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McIntyre TI, Valdez O, Kochhar NP, Davidson B, Samad B, Qiu L, Hu K, Combes AJ, Erlebacher A. KDM6B-dependent epigenetic programming of uterine fibroblasts in early pregnancy regulates parturition timing in mice. Cell 2025:S0092-8674(24)01432-6. [PMID: 39842437 DOI: 10.1016/j.cell.2024.12.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 09/03/2024] [Accepted: 12/13/2024] [Indexed: 01/24/2025]
Abstract
Current efforts investigating parturition timing mechanisms have focused on the proximal triggers of labor onset generated in late pregnancy. By studying the delayed parturition phenotype of mice with uterine fibroblast deficiencies in the histone H3K27me3 demethylase KDM6B, we provide evidence that parturition timing is regulated by events that take place in early pregnancy. Immediately after copulation, uterine fibroblasts engage in a locus-specific epigenetic program that abruptly adjusts H3K27me3 levels across their genome. In the absence of KDM6B, many of the adjusted loci over-accumulate H3K27me3. This over-accumulation leads to nearby genes being misexpressed in mid-to-late gestation, a delayed effect partly attributable to a second locus-specific but KDM6B-independent process initiated within uterine fibroblasts soon after implantation. This second process employs progressive H3K27me3 loss to temporally structure post-midgestational patterns of gene induction. Further dissection of the ways uterine programming controls parturition timing may have relevance to human pregnancy complications such as preterm labor.
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Affiliation(s)
- Tara I McIntyre
- Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Omar Valdez
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Nathan P Kochhar
- UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Brittany Davidson
- UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Bushra Samad
- UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Longhui Qiu
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Kenneth Hu
- Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Alexis J Combes
- UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Adrian Erlebacher
- Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Reproductive Science, School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
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Massri N, Arora R. Uterine stromal but not epithelial PTGS2 is critical for murine pregnancy success. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.24.620133. [PMID: 39484555 PMCID: PMC11527190 DOI: 10.1101/2024.10.24.620133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Use of non-steroidal anti-inflammatory drugs that target prostaglandin synthase (PTGS) enzymes have been implicated in miscarriage. Further, PTGS2-derived prostaglandins are reduced in the endometrium of patients with a history of implantation failure. However, in the mouse model of pregnancy, peri-implantation PTGS2 function is controversial. Some studies suggest that Ptgs2-/- mice display deficits in ovulation, fertilization, and implantation, while other studies suggest a role for PTGS2 only in ovulation but not implantation. Further, the uterine cell type responsible for PTGS2 function and role of PTGS2 in regulating implantation chamber formation is not known. To address this we generated tissue-specific deletion models of Ptgs2. We observed that PTGS2 ablation from the epithelium alone in Ltfcre/+; Ptgs2f/f mice and in both the epithelium and endothelium of the Pax2cre/+; Ptgs2f/f mice does not affect embryo implantation. Further, deletion of PTGS2 in the ovary, oviduct, and the uterus using Pgrcre/+; Ptgs2f/f does not disrupt pre-implantation events but instead interferes with post-implantation chamber formation, vascular remodeling and decidualization. While all embryos initiate chamber formation, more than half of the embryos fail to transition from blastocyst to epiblast stage, resulting in embryo death and resorbing decidual sites at mid-gestation. Thus, our results suggest no role for uterine epithelial PTGS2 in early pregnancy but instead highlight a role for uterine stromal PTGS2 in modulating post-implantation embryo and implantation chamber growth. Overall, our study provides clarity on the compartment-specific role of PTGS2 and provides a valuable model for further investigating the role of stromal PTGS2 in post-implantation embryo development.
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Affiliation(s)
- Noura Massri
- Cell and Molecular Biology Program, Michigan State University
- Institute for Quantitative Health Science and Engineering, Michigan State University
- Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University
| | - Ripla Arora
- Cell and Molecular Biology Program, Michigan State University
- Institute for Quantitative Health Science and Engineering, Michigan State University
- Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University
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Aikawa S, Matsuo M, Akaeda S, Sugimoto Y, Arita M, Isobe Y, Sugiura Y, Taira S, Maeda R, Shimizu-Hirota R, Takeda N, Hiratsuka D, He X, Ishizawa C, Iida R, Fukui Y, Hiraoka T, Harada M, Wada-Hiraike O, Osuga Y, Hirota Y. Spatiotemporally distinct roles of cyclooxygenase-1 and cyclooxygenase-2 at fetomaternal interface in mice. JCI Insight 2024; 9:e181865. [PMID: 39377223 PMCID: PMC11466189 DOI: 10.1172/jci.insight.181865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 08/21/2024] [Indexed: 10/09/2024] Open
Abstract
Embryo implantation is crucial for ensuring a successful pregnancy outcome and subsequent child health. The intrauterine environment during the peri-implantation period shows drastic changes in gene expression and cellular metabolism in response to hormonal stimuli and reciprocal communication with embryos. Here, we performed spatial transcriptomic analysis to elucidate the mechanisms underlying embryo implantation. Transcriptome data revealed that lipid metabolism pathways, especially arachidonic acid-related (AA-related) ones, were enriched in the embryo-receptive luminal epithelia. Cyclooxygenases (COXs), rate-limiting enzymes involved in prostaglandin production by AA, were spatiotemporally regulated in the vicinity of embryos during implantation, but the role of each COX isozyme in the uterus for successful pregnancy was unclear. We established uterine-specific COX2-knockout (uKO) and COX1/uterine COX2-double-KO (COX1/COX2-DKO) mice. COX2 uKO caused deferred implantation with failed trophoblast invasion, resulting in subfertility with reduced pregnancy rates and litter sizes. COX1/COX2 DKO induced complete infertility, owing to abrogated embryo attachment. These results demonstrate that both isozymes have distinct roles during embryo implantation. Spatial transcriptome and lipidome analyses revealed unique profiles of prostaglandin synthesis by each COX isozyme and spatiotemporal expression patterns of downstream receptors throughout the endometrium. Our findings reveal previously unappreciated roles of COXs at the fetomaternal interface to establish early pregnancy.
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Affiliation(s)
- Shizu Aikawa
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mitsunori Matsuo
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shun Akaeda
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yukihiko Sugimoto
- Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Makoto Arita
- Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
- Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan
| | - Yosuke Isobe
- Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
- Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan
| | - Yuki Sugiura
- Division of Multiomics Platform, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shu Taira
- Faculty of Food and Agricultural Sciences, Fukushima University, Fukushima, Japan
| | - Rae Maeda
- Division of Multiomics Platform, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ryoko Shimizu-Hirota
- Department of Internal Medicine, Center for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Norihiko Takeda
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Daiki Hiratsuka
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Xueting He
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Chihiro Ishizawa
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Rei Iida
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yamato Fukui
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takehiro Hiraoka
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Miyuki Harada
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Osamu Wada-Hiraike
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yasushi Hirota
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Faraji P, Kühn H, Ahmadian S. Multiple Roles of Apolipoprotein E4 in Oxidative Lipid Metabolism and Ferroptosis During the Pathogenesis of Alzheimer's Disease. J Mol Neurosci 2024; 74:62. [PMID: 38958788 PMCID: PMC11222241 DOI: 10.1007/s12031-024-02224-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 04/14/2024] [Indexed: 07/04/2024]
Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide and has a great socio-economic impact. Modified oxidative lipid metabolism and dysregulated iron homeostasis have been implicated in the pathogenesis of this disorder, but the detailed pathophysiological mechanisms still remain unclear. Apolipoprotein E (APOE) is a lipid-binding protein that occurs in large quantities in human blood plasma, and a polymorphism of the APOE gene locus has been identified as risk factors for AD. The human genome involves three major APOE alleles (APOE2, APOE3, APOE4), which encode for three subtly distinct apolipoprotein E isoforms (APOE2, APOE3, APOE4). The canonic function of these apolipoproteins is lipid transport in blood and brain, but APOE4 allele carriers have a much higher risk for AD. In fact, about 60% of clinically diagnosed AD patients carry at least one APOE4 allele in their genomes. Although the APOE4 protein has been implicated in pathophysiological key processes of AD, such as extracellular beta-amyloid (Aβ) aggregation, mitochondrial dysfunction, neuroinflammation, formation of neurofibrillary tangles, modified oxidative lipid metabolism, and ferroptotic cell death, the underlying molecular mechanisms are still not well understood. As for all mammalian cells, iron plays a crucial role in neuronal functions and dysregulation of iron homeostasis has also been implicated in the pathogenesis of AD. Imbalances in iron homeostasis and impairment of the hydroperoxy lipid-reducing capacity induce cellular dysfunction leading to neuronal ferroptosis. In this review, we summarize the current knowledge on APOE4-related oxidative lipid metabolism and the potential role of ferroptosis in the pathogenesis of AD. Pharmacological interference with these processes might offer innovative strategies for therapeutic interventions.
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Affiliation(s)
- Parisa Faraji
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
- Department of Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Hartmut Kühn
- Department of Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
| | - Shahin Ahmadian
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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Pan S, Yu X, Liu M, Liu J, Wang C, Zhang Y, Ge F, Fan A, Zhang D, Chen M. Banxia Xiexin decoction promotes gastric lymphatic pumping by regulating lymphatic smooth muscle cell contraction and energy metabolism in a stress-induced gastric ulceration rat model. JOURNAL OF ETHNOPHARMACOLOGY 2024; 328:118015. [PMID: 38499261 DOI: 10.1016/j.jep.2024.118015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 02/26/2024] [Accepted: 03/04/2024] [Indexed: 03/20/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The traditional Chinese medicine (TCM) formula Banxia Xiexin decoction (BXD) has definite therapeutic effect in treating stress-induced gastric ulceration (SIGU) and many other gastrointestinal diseases, but its effect on gastric lymphatic pumping (GLP) remains unclear. AIM OF THE STUDY Elucidating the role of GLP in SIGU and BXD treatment, and exploring the molecular mechanisms of GLP regulation. MATERIALS AND METHODS In vivo GLP imaging were performed on SIGU rat model, and the lymphatic dynamic parameters were evaluated. Gastric antrum tissues and serum were collected for macroscopic, histopathological and ulcerative parameters analysis. Gastric lymphatic vessel (GLV) tissues were collected for RNA-Seq assays. Differentially expressed genes (DEGs) were screened from RNA-Seq result and submitted for transcriptomic analysis. Key DEGs and their derivative proteins were measured by qRT-PCR and WB. RESULTS GLP was significantly suppressed in SIGU rats. BXD could recover GLP, ameliorate stomach lymphostasis, and alleviate the ulcerative damage. Transcriptome analysis of GLV showed the top up-DEGs were concentrated in smooth muscle contraction signaling pathway, while the top the down-DEGs were concentrated in energy metabolism pathways especially fatty acid degradation pathway, which indicated BXD can promote lymphatic smooth muscle contraction, regulate energy metabolism, and reduce fatty acid degradation. The most possible target of these mechanisms was the lymphatic smooth muscle cells (LSMCs) which drove the GLP. This speculation was further validated by the qRT-PCR and WB assessments for the level of key genes and proteins. CONCLUSIONS By activating the smooth muscle contraction signaling pathway, restoring energy supply, modulating energy metabolism program and reducing fatty acid degradation, BXD effectively recovered GLP, mitigated the accumulation of inflammatory cytokines and metabolic wastes in the stomach, which importantly contributes to its efficacy in treating SIGU.
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Affiliation(s)
- Shutao Pan
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Xue Yu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Mingyu Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Jiaqi Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Chunguo Wang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Yao Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Fei Ge
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Angran Fan
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Dongmei Zhang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing, 101121, China.
| | - Meng Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
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Zhang N, An B, Zhao L, Zhao D, Lv B, Liu S. Investigation of the mechanism of nephrotoxicity of nux-vomica by PTGS2/CYP2C9-mediated arachidonic acid pathway and Jian Pi Tong Luo compound's protective effect. Biomed Chromatogr 2024; 38:e5859. [PMID: 38618996 DOI: 10.1002/bmc.5859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/03/2024] [Accepted: 02/16/2024] [Indexed: 04/16/2024]
Abstract
The clinical effectiveness of nux-vomica in treating rheumatism and arthralgia is noteworthy; however, its nephrotoxicity has sparked global concerns. Hence, there is value in conducting studies on detoxification methods based on traditional Chinese medicine compatibility theory. Blood biochemistry, enzyme-linked immunosorbent assay, and pathological sections were used to evaluate both the nephrotoxicity of nux-vomica and the efficacy of the Jian Pi Tong Luo (JPTL) compound in mitigating this toxicity. Kidney metabolomics, using ultra-high-performance liquid chromatography-quadrupole-time-of-flight-MS (UPLC-Q-TOF-MS), was applied to elucidate the alterations in small-molecule metabolites in vivo. In addition, network pharmacology analysis was used to verify the mechanism and pathways underlying the nephrotoxicity associated with nux-vomica. Finally, essential targets were validated through molecular docking and western blotting. The findings indicated significant nephrotoxicity associated with nux-vomica, while the JPTL compound demonstrated the ability to alleviate this toxicity. The mechanism potentially involves nux-vomica activating the "PTGS2/CYP2C9-phosphatidylcholine-arachidonic acid metabolic pathway." This study establishes a scientific foundation for the clinical use of nux-vomica and lays groundwork for further research and safety assessment of toxic Chinese herbal medicines.
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Affiliation(s)
- Na Zhang
- Drug Safety Evaluation Centre, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Baisong An
- Drug Safety Evaluation Centre, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Liangyou Zhao
- Drug Safety Evaluation Centre, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Dapeng Zhao
- The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Bochuan Lv
- The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shumin Liu
- Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
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Mohammed ER, Abd-El-Fatah AH, Mohamed AR, Mahrouse MA, Mohammad MA. Discovery of new 2-(3-(naphthalen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole derivatives with potential analgesic and anti-inflammatory activities: In vitro, in vivo and in silico investigations. Bioorg Chem 2024; 147:107372. [PMID: 38653152 DOI: 10.1016/j.bioorg.2024.107372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/05/2024] [Accepted: 04/12/2024] [Indexed: 04/25/2024]
Abstract
Joining the global demand for the discovery of potent NSAIDs with minimized ulcerogenic effect, new pyrazole clubbed thiazole derivatives 5a-o were designed and synthesized. The new derivatives were initially evaluated for their analgesic activity. Eight compounds 5a, 5c, 5d, 5e, 5f, 5h, 5m, and 5o showed higher activity than Indomethacin (potency = 105-130 % vs. 100 %). Subsequently, they were picked for further evaluation of their anti-inflammatory activity, ulcerogenic liability as well as toxicological studies. Derivatives 5h and 5m showed a potential % edema inhibition after 3 h (79.39 % and 72.12 %, respectively), with a promising safety profile and low ulcer indices (3.80 and 3.20, respectively). The two compounds 5h and 5m were subjected to in vitro COX-1 and COX-2 inhibition assay. The candidate 5h showed nearly equipotent COX-1 inhibition (IC50 = 38.76 nM) compared to the non-selective reference drug Indomethacin (IC50 = 35.72 nM). Compound 5m expressed significant inhibitory activities and a higher COX-2 selectivity index (IC50 = 87.74 nM, SI = 2.05) in comparison with Indomethacin (SI = 0.52), with less selectivity than Celecoxib (SI = 8.31). Simulation docking studies were carried out to gain insights into the binding interaction of compounds 5h and 5m in the vicinity of COX-1 and COX-2 enzymes that illustrated the importance of pyrazole clubbed thiazole core in hydrogen bonding interactions. The thiazole motif of compounds 5h and 5m exhibited a well orientation toward COX-1 Arg120 key residue by hydrogen bonding interactions. Compound 5h revealed an additional arene-cation interaction with Arg120 that could rationalize its superior COX-1 inhibitory activity. Compounds 5h and 5m overlaid the co-crystallized ligand Celecoxib I differently in the active site of COX-2. Compound 5m showed an enhanced accommodation with binding energy of - 6.13 vs. - 1.70 kcal/mol of compounds 5h. The naphthalene ring of compound 5m adopted the Celecoxib I benzene sulfonamide region that is stabilized by hydrogen-arene interactions with the hydrophobic sidechains of the key residues Ser339 and Phe504. Further, the core structure of compound 5m, pyrazole clubbed thiazole, revealed deeper hydrophobic interactions with Ala513, Leu517 and Val509 residues. Finally, a sensitive and accurate UPLC-MS/MS method was developed for the simultaneous estimation of some selected promising pyrazole derivatives in rat plasma. Accordingly, compounds 5h and 5m were suggested to be promising potent analgesic and anti-inflammatory agents with improved safety profiles and a novel COX isozyme modulation activity.
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Affiliation(s)
- Eman R Mohammed
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
| | - Aliaa H Abd-El-Fatah
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Abdalla R Mohamed
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt.
| | - Marianne A Mahrouse
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Mohammad A Mohammad
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
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Gelen V, Gedikli S, Gelen SU, Şengül E, Makav M. Probiotic bacteria protect against indomethacin-induced gastric ulcers through modulation of oxidative stress, inflammation, and apoptosis. Mol Biol Rep 2024; 51:684. [PMID: 38796650 DOI: 10.1007/s11033-024-09627-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 05/08/2024] [Indexed: 05/28/2024]
Abstract
BACKGROUND Indomethacin is an anti-inflammatory drug that causes ulcers on the gastric mucosa due to its use. Probiotic bacteria are live microorganisms, and it has been stated by various studies that these bacteria have antioxidant and anti-inflammatory effects. In this study, we investigated the possible protective effect of various types of probiotic bacteria (Lactobacillus rhamnosus, Lactobacillus fermentum, and Lactobacillus brevis) against acute gastric mucosal damage caused by indomethacin. METHODS Control group - Physiological saline was administered daily for 10 days. Indo group-Physiological saline was administered daily for 10 days. Ranitidine + Indo group 5 mg/kg ranitidine dose was administered daily for 5 days. On day 11, a single dose of 100 mg/kg of indomethacin was given to the same group. Probiotic + Indo group 1 ml/kg of oral probiotic bacteria was administered daily for 10 days. On day 11, a single 100 mg/kg dose of indomethacin was given. After the application, the rats were anesthetized with ketamine xylazine, killed under appropriate conditions, the abdominal cavity was opened and the stomach tissues were removed. The obtained gastric tissues were used in the biochemical and histopathological analyses discussed below. All data were statistically evaluated by one-way ANOVA using SPSS 20.00, followed by Duncan Post hoc test. The data were expressed as mean ± SD. P < 0.05 was considered statistically significant. RESULTS As a result, the administration of indomethacin caused gastric damage, stimulating oxidative stress, inflammation, and apoptosis. We found that the use of probiotic bacteria reduces oxidative stress (TOC), increases the activity of antioxidant enzymes (TAC), suppresses inflammation (IL-6 and Tnf-α), and inhibits apoptosis (Bax and Bcl-2) (P < 0.05). CONCLUSION Probiotic treatment can mitigate gastric damage and apoptosis caused by indomethacin-induced gastric damage in rats. Probiotic also enhances the restoration of biochemical oxidative enzymes as it has anti-inflammatory, antioxidant, and antiapoptotic properties.
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Affiliation(s)
- Volkan Gelen
- Department of Physiology, Veterinary Faculty, Kafkas University, Kars, Turkey.
| | - Semin Gedikli
- Department of Histology, Veterinary Faculty, Ataturk University, Erzurum, Turkey
| | - Sevda Urçar Gelen
- Department of Food Hygiene and Technology, Faculty of Veterinary, Ataturk University, Erzurum, Turkey
| | - Emin Şengül
- Department of Physiology, Veterinary Faculty, Ataturk University, Erzurum, Turkey
| | - Mustafa Makav
- Department of Physiology, Veterinary Faculty, Kafkas University, Kars, Turkey
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9
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Geisert RD, Bazer FW, Lucas CG, Pfeiffer CA, Meyer AE, Sullivan R, Johns DN, Sponchiado M, Prather RS. Maternal recognition of pregnancy in the pig: A servomechanism involving sex steroids, cytokines and prostaglandins. Anim Reprod Sci 2024; 264:107452. [PMID: 38522133 DOI: 10.1016/j.anireprosci.2024.107452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/07/2024] [Accepted: 03/08/2024] [Indexed: 03/26/2024]
Abstract
Maternal recognition of pregnancy (MRP) is a term utilized in mammals to describe pathways in which the conceptus alters the endometrial environment to prevent regression of corpora lutea to ensure continued production of progesterone (P4) required for establishment and maintenance of pregnancy. For nearly 40 years after publication of the endocrine/exocrine theory, conceptus estrogen (E2) was considered the primary maternal recognition signal in the pig. Conceptus production of prostaglandin E2 (PGE2) was also considered to be a major factor in preventing luteolysis. An addition to E2 and PGE2, pig conceptuses produce interleukin 1B2 (IL1B2) and interferons (IFN) delta (IFND) and gamma (IFNG). The present review provides brief history of the discovery of E2, PGs and IFNS which led to research investigating the role of these conceptus secreted factors in establishing and maintaining pregnancy in the pig. The recent utilization of gene editing technology allowed a more direct approach to investigate the in vivo roles of IL1B2, E2, PGE2, AND IFNG for establishment of pregnancy. These studies revealed unknown functions for IFNG and ILB2 in addition to PGE2 and E2. Thus, pregnancy recognition signal is via a servomechanism in requiring sequential effects of P4, E2, IL1B2, PGE2 and IFNG. Results indicate that the original established dogma for the role of conceptus E2 and PGs in MRP is a far too simplified model that involves the interplay of numerous mechanisms for inhibiting luteolysis, inducing critical elongation of the conceptuses and resolution of inflammation in pigs.
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Affiliation(s)
- Rodney D Geisert
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA.
| | - Fuller W Bazer
- Department of Animal Science, Texas A&M University, College Station, TX 77843, USA
| | - Caroline G Lucas
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA
| | - Caroline A Pfeiffer
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA
| | - Ashley E Meyer
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA
| | - Riley Sullivan
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA
| | - Destiny N Johns
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA
| | - Mariana Sponchiado
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA
| | - Randall S Prather
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA
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10
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Li T, Ding N, Guo H, Hua R, Lin Z, Tian H, Yu Y, Fan D, Yuan Z, Gonzalez FJ, Wu Y. A gut microbiota-bile acid axis promotes intestinal homeostasis upon aspirin-mediated damage. Cell Host Microbe 2024; 32:191-208.e9. [PMID: 38237593 PMCID: PMC10922796 DOI: 10.1016/j.chom.2023.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/18/2023] [Accepted: 12/21/2023] [Indexed: 02/17/2024]
Abstract
Aspirin-related gastrointestinal damage is of growing concern. Aspirin use modulates the gut microbiota and associated metabolites, such as bile acids (BAs), but how this impacts intestinal homeostasis remains unclear. Herein, using clinical cohorts and aspirin-treated mice, we identified an intestinal microbe, Parabacteroides goldsteinii, whose growth is suppressed by aspirin. Mice supplemented with P. goldsteinii or its BA metabolite, 7-keto-lithocholic acid (7-keto-LCA), showed reduced aspirin-mediated damage of the intestinal niche and gut barrier, effects that were lost with a P. goldsteinii hdhA mutant unable to generate 7-keto-LCA. Specifically, 7-keto-LCA promotes repair of the intestinal epithelium by suppressing signaling by the intestinal BA receptor, farnesoid X receptor (FXR). 7-Keto-LCA was confirmed to be an FXR antagonist that facilitates Wnt signaling and thus self-renewal of intestinal stem cells. These results reveal the impact of oral aspirin on the gut microbiota and intestinal BA metabolism that in turn modulates gastrointestinal homeostasis.
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Affiliation(s)
- Ting Li
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Ning Ding
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Hanqing Guo
- Department of Gastroenterology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Rui Hua
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zehao Lin
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Huohuan Tian
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yue Yu
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Daiming Fan
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zuyi Yuan
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
| | - Frank J Gonzalez
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Yue Wu
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
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11
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Vinokurova M, Lopes-Pires ME, Cypaite N, Shala F, Armstrong PC, Ahmetaj-Shala B, Elghazouli Y, Nüsing R, Liu B, Zhou Y, Hao CM, Herschman HR, Mitchell JA, Kirkby NS. Widening the Prostacyclin Paradigm: Tissue Fibroblasts Are a Critical Site of Production and Antithrombotic Protection. Arterioscler Thromb Vasc Biol 2024; 44:271-286. [PMID: 37823267 PMCID: PMC10749679 DOI: 10.1161/atvbaha.123.318923] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 09/20/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND Prostacyclin is a fundamental signaling pathway traditionally associated with the cardiovascular system and protection against thrombosis but which also has regulatory functions in fibrosis, proliferation, and immunity. Prevailing dogma states that prostacyclin is principally derived from vascular endothelium, although it is known that other cells can also synthesize it. However, the role of nonendothelial sources in prostacyclin production has not been systematically evaluated resulting in an underappreciation of their importance relative to better characterized endothelial sources. METHODS To address this, we have used novel endothelial cell-specific and fibroblast-specific COX (cyclo-oxygenase) and prostacyclin synthase knockout mice and cells freshly isolated from mouse and human lung tissue. We have assessed prostacyclin release by immunoassay and thrombosis in vivo using an FeCl3-induced carotid artery injury model. RESULTS We found that in arteries, endothelial cells are the main source of prostacyclin but that in the lung, and other tissues, prostacyclin production occurs largely independently of endothelial and vascular smooth muscle cells. Instead, in mouse and human lung, prostacyclin production was strongly associated with fibroblasts. By comparison, microvascular endothelial cells from the lung showed weak prostacyclin synthetic capacity compared with those isolated from large arteries. Prostacyclin derived from fibroblasts and other nonendothelial sources was seen to contribute to antithrombotic protection. CONCLUSIONS These observations define a new paradigm in prostacyclin biology in which fibroblast/nonendothelial-derived prostacyclin works in parallel with endothelium-derived prostanoids to control thrombotic risk and potentially a broad range of other biology. Although generation of prostacyclin by fibroblasts has been shown previously, the scale and systemic activity was unappreciated. As such, this represents a basic change in our understanding and may provide new insight into how diseases of the lung result in cardiovascular risk.
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Affiliation(s)
- Maria Vinokurova
- National Heart and Lung Institute, Imperial College London, United Kingdom (M.V., M.E.L.-P., N.C., F.S., B.A.-S., Y.E., J.A.M., N.S.K.)
| | - Maria Elisa Lopes-Pires
- National Heart and Lung Institute, Imperial College London, United Kingdom (M.V., M.E.L.-P., N.C., F.S., B.A.-S., Y.E., J.A.M., N.S.K.)
| | - Neringa Cypaite
- National Heart and Lung Institute, Imperial College London, United Kingdom (M.V., M.E.L.-P., N.C., F.S., B.A.-S., Y.E., J.A.M., N.S.K.)
| | - Fisnik Shala
- National Heart and Lung Institute, Imperial College London, United Kingdom (M.V., M.E.L.-P., N.C., F.S., B.A.-S., Y.E., J.A.M., N.S.K.)
| | - Paul C. Armstrong
- Blizard Institute, Queen Mary University of London, United Kingdom (P.C.A.)
| | - Blerina Ahmetaj-Shala
- National Heart and Lung Institute, Imperial College London, United Kingdom (M.V., M.E.L.-P., N.C., F.S., B.A.-S., Y.E., J.A.M., N.S.K.)
| | - Youssef Elghazouli
- National Heart and Lung Institute, Imperial College London, United Kingdom (M.V., M.E.L.-P., N.C., F.S., B.A.-S., Y.E., J.A.M., N.S.K.)
| | - Rolf Nüsing
- Clinical Pharmacology and Pharmacotherapy Department, Goethe University, Frankfurt, Germany (R.N.)
| | - Bin Liu
- Cardiovascular Research Centre, Shantou University Medical College, China (B.L., Y.Z.)
| | - Yingbi Zhou
- Cardiovascular Research Centre, Shantou University Medical College, China (B.L., Y.Z.)
| | - Chuan-ming Hao
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China (C.-m.H.)
| | - Harvey R. Herschman
- Department of Molecular and Medical Pharmacology, University of California Los Angeles (H.R.H.)
| | - Jane A. Mitchell
- National Heart and Lung Institute, Imperial College London, United Kingdom (M.V., M.E.L.-P., N.C., F.S., B.A.-S., Y.E., J.A.M., N.S.K.)
| | - Nicholas S. Kirkby
- National Heart and Lung Institute, Imperial College London, United Kingdom (M.V., M.E.L.-P., N.C., F.S., B.A.-S., Y.E., J.A.M., N.S.K.)
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12
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Dai M, Peng W, Lin L, Wu ZE, Zhang T, Zhao Q, Cheng Y, Lin Q, Zhang B, Liu A, Rao Q, Huang J, Zhao J, Gonzalez FJ, Li F. Celastrol as an intestinal FXR inhibitor triggers tripolide-induced intestinal bleeding: Underlying mechanism of gastrointestinal injury induced by Tripterygium wilfordii. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 121:155054. [PMID: 37738906 DOI: 10.1016/j.phymed.2023.155054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 08/16/2023] [Accepted: 08/29/2023] [Indexed: 09/24/2023]
Abstract
BACKGROUND Tripterygium wilfordii has been widely used for the treatment of rheumatoid arthritis, which is frequently accompanied by severe gastrointestinal damage. The molecular mechanism underlying the gastrointestinal injury of Tripterygium wilfordii are yet to be elucidated. METHODS Transmission electron microscopy, and pathological and biochemical analyses were applied to assess intestinal bleeding. Metabolic changes in the serum and intestine were determined by metabolomics. In vivo (time-dependent effect and dose-response) and in vitro (double luciferase reporter gene system, DRATs, molecular docking, HepG2 cells and small intestinal organoids) studies were used to identify the inhibitory role of celastrol on intestinal farnesoid X receptor (FXR) signaling. Fxr-knockout mice and FXR inhibitors and agonists were used to evaluate the role of FXR in the intestinal bleeding induced by Tripterygium wilfordii. RESULTS Co-treatment with triptolide + celastrol (from Tripterygium wilfordii) induced intestinal bleeding in mice. Metabolomic analysis indicated that celastrol suppressed intestinal FXR signaling, and further molecular studies revealed that celastrol was a novel intestinal FXR antagonist. In Fxr-knockout mice or the wild-type mice pre-treated with pharmacological inhibitors of FXR, triptolide alone could activate the duodenal JNK pathway and induce intestinal bleeding, which recapitulated the pathogenic features obtained by co-treatment with triptolide and celastrol. Lastly, intestinal bleeding induced by co-treatment with triptolide and celastrol could be effectively attenuated by the FXR or gut-restricted FXR agonist through downregulation of the duodenal JNK pathway. CONCLUSIONS The synergistic effect between triptolide and celastrol contributed to the gastrointestinal injury induced by Tripterygium wilfordii via dysregulation of the FXR-JNK axis, suggesting that celastrol should be included in the quality standards system for evaluation of Tripterygium wilfordii preparations. Determining the mechanism of the FXR-JNK axis in intestinal bleeding could aid in the identification of additional therapeutic targets for the treatment of gastrointestinal hemorrhage diseases. This study also provides a new standard for the quality assessment of Tripterygium wilfordii used in the treatment of gastrointestinal disorders.
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Affiliation(s)
- Manyun Dai
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; School of Public Health, Ningbo University Health Science Center, Ningbo 315211, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Wan Peng
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lisha Lin
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Zhanxuan E Wu
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ting Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Qi Zhao
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yan Cheng
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiuxia Lin
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Binbin Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Aiming Liu
- School of Public Health, Ningbo University Health Science Center, Ningbo 315211, China
| | - Qianru Rao
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jianfeng Huang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Jinhua Zhao
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430074, China.
| | - Frank J Gonzalez
- Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Fei Li
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
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13
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Yarhorhosseini M, Javanshir S, Sadr AS, Noori M, Dastyafteh N, Esmkhani M, Iraji A, Mahdavi M. Environmentally friendly catalyst- and solvent-free synthesis of 2-anilino nicotinic acids derivatives as potential lead COX inhibitors. BMC Chem 2023; 17:160. [PMID: 37986120 PMCID: PMC10662667 DOI: 10.1186/s13065-023-01078-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 11/08/2023] [Indexed: 11/22/2023] Open
Abstract
In this study, an environmentally friendly, solvent- and catalyst-free synthesis of 2-anilino nicotinic acids derivatives is reported. This operationally simple and green procedure was applied to a selection of primary aromatic amines giving rise to 23 derivatives of 2-anilino nicotinic acids in a very short reaction time (15-120 min) with good to excellent yield. Next, similarity searches were executed on these derivatives to find the possible biological target. These products were screened for inhibition of COX-1 and COX-2 by molecular docking and dynamic studies. In silico studies revealed that among these derivatives, the structure 10 bearing meta-chlorine substitutions could act as COX-1 and COX-2 inhibitors. These results can be used in designing important lead compounds for further development as potential anti-inflammatory drugs.
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Affiliation(s)
- Mahsa Yarhorhosseini
- Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846-13114, Iran
| | - Shahrzad Javanshir
- Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846-13114, Iran.
| | - Ahmad Shahir Sadr
- Bioinformatics Research Center, Cheragh Medical Institute & Hospital, Kabul, Afghanistan.
| | - Milad Noori
- Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846-13114, Iran
| | - Navid Dastyafteh
- Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846-13114, Iran
| | - Maryam Esmkhani
- Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846-13114, Iran
| | - Aida Iraji
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
- Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mohammad Mahdavi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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14
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Liu M, Ji M, Cheng J, Li Y, Tian Y, Zhao H, Wang Y, Zhu S, Zhang L, Xu X, Feng GS, Liang X, Bao H, Tang Y, Kong S, Lu J, Wang H, Lu Z, Deng W. Deciphering a critical role of uterine epithelial SHP2 in parturition initiation at single cell resolution. Nat Commun 2023; 14:7356. [PMID: 37963860 PMCID: PMC10646072 DOI: 10.1038/s41467-023-43102-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 10/31/2023] [Indexed: 11/16/2023] Open
Abstract
The timely onset of female parturition is a critical determinant for pregnancy success. The highly heterogenous maternal decidua has been increasingly recognized as a vital factor in setting the timing of labor. Despite the cell type specific roles in parturition, the role of the uterine epithelium in the decidua remains poorly understood. This study uncovers the critical role of epithelial SHP2 in parturition initiation via COX1 and COX2 derived PGF2α leveraging epithelial specific Shp2 knockout mice, whose disruption contributes to delayed parturition initiation, dystocia and fetal deaths. Additionally, we also show that there are distinct types of epithelium in the decidua approaching parturition at single cell resolution accompanied with profound epithelium reformation via proliferation. Meanwhile, the epithelium maintains the microenvironment by communicating with stromal cells and macrophages. The epithelial microenvironment is maintained by a close interaction among epithelial, stromal and macrophage cells of uterine stromal cells. In brief, this study provides a previously unappreciated role of the epithelium in parturition preparation and sheds lights on the prevention of preterm birth.
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Affiliation(s)
- Meng Liu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Mengjun Ji
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Jianghong Cheng
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Yingzhe Li
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Yingpu Tian
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Hui Zhao
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yang Wang
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Sijing Zhu
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Leilei Zhang
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Xinmei Xu
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Gen-Sheng Feng
- Department of Pathology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA
| | - Xiaohuan Liang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Haili Bao
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yedong Tang
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Shuangbo Kong
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Jinhua Lu
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Haibin Wang
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China.
| | - Zhongxian Lu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China.
| | - Wenbo Deng
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China.
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15
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Tang G, Liu M, Ding G, Liu S, Chu Y, Cui Y, Wu J. The Efficacy of Cyclooxygenase-2 Inhibitors for the Male Treatment of Lower Urinary Tract Symptoms: A Systematic Review and Meta-Analysis. Am J Mens Health 2023; 17:15579883231176667. [PMID: 37249083 PMCID: PMC10236251 DOI: 10.1177/15579883231176667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/07/2023] [Accepted: 05/01/2023] [Indexed: 05/31/2023] Open
Abstract
To investigate the potential use of cyclooxygenase-2 (COX-2) inhibitors in the treatment of lower urinary tract symptoms (LUTS) in male patients, we conducted a comprehensive meta-analysis. Our study involved the identification and collection of randomized controlled trials (RCTs) from leading databases including PubMed, MEDLINE, EMBASE, and Cochrane Library. The primary objective of this analysis was to evaluate the effectiveness of COX-2 inhibitors for the treatment of LUTS. Our analysis involved six short-term (within 3 months) RCTs involving 707 patients. We found that COX-2 inhibitor treatment significantly improved the International Prostate Symptom Score (IPSS) of patients (mean difference [MD] = -2.99, 95% confidence interval (CI): -3.65 to -2.33, p < .00001), nocturia frequency (MD = -1.90; 95% CI: -3.18 to -0.61, p = .004), and maximum flow rate (Qmax) (MD = 1.02; 95% CI: 0.06 to 1.98, p = .04). However, no significant differences were found between patients in terms of changes in prostate-specific antigen (PSA) (MD = 0.02; 95% CI: -0.39 to 0.43, p = .92) and total prostate volume (TPV) (MD = -2.93; 95% CI: -6.45 to 0.59, p = .10). Therefore COX-2 inhibitors are an effective treatment for LUTS.
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Affiliation(s)
- Gonglin Tang
- Department of Urology, The Affiliated
Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Ming Liu
- Department of Urology, The Affiliated
Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
- Second Clinical Medical College,
Binzhou Medical University, Yantai, China
| | - Guixin Ding
- Department of Urology, The Affiliated
Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Shangjing Liu
- Department of Urology, The Affiliated
Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Yongli Chu
- Department of Scientific Research, The
Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Yuanshan Cui
- Department of Urology, The Affiliated
Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jitao Wu
- Department of Urology, The Affiliated
Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
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16
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Haroun M, Fesatidou M, Petrou A, Tratrat C, Zagaliotis P, Gavalas A, Venugopala KN, Kochkar H, Emeka PM, Younis NS, Elmaghraby DA, Almostafa MM, Chohan MS, Vizirianakis IS, Papadimitriou-Tsantarliotou A, Geronikaki A. Identification of Novel Cyclooxygenase-1 Selective Inhibitors of Thiadiazole-Based Scaffold as Potent Anti-Inflammatory Agents with Safety Gastric and Cytotoxic Profile. Molecules 2023; 28:molecules28083416. [PMID: 37110650 PMCID: PMC10142904 DOI: 10.3390/molecules28083416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/08/2023] [Accepted: 04/10/2023] [Indexed: 04/29/2023] Open
Abstract
Major obstacles faced by the use of nonsteroidal anti-inflammatory drugs (NSAID) are their gastrointestinal toxicity induced by non-selective inhibition of both cyclooxygenases (COX) 1 and 2 and their cardiotoxicity associated with a certain class of COX-2 selective inhibitors. Recent studies have demonstrated that selective COX-1 and COX-2 inhibition generates compounds with no gastric damage. The aim of the current study is to develop novel anti-inflammatory agents with a better gastric profile. In our previous paper, we investigated the anti-inflammatory activity of 4-methylthiazole-based thiazolidinones. Thus, based on these observations, herein we report the evaluation of anti-inflammatory activity, drug action, ulcerogenicity and cytotoxicity of a series of 5-adamantylthiadiazole-based thiazolidinone derivatives. The in vivo anti-inflammatory activity revealed that the compounds possessed moderate to excellent anti-inflammatory activity. Four compounds 3, 4, 10 and 11 showed highest potency (62.0, 66.7, 55.8 and 60.0%, respectively), which was higher than the control drug indomethacin (47.0%). To determine their possible mode of action, the enzymatic assay was conducted against COX-1, COX-2 and LOX. The biological results demonstrated that these compounds are effective COX-1 inhibitors. Thus, the IC50 values of the three most active compounds 3, 4 and 14 as COX-1 inhibitors were 1.08, 1.12 and 9.62 μΜ, respectively, compared to ibuprofen (12.7 μΜ) and naproxen (40.10 μΜ) used as control drugs. Moreover, the ulcerogenic effect of the best compounds 3, 4 and 14 were evaluated and revealed that no gastric damage was observed. Furthermore, compounds were found to be nontoxic. A molecular modeling study provided molecular insight to rationalize the COX selectivity. In summary, we discovered a novel class of selective COX-1 inhibitors that could be effectively used as potential anti-inflammatory agents.
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Affiliation(s)
- Michelyne Haroun
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Maria Fesatidou
- School of Pharmacy, Aristotle, University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Anthi Petrou
- School of Pharmacy, Aristotle, University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Christophe Tratrat
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Panagiotis Zagaliotis
- School of Pharmacy, Aristotle, University of Thessaloniki, 54124 Thessaloniki, Greece
- Division of Infectious Diseases, Weill Cornell Medicine, New York, NY 10065, USA
| | - Antonis Gavalas
- School of Pharmacy, Aristotle, University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Katharigatta N Venugopala
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
- Department of Biotechnology and Food Technology, Faculty of Applied Sciences, Durban University of Technology, Durban 4001, South Africa
| | - Hafedh Kochkar
- Department of Chemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
- Basic & Applied Scientific Research Center, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Promise M Emeka
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Nancy S Younis
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Dalia Ahmed Elmaghraby
- Department of Pharmacy Practice, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Mervt M Almostafa
- Department of Chemistry, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Muhammad Shahzad Chohan
- Biomedical Sciences Department, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Ioannis S Vizirianakis
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
- Department of Health Sciences, School of Life and Health Sciences, University of Nicosia, 2417 Nicosia, Cyprus
| | | | - Athina Geronikaki
- School of Pharmacy, Aristotle, University of Thessaloniki, 54124 Thessaloniki, Greece
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17
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Röhrl J, Piqué-Borràs MR, Jaklin M, Werner M, Werz O, Josef H, Hölz H, Ammendola A, Künstle G. Anti-Inflammatory Activities of Arnica montana Planta Tota versus Flower Extracts: Analytical, In Vitro and In Vivo Mouse Paw Oedema Model Studies. PLANTS (BASEL, SWITZERLAND) 2023; 12:1348. [PMID: 36987036 PMCID: PMC10053944 DOI: 10.3390/plants12061348] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 02/22/2023] [Accepted: 03/08/2023] [Indexed: 06/19/2023]
Abstract
Arnica montana is well known for its anti-inflammatory properties. While the anti-inflammatory activity of Arnica flowers (Arnicae flos) has been extensively studied, that of the whole plant (Arnicae planta tota) is less characterized. We compared the ability of Arnicae planta tota and Arnicae flos extracts to inhibit the pro-inflammatory NF-κB-eicosanoid pathway, using several in vitro and in vivo assays. We showed that Arnicae planta tota inhibited NF-κB reporter activation, with an IC50 of 15.4 μg/mL (vs. 52.5 μg/mL for Arnicae flos). Arnicae planta tota also inhibited LPS-induced expression of ALOX5 and PTGS2 genes in human differentiated macrophages. ALOX5 and PTGS2 encode the 5-lipoxygenase (5-LO) and cyclooxygenase-2 (COX-2) enzymes that initialize the conversion of arachidonic acid into leukotrienes and prostaglandins, respectively. Arnicae planta tota inhibited 5-LO and COX-2 enzymatic activity in vitro and in human primary peripheral blood cells, with lower IC50 compared to Arnicae flos. Finally, Arnicae planta tota applied topically reduced carrageenan-induced mouse paw oedema more efficiently than Arnicae flos. Altogether, Arnicae planta tota displayed a superior anti-inflammatory activity compared to Arnicae flos, suggesting that Arnicae-planta-tota-containing products might be more effective in alleviating the manifestations of acute inflammation than those based on Arnicae flos alone.
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Affiliation(s)
- Johann Röhrl
- Preclinical Development, Weleda AG, 4144 Arlesheim, Switzerland
| | | | - Manuela Jaklin
- Preclinical Development, Weleda AG, 4144 Arlesheim, Switzerland
| | - Markus Werner
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, 07743 Jena, Germany
| | - Oliver Werz
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, 07743 Jena, Germany
| | - Heinke Josef
- Quality Control, Weleda AG, 73525 Schwäbisch Gmünd, Germany
| | - Hubert Hölz
- Quality Control, Weleda AG, 73525 Schwäbisch Gmünd, Germany
| | - Aldo Ammendola
- Research and Development, Weleda AG, 4144 Arlesheim, Switzerland
| | - Gerald Künstle
- Preclinical Development, Weleda AG, 4144 Arlesheim, Switzerland
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18
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Liu X, Yang Y, Li Y, Zhang Q, Wang J, Guo J, Song Z, Liu Z, Zhang Y, Song X. Network Pharmacology-Based Approach for Investigating the Role of Xanthii Fructus in Treatment of Allergic Rhinitis. Chem Biodivers 2023; 20:e202200785. [PMID: 36855022 DOI: 10.1002/cbdv.202200785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 02/22/2023] [Accepted: 02/28/2023] [Indexed: 03/02/2023]
Abstract
Xanthii Fructus (XF) has been used for treatment of allergic rhinitis (AR), but its pharmacological mechanism of action remains unclear. We aimed to explore the potential mechanism of XF in treatment of AR by using a network pharmacology approach combined with in vivo verification experiments in this study. We identified 945 AR-related pathogenic genes, 11 active components in XF and 178 targets of those active components by corresponding databases. Finally, 54 targets of active components from XF in treatment of AR were identified by the Protein-protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, among which Tumor Necrosis Factor (TNF), Mitogen-activated Protein Kinase 3 (MAPK3), Prostaglandin G/H Synthase 2 (PTGS2), Epidermal Growth Factor Receptor (EGFR) showed strongest interactions. The molecular docking analysis showed that moupinamide could bind to EGFR at LEU704 and LEU703, and PTGS2 at TRP387; 24-Ethylcholest-4-en-3-one was identified to bind to MAPK3 at THR347. The validation of quantitative real-time reverse transcription PCR (RT-PCR) showed that XF decreased the levels of MAPK3, PTGS2, and EGFR expression in the nasal mucosa from AR mice gavaged with an XF water decoction. Meanwhile, the levels of interleukin (IL)-4, IL-5 and IL-13were also decreased after the treatment of XF by Enzyme-linked immunosorbent assay (ELISA). Our results provide the pharmacological mechanism and possible intervention targets of XF in treatment of AR.
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Affiliation(s)
- Xinyue Liu
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Yujuan Yang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Yumei Li
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Qiang Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Jianwei Wang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Jing Guo
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Zheying Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Zhen Liu
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Yu Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Xicheng Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
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19
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Wan S, Chen Q, Xiang Y, Sang Y, Tang M, Song Y, Feng G, Ye B, Bai L, Zhu Y. Interleukin-1 increases cyclooxygenase-2 expression and prostaglandin E2 production in human granulosa-lutein cell via nuclear factor kappa B/P65 and extracellular signal-regulated kinase 1/2 signaling pathways. Mol Cell Endocrinol 2023; 566-567:111891. [PMID: 36801432 DOI: 10.1016/j.mce.2023.111891] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 02/03/2023] [Accepted: 02/15/2023] [Indexed: 02/19/2023]
Abstract
A multitude of cytokines have been reported to participate in the folliculogenesis process in female. Interleukin-1 (IL-1), belonging to interleukin family, is originally identified as an important immune factor involved in inflammation response. Besides the immunity system, IL-1 is also expressed in reproductive system. However, the role of IL-1 in regulating ovarian follicle function remains to be elucidated. In the current study, using the primary human granulosa-lutein (hGL) and immortalized human granulosa-like tumor cell line (KGN) models, we demonstrated that both IL-1α and IL-1β increased prostaglandin E2 (PGE2) production via upregulating its cyclooxygenase (COX) enzyme COX-2 expression in human granulosa cells. Mechanistically, IL-1α and IL-1β treatment activated nuclear factor kappa B (NF-κB) signaling pathway. Using the specific siRNA to knock down endogenous gene expression, we found that the inhibition of p65 expression abolished IL-1α and IL-1β-induced upregulation of COX-2 expression whereas knockdown of p50 and p52 had no effect. Moreover, our results also showed that IL-1α and IL-1β promoted the nuclear translocation of p65. ChIP assay demonstrated the transcriptional regulation of p65 on COX-2 expression. Additionally, we also found that IL-1α and IL-1β could activate the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. The inhibition of ERK1/2 signaling pathway activation reversed IL-1α and IL-1β-induced upregulation of COX-2 expression. Our findings shed light on the cellular and molecular mechanisms by which IL-1 modulates the COX-2 expression through NF-κB/P65 and ERK1/2 signaling pathways in human granulosa cells.
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Affiliation(s)
- Shan Wan
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310002, China; Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310002, China
| | - Qingqing Chen
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310002, China; Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310002, China
| | - Yu Xiang
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310002, China; Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310002, China
| | - Yimiao Sang
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310002, China; Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310002, China
| | - Minyue Tang
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310002, China; Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310002, China
| | - Yang Song
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310002, China; Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310002, China
| | - Guofang Feng
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310002, China; Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310002, China
| | - Bingru Ye
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310002, China; Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310002, China
| | - Long Bai
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310002, China; Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310002, China.
| | - Yimin Zhu
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310002, China; Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310002, China.
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20
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Carlsen EØ, Lee Y, Magnus P, Jugessur A, Page CM, Nustad HE, Håberg SE, Lie RT, Magnus MC. An examination of mediation by DNA methylation on birthweight differences induced by assisted reproductive technologies. Clin Epigenetics 2022; 14:151. [PMID: 36443807 PMCID: PMC9703677 DOI: 10.1186/s13148-022-01381-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 11/16/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Children born after assisted reproductive technologies (ART) differ in birthweight from those naturally conceived. It has been hypothesized that this might be explained by epigenetic mechanisms. We examined whether cord blood DNA methylation mediated the birthweight difference between 890 newborns conceived by ART (764 by fresh embryo transfer and 126 frozen thawed embryo transfer) and 983 naturally conceived newborns from the Norwegian Mother, Father, and Child Cohort Study (MoBa). DNA methylation was measured by the Illumina Infinium MethylationEPIC array. We conducted mediation analyses to assess whether differentially methylated CpGs mediated the differences in birthweight observed between: (1) fresh embryo transfer and natural conception and (2) frozen and fresh embryo transfer. RESULTS We observed a difference in birthweight between fresh embryo transfer and naturally conceived offspring of - 120 g. 44% (95% confidence interval [CI] 26% to 81%) of this difference in birthweight between fresh embryo transfer and naturally conceived offspring was explained by differences in methylation levels at four CpGs near LOXL1, CDH20, and DRC1. DNA methylation differences at two CpGs near PTGS1 and RASGRP4 jointly mediated 22% (95% CI 8.1% to 50.3%) of the birthweight differences between fresh and frozen embryo transfer. CONCLUSION Our findings suggest that DNA methylation is an important mechanism in explaining birthweight differences according to the mode of conception. Further research should examine how gene regulation at these loci influences fetal growth.
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Affiliation(s)
- Ellen Ø. Carlsen
- grid.418193.60000 0001 1541 4204Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway ,grid.5510.10000 0004 1936 8921Department of Community Medicine, Institute of Health and Society, University of Oslo, Oslo, Norway
| | - Yunsung Lee
- grid.418193.60000 0001 1541 4204Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Per Magnus
- grid.418193.60000 0001 1541 4204Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Astanand Jugessur
- grid.418193.60000 0001 1541 4204Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway ,grid.7914.b0000 0004 1936 7443Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
| | - Christian M. Page
- grid.418193.60000 0001 1541 4204Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway ,grid.5510.10000 0004 1936 8921Department of Mathematics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
| | - Haakon E. Nustad
- grid.418193.60000 0001 1541 4204Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway ,Deepinsight, Oslo, Norway
| | - Siri E. Håberg
- grid.418193.60000 0001 1541 4204Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Rolv T. Lie
- grid.418193.60000 0001 1541 4204Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway ,grid.7914.b0000 0004 1936 7443Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
| | - Maria C. Magnus
- grid.418193.60000 0001 1541 4204Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
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21
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Hypertension and renal disease programming: focus on the early postnatal period. Clin Sci (Lond) 2022; 136:1303-1339. [PMID: 36073779 DOI: 10.1042/cs20220293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/18/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022]
Abstract
The developmental origin of hypertension and renal disease is a concept highly supported by strong evidence coming from both human and animal studies. During development there are periods in which the organs are more vulnerable to stressors. Such periods of susceptibility are also called 'sensitive windows of exposure'. It was shown that as earlier an adverse event occurs; the greater are the consequences for health impairment. However, evidence show that the postnatal period is also quite important for hypertension and renal disease programming, especially in rodents because they complete nephrogenesis postnatally, and it is also important during preterm human birth. Considering that the developing kidney is vulnerable to early-life stressors, renal programming is a key element in the developmental programming of hypertension and renal disease. The purpose of this review is to highlight the great number of studies, most of them performed in animal models, showing the broad range of stressors involved in hypertension and renal disease programming, with a particular focus on the stressors that occur during the early postnatal period. These stressors mainly include undernutrition or specific nutritional deficits, chronic behavioral stress, exposure to environmental chemicals, and pharmacological treatments that affect some important factors involved in renal physiology. We also discuss the common molecular mechanisms that are activated by the mentioned stressors and that promote the appearance of these adult diseases, with a brief description on some reprogramming strategies, which is a relatively new and promising field to treat or to prevent these diseases.
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22
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Kotas ME, Moore CM, Gurrola JG, Pletcher SD, Goldberg AN, Alvarez R, Yamato S, Bratcher PE, Shaughnessy CA, Zeitlin PL, Zhang IH, Li Y, Montgomery MT, Lee K, Cope EK, Locksley RM, Seibold MA, Gordon ED. IL-13-programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function. JCI Insight 2022; 7:e159832. [PMID: 35608904 PMCID: PMC9310525 DOI: 10.1172/jci.insight.159832] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/20/2022] [Indexed: 11/17/2022] Open
Abstract
Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single-cell RNA sequencing of airway epithelium and mouse modeling, we found that IL-13 expanded and programmed airway tuft cells toward eicosanoid metabolism and that tuft cell deficiency led to a reduction in airway prostaglandin E2 (PGE2) concentration. Allergic airway epithelia bore a signature of PGE2 activation, and PGE2 activation led to cystic fibrosis transmembrane receptor-dependent ion and fluid secretion and accelerated mucociliary transport. These data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.
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Affiliation(s)
- Maya E. Kotas
- Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Camille M. Moore
- Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA
- Department of Biostatistics and Informatics, University of Colorado, Aurora, Colorado, USA
| | - Jose G. Gurrola
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Steven D. Pletcher
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, California, USA
- Surgical Service, ENT Section, San Francisco VA Medical Center, San Francisco, California, USA
| | - Andrew N. Goldberg
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Raquel Alvarez
- Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Sheyla Yamato
- Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Preston E. Bratcher
- Department of Pediatrics, National Jewish Health, Denver, Colorado, USA
- Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, Colorado, USA
| | | | - Pamela L. Zeitlin
- Department of Pediatrics, National Jewish Health, Denver, Colorado, USA
- Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, Colorado, USA
| | - Irene H. Zhang
- Center for Applied Microbiome Sciences, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, USA
| | - Yingchun Li
- Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA
| | - Michael T. Montgomery
- Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA
| | - Keehoon Lee
- Center for Applied Microbiome Sciences, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, USA
| | - Emily K. Cope
- Center for Applied Microbiome Sciences, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, USA
| | - Richard M. Locksley
- Howard Hughes Medical Institute and
- Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Max A. Seibold
- Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA
- Department of Pediatrics, National Jewish Health, Denver, Colorado, USA
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado, USA
| | - Erin D. Gordon
- Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
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Eisenstein A, Hilliard BK, Pope SD, Zhang C, Taskar P, Waizman DA, Israni-Winger K, Tian H, Luan HH, Wang A. Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs. Immunity 2022; 55:1082-1095.e5. [PMID: 35588739 PMCID: PMC9205175 DOI: 10.1016/j.immuni.2022.04.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 03/08/2022] [Accepted: 04/21/2022] [Indexed: 12/21/2022]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes and are ubiquitously used for their anti-inflammatory properties. However, COX inhibition alone fails to explain numerous clinical outcomes of NSAID usage. Screening commonly used NSAIDs in primary human and murine myeloid cells demonstrated that NSAIDs could be differentiated by their ability to induce growth/differentiation factor 15 (GDF15), independent of COX specificity. Using genetic and pharmacologic approaches, NSAID-mediated GDF15 induction was dependent on the activation of nuclear factor erythroid 2-related factor 2 (NRF2) in myeloid cells. Sensing by Cysteine 151 of the NRF2 chaperone, Kelch-like ECH-associated protein 1 (KEAP1) was required for NSAID activation of NRF2 and subsequent anti-inflammatory effects both in vitro and in vivo. Myeloid-specific deletion of NRF2 abolished NSAID-mediated tissue protection in murine models of gout and endotoxemia. This highlights a noncanonical NRF2-dependent mechanism of action for the anti-inflammatory activity of a subset of commonly used NSAIDs.
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Affiliation(s)
- Anna Eisenstein
- Department of Dermatology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Brandon K Hilliard
- Department of Internal Medicine and Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Scott D Pope
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, New Haven, CT, USA
| | - Cuiling Zhang
- Department of Internal Medicine and Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Pranali Taskar
- NGM Biopharmaceuticals, South San Francisco, CA 94080, USA
| | - Daniel A Waizman
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | | | - Hui Tian
- NGM Biopharmaceuticals, South San Francisco, CA 94080, USA
| | - Harding H Luan
- NGM Biopharmaceuticals, South San Francisco, CA 94080, USA.
| | - Andrew Wang
- Department of Internal Medicine and Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
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Mohammadi A, Khanbabaei H, Zandi F, Ahmadi A, Haftcheshmeh SM, Johnston TP, Sahebkar A. Curcumin: A therapeutic strategy for targeting the Helicobacter pylori-related diseases. Microb Pathog 2022; 166:105552. [DOI: 10.1016/j.micpath.2022.105552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 04/16/2022] [Accepted: 04/19/2022] [Indexed: 12/12/2022]
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Mas-Bargues C, Borrás C, Viña J. The multimodal action of genistein in Alzheimer's and other age-related diseases. Free Radic Biol Med 2022; 183:127-137. [PMID: 35346775 DOI: 10.1016/j.freeradbiomed.2022.03.021] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 02/07/2023]
Abstract
Genistein is a phytoestrogen that, due to its structural similarity with estrogen, can both mimic and antagonize estrogen effects. Early analysis proved that at high concentrations, genistein inhibits breast cancer cell proliferation, thereby suggesting an anticancer activity. Since then, many discoveries have identified the genistein mechanism of action, including cell cycle arrest, apoptosis induction, as well as angiogenesis, and metastasis inhibition. In this review, we aim to discuss the multimodal action of genistein as an antioxidant, anti-inflammatory, anti-amyloid β, and autophagy promoter, which could be responsible for the genistein beneficial effect on Alzheimer's. Furthermore, we pinpoint the main signal transduction pathways that are known to be modulated by genistein. Genistein has thus several beneficial effects in several diseases, many of them associated with age, such as the above mentioned Alzheimer disease. Indeed, the beneficial effects of genistein for health promotion depend on each multimodality. In the context of geroscience, genistein has promising beneficial effects due to its multimodal action to treat age associated-diseases.
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Affiliation(s)
- Cristina Mas-Bargues
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, Valencia, 46010, Spain.
| | - Consuelo Borrás
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, Valencia, 46010, Spain.
| | - José Viña
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, Valencia, 46010, Spain
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Contribution of cyclooxygenase-1-dependent prostacyclin synthesis to bradykinin-induced dermal extravasation. Biomed Pharmacother 2022; 148:112786. [PMID: 35259564 DOI: 10.1016/j.biopha.2022.112786] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/02/2022] [Accepted: 03/02/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Non-allergic angioedema is a potentially life-threatening condition caused by accumulation of bradykinin and subsequent activation of bradykinin type 2 receptors (B2). Since COX activity plays a pivotal role in B2 signaling, the aim of this study was to determine which prostaglandins are the key mediators and which COX, COX-1 or COX-2, is predominantly involved. METHODS We used Miles assays to assess the effects of inhibitors of COX, 5-lipoxygenase, epoxyeicosatrienoic acid generation, cytosolic phospholipase A2α and a variety of prostaglandin receptor antagonists on bradykinin-induced dermal extravasation in C57BL/6 and COX-1-deficient mice (COX-1-/-). In addition, the prostacyclin metabolite 6-keto-PGF1α was quantified by ELISA in subcutaneous tissue from C57BL/6 and human dermal microvascular endothelial cells. In the latter, 6-keto-PGF1α was also quantified and identified by LC-MS/MS. RESULTS Unspecific COX inhibition by ibuprofen and diclofenac significantly reduced B2-mediated dermal extravasation in C57BL/6 but not COX-1-/-. Likewise, inhibition of cytosolic phospholipase A2α showed similar effects. Furthermore, extravasation in COX-1-/- was generally lower than in C57BL/6. Of the prostaglandin antagonists used, only the prostacyclin receptor antagonist RO1138452 showed a significant reduction of dermal extravasation. Moreover, 6-keto-PGF1α concentrations were increased after bradykinin treatment in subcutaneous tissue from C57BL/6 as well as in human dermal microvascular endothelial cells and this increase was abolished by diclofenac. CONCLUSION Our findings suggest that COX-1-dependent prostacyclin production is critically involved in dermal extravasation after activation of B2 in small dermal blood vessels. Targeting prostacyclin production and/or signaling appears to be a suitable option for acute treatment of non-allergic angioedema.
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Tran-Guzman A, Culty M. Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs. FRONTIERS IN TOXICOLOGY 2022; 4:842565. [PMID: 35295224 PMCID: PMC8915844 DOI: 10.3389/ftox.2022.842565] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/09/2022] [Indexed: 11/13/2022] Open
Abstract
Increasing rates of infertility associated with declining sperm counts and quality, as well as increasing rates of testicular cancer are contemporary issues in the United States and abroad. These conditions are part of the Testicular Dysgenesis Syndrome, which includes a variety of male reproductive disorders hypothesized to share a common origin based on disrupted testicular development during fetal and neonatal stages of life. Male reproductive development is a highly regulated and complex process that relies on an intricate coordination between germ, Leydig, and Sertoli cells as well as other supporting cell types, to ensure proper spermatogenesis, testicular immune privilege, and endocrine function. The eicosanoid system has been reported to be involved in the regulation of fetal and neonatal germ cell development as well as overall testicular homeostasis. Moreover, non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics with abilities to block eicosanoid synthesis by targeting either or both isoforms of cyclooxygenase enzymes, have been found to adversely affect male reproductive development. This review will explore the current body of knowledge on the involvement of the eicosanoid system in male reproductive development, as well as discuss adverse effects of NSAIDs and analgesic drugs administered perinatally, focusing on toxicities reported in the testis and on major testicular cell types. Rodent and epidemiological studies will be corroborated by findings in invertebrate models for a comprehensive report of the state of the field, and to add to our understanding of the potential long-term effects of NSAID and analgesic drug administration in infants.
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Thrikawala S, Niu M, Keller NP, Rosowski EE. Cyclooxygenase production of PGE2 promotes phagocyte control of A. fumigatus hyphal growth in larval zebrafish. PLoS Pathog 2022; 18:e1010040. [PMID: 35333905 PMCID: PMC8986117 DOI: 10.1371/journal.ppat.1010040] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 04/06/2022] [Accepted: 03/03/2022] [Indexed: 11/30/2022] Open
Abstract
Invasive aspergillosis is a common opportunistic infection, causing >50% mortality in infected immunocompromised patients. The specific molecular mechanisms of the innate immune system that prevent pathogenesis of invasive aspergillosis in immunocompetent individuals are not fully understood. Here, we used a zebrafish larva-Aspergillus infection model to identify cyclooxygenase (COX) enzyme signaling as one mechanism that promotes host survival. Larvae exposed to the pan-COX inhibitor indomethacin succumb to infection at a significantly higher rate than control larvae. COX signaling is both macrophage- and neutrophil-mediated. However, indomethacin treatment has no effect on phagocyte recruitment. Instead, COX signaling promotes phagocyte-mediated inhibition of germination and invasive hyphal growth. Increased germination and invasive hyphal growth is also observed in infected F0 crispant larvae with mutations in genes encoding for COX enzymes (ptgs2a/b). Protective COX-mediated signaling requires the receptor EP2 and exogenous prostaglandin E2 (PGE2) rescues indomethacin-induced decreased immune control of fungal growth. Collectively, we find that COX signaling activates the PGE2-EP2 pathway to increase control A. fumigatus hyphal growth by phagocytes in zebrafish larvae.
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Affiliation(s)
- Savini Thrikawala
- Department of Biological Sciences, Clemson University, Clemson, South Carolina, United States of America
| | - Mengyao Niu
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Nancy P. Keller
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Emily E. Rosowski
- Department of Biological Sciences, Clemson University, Clemson, South Carolina, United States of America
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Majumder R, Dhara M, Adhikari L, Panigrahi A. Comparative evaluation of anti-inflammatory activity between n-butanol fraction, leaf and stem methanolic extract obtained from Olaxpsittacorum. JOURNAL OF ETHNOPHARMACOLOGY 2022; 283:114697. [PMID: 34626778 DOI: 10.1016/j.jep.2021.114697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/14/2021] [Accepted: 09/27/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Olax psittacorum (Lam.) Vahl. traditionally used by the tribal communities of 'INDIA' to heal conditions such as pain, psoriasis, mouthulcer, anemia, constipation as well as diabetes followed by scientific evidences like antipyretic, anti-inflammatory, antimicrobial, anti-viral, and anti-cancer property too. AIM OF THE EXPERIMENT Solvent fractionation process by using chloroform, distilled water and n-butanol has been developed to get the precipitate as a fraction (encrypted as FrAE-ISO) of leaf methanolic extract (LME) and established GC-MS and antiinflammatory evaluation. The aim was to enumerate the potency against inflammation of FrAE-ISO comparing with LME, SME (Stem methanolic extract) and Diclofenac. TLC of LME extract has been developed too for separation & evaluation of the compounds appeared as bands obtained by scraping process. The motive of the experiment was to acquire an isolate from LME that can able to show an emense anti-inflammatory action compared to LME and SME. MATERIALS AND METHODS Priliminary phytochemical screening upon LME, SME and FrAE-ISO preformed by the standard methods of literatures. Scrapped portions of developed TLC plate (G-254 graded silica) of LME (n-Hexane:Ethylacetate; 7.5:2.5) were introduced to GC-MS evaluation. FrAE-ISO has introduced at a minute quantity (5 and 10 mg/kg/bw) within Wister albino rats (per os) against inflammation (model: carrageenan-induced paw edema) to evaluate its potency as compared to LME (25 mg/kg/bw), SME (25 mg/kg/bw) and Diclofenac (100 mg/kg). GC-MS evaluation has been conducted in both FrAE-ISO and scrapped sections to evaluate the presence of compounds qualitatively. RESULTS LME and SME, qualitatively through different screening processes confirm the presence of glycosides, flavonoids, amino acids, tannins, and saponins respectively. According to the quantitative study of the extracts concerning total phenolic, flavonoid, tannin, and saponin content equivalent to gallic acid, quercetin, tannic acid, and diosgenin respectively have shown less amount of phenolic, flavonoid, and saponin content in SME (30.95, 205.33 and 30.82 mg/g extract respectively) as compared to LME (95.68, 713.33 and 66.41 mg/g extract respectively). Quantitative estimation has shown the presence of 825.27 mg of saponin equivalent to diosgenin per gram of FrAE-ISO. The GC-MS study has revealed that every section of the leaf extract has " Hexadecanoic acid, methyl ester " in common with other important compounds responsible for its potent contribution towards the anti-inflammatory property. The scrapped portions of the TLC plate having mixture of compounds but FrAE-ISO has shown a sharp peak in GC-MS (up to 34 min of run time) as well as few crystals like structures under the binocular microscope. Compact doses of FrAEISO (yield = 1.645%) i.e. 5 and 10 mg/kg body weight was able to compete with 100 mg/kg Diclofenac portraying 88%-95% inhibition respectively throughout all phases of inflammation with no-significant differences compared to standard evaluated by ANOVA (in SPSS). CONCLUSION Olax psittacorum (Lam.) Vahl. could be a good choice to explore its importance within the pharmacognostic field of drug development and might be a better source of herbal-derived lead compounds which can help to treat other various activities like ulcer healing or anti-anemic property etc.
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Affiliation(s)
- Raja Majumder
- Department of Pharmaceutics, Bengal School of Technology, A College of Pharmacy, Delhi-Road, Sugandha, Hooghly, West-Bengal, 712102, India.
| | - Moonmun Dhara
- Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Siksha 'O' Anusandhan (SOA) Deemed to be University, Bhubaneswar, Odisha, 751003, India.
| | - Lopamudra Adhikari
- Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Siksha 'O' Anusandhan (SOA) Deemed to be University, Bhubaneswar, Odisha, 751003, India.
| | - Amitav Panigrahi
- Hi-Tech Hospital Road, Pandra, Rasulgarh, Bhubaneswar, Odisha, 751025, India.
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Upmacis RK, Becker WL, Rattendi DM, Bell RS, Jordan KD, Saniei S, Mejia E. Analysis of Sex-Specific Prostanoid Production Using a Mouse Model of Selective Cyclooxygenase-2 Inhibition. Biomark Insights 2022; 17:11772719221142151. [DOI: 10.1177/11772719221142151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 11/11/2022] [Indexed: 12/14/2022] Open
Abstract
Background: Prostanoids are a family of lipid mediators formed from arachidonic acid by cyclooxygenase enzymes and serve as biomarkers of vascular function. Prostanoid production may be different in males and females indicating that different therapeutic approaches may be required during disease. Objectives: We examined sex-dependent differences in COX-related metabolites in genetically modified mice that produce a cyclooxygenase-2 (COX2) enzyme containing a tyrosine 385 to phenylalanine (Y385F) mutation. This mutation renders the COX2 enzyme unable to form a key intermediate radical required for complete arachidonic acid metabolism and provides a model of selective COX2 inhibition. Design and Methods: Mice heterozygous for the Y385F mutation in COX2 were mated to produce cohorts of wild-type, heterozygous, and COX2 mutant mice. We investigated whether the genotype distribution followed Mendelian genetics and studied whether sex-specific differences could be found in certain prostanoid levels measured in peritoneal macrophages and in urinary samples. Results: The inheritance of the COX2 mutation displayed a significant deviation with respect to Mendel’s laws of genetics, with a lower-than-expected progeny of weaned COX2 mutant pups. In macrophages, prostaglandin E2 (PGE2) production following lipopolysaccharide (LPS) and interferon gamma (IFNγ) stimulation was COX2-dependent in both males and females, and data indicated that crosstalk between the nitric oxide (NO) and COX2 pathways may be sex specific. We observed significant differences in urinary PGE2 production by male and female COX2 mutant mice, with the loss of COX2 activity in male mice decreasing their ability to produce urinary PGE2. Finally, female mice across all 3 genotypes produced similar levels of urinary thromboxane (measured as 11-dehydro TxB2) at significantly higher levels than males, indicating a sex-related difference that is likely COX1-derived. Conclusions: Our findings clearly demonstrate that sex-related differences in COX-derived metabolites can be observed, and that other pathways (such as the NO pathway) are affected.
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Affiliation(s)
- Rita K Upmacis
- The Haskins Laboratory, Department of Chemistry & Physical Sciences, Pace University, New York, NY, USA
| | - Wendy L Becker
- The Haskins Laboratory, Department of Chemistry & Physical Sciences, Pace University, New York, NY, USA
| | - Donna M Rattendi
- The Haskins Laboratory, Department of Chemistry & Physical Sciences, Pace University, New York, NY, USA
| | - Raven S Bell
- The Haskins Laboratory, Department of Chemistry & Physical Sciences, Pace University, New York, NY, USA
| | - Kelsey D Jordan
- The Haskins Laboratory, Department of Chemistry & Physical Sciences, Pace University, New York, NY, USA
| | - Shayan Saniei
- The Haskins Laboratory, Department of Chemistry & Physical Sciences, Pace University, New York, NY, USA
| | - Elena Mejia
- The Haskins Laboratory, Department of Chemistry & Physical Sciences, Pace University, New York, NY, USA
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Zhang XX, Liang X, Li SR, Guo KJ, Li DF, Li TF. Bone Marrow Mesenchymal Stem Cells Overexpressing HIF-1α Prevented the Progression of Glucocorticoid-Induced Avascular Osteonecrosis of Femoral Heads in Mice. Cell Transplant 2022; 31:9636897221082687. [PMID: 35287482 PMCID: PMC8928352 DOI: 10.1177/09636897221082687] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Glucocorticoid (GC)-induced avascular osteonecrosis of femoral head (AOFH) is a devastating complication, and no cures are currently available for it. Previous studies have demonstrated that implantation of bone marrow mesenchymal stem cells (BMMSCs) may prevent the progression of pre-collapse AOFH. Based on previous observations, we hypothesized that GCs induce AOFH via the COX-2 (cyclooxygenase-2)-PGE-2 (prostaglandin E2)-HIF-1α (hypoxia-inducible factor-1α) axis, and that modification of BMMSCs may improve the efficacy of their implantation. BMMSCs isolated from wild-type (WT) mice were treated with dexamethasone (Dex) and the results showed that Dex repressed the expression of COX-2. Femoral head samples harvested from both WT and COX-2 knock-out (COX-2-/-) mice were subjected to micro-computed tomography and histological examinations. Compared with their WT littermates, COX-2-/- mice had larger trabecular separations, diminished microvasculature, and reduced HIF-1α expression in their femoral heads. In vitro angiogenesis assays with tube formation and fetal metatarsal sprouting demonstrated that Dex repressed angiogenesis and PGE-2 antagonized its effects. An AOFH model was successfully established in C57BL/6J mice. In vitro experiment showed that BMMSCs infected with Lentivirus encoding HIF-1α (Lenti-HIF-1α) resulted in a robust increase in the production of HIF-1α protein. Implantation of BMMSCs overexpressing HIF-1α into femoral heads of AOFH mice significantly reduced osteonecrotic areas and enhanced bone repair, thus largely preserving the structural integrity of femoral heads. Our studies provide strong rationales for early intervention with core decompression and implantation of modified BMMSCs for GC-induced AOFH, which may spare patients from expensive and difficult surgical procedures.
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Affiliation(s)
- Xin-Xin Zhang
- Department of Rheumatology, Zhengzhou University First Affiliated Hospital, Zhengzhou, China
| | - Xu Liang
- Department of Rheumatology, Zhengzhou University First Affiliated Hospital, Zhengzhou, China
| | - Sen-Rui Li
- Department of Rheumatology, Zhengzhou University First Affiliated Hospital, Zhengzhou, China
| | - Kuang-Jin Guo
- Department of Rheumatology, Zhengzhou University First Affiliated Hospital, Zhengzhou, China
| | - Dai-Feng Li
- Department of Orthopaedics, Zhengzhou University First Affiliated Hospital, Zhengzhou, China.,Department of Magnetic Resonance Imaging, Henan Key Laboratory of Functional Magnetic Resonance Imaging and Molecular Imaging, Zhengzhou University First Affiliated Hospital, Zhengzhou, China
| | - Tian-Fang Li
- Department of Rheumatology, Zhengzhou University First Affiliated Hospital, Zhengzhou, China
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Application potential of modulation of cyclooxygenase-2 activity: a cognitive approach. POSTEP HIG MED DOSW 2021. [DOI: 10.2478/ahem-2021-0022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Cognitive functions of the brain depend largely on the condition of the cell membranes and the proportion of fatty acids. It is known and accepted that arachidonic acid (AA) is one of the main ω-6 fatty acids (phospholipids) in brain cells. Metabolism of that fatty acid depends on the functionality and presence of cyclooxygenase (COX). COX is a primary enzyme in the cycle of transformation of AA to prostanoids, which may mediate response of immune cells, contributing to brain function and cognition. Two COX isoforms (COX-1 and COX-2), as well as a splice variant (COX-3), have been detected in the brain. Findings released in the last decade showed that COX-2 may play an important role in cognition. There are many preclinical and clinical reports showing its engagement in Alzheimer disease, spatial learning, and plasticity. This manuscript focuses on summarizing the above-mentioned discoveries.
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Hamers A, Primus CP, Whitear C, Kumar NA, Masucci M, Montalvo Moreira SA, Rathod K, Chen J, Bubb K, Colas R, Khambata RS, Dalli J, Ahluwalia A. 20-HETE is a pivotal endogenous ligand for TRPV1-mediated neurogenic inflammation in the skin. Br J Pharmacol 2021; 179:1450-1469. [PMID: 34755897 DOI: 10.1111/bph.15726] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 10/11/2021] [Accepted: 10/26/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND AND PURPOSE Transient receptor potential cation channel subfamily V member 1 (TRPV1) is localised to sensory C-fibres and its opening leads to membrane depolarization, resulting in neuropeptide release and neurogenic inflammation. However, the identity of the endogenous activator of TRPV1 in this setting is unknown. The arachidonic acid (AA) metabolites 12-hydroperoxyeicosatetraenoyl acid (12-HpETE) and 20-hydroxyeicosatetraenoic acid (20-HETE) have emerged as potential endogenous activators of TRPV1 however, whether these lipids underlie TRPV1-mediated neurogenic inflammation remains unknown. EXPERIMENTAL APPROACH we analysed human cantharidin-induced blister samples and inflammatory responses in TRPV1 transgenic mice. KEY RESULTS In a human cantharidin-blister model the potent TRPV1 activators 20-HETE but not 12-HETE (stable metabolite of 12-HpETE) correlated with AA levels. Similarly, in mice levels of 20-HETE (but not 12-HETE) and AA were strongly positively correlated within the inflammatory milieu. Furthermore, LPS-induced oedema formation and neutrophil recruitment were substantially and significantly attenuated by pharmacological block or genetic deletion of TRPV1 channels, inhibition of 20-HETE formation or SP receptor neurokinin 1 (NK1 ) blockade. LPS treatment also increased cytochrome-P450 ώ-hydroxylase gene expression, the enzyme responsible for 20-HETE production. CONCLUSIONS AND IMPLICATIONS Taken together, our findings suggest that endogenously generated 20-HETE activates TRPV1 causing C-fibre activation and consequent oedema formation. These findings identify a novel pathway that may be useful in the therapeutics of diseases/conditions characterized by a prominent neurogenic inflammation, as in several skin diseases.
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Affiliation(s)
- Alexander Hamers
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London
| | - Christopher P Primus
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London
| | - Charlotte Whitear
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London
| | - Nitin Ajit Kumar
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London
| | - Michael Masucci
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London
| | - Shanik A Montalvo Moreira
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London
| | - Krishnaraj Rathod
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London
| | - Jianmin Chen
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London
| | - Kristen Bubb
- Monash Cardiovascular Research Centre, Monash University, Melbourne, Australia
| | - Romain Colas
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London
| | - Rayomand S Khambata
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London
| | - Jesmond Dalli
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London
| | - Amrita Ahluwalia
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London
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Effect of Quercetin on Injury to Indomethacin-Treated Human Embryonic Kidney 293 Cells. Life (Basel) 2021; 11:life11111134. [PMID: 34833010 PMCID: PMC8623736 DOI: 10.3390/life11111134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 12/03/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat inflammation and pain and even to prevent the progression of cardiovascular disease. They have become widely used because of their effectiveness, especially among athletes performing high-intensity training. Indomethacin is used for pain management in sports medicine and is highly effective and versatile. However, several clinical studies have reported that indomethacin induces acute renal damage. In the present study, we determined that indomethacin reduced human embryonic kidney 293 (HEK293) cell viability in a concentration-dependent manner by triggering apoptosis. In addition, we demonstrated the effect of quercetin on indomethacin-treated HEK293 cells by inactivating the caspase-3 and caspase-9 signals. Furthermore, quercetin reduced ROS production and increased mitochondrial membrane potential (ΔΨm) in indomethacin-treated HEK293 cells. Our results indicate that quercetin can interrupt the activated caspase and mitochondrial pathway induced by indomethacin in HEK293 cells and affect apoptotic mRNA expression. Quercetin can protect against indomethacin-induced HEK293 cell apoptosis by regulating abnormal ΔΨm and apoptotic mRNA expression.
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Zhang G, Lv Z, Zhao Y, Chen R, Zhan X, Wang W, Sui H. Inhibitory effect of tumor necrosis factor-α on the basolateral Kir4.1/Kir5.1 channels in the thick ascending limb during diabetes. Exp Ther Med 2021; 22:1242. [PMID: 34539838 DOI: 10.3892/etm.2021.10677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 08/13/2021] [Indexed: 12/25/2022] Open
Abstract
Diabetic nephropathy is a major contributor to the morbidity and mortality of patients with diabetes. TNF-α expression is elevated during diabetes and is implicated in the pathogenesis of diabetic nephropathy; however, its underlying molecular mechanisms remain unclear. The present study aimed to investigate the effect and molecular mechanism of TNF-α on the basolateral inwardly rectifying potassium (Kir)4.1/Kir5.1 channels in the thick ascending limb (TAL) of rat kidneys using western blotting and the patch clamp technique to provide a theoretical basis for the cause of the decrease in kidney concentrating capacity during diabetes. The results demonstrated that urinary TNF-α excretion and protein TNF-α expression in the TAL increased and basolateral Kir4.1/Kir5.1 channel activity decreased during diabetes; however, diabetic rats exhibited amelioration of Kir4.1/Kir5.1 activity with a soluble TNF-α antagonist, TNF receptor fusion protein (TNFR:Fc). These results suggested that TNF-α inhibited the activity of the basolateral Kir4.1/Kir5.1 channel in the TAL of rat kidneys during diabetes. In addition, the protein expression levels of phospholipase A2 (PLA2) and cyclooxygenase-2 (COX2) increased in diabetic rats, the effects of which deceased following treatment with TNFR:Fc compared with the diabetic group. Furthermore, an agonist of PLA2 (melittin) and COX2 production [prostaglandin E2 (PGE2)] inhibited the basolateral Kir4.1/Kir5.1 channels. Taken together, the results of the present study suggested that the inhibitory effect of TNF-α on the basolateral Kir4.1/Kir5.1 channels in the TAL during diabetes is mediated by the PLA2/COX2/PGE2 signaling pathway.
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Affiliation(s)
- Guoyan Zhang
- Department of Urology and Endocrinology, First Affiliated Hospital, Jiamusi University, Jiamusi, Heilongjiang 154003, P.R. China
| | - Zhiming Lv
- Department of Urology and Endocrinology, First Affiliated Hospital, Jiamusi University, Jiamusi, Heilongjiang 154003, P.R. China
| | - Yang Zhao
- Department of Physiology, Basic Medical College, Jiamusi University, Jiamusi, Heilongjiang 154007, P.R. China
| | - Rui Chen
- Department of Physiology, Basic Medical College, Jiamusi University, Jiamusi, Heilongjiang 154007, P.R. China
| | - Xiangyu Zhan
- Department of Physiology, Basic Medical College, Jiamusi University, Jiamusi, Heilongjiang 154007, P.R. China
| | - Weiqun Wang
- Department of Physiology, Basic Medical College, Jiamusi University, Jiamusi, Heilongjiang 154007, P.R. China
| | - Hongyu Sui
- Department of Physiology, Basic Medical College, Jiamusi University, Jiamusi, Heilongjiang 154007, P.R. China
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36
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Gastroprotective Effect of Enteral Nutrition Formula in Mice Injected Subcutaneously with Indomethacin. Nutrients 2021; 13:nu13093297. [PMID: 34579173 PMCID: PMC8468157 DOI: 10.3390/nu13093297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 09/01/2021] [Accepted: 09/17/2021] [Indexed: 11/17/2022] Open
Abstract
We have previously shown that two enteral nutrition formulas suppressed gastric lesions induced by the oral administration of indomethacin (IND) in mice. However, the mechanism of their protective effect is unknown. In this study, the effect of the two enteral nutrition formulas on gastric lesions induced by subcutaneous IND injection was investigated, with the objective of exploring the possibility that they may interact directly with IND in the gastrointestinal tract. Ten-week-old, male, ICR mice were fasted, then orally given either purified water, Mermed® One, or 2-fold diluted Terumeal® 2.0α as enteral nutrition formula (25 mL/kg). IND was injected subcutaneously at 20 mg/kg after 30 min, and the stomach was removed 6 h later and fixed in formalin. The number and area of lesions in the stomachs of mice given enteral nutrition formula was reduced to 56–89% and 34–61%, respectively, compared with the mice given purified water. The time courses of plasma IND concentrations were comparable among the three groups. These results suggested that the effect of these enteral nutrition formulas on gastric lesions did not originate from their direct interaction with IND in the gastrointestinal tract or their effect on the disposition of IND.
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In situ imaging reveals disparity between prostaglandin localization and abundance of prostaglandin synthases. Commun Biol 2021; 4:966. [PMID: 34389796 PMCID: PMC8363604 DOI: 10.1038/s42003-021-02488-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 07/22/2021] [Indexed: 12/14/2022] Open
Abstract
Prostaglandins are important lipids involved in mediating many physiological processes, such as allergic responses, inflammation, and pregnancy. However, technical limitations of in-situ prostaglandin detection in tissue have led researchers to infer prostaglandin tissue distributions from localization of regulatory synthases, such as COX1 and COX2. Herein, we apply a novel mass spectrometry imaging method for direct in situ tissue localization of prostaglandins, and combine it with techniques for protein expression and RNA localization. We report that prostaglandin D2, its precursors, and downstream synthases co-localize with the highest expression of COX1, and not COX2. Further, we study tissue with a conditional deletion of transformation-related protein 53 where pregnancy success is low and confirm that PG levels are altered, although localization is conserved. Our studies reveal that the abundance of COX and prostaglandin D2 synthases in cellular regions does not mirror the regional abundance of prostaglandins. Thus, we deduce that prostaglandins tissue localization and abundance may not be inferred by COX or prostaglandin synthases in uterine tissue, and must be resolved by an in situ prostaglandin imaging. Duncan et al. use a mass spectrometry imaging method to assess the localization and concentration of prostaglandins (PGs) in mouse tissues during pregnancy. This study brings new biological insights into the spatial evaluation of PGs in tissues, which could reveal the functional significance of each PGs during different stages of embryo development/pregnancy.
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Esh CJ, Chrismas BCR, Mauger AR, Taylor L. Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition? Pharmacol Res Perspect 2021; 9:e00835. [PMID: 34278737 PMCID: PMC8287062 DOI: 10.1002/prp2.835] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/04/2021] [Indexed: 12/12/2022] Open
Abstract
The precise mechanistic action of acetaminophen (ACT; paracetamol) remains debated. ACT's analgesic and antipyretic actions are attributed to cyclooxygenase (COX) inhibition preventing prostaglandin (PG) synthesis. Two COX isoforms (COX1/2) share 60% sequence structure, yet their functions vary. COX variants have been sequenced among various mammalian species including humans. A COX1 splice variant (often termed COX3) is purported by some as the elusive target of ACT's mechanism of action. Yet a physiologically functional COX3 isoform has not been sequenced in humans, refuting these claims. ACT may selectively inhibit COX2, with evidence of a 4.4-fold greater COX2 inhibition than COX1. However, this is markedly lower than other available selective COX2 inhibitors (up to 433-fold) and tempered by proof of potent COX1 inhibition within intact cells when peroxide tone is low. COX isoform inhibition by ACT may depend on subtle in vivo physiological variations specific to ACT. In vivo ACT efficacy is reliant on intact cells and low peroxide tone while the arachidonic acid concentration state can dictate the COX isoform preferred for PG synthesis. ACT is an effective antipyretic (COX2 preference for PG synthesis) and can reduce afebrile core temperature (likely COX1 preference for PG synthesis). Thus, we suggest with specificity to human in vivo physiology that ACT: (i) does not act on a third COX isoform; (ii) is not selective in its COX inhibition; and (iii) inhibition of COX isoforms are determined by subtle and nuanced physiological variations. Robust research designs are required in humans to objectively confirm these hypotheses.
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Affiliation(s)
- Christopher J Esh
- Aspetar-Qatar Orthopaedic and Sports Medicine Hospital, Research and Scientific Support, Aspire Zone, Doha, Qatar
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Bryna C R Chrismas
- Department of Physical Education, College of Education, Qatar University, Doha, Qatar
| | - Alexis R Mauger
- Endurance Research Group, School of Sport and Exercise Sciences, University of Kent, Chatham Maritime, UK
| | - Lee Taylor
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
- School of Sport, Exercise and Rehabilitation, Faculty of Health, University of Technology Sydney (UTS), Sydney, Australia
- Human Performance Research Centre, Faculty of Health, University of Technology Sydney (UTS), Sydney, Australia
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Leverrier-Penna S, Michel A, Lecante LL, Costet N, Suglia A, Desdoits-Lethimonier C, Boulay H, Viel R, Chemouny JM, Becker E, Lavoué V, Rolland AD, Dejucq-Rainsford N, Vigneau C, Mazaud-Guittot S. Exposure of human fetal kidneys to mild analgesics interferes with early nephrogenesis. FASEB J 2021; 35:e21718. [PMID: 34105801 DOI: 10.1096/fj.202100050r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 05/14/2021] [Accepted: 05/19/2021] [Indexed: 11/11/2022]
Abstract
Acetaminophen, aspirin, and ibuprofen are mild analgesics commonly used by pregnant women, the sole current recommendation being to avoid ibuprofen from the fifth month of gestation. The nephrotoxicity of these three analgesics is well documented in adults, as is their interference with prostaglandins biosynthesis. Here we investigated the effect of these analgesics on human first trimester kidneys ex vivo. We first evaluated prostaglandins biosynthesis functionality by performing a wide screening of prostaglandin expression patterns in first trimester human kidneys. We demonstrated that prostaglandins biosynthesis machinery is functional during early nephrogenesis. Human fetal kidney explants aged 7-12 developmental weeks were exposed ex vivo to ibuprofen, aspirin or acetaminophen for 7 days, and analyzed by histology, immunohistochemistry, and flow cytometry. This study has revealed that these analgesics induced a spectrum of abnormalities within early developing structures, ranging from cell death to a decline in differentiating glomeruli density. These results warrant caution for the use of these medicines during the first trimester of pregnancy.
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Affiliation(s)
- Sabrina Leverrier-Penna
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France.,Univ Poitiers, STIM, CNRS ERL7003, Poitiers, France
| | - Alain Michel
- Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Laetitia L Lecante
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Nathalie Costet
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Antonio Suglia
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Christèle Desdoits-Lethimonier
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Hugoline Boulay
- Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Roselyne Viel
- University Rennes 1, CNRS, Inserm UMS Biosit, Core Facility H2P2, Rennes, France
| | - Jonathan M Chemouny
- Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Emmanuelle Becker
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Vincent Lavoué
- CHU Rennes, Service Gynécologie et Obstétrique, Rennes, France
| | - Antoine D Rolland
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Nathalie Dejucq-Rainsford
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Cécile Vigneau
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France.,Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Séverine Mazaud-Guittot
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
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40
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McEvoy L, Carr DF, Pirmohamed M. Pharmacogenomics of NSAID-Induced Upper Gastrointestinal Toxicity. Front Pharmacol 2021; 12:684162. [PMID: 34234675 PMCID: PMC8256335 DOI: 10.3389/fphar.2021.684162] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/11/2021] [Indexed: 12/19/2022] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of drugs which are widely used globally for the treatment of pain and inflammation, and in the case of aspirin, for secondary prevention of cardiovascular disease. Chronic non-steroidal anti-inflammatory drug use is associated with potentially serious upper gastrointestinal adverse drug reactions (ADRs) including peptic ulcer disease and gastrointestinal bleeding. A few clinical and genetic predisposing factors have been identified; however, genetic data are contradictory. Further research is needed to identify clinically relevant genetic and non-genetic markers predisposing to NSAID-induced peptic ulceration.
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Affiliation(s)
- L McEvoy
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - D F Carr
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - M Pirmohamed
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
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41
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Petrou A, Fesatidou M, Geronikaki A. Thiazole Ring-A Biologically Active Scaffold. Molecules 2021; 26:3166. [PMID: 34070661 PMCID: PMC8198555 DOI: 10.3390/molecules26113166] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/15/2021] [Accepted: 05/20/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Thiazole is a good pharmacophore nucleus due to its various pharmaceutical applications. Its derivatives have a wide range of biological activities such as antioxidant, analgesic, and antimicrobial including antibacterial, antifungal, antimalarial, anticancer, antiallergic, antihypertensive, anti-inflammatory, and antipsychotic. Indeed, the thiazole scaffold is contained in more than 18 FDA-approved drugs as well as in numerous experimental drugs. OBJECTIVE To summarize recent literature on the biological activities of thiazole ring-containing compounds Methods: A literature survey regarding the topics from the year 2015 up to now was carried out. Older publications were not included, since they were previously analyzed in available peer reviews. RESULTS Nearly 124 research articles were found, critically analyzed, and arranged regarding the synthesis and biological activities of thiazoles derivatives in the last 5 years.
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Affiliation(s)
| | | | - Athina Geronikaki
- School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.P.); (M.F.)
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42
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Anamthathmakula P, Winuthayanon W. Prostaglandin-Endoperoxide Synthase 2 (PTGS2) in the Oviduct: Roles in Fertilization and Early Embryo Development. Endocrinology 2021; 162:6128831. [PMID: 33539521 PMCID: PMC7901659 DOI: 10.1210/endocr/bqab025] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Indexed: 11/19/2022]
Abstract
The mammalian oviduct is a dynamic organ where important events such as final maturation of oocytes, transport of gametes, sperm capacitation, fertilization, embryo development, and transport take place. Prostaglandin-endoperoxide synthase 2 (PTGS2), also known as cyclooxygenase 2 (COX-2), is the rate-limiting enzyme in the production of prostaglandins (PGs) and plays an essential role during early pregnancy, including ovulation, fertilization, implantation, and decidualization. Even though the maternal-embryo communication originates in the oviduct, not many studies have systemically investigated PTGS2 signaling during early development. Most of the studies investigating implantation and decidualization processes in Ptgs2-/- mice employed embryo transfer into the uterus, thereby bypassing the mammalian oviduct. Consequently, an understanding of the mechanistic action as well as the regulation of PTGS2 and derived PGs in oviductal functions is far from complete. In this review, we aim to focus on the importance of PTGS2 and associated PGs signaling in the oviduct particularly in humans, farm animals, and laboratory rodents to provide a broad perspective to guide further research in this field. Specifically, we review the role of PTGS2-derived PGs in fertilization, embryo development, and transport. We focus on the actions of ovarian steroid hormones on PTGS2 regulation in the oviduct. Understanding of cellular PTGS2 function during early embryo development and transport in the oviduct will be an important step toward a better understanding of reproduction and may have potential implication in the assisted reproductive technology.
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Affiliation(s)
- Prashanth Anamthathmakula
- School of Molecular Biosciences, Center for Reproductive Biology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
- Correspondence: Wipawee Winuthayanon, PhD, BSN,Washington State University, Pullman, WA 99164, USA. E-mail: ; and Prashanth Anamthathmakula, PhD, Washington State University, Pullman, WA 99164, USA. E-mail:
| | - Wipawee Winuthayanon
- School of Molecular Biosciences, Center for Reproductive Biology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
- Correspondence: Wipawee Winuthayanon, PhD, BSN,Washington State University, Pullman, WA 99164, USA. E-mail: ; and Prashanth Anamthathmakula, PhD, Washington State University, Pullman, WA 99164, USA. E-mail:
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Mitchell JA, Shala F, Pires MEL, Loy RY, Ravendren A, Benson J, Urquhart P, Nicolaou A, Herschman HR, Kirkby NS. Endothelial cyclooxygenase-1 paradoxically drives local vasoconstriction and atherogenesis despite underpinning prostacyclin generation. SCIENCE ADVANCES 2021; 7:7/12/eabf6054. [PMID: 33741600 PMCID: PMC7978428 DOI: 10.1126/sciadv.abf6054] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 02/02/2021] [Indexed: 05/03/2023]
Abstract
Endothelial cyclooxygenase-1-derived prostanoids, including prostacyclin, have clear cardioprotective roles associated with their anti-thrombotic potential but have also been suggested to have paradoxical pathological activities within arteries. To date it has not been possible to test the importance of this because no models have been available that separate vascular cyclooxygenase-1 products from those generated elsewhere. Here, we have used unique endothelial-specific cyclooxygenase-1 knockout mice to show that endothelial cyclooxygenase-1 produces both protective and pathological products. Functionally, however, the overall effect of these was to drive pathological responses in the context of both vasoconstriction in vitro and the development of atherosclerosis and vascular inflammation in vivo. These data provide the first demonstration of a pathological role for the vascular cyclooxygenase-1 pathway, highlighting its potential as a therapeutic target. They also emphasize that, across biology, the role of prostanoids is not always predictable due to unique balances of context, products, and receptors.
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Affiliation(s)
- Jane A Mitchell
- Cardio-Respiratory Interface Section, National Heart and Lung Institute, Imperial College London, London, UK
| | - Fisnik Shala
- Cardio-Respiratory Interface Section, National Heart and Lung Institute, Imperial College London, London, UK
| | - Maria Elisa Lopes Pires
- Cardio-Respiratory Interface Section, National Heart and Lung Institute, Imperial College London, London, UK
| | - Rachel Y Loy
- Cardio-Respiratory Interface Section, National Heart and Lung Institute, Imperial College London, London, UK
| | - Andrew Ravendren
- Cardio-Respiratory Interface Section, National Heart and Lung Institute, Imperial College London, London, UK
| | - Joshua Benson
- Cardio-Respiratory Interface Section, National Heart and Lung Institute, Imperial College London, London, UK
| | - Paula Urquhart
- Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PL, UK
| | - Anna Nicolaou
- Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PL, UK
| | - Harvey R Herschman
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
| | - Nicholas S Kirkby
- Cardio-Respiratory Interface Section, National Heart and Lung Institute, Imperial College London, London, UK.
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Jewell DE, Panickar KS. Botanicals Reduce Circulating Concentrations of Cholesterol and Triglycerides and Work Synergistically With Arachidonic Acid to Reduce Inflammatory Cytokines in Cats. Front Vet Sci 2021; 8:620447. [PMID: 33614765 PMCID: PMC7889966 DOI: 10.3389/fvets.2021.620447] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 01/12/2021] [Indexed: 12/27/2022] Open
Abstract
Forty Eight cats were used to measure the effects of feeding a traditional adult cat food supplemented with either arachidonic acid (ARA), a botanical mix (botanicals) or both on circulating biochemical parameters and inflammatory cytokines. The cats were healthy adults (mean age, 3.0; range, 1.3-6.4 years). The adult cats were fed one of four foods (n = 12 per group) for 84 days (dietary changes reported as fed): a traditional adult cat food (control, 0.05% ARA no added botanicals), or control food supplemented with arachidonic acid from chicken liver (0.13% ARA when supplemented), control food supplemented with botanicals (green tea 0.5%, fenugreek 0.05%, and tulsi 0.003%), and control plus ARA (0.13% as fed) with botanicals (green tea 0.5%, fenugreek 0.05%, and tulsi 0.003%). Response variables were compared between treatments: initially, and at 84 days (end of study). The measurements were standard complete blood counts and chemistries as well as circulating cytokines. Botanical inclusion reduced (P < 0.05) circulating cholesterol and triglycerides while arachidonic acid increased (P < 0.05) their concentrations. The pro-inflammatory cytokines MCP-1, TNFα, SDF-1, Flt3L, IL-8, IL-12p40, IL-13, and IL-18 were all reduced (P < 0.05) in cats after consuming the ARA + botanicals food for 84 days with little change after consuming the other foods. Therefore, this combination of ARA and botanicals may be of value in reducing inflammation.
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Affiliation(s)
- Dennis E Jewell
- Department of Grain Science and Industry, Kansas State University, Manhattan, KS, United States
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45
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Faki Y, Er A. Different Chemical Structures and Physiological/Pathological Roles of Cyclooxygenases. Rambam Maimonides Med J 2021; 12:RMMJ.10426. [PMID: 33245277 PMCID: PMC7835113 DOI: 10.5041/rmmj.10426] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
This review describes cyclooxygenase (COX), which synthesizes prostanoids that play an important role in living things. The authors conducted a national and international literature review on the subject. The COX enzyme uses arachidonic acid to form prostanoids, which play a role in several physiological and pathological conditions. This enzyme has different isoforms, mainly COX-1 and COX-2. The constitutive isoform is COX-1, while COX-2 is the inducible isoform. Both are expressed in different tissues and at different levels, but they may also coexist within the same tissue. Both isoforms show essentially the same mode of action, but their substrates and inhibitors may differ. The COX-1 isoform, which plays a role in the continuation of physiological events, has an increased expression level in various carcinomas, and the COX-2 isoform, which is increased in inflammatory conditions, is typically expressed at low physiological levels in some tissues such as the brain, kidney, and uterus. In addition to investigating the efficacies of the COX-1 and COX-2 isoforms, the discovery of potential new COX enzymes and their effect continues. This review also looks at the roles of the COX enzyme in certain physiological and pathological conditions.
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Affiliation(s)
| | - Ayse Er
- To whom correspondence should be addressed. E-mail:
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46
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Li WJ, Lu JW, Zhang CY, Wang WS, Ying H, Myatt L, Sun K. PGE2 vs PGF2α in human parturition. Placenta 2020; 104:208-219. [PMID: 33429118 DOI: 10.1016/j.placenta.2020.12.012] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/15/2020] [Accepted: 12/21/2020] [Indexed: 11/16/2022]
Abstract
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.
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Affiliation(s)
- Wen-Jiao Li
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China; Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Jiang-Wen Lu
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, PR China
| | - Chu-Yue Zhang
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, PR China
| | - Wang-Sheng Wang
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, PR China
| | - Hao Ying
- Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China.
| | - Leslie Myatt
- Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Kang Sun
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, PR China.
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47
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Wan Q, Kong D, Liu Q, Guo S, Wang C, Zhao Y, Ke ZJ, Yu Y. Congestive heart failure in COX2 deficient rats. SCIENCE CHINA-LIFE SCIENCES 2020; 64:1068-1076. [DOI: 10.1007/s11427-020-1792-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 08/07/2020] [Indexed: 11/30/2022]
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48
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Herminghaus A, Buitenhuis AJ, Schulz J, Truse R, Vollmer C, Relja B, Bauer I, Picker O. Indomethacin Increases the Efficacy of Oxygen Utilization of Colonic Mitochondria and Uncouples Hepatic Mitochondria in Tissue Homogenates From Healthy Rats. Front Med (Lausanne) 2020; 7:463. [PMID: 32974368 PMCID: PMC7472952 DOI: 10.3389/fmed.2020.00463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 07/10/2020] [Indexed: 11/13/2022] Open
Affiliation(s)
- Anna Herminghaus
- Department of Anaesthesiology, University Hospital Duesseldorf, Duesseldorf, Germany
- *Correspondence: Anna Herminghaus
| | - Albert J. Buitenhuis
- Department of Anaesthesiology, University Hospital Duesseldorf, Duesseldorf, Germany
| | - Jan Schulz
- Department of Anaesthesiology, University Hospital Duesseldorf, Duesseldorf, Germany
| | - Richard Truse
- Department of Anaesthesiology, University Hospital Duesseldorf, Duesseldorf, Germany
| | - Christian Vollmer
- Department of Anaesthesiology, University Hospital Duesseldorf, Duesseldorf, Germany
| | - Borna Relja
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto von Guericke University, Magdeburg, Germany
| | - Inge Bauer
- Department of Anaesthesiology, University Hospital Duesseldorf, Duesseldorf, Germany
| | - Olaf Picker
- Department of Anaesthesiology, University Hospital Duesseldorf, Duesseldorf, Germany
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49
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Crescente M, Armstrong PC, Kirkby NS, Edin ML, Chan MV, Lih FB, Jiao J, Maffucci T, Allan HE, Mein CA, Gaston-Massuet C, Cottrell GS, Mitchell JA, Zeldin DC, Herschman HR, Warner TD. Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin. FASEB J 2020; 34:10027-10040. [PMID: 32592197 PMCID: PMC9359103 DOI: 10.1096/fj.202000312r] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 12/25/2022]
Abstract
Aspirin prevents thrombosis by inhibiting platelet cyclooxygenase (COX)-1 activity and the production of thromboxane (Tx)A2, a pro-thrombotic eicosanoid. However, the non-platelet actions of aspirin limit its antithrombotic effects. Here, we used platelet-COX-1-ko mice to define the platelet and non-platelet eicosanoids affected by aspirin. Mass-spectrometry analysis demonstrated blood from platelet-COX-1-ko and global-COX-1-ko mice produced similar eicosanoid profiles in vitro: for example, formation of TxA2, prostaglandin (PG) F2α, 11-hydroxyeicosatraenoic acid (HETE), and 15-HETE was absent in both platelet- and global-COX-1-ko mice. Conversely, in vivo, platelet-COX-1-ko mice had a distinctly different profile from global-COX-1-ko or aspirin-treated control mice, notably significantly higher levels of PGI2 metabolite. Ingenuity Pathway Analysis (IPA) predicted that platelet-COX-1-ko mice would be protected from thrombosis, forming less pro-thrombotic TxA2 and PGE2. Conversely, aspirin or lack of systemic COX-1 activity decreased the synthesis of anti-aggregatory PGI2 and PGD2 at non-platelet sites leading to predicted thrombosis increase. In vitro and in vivo thrombosis studies proved these predictions. Overall, we have established the eicosanoid profiles linked to inhibition of COX-1 in platelets and in the remainder of the cardiovascular system and linked them to anti- and pro-thrombotic effects of aspirin. These results explain why increasing aspirin dosage or aspirin addition to other drugs may lessen antithrombotic protection.
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Affiliation(s)
- Marilena Crescente
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Paul C Armstrong
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Nicholas S Kirkby
- National Heart & Lung Institute, Imperial College London, London, UK
| | - Matthew L Edin
- Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
| | - Melissa V Chan
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Fred B Lih
- Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
| | - Jing Jiao
- Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Tania Maffucci
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Harriet E Allan
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Charles A Mein
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Carles Gaston-Massuet
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Graeme S Cottrell
- Reading School of Pharmacy and ICMR, University of Reading, Reading, UK
| | - Jane A Mitchell
- National Heart & Lung Institute, Imperial College London, London, UK
| | - Darryl C Zeldin
- Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
| | - Harvey R Herschman
- Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Timothy D Warner
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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50
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Palma-Barqueros V, Bohdan N, Revilla N, Vicente V, Bastida JM, Rivera J. PTGS1 gene variations associated with bleeding and platelet dysfunction. Platelets 2020; 32:710-716. [PMID: 32584621 DOI: 10.1080/09537104.2020.1782370] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
| | - Natalia Bohdan
- Universidad de Murcia, IMIB-Arrixaca, CIBERER-U765, Murcia, Spain
| | - Nuria Revilla
- Universidad de Murcia, IMIB-Arrixaca, CIBERER-U765, Murcia, Spain
| | - Vicente Vicente
- Universidad de Murcia, IMIB-Arrixaca, CIBERER-U765, Murcia, Spain
| | - José M Bastida
- Department of Hematology, IBSAL-Hospital Universitario de Salamanca, Salamanca, Spain.,On Behalf of the "Inherited Platelet Disorders Project", Hemorrhagic Diathesis Working Group, SETH
| | - José Rivera
- Universidad de Murcia, IMIB-Arrixaca, CIBERER-U765, Murcia, Spain.,On Behalf of the "Inherited Platelet Disorders Project", Hemorrhagic Diathesis Working Group, SETH
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