenuates nociceptor sensitization, in the setting of inflammation. HMWH attenuated...
We evaluated the mechanism by which high-molecular-weight hyaluronan (HMWH) attenuates nociceptor sensitization, in the setting of inflammation. HMWH attenuated mechanical hyperalgesia induced by the inflammatory mediator prostaglandin E2 (PGE) in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to mRNA for cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuated antihyperalgesia induced by HMWH. In male rats, HMWH also signals via Toll-like receptor 4 (TLR4), and AS-ODN for TLR4 mRNA administered intrathecally, attenuated HMWH-induced antihyperalgesia. Since HMWH signaling is dependent on CD44 clustering in lipid rafts, we pretreated animals with methyl-β-cyclodextrin (MβCD), which disrupts lipid rafts. MβCD markedly attenuated HMWH-induced antihyperalgesia. Inhibitors for components of intracellular signaling pathways activated by CD44, including phospholipase C and phosphoinositide 3-kinase (PI3K), also attenuated HMWH-induced antihyperalgesia. Furthermore, application of HMWH attenuated PGE-induced sensitization of tetrodotoxin-resistant sodium current, in small-diameter dorsal root ganglion neurons, an effect that was attenuated by a PI3K inhibitor. Our results indicate a central role of CD44 signaling in HMWH-induced antihyperalgesia and suggest novel therapeutic targets, downstream of CD44, for the treatment of pain generated by nociceptor sensitization. High-molecular-weight-hyaluronan (HMWH) is used to treat osteoarthritis and other pain syndromes. In this study we demonstrate that attenuation of inflammatory hyperalgesia by HMWH is mediated by its action at cluster of differentiation 44 (CD44) and activation of its downstream signaling pathways, including RhoGTPases (RhoA and Rac1), phospholipases (phospholipases Cε and Cγ1), and phosphoinositide 3-kinase, in nociceptors. These findings contribute to our understanding of the antihyperalgesic effect of HMWH and support the hypothesis that CD44 and its downstream signaling pathways represent novel therapeutic targets for the treatment of inflammatory pain.
Topics: Animals; Cells, Cultured; Dinoprostone; Female; Ganglia, Spinal; Hyaluronan Receptors; Hyaluronic Acid; Hyperalgesia; Male; Nociception; Rats, Sprague-Dawley; Signal Transduction; Toll-Like Receptor 4
PubMed: 32665406
DOI: 10.1523/JNEUROSCI.0166-20.2020 -
Cancer Science Oct 2023Triple-negative breast cancer (TNBC) is a special pathological type of breast cancer (BC) with poor prognosis. Obesity is shown to be involved in TNBC tumor progression....
Triple-negative breast cancer (TNBC) is a special pathological type of breast cancer (BC) with poor prognosis. Obesity is shown to be involved in TNBC tumor progression. The interaction between obesity and BC has generated great attention in recent years, however, the mechanism is still unclear. Here, we showed that leptin secreted by adipocytes upregulated PD-L1 expression in TNBC through the p-STAT3 signaling pathway and that baicalein inhibited PD-L1 expression in tumor microenvironment by suppressing leptin transcription of adipocytes. Collectively, our findings suggest that leptin may be the key factor participating in obesity-related tumor progression and that baicalein can break through the dilemma to boost the anti-tumor immune response.
Topics: Humans; Triple Negative Breast Neoplasms; Leptin; B7-H1 Antigen; Adipocytes; Obesity; Immunity; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37489486
DOI: 10.1111/cas.15916 -
Cells Feb 2022Metastasis requires that cancer cells survive in the circulation, colonize distant organs, and grow. Despite platelets being central contributors to hemostasis,... (Review)
Review
Metastasis requires that cancer cells survive in the circulation, colonize distant organs, and grow. Despite platelets being central contributors to hemostasis, leukocyte trafficking during inflammation, and vessel stability maintenance, there is significant evidence to support their essential role in supporting metastasis through different mechanisms. In addition to their direct interaction with cancer cells, thus forming heteroaggregates such as leukocytes, platelets release molecules that are necessary to promote a disseminating phenotype in cancer cells via the induction of an epithelial-mesenchymal-like transition. Therefore, agents that affect platelet activation can potentially restrain these prometastatic mechanisms. Although the primary adhesion of platelets to cancer cells is mainly independent of G protein-mediated signaling, soluble mediators released from platelets, such as ADP, thromboxane (TX) A, and prostaglandin (PG) E, act through G protein-coupled receptors (GPCRs) to cause the activation of more additional platelets and drive metastatic signaling pathways in cancer cells. In this review, we examine the contribution of the GPCRs of platelets and cancer cells in the development of cancer metastasis. Finally, the possible use of agents affecting GPCR signaling pathways as antimetastatic agents is discussed.
Topics: Blood Platelets; Humans; Neoplasms; Platelet Activation; Platelet Aggregation Inhibitors; Receptors, G-Protein-Coupled; Thromboxane A2
PubMed: 35203374
DOI: 10.3390/cells11040725