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Saadh MJ, Ahmed HH, Kareem RA, Jain V, Ballal S, Singh A, Sharma GC, Devi A, Nasirov A, Sameer HN, Yaseen A, Athab ZH, Adil M. In Silico design and molecular dynamics analysis of imidazole derivatives as selective cyclooxygenase-2 inhibitors. Comput Biol Chem 2025; 115:108341. [PMID: 39808951 DOI: 10.1016/j.compbiolchem.2025.108341] [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: 12/08/2024] [Revised: 12/23/2024] [Accepted: 01/03/2025] [Indexed: 01/16/2025]
Abstract
Cyclooxygenase-2 (COX-2), a key enzyme in the inflammatory pathway, is the target for various nonsteroidal anti-inflammatory drugs (NSAIDs) and selective inhibitors known as coxibs. This study focuses on the development of novel imidazole derivatives as COX-2 inhibitors, utilizing a Structure-Activity Relationship (SAR) approach to enhance binding affinity and selectivity. Molecular docking was performed using Autodock Vina, revealing binding energies of -6.928, -7.187, and -7.244 kJ/mol for compounds 5b, 5d, and 5e, respectively. Molecular dynamics simulations using GROMACS provided insights into the stability and conformational changes of the protein-ligand complexes. Key metrics such as RMSD, RMSF, Rg, SASA, and hydrogen bond analysis were employed to assess the interactions. The binding free energy of the inhibitors was estimated using the MMPBSA method, highlighting compound 5b (N-[(3-benzyl-2-methylsulfonylimidazol-4-yl)methyl]-4-methoxyaniline) with the lowest binding energy of -162.014 kcal/mol. ADMET analysis revealed that compound 5b exhibited the most favorable pharmacokinetic properties and safety profile. Overall, this investigation underscores the potential of these novel imidazole derivatives as effective COX-2 inhibitors, with compound 5b emerging as the most promising candidate for further development.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | | | | | - Vicky Jain
- Marwadi University Research Center, Department of Chemistry, Faculty of Science, Marwadi University, Rajkot, Gujarat 360003, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Abhayveer Singh
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab 140401, India
| | - Girish Chandra Sharma
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - Anita Devi
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab 140307, India
| | - Abdulaziz Nasirov
- Department of Psychiatry, narcology and pediatric narcology, medical psychology and psychotherapy, Tashkent Pediatric Medical Institute, Bogishamol Street 223, Tashkent 100140, Uzbekistan
| | - Hayder Naji Sameer
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar, 64001, Iraq
| | | | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
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Pandian K, van Zonneveld AJ, Harms A, Hankemeier T. Metabolic alterations of endothelial cells under transient and persistent hypoxia: study using a 3D microvessels-on-chip model. Tissue Barriers 2024:2431416. [PMID: 39584359 DOI: 10.1080/21688370.2024.2431416] [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: 09/25/2024] [Revised: 11/08/2024] [Accepted: 11/12/2024] [Indexed: 11/26/2024] Open
Abstract
Numerous signaling pathways are activated during hypoxia to facilitate angiogenesis, promoting interactions among endothelial cells and initiating downstream signaling cascades. Although the pivotal role of the nitric oxide (NO) response pathway is well-established, the involvement of arginine-specific metabolism and bioactive lipid mechanisms in 3D flow-activated in vitro models remains less understood. In this study, we explored the levels of arginine-specific metabolites and bioactive lipids in human coronary artery endothelial cells (HCAECs) under both transient and persistent hypoxia. We compared targeted metabolite levels between a 2D static culture model and a 3D microvessels-on-chip model. Notably, we observed robust regulation of NO metabolites in both transient and persistent hypoxic conditions. In the 2D model under transient hypoxia, metabolic readouts of bioactive lipids revealed increased oxidative stress markers, a phenomenon not observed in the 3D microvessels. Furthermore, we made a novel discovery that the responses of bioactive lipids were regulated by hypoxia inducible factor-1α (HIF-1α) in the 2D cell culture model and partially by HIF-1α and flow-induced shear stress in the 3D microvessels. Immunostaining confirmed the HIF-1α-induced regulation under both hypoxic conditions. Real-time oxygen measurements in the 3D microvessels using an oxygen probe validated that oxygen levels were maintained in the 3D model. Overall, our findings underscore the critical regulatory roles of HIF-1α and shear stress in NO metabolites and bioactive lipids in both 2D and 3D cell culture models.
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Affiliation(s)
- Kanchana Pandian
- Division of Systems Biomedicine and Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
| | - Anton Jan van Zonneveld
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Amy Harms
- Division of Systems Biomedicine and Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
| | - Thomas Hankemeier
- Division of Systems Biomedicine and Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
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3
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Chen L, Xing J, Lv J, Si S, Wang H, Yu W. Corynoxine suppresses lung adenocarcinoma proliferation and metastasis via inhibiting PI3K/AKT pathway and suppressing Cyclooxygenase-2 expression. Hereditas 2024; 161:41. [PMID: 39511658 PMCID: PMC11542349 DOI: 10.1186/s41065-024-00343-x] [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: 06/06/2024] [Accepted: 10/29/2024] [Indexed: 11/15/2024] Open
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) is the most common lung cancer subtype, and the prognosis of affected patients is generally poor. The traditional Chinese medicine Uncaria rhychophaylla has been reported to exhibit anti-lung cancer properties. Accordingly, the main bioactive ingredient in Uncaria rhychophaylla, Corynoxine, may hold great value as a treatment for lung cancer. METHODS The impact of Corynoxine on the viability of LUAD cells was assessed using the Cell Counting Kit-8 (CCK-8) assay. Apoptosis in A549 cells was evaluated via flow cytometry. Migration and invasion capabilities were determined through wound healing and Transwell assays, respectively. The key pathways targeted by Corynoxine in LUAD were identified using a network pharmacology approach. Additionally, Western immunoblotting, quantitative real-time PCR (qRT-PCR), and ELISA assays were conducted to validate the underlying mechanisms. The in vivo anti-tumor efficacy of Corynoxine was assessed in xenograft nude mice. RESULTS In this study, Corynoxine treatment was found to markedly suppress in vitro LUAD cell proliferative, migratory, and invasive activity. It additionally downregulated Vimentin and promoted E-cadherin upregulation consistent with the disruption of epithelial-mesenchymal transition (EMT) induction while also accelerating apoptotic death. Furthermore, network pharmacology analysis revealed that the PI3K/AKT pathway is a potential target of Corynoxine in LUAD. In vitro assays demonstrated that treatment with Corynoxine resulted in the suppression of PI3K/AKT signaling and a consequent drop in cyclooxygenase-2 (COX-2) expression. These findings were further confirmed in vivo in mice harboring A549 tumor xenografts in which Corynoxine was able to interfere with the PI3K/AKT/COX-2 signaling axis. CONCLUSION This study elucidated the potential effects of Corynoxine in suppressing proliferation and metastasis in LUAD, along with investigating the underlying mechanisms. These data highlight the promise of Corynoxine as a novel therapeutic tool for the treatment of individuals diagnosed with LUAD.
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Affiliation(s)
- Liping Chen
- Department of Central Laboratory, The Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, China.
- Department of Respiratory, The Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, China.
| | - Jing Xing
- Department of Central Laboratory, The Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Jiapei Lv
- Department of Respiratory, The Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Sainv Si
- Department of Respiratory, The Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Huaying Wang
- Department of Respiratory, The Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Wanjun Yu
- Department of Respiratory, The Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, China.
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Parchem K, Letsiou S, Petan T, Oskolkova O, Medina I, Kuda O, O'Donnell VB, Nicolaou A, Fedorova M, Bochkov V, Gladine C. Oxylipin profiling for clinical research: Current status and future perspectives. Prog Lipid Res 2024; 95:101276. [PMID: 38697517 DOI: 10.1016/j.plipres.2024.101276] [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: 12/12/2023] [Revised: 04/24/2024] [Accepted: 04/29/2024] [Indexed: 05/05/2024]
Abstract
Oxylipins are potent lipid mediators with increasing interest in clinical research. They are usually measured in systemic circulation and can provide a wealth of information regarding key biological processes such as inflammation, vascular tone, or blood coagulation. Although procedures still require harmonization to generate comparable oxylipin datasets, performing comprehensive profiling of circulating oxylipins in large studies is feasible and no longer restricted by technical barriers. However, it is essential to improve and facilitate the biological interpretation of complex oxylipin profiles to truly leverage their potential in clinical research. This requires regular updating of our knowledge about the metabolism and the mode of action of oxylipins, and consideration of all factors that may influence circulating oxylipin profiles independently of the studied disease or condition. This review aims to provide the readers with updated and necessary information regarding oxylipin metabolism, their different forms in systemic circulation, the current limitations in deducing oxylipin cellular effects from in vitro bioactivity studies, the biological and technical confounding factors needed to consider for a proper interpretation of oxylipin profiles.
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Affiliation(s)
- Karol Parchem
- Department of Food Chemistry, Technology and Biotechnology, Faculty of Chemistry, Gdańsk University of Technology, 11/12 Gabriela Narutowicza St., 80-233 Gdańsk, Poland; Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 53210 Pardubice, Czech Republic.
| | - Sophia Letsiou
- Department of Biomedical Sciences, University of West Attica, Ag. Spiridonos St. Egaleo, 12243 Athens, Greece.
| | - Toni Petan
- Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova cesta 39, SI-1000 Ljubljana, Slovenia.
| | - Olga Oskolkova
- Institute of Pharmaceutical Sciences, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria.
| | - Isabel Medina
- Instituto de Investigaciones Marinas-Consejo Superior de Investigaciones Científicas (IIM-CSIC), Eduardo Cabello 6, E-36208 Vigo, Spain.
| | - Ondrej Kuda
- Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 14200 Prague, Czech Republic.
| | - Valerie B O'Donnell
- Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
| | - Anna Nicolaou
- School of Health Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK.
| | - Maria Fedorova
- Center of Membrane Biochemistry and Lipid Research, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, 01307 Dresden, Germany.
| | - Valery Bochkov
- Institute of Pharmaceutical Sciences, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria.
| | - Cécile Gladine
- Université Clermont Auvergne, INRAE, UNH, Clermont-Ferrand, France.
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Song H, Ren J, Yang L, Sun H, Yan G, Han Y, Wang X. Elucidation for the pharmacological effects and mechanism of Shen Bai formula in treating myocardial injury based on energy metabolism and serum metabolomic approaches. JOURNAL OF ETHNOPHARMACOLOGY 2024; 323:117670. [PMID: 38160867 DOI: 10.1016/j.jep.2023.117670] [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: 09/23/2023] [Revised: 12/24/2023] [Accepted: 12/25/2023] [Indexed: 01/03/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Shen Bai formula (SBF) is a proven effective traditional Chinese medicine for treating viral myocarditis (VMC) sequelae in clinic, and myocardial injury is the pathological basis of VMC sequelae. However, the pharmacological action and mechanism of SBF have not been systematically elucidated. AIM OF THE STUDY In present research, the doxorubicin-induced myocardial injury rat model was used to evaluate the efficacy of SBF, and energy metabolism and metabolomics approaches were applied to elucidate the effects of SBF on myocardial injury. MATERIALS AND METHODS Through energy metabolism measurement system and UPLC-Q-TOF-MS/MS oriented blood metabolomics, directly reflected the therapeutic effect of SBF at a macro level, and identified biomarkers of myocardial injury in microcosmic, revealing its metabolomic mechanism. RESULTS Results showed that SBF significantly improved the electrocardiogram (ECG), heart rate (HR), extent of myocardial tissue lesion, and ratio of heart and spleen. In addition, the serum levels of AST, CK, LDH, α-HBDH, cTnI, BNP, and MDA decreased, whereas SOD and ATP activity and content increased. Moreover, SBF increased locomotor activity and basic daily metabolism in rats with myocardial injury, restoring their usual level of energy metabolism. A total of 45 potential metabolomic biomarkers were identified. Among them, 44 biomarkers were significantly recalled by SBF, including representative biomarkers arachidonic acid (AA), 12-HETE, prostaglandin J2 (PGJ2), 15-deoxy-Δ-12,14-PGJ2, 15-keto-PGE2, 15(S)-HPETE, 15(S)-HETE, 8,11,14-eicosatrienoic acid and 9(S)-HODE, which involved AA metabolism, biosynthesis of unsaturated fatty acids and linoleic acid metabolism. CONCLUSION We successfully replicated a myocardial injury rat model with the intraperitoneal injection of doxorubicin, and elucidated the mechanism of SBF in treating myocardial injury. This key mechanism may be achieved by targeting action on COX, Alox, CYP, and 15-PGDH to increase or decrease the level of myocardial injury biomarker, and then emphatically interven in AA metabolism, biosynthesis of unsaturated fatty acids and linoleic acid metabolism, and participate in regulating purine metabolism, sphingolipid metabolism, primary bile acid biosynthesis, and steroid hormone synthesis.
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Affiliation(s)
- Hongwei Song
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Junling Ren
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau
| | - Le Yang
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou, China
| | - Hui Sun
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China.
| | - Guangli Yan
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Ying Han
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Xijun Wang
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau; State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou, China.
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6
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Lin YC, Swendeman S, Moreira IS, Ghosh A, Kuo A, Rosário-Ferreira N, Guo S, Culbertson A, Levesque MV, Cartier A, Seno T, Schmaier A, Galvani S, Inoue A, Parikh SM, FitzGerald GA, Zurakowski D, Liao M, Flaumenhaft R, Gümüş ZH, Hla T. Designer high-density lipoprotein particles enhance endothelial barrier function and suppress inflammation. Sci Signal 2024; 17:eadg9256. [PMID: 38377179 PMCID: PMC10954247 DOI: 10.1126/scisignal.adg9256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 01/31/2024] [Indexed: 02/22/2024]
Abstract
High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile inflammation suppressed neutrophil influx and inflammatory mediator secretion. Moreover, systemic A1M administration led to a sustained increase in circulating HDL-bound S1P and suppressed inflammation in a murine model of LPS-induced endotoxemia. We propose that A1M administration may enhance vascular endothelial barrier function, suppress cytokine storm, and promote resilience of the vascular endothelium.
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Affiliation(s)
- Yueh-Chien Lin
- Vascular Biology Program, Boston Children’s Hospital and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA
| | - Steven Swendeman
- Vascular Biology Program, Boston Children’s Hospital and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA
| | - Irina S. Moreira
- Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456, Coimbra, Portugal
- CNC - Center for Neuroscience and Cell Biology, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3000-456, Coimbra, Portugal
| | - Avishek Ghosh
- Vascular Biology Program, Boston Children’s Hospital and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA
| | - Andrew Kuo
- Vascular Biology Program, Boston Children’s Hospital and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA
| | - Nícia Rosário-Ferreira
- CNC - Center for Neuroscience and Cell Biology, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3000-456, Coimbra, Portugal
| | | | - Alan Culbertson
- Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - Michel V. Levesque
- Vascular Biology Program, Boston Children’s Hospital and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA
| | - Andreane Cartier
- Vascular Biology Program, Boston Children’s Hospital and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA
| | - Takahiro Seno
- Vascular Biology Program, Boston Children’s Hospital and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA
| | - Alec Schmaier
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02115, USA
| | - Sylvain Galvani
- Vascular Biology Program, Boston Children’s Hospital and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA
| | - Asuka Inoue
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan
| | - Samir M. Parikh
- Division of Nephrology and Department of Medicine, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, 75235, USA
| | - Garret A. FitzGerald
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA
| | - David Zurakowski
- Department of Anesthesia and Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Maofu Liao
- Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA
- Department of Chemical Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
- Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, 518055, China
| | | | - Zeynep H. Gümüş
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA and Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Timothy Hla
- Vascular Biology Program, Boston Children’s Hospital and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA
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7
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Ahmad AA, Hussain K, Shah MR, Ashhad Halimi SM, Rabbi F, Ahmad Z, Khan I, Rauf A, Alshammari A, Alharbi M, Rasul Suleria HA. Molecular Insights into the In Vivo Analgesic and Anti-Inflammatory Activity of Indomethacin Analogues. ACS OMEGA 2023; 8:30048-30056. [PMID: 37636936 PMCID: PMC10448495 DOI: 10.1021/acsomega.3c02033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 07/31/2023] [Indexed: 08/29/2023]
Abstract
The primary objective of this research was to identify and explore the most potent and efficacious cyclooxygenase inhibitors, utilizing indole acetic acid drugs as a lead molecule. To achieve this objective, various derivatives (2a-2c and 2e-2g) of the selected lead molecule, indomethacin, were synthesized using a reflux condensation process, targeting the hydroxyl group. The synthesized analogues were subjected to different spectroscopic procedures to determine their structure and confirm their analogues. These derivatives were further screened for acute toxicity and anti-nociceptive and anti-inflammatory activity using established protocols. Docking analysis was performed to evaluate the possible protein-ligand interaction. The test compounds were found to be safe at doses of 50, 75, 100, and 200 mg/kg, i.p. The pharmacological screening revealed that test compounds 2a-2f had a superior peripheral analgesic effect at a dose of 10 mg/kg, in comparison to the parent drug indomethacin, while compound 2g exhibited slightly lower activity at the same dose. The hot plate results showed lower central analgesic activity of the test compounds compared to the standard Tramal, but it was still significant. Anti-inflammatory results were significant, comparable to Diclofenac sodium and indomethacin, except for compounds 2b, 2c, and 2e at a dose of 10 mg/kg body weight. Molecular docking analysis demonstrated that the derived compounds had augmented negative binding energies (-149.39, -146.72, -160.85, -159.34, -140.03, and -150.91 KJ/mol) compared to the parent drugs (-141.07), which supported the research's theme of producing stronger derivatives of standard drugs with significant anti-nociceptive and anti-inflammatory potential. The derived compounds exhibited significant analgesic and anti-inflammatory activities and, therefore, have the potential to be studied further as new drug candidates for pain and inflammation.
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Affiliation(s)
- Abid Ali Ahmad
- Department
of Pharmacy, University of Peshawar, Peshawar, Khyber Pakhtunkhwa 25120, Pakistan
| | - Kashif Hussain
- HEJ,
Research Institute of Chemistry, ICCBS, University of Karachi, Karachi, Sindh 75270, Pakistan
| | - Muhammad Raza Shah
- HEJ,
Research Institute of Chemistry, ICCBS, University of Karachi, Karachi, Sindh 75270, Pakistan
| | | | - Fazle Rabbi
- Department
of Pharmacy, Abasyn University Peshawar, Peshawar, Khyber Pakhtunkhwa 25000, Pakistan
| | - Zahoor Ahmad
- Department
of Pharmacy, University of Peshawar, Peshawar, Khyber Pakhtunkhwa 25120, Pakistan
| | - Inamullah Khan
- Department
of Pharmacy, University of Peshawar, Peshawar, Khyber Pakhtunkhwa 25120, Pakistan
| | - Abdur Rauf
- Department
of Chemistry, University of Swabi, Swabi, Anbar, Khyber Pakhtunkhwa 23561, Pakistan
| | - Abdulrahman Alshammari
- Department
of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Metab Alharbi
- Department
of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Hafiz Ansar Rasul Suleria
- School of
Agriculture and Food, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
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8
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Wang P, Chen Q, Tang Z, Wang L, Gong B, Li M, Li S, Yang M. Uncovering ferroptosis in Parkinson's disease via bioinformatics and machine learning, and reversed deducing potential therapeutic natural products. Front Genet 2023; 14:1231707. [PMID: 37485340 PMCID: PMC10358855 DOI: 10.3389/fgene.2023.1231707] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 06/27/2023] [Indexed: 07/25/2023] Open
Abstract
Objective: Ferroptosis, a novel form of cell death, is closely associated with excessive iron accumulated within the substantia nigra in Parkinson's disease (PD). Despite extensive research, the underlying molecular mechanisms driving ferroptosis in PD remain elusive. Here, we employed a bioinformatics and machine learning approach to predict the genes associated with ferroptosis in PD and investigate the interactions between natural products and their active ingredients with these genes. Methods: We comprehensively analyzed differentially expressed genes (DEGs) for ferroptosis associated with PD (PDFerDEGs) by pairing 3 datasets (GSE7621, GSE20146, and GSE202665) from the NCBI GEO database and the FerrDb V2 database. A machine learning approach was then used to screen PDFerDEGs for signature genes. We mined the interacted natural product components based on screened signature genes. Finally, we mapped a network combined with ingredients and signature genes, then carried out molecular docking validation of core ingredients and targets to uncover potential therapeutic targets and ingredients for PD. Results: We identified 109 PDFerDEGs that were significantly enriched in biological processes and KEGG pathways associated with ferroptosis (including iron ion homeostasis, iron ion transport and ferroptosis, etc.). We obtained 29 overlapping genes and identified 6 hub genes (TLR4, IL6, ADIPOQ, PTGS2, ATG7, and FADS2) by screening with two machine learning algorithms. Based on this, we screened 263 natural product components and subsequently mapped the "Overlapping Genes-Ingredients" network. According to the network, top 5 core active ingredients (quercetin, 17-beta-estradiol, glycerin, trans-resveratrol, and tocopherol) were molecularly docked to hub genes to reveal their potential role in the treatment of ferroptosis in PD. Conclusion: Our findings suggested that PDFerDEGs are associated with ferroptosis and play a role in the progression of PD. Taken together, core ingredients (quercetin, 17-beta-estradiol, glycerin, trans-resveratrol, and tocopherol) bind well to hub genes (TLR4, IL6, ADIPOQ, PTGS2, ATG7, and FADS2), highlighting novel biomarkers for PD.
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Affiliation(s)
- Peng Wang
- Postgraduate School, Medical School of Chinese PLA, Beijing, China
- Department of Traditional Chinese Medicine, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Qi Chen
- Department of Traditional Chinese Medicine, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhuqian Tang
- School of Pharmacy, Key Laboratory for Modern Research of Traditional Chinese Medicine of Jiangsu, Nanjing University of Chinese Medicine, Nan Jing, Jiangsu, China
| | - Liang Wang
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Bizhen Gong
- Postgraduate School, Medical School of Chinese PLA, Beijing, China
- Department of Traditional Chinese Medicine, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Min Li
- Department of Traditional Chinese Medicine, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Shaodan Li
- Department of Traditional Chinese Medicine, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Minghui Yang
- Department of Traditional Chinese Medicine, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
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9
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Wang X, Chen J, Zheng J. The roles of COX-2 in protozoan infection. Front Immunol 2023; 14:955616. [PMID: 36875123 PMCID: PMC9978824 DOI: 10.3389/fimmu.2023.955616] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 02/06/2023] [Indexed: 02/18/2023] Open
Abstract
Protozoan diseases cause great harm in animal husbandry and require human-provided medical treatment. Protozoan infection can induce changes in cyclooxygenase-2 (COX-2) expression. The role played by COX-2 in the response to protozoan infection is complex. COX-2 induces and regulates inflammation by promoting the synthesis of different prostaglandins (PGs), which exhibit a variety of biological activities and participate in pathophysiological processes in the body in a variety of ways. This review explains the roles played by COX-2 in protozoan infection and analyzes the effects of COX-2-related drugs in protozoan diseases.
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Affiliation(s)
- Xinlei Wang
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Jilin University, Changchun, China
| | - Jie Chen
- Institute of Theoretical Chemistry, Jilin University, Changchun, China
| | - Jingtong Zheng
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, China
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10
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Menter DG, Bresalier RS. An Aspirin a Day: New Pharmacological Developments and Cancer Chemoprevention. Annu Rev Pharmacol Toxicol 2023; 63:165-186. [PMID: 36202092 DOI: 10.1146/annurev-pharmtox-052020-023107] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Chemoprevention refers to the use of natural or synthetic agents to reverse, suppress, or prevent the progression or recurrence of cancer. A large body of preclinical and clinical data suggest the ability of aspirin to prevent precursor lesions and cancers, but much of the clinical data are inferential and based on descriptive epidemiology, case control, and cohort studies or studies designed to answer other questions (e.g., cardiovascular mortality). Multiple pharmacological, clinical, and epidemiologic studies suggest that aspirin can prevent certain cancers but may also cause other effects depending on the tissue or disease and organ site in question. The best-known biological targets of aspirin are cyclooxygenases, which drive a wide variety of functions, including hemostasis, inflammation, and immune modulation. Newly recognized molecular and cellular interactions suggest additional modifiable functional targets, and the existence of consensus molecular cancer subtypes suggests that aspirin may have differential effects based on tumor heterogeneity. This review focuses on new pharmacological developments and innovations in biopharmacology that clarify the potential role of aspirin in cancer chemoprevention.
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Affiliation(s)
- David G Menter
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Robert S Bresalier
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA;
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11
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Quaranta A, Revol-Cavalier J, Wheelock CE. The octadecanoids: an emerging class of lipid mediators. Biochem Soc Trans 2022; 50:1569-1582. [PMID: 36454542 PMCID: PMC9788390 DOI: 10.1042/bst20210644] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/11/2022] [Accepted: 10/24/2022] [Indexed: 10/27/2023]
Abstract
Oxylipins are enzymatic and non-enzymatic metabolites of mono- or polyunsaturated fatty acids that encompass potent lipid mediators including the eicosanoids and docosanoids. Previously considered of low interest and often dismissed as 'just fat', octadecanoid oxylipins have only recently begun to be recognized as lipid mediators in humans. In the last few years, these compounds have been found to be involved in the mediation of multiple biological processes related to nociception, tissue modulation, cell proliferation, metabolic regulation, inflammation, and immune regulation. At the same time, the study of octadecanoids is hampered by a lack of standardization in the field, a paucity of analytical standards, and a lack of domain expertise. These issues have collectively limited the investigation of the biosynthesis and bioactivity of octadecanoids. Here, we present an overview of the primary enzymatic pathways for the oxidative metabolism of 18-carbon fatty acids in humans and of the current knowledge of the major biological activity of the resulting octadecanoids. We also propose a systematic nomenclature system based upon that used for the eicosanoids in order to avoid ambiguities and resolve multiple designations for the same octadecanoid. The aim of this review is to provide an initial framework for the field and to assist in its standardization as well as to increase awareness of this class of compounds in order to stimulate research into this interesting group of lipid mediators.
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Affiliation(s)
- Alessandro Quaranta
- Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Johanna Revol-Cavalier
- Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden
- Larodan Research Laboratory, Karolinska Institutet, 171 65 Stockholm, Sweden
| | - Craig E. Wheelock
- Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden
- Department of Respiratory Medicine and Allergy, Karolinska University Hospital, 171 76 Stockholm, Sweden
- Gunma University Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Gunma 371-8511, Japan
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12
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Jiang ST, Liu YG, Zhang L, Sang XT, Xu YY, Lu X. Systems biology approach reveals a common molecular basis for COVID-19 and non-alcoholic fatty liver disease (NAFLD). Eur J Med Res 2022; 27:251. [PMCID: PMC9664052 DOI: 10.1186/s40001-022-00865-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/24/2022] [Indexed: 11/16/2022] Open
Abstract
Abstract
Background
Patients with non-alcoholic fatty liver disease (NAFLD) may be more susceptible to coronavirus disease 2019 (COVID-19) and even more likely to suffer from severe COVID-19. Whether there is a common molecular pathological basis for COVID-19 and NAFLD remains to be identified. The present study aimed to elucidate the transcriptional alterations shared by COVID-19 and NAFLD and to identify potential compounds targeting both diseases.
Methods
Differentially expressed genes (DEGs) for COVID-19 and NAFLD were extracted from the GSE147507 and GSE89632 datasets, and common DEGs were identified using the Venn diagram. Subsequently, we constructed a protein–protein interaction (PPI) network based on the common DEGs and extracted hub genes. Then, we performed gene ontology (GO) and pathway analysis of common DEGs. In addition, transcription factors (TFs) and miRNAs regulatory networks were constructed, and drug candidates were identified.
Results
We identified a total of 62 common DEGs for COVID-19 and NAFLD. The 10 hub genes extracted based on the PPI network were IL6, IL1B, PTGS2, JUN, FOS, ATF3, SOCS3, CSF3, NFKB2, and HBEGF. In addition, we also constructed TFs–DEGs, miRNAs–DEGs, and protein–drug interaction networks, demonstrating the complex regulatory relationships of common DEGs.
Conclusion
We successfully extracted 10 hub genes that could be used as novel therapeutic targets for COVID-19 and NAFLD. In addition, based on common DEGs, we propose some potential drugs that may benefit patients with COVID-19 and NAFLD.
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13
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Uddin MJ, Lo JHJ, Oltman CG, Crews BC, Huda T, Liu J, Kingsley PJ, Lin S, Milad M, Aleem AM, Asaduzzaman A, McIntyre JO, Duvall CL, Marnett LJ. Discovery of a Redox-Activatable Chemical Probe for Detection of Cyclooxygenase-2 in Cells and Animals. ACS Chem Biol 2022; 17:1714-1722. [PMID: 35786843 PMCID: PMC10464600 DOI: 10.1021/acschembio.1c00961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Cyclooxygenase-2 (COX-2) expression is up-regulated in inflammatory tissues and many premalignant and malignant tumors. Assessment of COX-2 protein in vivo, therefore, promises to be a powerful strategy to distinguish pathologic cells from normal cells in a complex disease setting. Herein, we report the first redox-activatable COX-2 probe, fluorocoxib Q (FQ), for in vivo molecular imaging of pathogenesis. FQ inhibits COX-2 selectively in purified enzyme and cell-based assays. FQ exhibits extremely low fluorescence and displays time- and concentration-dependent fluorescence enhancement upon exposure to a redox environment. FQ enters the cells freely and binds to the COX-2 enzyme. FQ exhibits high circulation half-life and metabolic stability sufficient for target site accumulation and demonstrates COX-2-targeted uptake and retention in cancer cells and pathologic tissues. Once taken up, it undergoes redox-mediated transformation into a fluorescent compound fluorocoxib Q-H that results in high signal-to-noise contrast and differentiates pathologic tissues from non-pathologic tissues for real-time in vivo imaging.
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Affiliation(s)
- Md. Jashim Uddin
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Justin Han-Je Lo
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 USA
| | - Connor G. Oltman
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Brenda C. Crews
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Tamanna Huda
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Justin Liu
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
- Department of Neuroscience, Columbia University, New York City, New York, 10027 USA
| | - Philip J. Kingsley
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Shuyang Lin
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Mathew Milad
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Ansari M. Aleem
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Abu Asaduzzaman
- Department of Electrical Engineering and Computer Science, Wichita State University, Wichita, Kansas 67260 USA
| | - J. Oliver McIntyre
- Departments of Radiology and Radiological Sciences, and Pharmacology, Vanderbilt Institute of Imaging Science, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 USA
| | - Craig L. Duvall
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Lawrence J. Marnett
- Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 USA
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Exploring the composition of Syringa reticulata subsp. amurensis seed and its underlying mechanism against chronic bronchitis. CHINESE JOURNAL OF ANALYTICAL CHEMISTRY 2022. [DOI: 10.1016/j.cjac.2022.100132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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15
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Medina-Díaz IM, Ponce-Ruíz N, Rojas-García AE, Zambrano-Zargoza JF, Bernal-Hernández YY, González-Arias CA, Barrón-Vivanco BS, Herrera-Moreno JF. The Relationship between Cancer and Paraoxonase 1. Antioxidants (Basel) 2022; 11:antiox11040697. [PMID: 35453382 PMCID: PMC9028432 DOI: 10.3390/antiox11040697] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 12/13/2022] Open
Abstract
Extensive research has been carried out to understand and elucidate the mechanisms of paraoxonase 1 (PON1) in the development of diseases including cancer, cardiovascular diseases, neurological diseases, and inflammatory diseases. This review focuses on the relationship between PON1 and cancer. The data suggest that PON1, oxidative stress, chronic inflammation, and cancer are closely linked. Certainly, the gene expression of PON1 will remain challenging to study. Therefore, targeting PON1, redox-sensitive pathways, and transcription factors promise prevention and therapy in the development of several diseases, including cancer.
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Affiliation(s)
- Irma Martha Medina-Díaz
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Tepict 63000, Mexico; (N.P.-R.); (A.E.R.-G.); (Y.Y.B.-H.); (C.A.G.-A.); (B.S.B.-V.); (J.F.H.-M.)
- Correspondence:
| | - Néstor Ponce-Ruíz
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Tepict 63000, Mexico; (N.P.-R.); (A.E.R.-G.); (Y.Y.B.-H.); (C.A.G.-A.); (B.S.B.-V.); (J.F.H.-M.)
| | - Aurora Elizabeth Rojas-García
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Tepict 63000, Mexico; (N.P.-R.); (A.E.R.-G.); (Y.Y.B.-H.); (C.A.G.-A.); (B.S.B.-V.); (J.F.H.-M.)
| | | | - Yael Y. Bernal-Hernández
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Tepict 63000, Mexico; (N.P.-R.); (A.E.R.-G.); (Y.Y.B.-H.); (C.A.G.-A.); (B.S.B.-V.); (J.F.H.-M.)
| | - Cyndia Azucena González-Arias
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Tepict 63000, Mexico; (N.P.-R.); (A.E.R.-G.); (Y.Y.B.-H.); (C.A.G.-A.); (B.S.B.-V.); (J.F.H.-M.)
| | - Briscia S. Barrón-Vivanco
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Tepict 63000, Mexico; (N.P.-R.); (A.E.R.-G.); (Y.Y.B.-H.); (C.A.G.-A.); (B.S.B.-V.); (J.F.H.-M.)
| | - José Francisco Herrera-Moreno
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Tepict 63000, Mexico; (N.P.-R.); (A.E.R.-G.); (Y.Y.B.-H.); (C.A.G.-A.); (B.S.B.-V.); (J.F.H.-M.)
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16
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Biotechnological Advances in Pharmacognosy and In Vitro Manipulation of Pterocarpus marsupium Roxb. PLANTS 2022; 11:plants11030247. [PMID: 35161227 PMCID: PMC8839240 DOI: 10.3390/plants11030247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 11/17/2022]
Abstract
Trees are vital resources for economic, environmental, and industrial growth, supporting human life directly or indirectly through a wide variety of therapeutic compounds, commodities, and ecological services. Pterocarpus marsupium Roxb. (Fabaceae) is one of the most valuable multipurpose forest trees in India and Sri Lanka, as it is cultivated for quality wood as well as pharmaceutically bioactive compounds, especially from the stem bark and heartwood. However, propagation of the tree in natural conditions is difficult due to the low percentage of seed germination coupled with overexploitation of this species for its excellent multipurpose properties. This overexploitation has ultimately led to the inclusion of P. marsupium on the list of endangered plant species. However, recent developments in plant biotechnology may offer a solution to the overuse of such valuable species if such advances are accompanied by technology transfer in the developing world. Specifically, techniques in micropropagation, genetic manipulation, DNA barcoding, drug extraction, delivery, and targeting as well as standardization, are of substantial concern. To date, there are no comprehensive and detailed reviews of P. marsupium in terms of biotechnological research developments, specifically pharmacognosy, pharmacology, tissue culture, authentication of genuine species, and basic gene transfer studies. Thus, the present review attempts to present a comprehensive overview of the biotechnological studies centered on this species and some of the recent novel approaches for its genetic improvement.
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17
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Abdelgawad MA, Al-Sanea MM, Musa A, Elmowafy M, El-Damasy AK, Azouz AA, Ghoneim MM, Bakr RB. Docking Study, Synthesis, and Anti-Inflammatory Potential of Some New Pyridopyrimidine-Derived Compounds. J Inflamm Res 2022; 15:451-463. [PMID: 35125880 PMCID: PMC8807947 DOI: 10.2147/jir.s343263] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 01/07/2022] [Indexed: 12/31/2022] Open
Abstract
Background and Purpose Because of gastrointestinal irritation and kidney toxicity associated with non-steroidal anti-inflammatory drugs and the cardiovascular problems of Coxibs use, developing novel anti-inflammatory agents with reduced toxicity and improved selectivity remains a major challenge. Depending on our previous work, a novel series of pyridopyrimidinones IIIa-i has been synthesized via reaction of 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (I) and phenyldiazenyl aromatic aldehydes (IIa-i). All the new constructed compounds were fully characterized by elemental and spectral analysis. Methods The target compounds IIIa–i were investigated for their potential towards COX inhibition, anti-inflammatory properties using carrageenan induced edema model in rat paw, and the ulcer indices of the most active members. Results The ethyl pyridopyrmidinone-benzoates IIIf, IIIg and IIIh showed superior inhibitory activity of carrageenan induced edema to celecoxib. Furthermore, the pyridopyrimidinones IIId, IIIf, IIIg, and IIIi exerted improved COX-2 inhibitory activity (IC50 = 0.67–1.02 µM) comparing to celecoxib (IC50 = 1.11 µM). Moreover, the gastric ulcerogenic potential assay of compounds IIIf–h revealed their lower ulcerogenic liability than indomethacin with comparable effect to celecoxib. Conclusion Virtual docking investigation of the most active candidates IIId, IIIf, IIIg and IIIi in the active site of COX-2 enzyme showed that these compounds implied interaction and binding motif similar to the cocrystallized ligand bromocelecoxib.
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Affiliation(s)
- Mohamed A Abdelgawad
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al Jouf, 72341, Saudi Arabia
- Correspondence: Mohamed A Abdelgawad, Tel +966595435214, Fax +966-14 2317958, Email ;
| | - Mohammad M Al-Sanea
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al Jouf, 72341, Saudi Arabia
| | - Arafa Musa
- Department of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka, 72341, Saudi Arabia
| | - Mohammed Elmowafy
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
| | - Ashraf K El-Damasy
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Amany A Azouz
- Department of Pharmacology and Toxicology, Beni-Suef University, Beni-Suef, 62514, Egypt
| | - Mohammed M Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah, 13713, Saudi Arabia
| | - Rania B Bakr
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni- Suef, 62514, Egypt
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18
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Hamid I, Nadeem H, Ansari SF, Khiljee S, Abbasi I, Bukhari A, Arif M, Imran M. 2-Substituted Benzoxazoles as Potent Anti-Inflammatory Agents: Synthesis, Molecular Docking and In Vivo Anti-Ulcerogenic Studies. Med Chem 2021; 18:791-809. [PMID: 34931968 DOI: 10.2174/1573406418666211220125344] [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: 09/08/2021] [Revised: 10/25/2021] [Accepted: 10/31/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonly used therapeutic interventions of inflammation and pain that competitively inhibit the cyclooxygenase (COX) enzymes. Several side effects like gastrointestinal and renal toxicities are associated with the use of these drugs. The therapeutic anti-inflammatory benefits of NSAIDs are produced by the inhibition of COX-2 enzymes, while undesirable side effects arise from the inhibition of COX-1 enzymes. OBJECTIVES In the present study, a new series of 2-substituted benzoxazole derivatives 2(a-f) and 3(a-e) were synthesized in our lab as potent anti-inflammatory agents with outstanding gastro-protective potential. The new analogs 2(a-f) and 3(a-e) were designed depending upon the literature review to serve as ligands for the development of selective COX-2 inhibitors. METHODS The synthesized analogs were characterized using different spectroscopic techniques (FTIR, 1HNMR, 13CNMR) and elemental analysis. All synthesized compounds were screened for their binding potential in the protein pocket of COX-2 and evaluated for their anti-inflammatory potential in animals using the carrageenan-induced paw edema method. Further 5 compounds were selected to assess the in vivo anti-ulcerogenic activity in an ethanol-induced anti-ulcer rat model. RESULTS Five compounds (2a, 2b, 3a, 3b and 3c) exhibited potent anti-inflammatory activity and significant binding potential in the COX-2 protein pocket. Similarly, these five compounds demonstrated a significant gastro-protective effect (p<0.01) in comparison to the standard drug, Omeprazole. CONCLUSION Depending upon our results, we hypothesize that 2-substituted benzoxazole derivatives have excellent potential to serve as candidates for the development of selective anti-inflammatory agents (COX-2 inhibitors). However, further assessments are required to delineate their underlying mechanisms.
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Affiliation(s)
- Iqra Hamid
- Riphah Institute of Pharmaceutical Sciences, Riphah International University Islamabad, 44000, Pakistan
| | - Humaira Nadeem
- Riphah Institute of Pharmaceutical Sciences, Riphah International University Islamabad, 44000, Pakistan
| | - Sameen Fatima Ansari
- Riphah Institute of Pharmaceutical Sciences, Riphah International University Islamabad, 44000, Pakistan
| | - Sonia Khiljee
- Shahida Islam College of Pharmacy, Lodhran, Punjab , Pakistan
| | - Inzamam Abbasi
- Department of Chemistry, Quaid-e-Azam University Islamabad, 44000, Pakistan
| | - Asma Bukhari
- Riphah Institute of Pharmaceutical Sciences, Riphah International University Islamabad, 44000, Pakistan
| | - Muazzam Arif
- Riphah Institute of Pharmaceutical Sciences, Riphah International University Islamabad, 44000, Pakistan
| | - Muhammad Imran
- Department of Pharmacy, Iqra University Islamabad Campus, Islamabad 44000, Pakistan
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Precision Autism: Genomic Stratification of Disorders Making Up the Broad Spectrum May Demystify Its "Epidemic Rates". J Pers Med 2021; 11:jpm11111119. [PMID: 34834471 PMCID: PMC8620644 DOI: 10.3390/jpm11111119] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/16/2022] Open
Abstract
In the last decade, Autism has broadened and often shifted its diagnostics criteria, allowing several neuropsychiatric and neurological disorders of known etiology. This has resulted in a highly heterogeneous spectrum with apparent exponential rates in prevalence. I ask if it is possible to leverage existing genetic information about those disorders making up Autism today and use it to stratify this spectrum. To that end, I combine genes linked to Autism in the SFARI database and genomic information from the DisGeNET portal on 25 diseases, inclusive of non-neurological ones. I use the GTEx data on genes’ expression on 54 human tissues and ask if there are overlapping genes across those associated to these diseases and those from SFARI-Autism. I find a compact set of genes across all brain-disorders which express highly in tissues fundamental for somatic-sensory-motor function, self-regulation, memory, and cognition. Then, I offer a new stratification that provides a distance-based orderly clustering into possible Autism subtypes, amenable to design personalized targeted therapies within the framework of Precision Medicine. I conclude that viewing Autism through this physiological (Precision) lens, rather than viewing it exclusively from a psychological behavioral construct, may make it a more manageable condition and dispel the Autism epidemic myth.
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20
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Loganathan Y, Jain M, Thiyagarajan S, Shanmuganathan S, Mariappan SK, Kizhakedathil MPJ, Saravanakumar T. An Insilico evaluation of phytocompounds from Albizia amara and Phyla nodiflora as cyclooxygenase-2 enzyme inhibitors. ACTA ACUST UNITED AC 2021; 29:311-320. [PMID: 34415547 DOI: 10.1007/s40199-021-00408-6] [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: 03/30/2021] [Accepted: 07/14/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE The enzyme Cyclooxygenases (COX-1 and COX-2) catalyze the formation of prostaglandin, a mediator of the inflammatory pathway. Inflammation related pathological conditions may be alleviated by targeting the Cox enzymes.COX-2 inhibitors that are currently available in the market causes undesirable side effects. Our present study focuses on the in-silico inhibition of COX -2 enzyme by the phytocompounds from Albizia amara and Phyla nodiflora. METHODS The phytochemicals present in Albizia amara and Phyla nodiflora were analyzed for their COX-2 inhibition potential. Eight compounds from Albizia amara and eleven compounds from Phyla nodiflora obtained from GC-MS analysis was used for the current study. Molecular docking was performed using AutoDock vina. The crystal structure of COX-2 (PDB ID: 5IKR) was obtained from Protein data bank. PyMol was used to remove any solvent, organic and inorganic molecules. Energy minimization of the protein was carried out using SPDBV software. Geometrical optimizations of the ligands were performed using Avogadro software. Celecoxib was used as the positive control. ADMET properties of the compounds were analyzed using SwissADME and ProtoxII online servers. Molecular mechanics/generalized born surface area (MM/GBSA) calculations were performed to evaluate the binding efficiency. Molecular dynamics of the protein and protein-ligand complex was studied for about 100 ns using Desmond package of Schrodinger suite. RESULTS Among the eighteen compounds, Squalene present in both the plants showed a better binding energy of -7.7 kcal/mol, when compare to other phytocompounds present in the extract. The control celecoxib showed a binding energy of about - 9.4 kcal/mol. The toxicity and ADMET properties of squalene indicated that it is non-toxic and followed Lipinski's rule. Molecular Dynamics (MD) analysis showed that the binding of squalene to the enzyme was stable. CONCLUSION Squalene could potentially inhibit COX2 and o wing to its properties, squalene can be formulated in gels/creams and could be possibly used for external edema and inflammation.
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Affiliation(s)
- Yukeswaran Loganathan
- Department of Biotechnology, Bannari Amman Institute of Technology, Sathyamangalam, Erode, Tamil Nadu, India, 638401
| | - Manav Jain
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, 160012
| | - Subhashini Thiyagarajan
- Department of Biotechnology, Bannari Amman Institute of Technology, Sathyamangalam, Erode, Tamil Nadu, India, 638401
| | - Shreeranjana Shanmuganathan
- Department of Biotechnology, Bannari Amman Institute of Technology, Sathyamangalam, Erode, Tamil Nadu, India, 638401
| | - Suresh Kumar Mariappan
- Department of Biotechnology, Bannari Amman Institute of Technology, Sathyamangalam, Erode, Tamil Nadu, India, 638401
| | - Moni Philip Jacob Kizhakedathil
- Department of Biotechnology, Bannari Amman Institute of Technology, Sathyamangalam, Erode, Tamil Nadu, India, 638401.,Bioinformatics Laboratory, Department of Biotechnology, Bannari Amman Institute of Technology, Sathyamangalam, Erode, Tamil Nadu, India, 638401
| | - Tamilselvi Saravanakumar
- Department of Biotechnology, Bannari Amman Institute of Technology, Sathyamangalam, Erode, Tamil Nadu, India, 638401.
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21
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Copeland RA. Chance Favors the Perplexed Mind: The Critical Role of Mechanistic Biochemistry in Drug Discovery. Biochemistry 2021; 60:2275-2284. [PMID: 34259514 DOI: 10.1021/acs.biochem.1c00345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Scientific discoveries often start with an observation that does not quite make sense, within the framework of a well-established hypothesis. It is when researchers delve deeply to understand such perplexing data that established hypotheses are modified or replaced, and new and expanded knowledge of the system can be gained. This is often the case in the field of drug discovery. In this Perspective, case studies demonstrate how an understanding of perplexing data can lead to novel discoveries regarding the biological function of drug targets, or the mechanisms of compound-target interactions, that can ultimately result in new drugs entering the clinic. These case studies reinforce two interdependent themes: (1) that understanding the pathophysiological context in which drug targets function and the mechanistic details of drug-target interactions are critical to efficient and effective drug discovery and (2) that investing time and energy into following up on perplexing data can lead to novel discoveries that can drive the development of new and improved medicines.
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Affiliation(s)
- Robert A Copeland
- Accent Therapeutics, Inc., 65 Hayden Avenue, Lexington, Massachusetts 02421, United States
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22
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Monteiro de Barros MR, Davies-Morel MCG, Mur LAJ, Creevey CJ, Alison RH, Nash DM. Characterization of an Ex Vivo Equine Endometrial Tissue Culture Model Using Next-Generation RNA-Sequencing Technology. Animals (Basel) 2021; 11:ani11071995. [PMID: 34359123 PMCID: PMC8300099 DOI: 10.3390/ani11071995] [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: 05/26/2021] [Revised: 06/21/2021] [Accepted: 06/30/2021] [Indexed: 11/30/2022] Open
Abstract
Simple Summary Notwithstanding extensive research into fertility problems in mares, pregnancy rates have remained low mainly because of endometrial inflammation (endometritis). In the field of equine research, endometrial explants have been used to carry out in vitro studies of the mare’s endometrium. However, there has been no wide-ranging assessment of relative stability of this model over time. The aim of this study was to perform an in-depth transcriptomic assessment of endometrial explants over a culture period of 72 h and assess if they are representative of the whole mare. Explants at 24 h demonstrated significant changes when compared to biopsies at 0 h as expected. Even though gene expression changes were seen between 24 and 48 h of culture, prior to this window changes were dominated by the effects of explanting and culture and subsequently, transcription was generally compromised. Our results, therefore have defined the optimal period when explants can be used to study equine endometritis and how the endometrium is modulated during inflammation. It highlights the use of abattoir derived samples to understand the physiology and pathophysiology of the equine endometrium, negating the need to collect repeated uterine biopsies from living mares. Abstract Persistent mating-induced endometritis is a major cause of poor fertility rates in the mare. Endometritis can be investigated using an ex vivo equine endometrial explant system which measures uterine inflammation using prostaglandin F2α as a biomarker. However, this model has yet to undergo a wide-ranging assessment through transcriptomics. In this study, we assessed the transcriptomes of cultured endometrial explants and the optimal temporal window for their use. Endometrium harvested immediately post-mortem from native pony mares (n = 8) were sampled (0 h) and tissue explants were cultured for 24, 48 and 72 h. Tissues were stored in RNALater, total RNA was extracted and sequenced. Differentially expressed genes (DEGs) were defined using DESeq2 (R/Bioconductor). Principal component analysis indicated that the greatest changes in expression occurred in the first 24 h of culture when compared to autologous biopsies at 0 h. Fewer DEGs were seen between 24 and 48 h of culture suggesting the system was more stable than during the first 24 h. No genes were differentially expressed between 48 and 72 h but the low number of background gene expression suggested that explant viability was compromised after 48 h. ESR1, MMP9, PTGS2, PMAIP1, TNF, GADD45B and SELE genes were used as biomarkers of endometrial function, cell death and inflammation across tissue culture timepoints. STRING assessments of gene ontology suggested that DEGs between 24 and 48 h were linked to inflammation, immune system, cellular processes, environmental information processing and signal transduction, with an upregulation of most biomarker genes at 24 h. Taken together our observations indicated that 24–48 h is the optimal temporal window when the explant model can be used, as explants restore microcirculation, perform wound healing and tackle inflammation during this period. This key observation will facilitate the appropriate use of this as a model for further research into the equine endometrium and potentially the progression of mating-induced endometritis to persistent inflammation between 24 and 48 h.
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Affiliation(s)
- Maithê R. Monteiro de Barros
- Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth SY23 3FG, UK; (M.C.G.D.-M.); (L.A.J.M.); (D.M.N.)
- Correspondence:
| | - Mina C. G. Davies-Morel
- Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth SY23 3FG, UK; (M.C.G.D.-M.); (L.A.J.M.); (D.M.N.)
| | - Luis A. J. Mur
- Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth SY23 3FG, UK; (M.C.G.D.-M.); (L.A.J.M.); (D.M.N.)
| | - Christopher J. Creevey
- Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast BT7 1NN, UK;
| | - Roger H. Alison
- Pathology Consultancy Services, Caerfyrddin Fach, Cilcennin, Lampeter SA48 8RN, UK;
| | - Deborah M. Nash
- Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth SY23 3FG, UK; (M.C.G.D.-M.); (L.A.J.M.); (D.M.N.)
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23
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Kumari P, Singh P, Kaur J, Bhatti R. Design, Synthesis, and Activity Evaluation of Stereoconfigured Tartarate Derivatives as Potential Anti-inflammatory Agents In Vitro and In Vivo. J Med Chem 2021; 64:9550-9566. [PMID: 34137625 DOI: 10.1021/acs.jmedchem.1c00880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Preclinical and clinical data reveal that inflammation is strongly correlated with the pathogenesis of a number of diseases including those of cancer, Alzheimer, and diabetes. The inflammatory cascade involves a multitude of cytokines ending ultimately with the activation of COX-2/LOX for the production of prostaglandins and leukotrienes. While the available inhibitors for these enzymes suffer from nonoptimal selectivity, in particular for COX-2, we present here the results of purposely designed tartarate derivatives that exhibit favorable selectivity and significant effectiveness against COX-2 and LOX. Integrated approaches of molecular simulation, organic synthesis, and biochemical/physical experiments identified 15 inhibiting COX-2 and LOX with respective IC50 4 and 7 nM. At a dose of 5 mg kg-1 to Swiss albino mice, 15 reversed algesia by 65% and inflammation by 33% in 2-3 h. We find good agreement between experiments and simulations and use the simulations to rationalize our observations.
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24
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Marahatha R, Gyawali K, Sharma K, Gyawali N, Tandan P, Adhikari A, Timilsina G, Bhattarai S, Lamichhane G, Acharya A, Pathak I, Devkota HP, Parajuli N. Pharmacologic activities of phytosteroids in inflammatory diseases: Mechanism of action and therapeutic potentials. Phytother Res 2021; 35:5103-5124. [PMID: 33957012 DOI: 10.1002/ptr.7138] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 04/05/2021] [Accepted: 04/10/2021] [Indexed: 12/13/2022]
Abstract
Natural products and their derivatives are known to be useful for treating numerous diseases since ancient times. Because of their high therapeutic potentials, the use of different medicinal plants is possible to treat varied inflammation-mediated chronic diseases. Among natural products, phytosteroids have emerged as promising compounds mostly because they have diverse pharmacological activities. Currently, available medications exert numerous systemic toxicities, including hypertension, immune suppression, osteoporosis, and metabolic abnormalities. Thus, further research on phytosteroids to subside these complications is of significant importance. In this study, the information on phytosteroids, their types, and actions against inflammation, and allergic complications was collected by a systematic survey of literature on several scientific search engines. The literature review suggested that phytosteroids exhibit antiinflammatory action via different modes through transrepression or selective COX-2 enzymes. Also, in silico ADMET analysis was carried out on available phytosteroids to uncover their pharmacokinetic properties. Our analysis has shown that eight compounds: withaferin A, stigmasterol, β-sitosterol, guggulsterone, diosgenin, sarsasapogenin, physalin A, and dioscin, -isolated from medicinal plants show similar pharmacokinetic properties as compared to dexamethasone, commercially available glucocorticoid. These phytosteroids could be useful for the treatment of inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, asthma, and cardiovascular diseases. Thus, systematic research is required to explore potent phytosteroids with lesser side effects, which might substitute the current medications.
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Affiliation(s)
- Rishab Marahatha
- Biological Chemistry Lab, Central Department of Chemistry, Tribhuvan University, Kirtipur, Nepal
| | - Kabita Gyawali
- Biological Chemistry Lab, Central Department of Chemistry, Tribhuvan University, Kirtipur, Nepal
| | - Kabita Sharma
- Biological Chemistry Lab, Central Department of Chemistry, Tribhuvan University, Kirtipur, Nepal
| | - Narayan Gyawali
- Biological Chemistry Lab, Central Department of Chemistry, Tribhuvan University, Kirtipur, Nepal
| | - Parbati Tandan
- Biological Chemistry Lab, Central Department of Chemistry, Tribhuvan University, Kirtipur, Nepal
| | - Ashma Adhikari
- Biological Chemistry Lab, Central Department of Chemistry, Tribhuvan University, Kirtipur, Nepal
| | - Grishma Timilsina
- Biological Chemistry Lab, Central Department of Chemistry, Tribhuvan University, Kirtipur, Nepal
| | - Salyan Bhattarai
- Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Canada
| | - Ganesh Lamichhane
- Biological Chemistry Lab, Central Department of Chemistry, Tribhuvan University, Kirtipur, Nepal
| | - Ashis Acharya
- Central Department of Geology, Tribhuvan University, Kirtipur, Nepal
| | - Ishwor Pathak
- Department of Chemistry, Amrit Campus, Tribhuvan University, Thamel, Nepal
| | - Hari Prasad Devkota
- Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Niranjan Parajuli
- Biological Chemistry Lab, Central Department of Chemistry, Tribhuvan University, Kirtipur, Nepal
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25
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Synthesis of new hexahydropyrimido[1,2- a]azepine derivatives bearing functionalized aryl and heterocyclic moieties as anti-inflammatory agents. Future Med Chem 2021; 13:625-641. [PMID: 33624540 DOI: 10.4155/fmc-2020-0298] [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] [Indexed: 12/18/2022] Open
Abstract
New hexahydropyrimido[1,2-a]azepine derivatives bearing functionalized aryl and heterocyclic moieties were synthesized as anti-inflammatory agents with better safety profiles. All synthesized compounds were assessed in vitro for their COX-1 and COX-2 inhibition activities. The most selective compounds, 2f, 5 and 6, were further evaluated for their in vivo anti-inflammatory activity and PGE2 inhibitory activity. To rationalize their selectivity, molecular docking within COX-1 and COX-2 binding sites was performed. Their physicochemical properties and drug-like nature profile were also calculated. The good activity and selectivity of compounds 2f, 5 and 6 were rationalized using a molecular docking study and supported by in vivo studies. These promising findings are encouraging for performing future investigations of these derivatives.
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26
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Fan X, Guo X, Li Y, Xu M. Utilizing Network Pharmacology to Explore the Possible Mechanism of Coptidis Rhizoma in Kawasaki Disease. Front Pediatr 2021; 9:708553. [PMID: 34589453 PMCID: PMC8473743 DOI: 10.3389/fped.2021.708553] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/17/2021] [Indexed: 12/20/2022] Open
Abstract
Background: The purpose of the research is to identify the main active ingredients in Coptidis Rhizoma (CR) and explore the possible molecular mechanisms in the treatment of Kawasaki disease (KD). Materials and Methods: A total of 58 children with KD were randomly divided into a control group and a Berberine treatment group. The therapeutic indicators of the two groups before and after treatment were compared. Then, compounds and drug targets of CR from the TCMSP, SWISS, SEA, and the STITCH were collected, and targeted KD genes were retrieved from the DisGeNET, DrugBank, and GeneCards databases. The network pharmacology approach involved network construction, target prediction, and module analysis. GO and KEGG enrichment analysis were performed to investigate the possible pathways related to CR for KD treatments. Finally, protein expression was determined to verify the core targets using Western blotting in the cell experiment. Results: In total, nine compounds, 369 relative drug targets, and 624 KD target genes were collected in the above database. The network analysis revealed that 41 targets might be the therapeutic targets of CR on KD. GO and KEGG enrichment analysis revealed that the biological processes, namely, response to hormone, response to inorganic substance, and enzyme-linked receptor protein signaling pathway, and Pathways in cancer, Toll-like receptor signaling pathway, and Pancreatic cancer are the most significant. Protein expression of CASP3, PTGS2, and SRC was upregulated and AKT1 and ERK were downregulated. Conclusion: We provided useful resources to understand the molecular mechanism and the potential targets for novel therapy of KD.
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Affiliation(s)
- Xue Fan
- Department of Pediatric Cardiology, Shenzhen Children's Hospital, China Medical University, Shenzhen, China
| | - Xin Guo
- Department of Pediatric, Longgang District Maternal and Children Health Care Hospital, Shenzhen, China
| | - Ying Li
- Department of Pediatric Cardiology, Shenzhen Children's Hospital, China Medical University, Shenzhen, China
| | - Mingguo Xu
- Department of Pediatric, Longgang District Maternal and Children Health Care Hospital, Shenzhen, China
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Ali H, Khan A, Ali J, Ullah H, Khan A, Ali H, Irshad N, Khan S. Attenuation of LPS-induced acute lung injury by continentalic acid in rodents through inhibition of inflammatory mediators correlates with increased Nrf2 protein expression. BMC Pharmacol Toxicol 2020; 21:81. [PMID: 33239093 PMCID: PMC7687815 DOI: 10.1186/s40360-020-00458-7] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 11/05/2020] [Indexed: 01/11/2023] Open
Abstract
Background Acute lung injury (ALI) together with acute respiratory distress syndrome (ARDS) are associated with high rate of mortality and morbidity in patients. In the current study, the anti-inflammatory effects of continentalic acid (CNT) in LPS-induced acute lung injury model was explored. Methods The acute lung injury model was established by administering LPS (5 mg/kg) intraperitonealy. Following LPS administration, the survival rate, temperature changes and lung Wet/Dry ratio were assessed. The antioxidants (GSH, GST, Catalase and SOD) and oxidative stress markers (MDA, NO, MPO) were evaluated in all the treated groups. Similarly, the cytokines such as IL-1β, IL-6 and TNF-α were analyzed using ELISA assay. The histological changes were determined using H and E staining, while Nrf2 and iNOS level were determined using immunohistochemistry analysis. The molecular docking analysis was performed to assess the pharmacokinetics parameters and interaction of the CNT with various protein targets. Results The results showed that CNT dose dependently (10, 50 and 100 mg/kg) reduced mortality rate, body temperature and lungs Wet/Dry ratio. CNT post-treatment significantly inhibited LPS-induced production of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. The CNT post-treatment markedly improved the hematological parameters, while significantly reduced the MPO (indicator of the neutrophilic infiltration) activity compared to the LPS treated group. Furthermore, the CNT (100 mg/kg) post-administration remarkably inhibited the lung Wet/Dry ratio. The CNT (100 mg/kg) treated group showed marked reduction in the oxidative stress markers such as malonaldehyde (MDA) and Nitric oxide (NO) concentration, while induced the level of the anti-oxidant enzymes such as GST, GSH, Catalase and SOD. Similarly, the CNT markedly reduced the iNOS expression level, while induced the Nrf2 protein expression. Additionally, the molecular docking study showed significant binding interaction with the Nrf2, p65, Keap1, HO-1, IL-1β, IL-6, TNF-α and COX-2, while exhibited excellent physicochemical properties. Conclusion The CNT showed marked protection against the LPS-induced lung injury and improved the behavioral, biochemical and histological parameters. Furthermore, the CNT showed significant interaction with several protein targets and exhibited better physicochemical properties.
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Affiliation(s)
- Hassan Ali
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Ashrafullah Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Jawad Ali
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Hadayat Ullah
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Adnan Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Hussain Ali
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Nadeem Irshad
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Salman Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Clark MOC, Stahl TC, Erickson PS. The effect of meloxicam on neonatal dairy calves: Immunoglobulin G uptake and preweaning performance. J Dairy Sci 2020; 103:11363-11374. [PMID: 33041029 PMCID: PMC7544632 DOI: 10.3168/jds.2020-18501] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 07/30/2020] [Indexed: 11/19/2022]
Abstract
Objectives of this study were to determine effects of meloxicam administered in 2 forms on IgG uptake, growth, and health of preweaned calves. Sixteen Holstein bulls and 14 heifers with a body weight (BW) of 44.3 ± 5.24 kg were blocked by birth date in a randomized complete block design. Calves were removed from the dam before suckling, weighed, and randomly assigned to 1 of 3 treatments: (1) colostrum replacer (CR) at 0 h with no meloxicam (control; CON), (2) 1 mg/kg of BW of meloxicam in pill form before CR (PL), or (3) 1 mg/kg of BW of meloxicam mixed in solution with CR (SL). Calves were fed 675 g of dry matter of CR, providing a volume of 3 L and 180 g of IgG. Blood samples were collected at 0 h to analyze initial IgG and ketone concentrations, and at 6, 12, 18, and 24 h to analyze IgG uptake. At 24 h, calves were fed 432 g of dry matter of 24% crude protein milk replacer (MR) split in 2 feedings, and free choice starter and water until 42 d. Weekly blood samples were analyzed for glucose, plasma urea nitrogen, and ketone concentrations. Time of consumption of MR, BW, length, hip and withers height, and heart girth were recorded weekly. All calves achieved adequate transfer of immunity. Meloxicam did not affect apparent efficiency of absorption, serum total protein, or IgG uptake at 6, 18, and 24 h; however, meloxicam-treated calves had lesser IgG concentrations at 12 h (24.40 and 22.59 g/L for PL and SL, respectively) compared with CON (28.47 g/L). Meloxicam treatment did not affect BW. Calves that received PL tended to gain length at a faster rate (0.24 cm/d) than those that received SL (0.19 cm/d). Meloxicam treatment did not affect MR intake, time of consumption of MR, total dry matter intake, or feed efficiency. Meloxicam-treated calves tended to consume more starter (560.4 and 515.4 g/d for PL and SL, respectively) than those that received CON (452.6 g/d). Ketone levels tended to be greater in meloxicam-treated calves (0.15 and 0.17 mmol/L for PL and SL, respectively), suggesting improved rumen development compared with those that received CON (0.12 mmol/L). Meloxicam treatment did not affect plasma urea nitrogen . Glucose concentrations of calves that received PL (73.2 mg/dL) were less than those that received SL (83.3 mg/dL). Results of this study suggest that meloxicam given at 0 h offers positive effects on starter intake, and possibly rumen development, of preweaned dairy calves. Treatment PL, as compared with SL, offered positive results for rumen development, indicated by lower blood glucose levels.
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Affiliation(s)
- M O C Clark
- Department of Agriculture, Nutrition, and Food Systems, University of New Hampshire, Durham, 03824
| | - T C Stahl
- Department of Agriculture, Nutrition, and Food Systems, University of New Hampshire, Durham, 03824
| | - P S Erickson
- Department of Agriculture, Nutrition, and Food Systems, University of New Hampshire, Durham, 03824.
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Lopes D, Melo T, Rey F, Meneses J, Monteiro FL, Helguero LA, Abreu MH, Lillebø AI, Calado R, Domingues MR. Valuing Bioactive Lipids from Green, Red and Brown Macroalgae from Aquaculture, to Foster Functionality and Biotechnological Applications. Molecules 2020; 25:E3883. [PMID: 32858862 PMCID: PMC7504498 DOI: 10.3390/molecules25173883] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/20/2020] [Accepted: 08/20/2020] [Indexed: 01/18/2023] Open
Abstract
Marine edible macroalgae have functional proprieties that might improve human health and wellbeing. Lipids represent a minor fraction of macroalgae, yet with major interest as main carriers of omega 3 polyunsaturated fatty acids and intrinsic bioactive properties. In this study, we used lipid extracts from the green macroalgae Ulva rigida and Codium tomentosum; the red Gracilaria gracilis,Palmaria palmata and Porphyra dioica; and the brown Fucus vesiculosus, produced in a land-based integrated multitrophic aquaculture (IMTA) system. We determined the lipid quality indices based on their fatty acid profiles and their bioactivities as putative antioxidant, anti-inflammatory and antiproliferative agents. The results reveal to be species-specific, namely U. rigida displayed the lowest atherogenicity and thrombogenicity indices. Palmaria palmata and F. vesiculosus lipid extracts displayed the lowest inhibitory concentration in the free radical scavenging antioxidant assays. Ulva rigida, C. tomentosum, P. palmata and P. dioica inhibited COX-2 activity by up to 80%, while P. dioica and P. palmata extracts showed the highest cytotoxic potential in the MDA-MB-231 breast cancer cells. This work enhances the valorization of macroalgae as functional foods and promising ingredients for sustainable and healthy diets and fosters new applications of high-valued algal biomass, in a species-specific context.
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Affiliation(s)
- Diana Lopes
- Mass Spectrometry Centre, LAQV REQUIMTE, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal; (T.M.); (F.R.); (J.M.)
- Centre for Environmental and Marine Studies, CESAM, ECOMARE, Department of Biology, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal; (A.I.L.); (R.C.)
- Centre for Environmental and Marine Studies, CESAM, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal
| | - Tânia Melo
- Mass Spectrometry Centre, LAQV REQUIMTE, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal; (T.M.); (F.R.); (J.M.)
- Centre for Environmental and Marine Studies, CESAM, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal
| | - Felisa Rey
- Mass Spectrometry Centre, LAQV REQUIMTE, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal; (T.M.); (F.R.); (J.M.)
- Centre for Environmental and Marine Studies, CESAM, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal
| | - Joana Meneses
- Mass Spectrometry Centre, LAQV REQUIMTE, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal; (T.M.); (F.R.); (J.M.)
| | - Fátima Liliana Monteiro
- iBIMED-Institute of Biomedicine, Department of Medical Sciences, Universidade de Aveiro, Agra do Crasto, 3810-193 Aveiro, Portugal; (F.L.M.); (L.A.H.)
| | - Luisa A. Helguero
- iBIMED-Institute of Biomedicine, Department of Medical Sciences, Universidade de Aveiro, Agra do Crasto, 3810-193 Aveiro, Portugal; (F.L.M.); (L.A.H.)
| | - Maria Helena Abreu
- ALGAplus-Production and Trading of Seaweeds and Derived Products Lda., 3830-196 Ílhavo, Portugal;
| | - Ana Isabel Lillebø
- Centre for Environmental and Marine Studies, CESAM, ECOMARE, Department of Biology, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal; (A.I.L.); (R.C.)
| | - Ricardo Calado
- Centre for Environmental and Marine Studies, CESAM, ECOMARE, Department of Biology, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal; (A.I.L.); (R.C.)
| | - Maria Rosário Domingues
- Mass Spectrometry Centre, LAQV REQUIMTE, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal; (T.M.); (F.R.); (J.M.)
- Centre for Environmental and Marine Studies, CESAM, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal
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Wan Mohd Kamaluddin WNF, Rismayuddin NAR, Ismail AF, Mohamad Aidid E, Othman N, Mohamad NAH, Arzmi MH. Probiotic inhibits oral carcinogenesis: A systematic review and meta-analysis. Arch Oral Biol 2020; 118:104855. [PMID: 32801092 DOI: 10.1016/j.archoralbio.2020.104855] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/23/2020] [Accepted: 07/26/2020] [Indexed: 02/06/2023]
Abstract
OBJECTIVES This systematic review aimed to investigate the effects if probiotics can inhibit oral carcinogenesis. DESIGN PubMed, Web of Science, Scopus, and PLOS databases were searched up to February 2020 to identify randomised controlled trials that fulfilled the eligibility criteria. Joanna Briggs Institute (JBI) Critical Appraisal Tool was used for quality assessment of articles. This review was performed according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA-P) 2015 protocol guidelines. RESULT The initial search retrieved 774 articles. Of these, only five articles were included in the qualitative synthesis. Two out of the five papers were further analysed for quantitative synthesis in meta-analysis. The majority of the included studies were found to be of "moderate quality". The qualitative synthesis found four probiotics that exhibited potential therapeutic effects in oral carcinogenesis, includingAcetobacter syzygii, AJ2, Lactobacillus plantarum, and Lactobacillus salivarius REN. Among them, the application of L. salivarius REN resulted in a 95 % lower risk for developing oral cancer (p < 0.05). CONCLUSION It is known that probiotics have the potential to inhibit oral carcinogenesis, thus supporting the hypothesis of the study. The ability of L. salivarius REN to inhibit the development of oral cancer suggested that this bacterium can be a potential inhibitory agent against oral carcinogenesis.
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Affiliation(s)
- Wan Nur Fatihah Wan Mohd Kamaluddin
- Department of Basic Medical Science, Kulliyyah of Nursing, International Islamic University Malaysia, Kuantan, Pahang, Malaysia; Cluster of Oral Cancer Research International Islamic University Malaysia (COCRII), International Islamic University Malaysia, Kuantan, Pahang, Malaysia
| | - Nurul Alia Risma Rismayuddin
- Department of Basic Medical Science, Kulliyyah of Nursing, International Islamic University Malaysia, Kuantan, Pahang, Malaysia; Cluster of Oral Cancer Research International Islamic University Malaysia (COCRII), International Islamic University Malaysia, Kuantan, Pahang, Malaysia
| | - Ahmad Faisal Ismail
- Department of Paediatric Dentistry and Public Health, Kulliyyah of Dentistry, International Islamic University Malaysia, Kuantan, Pahang, Malaysia; Cluster of Oral Cancer Research International Islamic University Malaysia (COCRII), International Islamic University Malaysia, Kuantan, Pahang, Malaysia
| | - Edre Mohamad Aidid
- Kulliyyah of Medicine, International Islamic University Malaysia, Pahang, Malaysia; Cluster of Oral Cancer Research International Islamic University Malaysia (COCRII), International Islamic University Malaysia, Kuantan, Pahang, Malaysia
| | - Noratikah Othman
- Department of Basic Medical Science, Kulliyyah of Nursing, International Islamic University Malaysia, Kuantan, Pahang, Malaysia; Cluster of Oral Cancer Research International Islamic University Malaysia (COCRII), International Islamic University Malaysia, Kuantan, Pahang, Malaysia
| | - Noor Afifah Hanin Mohamad
- Department of Basic Medical Science, Kulliyyah of Nursing, International Islamic University Malaysia, Kuantan, Pahang, Malaysia; Cluster of Oral Cancer Research International Islamic University Malaysia (COCRII), International Islamic University Malaysia, Kuantan, Pahang, Malaysia
| | - Mohd Hafiz Arzmi
- Department of Fundamental Dental and Medical Sciences, Kulliyyah of Dentistry, International Islamic University Malaysia, Kuantan, Pahang, Malaysia; Cluster of Oral Cancer Research International Islamic University Malaysia (COCRII), International Islamic University Malaysia, Kuantan, Pahang, Malaysia.
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Jang Y, Seo SH. Gene expression pattern differences in primary human pulmonary epithelial cells infected with MERS-CoV or SARS-CoV-2. Arch Virol 2020; 165:2205-2211. [PMID: 32651741 PMCID: PMC7348575 DOI: 10.1007/s00705-020-04730-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 06/11/2020] [Indexed: 01/08/2023]
Abstract
Coronaviruses such as MERS-CoV and SARS-CoV-2 infect the human respiratory tract and can cause severe pneumonia. Disease severity and outcomes are different for these two infections: the human mortality rate for MERS-CoV and SARS-CoV-2 is over 30% and less than 10%, respectively. Here, using microarray assay, we analyzed the global alterations in gene expression induced by MERS-CoV or SARS-CoV-2 infections in primary human pulmonary epithelial cells. Overall, the number of differentially expressed genes was higher in human lung cells infected with MERS-CoV than in cells with SARS-CoV-2. Out of 44,556 genes analyzed, 127 and 50 were differentially expressed in cells infected with MERS-CoV and SARS-CoV-2, respectively (> 2-fold increase, compared to uninfected cells). Of these, only eight genes, including the one coding for CXCL8, were similarly modulated (upregulated or downregulated) by the two coronaviruses. Importantly, these results were virus-specific and not conditioned by differences in viral load, and viral growth curves were similar in human lung cells infected with both viruses. Our results suggest that these distinct gene expression profiles, detected early after infection by these two coronaviruses, may help us understand the differences in clinical outcomes of MERS-CoV and SARS-CoV-2 infections.
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Affiliation(s)
- Yunyueng Jang
- Laboratory of Influenza Research, College of Veterinary Medicine, Chungnam National University, 99 Dae-Hak Ro, Yuseong Gu, Daejeon, 34134, Republic of Korea.,Institute of Influenza Virus, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Sang Heui Seo
- Laboratory of Influenza Research, College of Veterinary Medicine, Chungnam National University, 99 Dae-Hak Ro, Yuseong Gu, Daejeon, 34134, Republic of Korea. .,Institute of Influenza Virus, Chungnam National University, Daejeon, 34134, Republic of Korea.
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Park TY, Oh HC, Fogel EL, Lehman GA. Prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis with rectal non-steroidal anti-inflammatory drugs. Korean J Intern Med 2020; 35:535-543. [PMID: 32392660 PMCID: PMC7214369 DOI: 10.3904/kjim.2020.069] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 03/25/2020] [Indexed: 12/29/2022] Open
Abstract
Acute pancreatitis is the most common and feared adverse event associated with performance of endoscopic retrograde cholangiopancreatography (ERCP). Unremitting effort has been made for over 40 years to minimize the frequency and severity of this complication. Recently, the use of rectal non-steroidal anti-inflammatory drugs (NSAIDs) have opened a new era for its prevention. This review focuses on the role of NSAIDs in pancreatitis, the pharmacokinetics of these agents, and summarizes the results of clinical trials with rectal NSAIDs alone and combination regimens in the prevention of post-ERCP pancreatitis.
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Affiliation(s)
- Tae Young Park
- Department of Internal Medicine, Inje University Seoul Paik Hospital, Seoul, Korea
| | - Hyoung-Chul Oh
- Division of Gastroenterology, Chung-Ang University College of Medicine, Seoul, Korea
- Correspondence to Hyoung-Chul Oh, M.D. Division of Gastroenterology, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul 06973, Korea Tel: +82-2-6299-3149 Fax: +82-2-6299-3119 E-mail:
| | - Evan L. Fogel
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Glen A. Lehman
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
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Huang K, Masuda A, Chen G, Bushra S, Kamon M, Araki T, Kinoshita M, Ohkawara B, Ito M, Ohno K. Inhibition of cyclooxygenase-1 by nonsteroidal anti-inflammatory drugs demethylates MeR2 enhancer and promotes Mbnl1 transcription in myogenic cells. Sci Rep 2020; 10:2558. [PMID: 32054946 PMCID: PMC7018979 DOI: 10.1038/s41598-020-59517-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 01/30/2020] [Indexed: 12/12/2022] Open
Abstract
Muscleblind-like 1 (MBNL1) is a ubiquitously expressed RNA-binding protein, which is highly expressed in skeletal muscle. Abnormally expanded CUG-repeats in the DMPK gene cause myotonic dystrophy type 1 (DM1) by sequestration of MBNL1 to nuclear RNA foci and by upregulation of another RNA-binding protein, CUG-binding protein 1 (CUGBP1). We previously reported that a nonsteroidal anti-inflammatory drug (NSAID), phenylbutazone, upregulates MBNL1 expression in DM1 mouse model by demethylation of MeR2, an enhancer element in Mbnl1 intron 1. NSAIDs inhibit cyclooxygenase (COX), which is comprised of COX-1 and COX-2 isoforms. In this study, we screened 29 NSAIDs in C2C12 myoblasts, and found that 13 NSAIDs enhanced Mbnl1 expression, where COX-1-selective NSAIDs upregulated Mbnl1 more than COX-2-selective NSAIDs. Consistently, knockdown of COX-1, but not of COX-2, upregulated MBNL1 expression in C2C12 myoblasts and myotubes, as well as in myotubes differentiated from DM1 patient-derived induced pluripotent stem cells (iPSCs). Luciferase assay showed that COX-1-knockdown augmented the MeR2 enhancer activity. Furthermore, bisulfite sequencing analysis demonstrated that COX-1-knockdown suppressed methylation of MeR2. These results suggest that COX-1 inhibition upregulates Mbnl1 transcription through demethylation of the MeR2 enhancer. Taken together, our study provides new insights into the transcriptional regulation of Mbnl1 by the COX-1-mediated pathway.
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Affiliation(s)
- Kun Huang
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Akio Masuda
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
| | - Guiying Chen
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Samira Bushra
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Masayoshi Kamon
- Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
| | - Toshiyuki Araki
- Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
| | | | - Bisei Ohkawara
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Mikako Ito
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Kinji Ohno
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
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35
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Hajeyah AA, Griffiths WJ, Wang Y, Finch AJ, O’Donnell VB. The Biosynthesis of Enzymatically Oxidized Lipids. Front Endocrinol (Lausanne) 2020; 11:591819. [PMID: 33329396 PMCID: PMC7711093 DOI: 10.3389/fendo.2020.591819] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/26/2020] [Indexed: 12/14/2022] Open
Abstract
Enzymatically oxidized lipids are a specific group of biomolecules that function as key signaling mediators and hormones, regulating various cellular and physiological processes from metabolism and cell death to inflammation and the immune response. They are broadly categorized as either polyunsaturated fatty acid (PUFA) containing (free acid oxygenated PUFA "oxylipins", endocannabinoids, oxidized phospholipids) or cholesterol derivatives (oxysterols, steroid hormones, and bile acids). Their biosynthesis is accomplished by families of enzymes that include lipoxygenases (LOX), cyclooxygenases (COX), cytochrome P450s (CYP), and aldo-keto reductases (AKR). In contrast, non-enzymatically oxidized lipids are produced by uncontrolled oxidation and are broadly considered to be harmful. Here, we provide an overview of the biochemistry and enzymology of LOXs, COXs, CYPs, and AKRs in humans. Next, we present biosynthetic pathways for oxylipins, oxidized phospholipids, oxysterols, bile acids and steroid hormones. Last, we address gaps in knowledge and suggest directions for future work.
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Affiliation(s)
- Ali A. Hajeyah
- Systems Immunity Research Institute and Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
- *Correspondence: Ali A. Hajeyah,
| | - William J. Griffiths
- Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom
| | - Yuqin Wang
- Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom
| | - Andrew J. Finch
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Valerie B. O’Donnell
- Systems Immunity Research Institute and Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
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Lin C, Yuan H, Wang W, Zhu Z, Lu Y, Wang J, Feng F, Wu J. Importance of PNO1 for growth and survival of urinary bladder carcinoma: Role in core-regulatory circuitry. J Cell Mol Med 2019; 24:1504-1515. [PMID: 31800162 PMCID: PMC6991670 DOI: 10.1111/jcmm.14835] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 10/20/2019] [Indexed: 02/06/2023] Open
Abstract
PNO1 (partner of Nob1) was known as a RNA‐binding protein in humans, and its ortholog PNO1 was reported to participate ribosome and proteasome biogenesis in yeasts. Yet there have been few studies about its functions in mammalian cells, and so far its role in human cells has never been reported, especially in urinary bladder cancer (UBC).We interrogated the cellular functions and clinical significance of PNO1 in, and its molecular mechanism through microarrays and bioinformatics analysis. Our findings support that PNO1 participates in promoting proliferation and colonogenesis, while reducing apoptosis of UBC cells, and is also predicted to be associated with the migration and metastasis of UBC PNO1 knockdown (KD) attenuated the tumorigenesis ability of UBC in mouse. PNO1 KD led to the altered expression of 1543 genes that are involved in a number of signalling pathways, biological functions and regulation networks. CD44, PTGS2, cyclin D1, CDK1, IL‐8, FRA1, as well as mTOR, p70 S6 kinase, p38 and Caspase‐3 proteins were all down‐regulated in PNO1 KD cells, suggesting the involvement of PNO1 in inflammatory responses, cell cycle regulation, chemotaxis, cell growth and proliferation, apoptosis, cell migration and invasiveness. This study will enhance our understanding of the molecular mechanism of UBC and may eventually provide novel targets for individualized cancer therapy.
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Affiliation(s)
- Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Hejia Yuan
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Wenting Wang
- The Central Laboratory, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Zhe Zhu
- Division of Regenerative Medicine, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Youyi Lu
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jiahui Wang
- The Central Laboratory, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Fan Feng
- 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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Lin Q, Ye X, Huang Z, Yang B, Fang X, Chen H, Kong J. Graphene Oxide-Based Suppression of Nonspecificity in Loop-Mediated Isothermal Amplification Enabling the Sensitive Detection of Cyclooxygenase-2 mRNA in Colorectal Cancer. Anal Chem 2019; 91:15694-15702. [PMID: 31725282 DOI: 10.1021/acs.analchem.9b03861] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cyclooxygenase-2 (COX2) mRNA represents a key biomarker for identifying subjects with colorectal cancer (CRC), while there is still no rapid and sensitive detection method for COX2 mRNA. Loop-mediated isothermal amplification (LAMP) is extensively developed for the amplification of nucleic acids; however, its application is frequently hindered by serious nonspecific amplification. Herein, this work reported a graphene oxide (GO)-based LAMP method to enable the one-step detection of COX2 mRNA in cancer cells and serum samples. We found that GO greatly enhanced the specificity of LAMP through decreasing nonspecific hybridization and the fluorescence background signal because of the simultaneous adsorption of single-stranded primers and DNA staining dyes on GO. The detection limit of developed GO-based LAMP was 2 orders of magnitude more sensitive compared to that of classical LAMP. Then a GO-based reverse transcription (RT)-LAMP strategy was further developed and applied to detect COX2 mRNA in CRC cancer cells and serum samples with high specificity. The GO-based LAMP platform with advantages of low cost, simplicity, high specificity, and sensitivity holds considerable potential for real-time fluorescence monitoring of nucleic acid amplification in a wide range of fields.
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Affiliation(s)
- Qiuyuan Lin
- Department of Chemistry , Fudan University , Shanghai 200438 , P. R. China
| | - Xin Ye
- Department of Chemistry , Fudan University , Shanghai 200438 , P. R. China
| | - Zhipeng Huang
- Department of Chemistry , Fudan University , Shanghai 200438 , P. R. China
| | - Bin Yang
- Department of Chemistry , Fudan University , Shanghai 200438 , P. R. China
| | - Xueen Fang
- Department of Chemistry , Fudan University , Shanghai 200438 , P. R. China
| | - Hui Chen
- Department of Chemistry , Fudan University , Shanghai 200438 , P. R. China
| | - Jilie Kong
- Department of Chemistry , Fudan University , Shanghai 200438 , P. R. China
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Lai ZZ, Yang HL, Ha SY, Chang KK, Mei J, Zhou WJ, Qiu XM, Wang XQ, Zhu R, Li DJ, Li MQ. Cyclooxygenase-2 in Endometriosis. Int J Biol Sci 2019; 15:2783-2797. [PMID: 31853218 PMCID: PMC6909960 DOI: 10.7150/ijbs.35128] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 07/28/2019] [Indexed: 12/11/2022] Open
Abstract
Endometriosis (EMS) is the most common gynecological disease in women of reproductive age, and it is associated with chronic pelvic pain, dyspareunia and infertility. As a consequence of genetic, immune and environmental factors, endometriotic lesions have high cyclooxygenase (COX)-2 and COX-2-derived prostaglandin E2 (PGE2) biosynthesis compared with the normal endometrium. The transcription of the PTGS2 gene for COX-2 is associated with multiple intracellular signals, which converge to cause the activation of mitogen-activated protein kinases (MAPKs). COX-2 expression can be regulated by several factors, such as estrogen, hypoxia, proinflammatory cytokines, environmental pollutants, metabolites and metabolic enzymes, and platelets. High concentrations of COX-2 lead to high cell proliferation, a low level of apoptosis, high invasion, angiogenesis, EMS-related pain and infertility. COX-2-derived PGE2 performs a crucial function in EMS development by binding to EP2 and EP4 receptors. These basic findings have contributed to COX-2-targeted treatment in EMS, including COX-2 inhibitors, hormone drugs and glycyrrhizin. In this review, we summarize the most recent basic research in detail and provide a short summary of COX-2-targeted treatment.
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Affiliation(s)
- Zhen-Zhen Lai
- NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China
| | - Hui-Li Yang
- NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China
| | - Si-Yao Ha
- NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China
| | - Kai-Kai Chang
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China
| | - Jie Mei
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, People's Republic of China
| | - We-Jie Zhou
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People's Republic of China
| | - Xue-Min Qiu
- NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China
| | - Xiao-Qiu Wang
- NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China
| | - Rui Zhu
- Center for Human Reproduction and Genetics, Suzhou Municipal Hospital, Suzhou 215008, People's Republic of China
| | - Da-Jin Li
- NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China
| | - Ming-Qing Li
- NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China
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Urrego D, Liwa AC, Cole WC, Wood SL, Slater DM. Cyclooxygenase inhibitors for treating preterm labour: What is the molecular evidence? 1. Can J Physiol Pharmacol 2019; 97:222-231. [PMID: 30661374 DOI: 10.1139/cjpp-2018-0380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Preterm birth (<37 weeks of gestation) significantly increases the risk of neonatal mortality and morbidity. As many as half of all preterm births occur following spontaneous preterm labour. Since in such cases there are no known reasons for the initiation of labour, treatment of preterm labour (tocolysis) has sought to stop labour contractions and delay delivery. Despite some success, the use of cyclooxygenase (COX) inhibitors is associated with maternal/fetal side effects, and possibly increased risk of preterm birth. Clinical use of these drugs predates the collection of molecular and biochemical evidence in vitro, examining the expression and activity of COX enzymes in pregnant uterine tissues with and without labour. Such evidence is important to the rationale that COX enzymes are, or are not, appropriate targets for the tocolysis. The current study systematically searched existing scientific evidence to address the hypothesis that COX expression/activity is increased with the onset of human labour, in an effort to determine whether there is a rationale for the use of COX inhibitors as tocolytics. Our review identified 44 studies, but determined that there is insufficient evidence to support or refute a role of COX-1/-2 in the onset of preterm labour that supports COX-targeted tocolysis.
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Affiliation(s)
- Daniela Urrego
- a Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW Calgary, AB T2N 4N1, Canada
| | - Anthony C Liwa
- a Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW Calgary, AB T2N 4N1, Canada.,b Department of Clinical Pharmacology, Weill School of Medicine, Catholic University of Health and Allied Sciences, PO Box 1464, Mwanza, Tanzania
| | - William C Cole
- a Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW Calgary, AB T2N 4N1, Canada
| | - Stephen L Wood
- c Department of Obstetrics and Gynaecology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW Calgary, AB T2N 1N4, Canada
| | - Donna M Slater
- a Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW Calgary, AB T2N 4N1, Canada.,c Department of Obstetrics and Gynaecology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW Calgary, AB T2N 1N4, Canada
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Turan OM, Driscoll C, Cetinkaya-Demir B, Gabbay-Benziv R, Turan S, Kopelman JN, Harman C. Prolonged early antenatal indomethacin exposure is safe for fetus and neonate . J Matern Fetal Neonatal Med 2019;34:167-176. [PMID: 30905227 DOI: 10.1080/14767058.2019.1599351] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Objective: To evaluate fetal and neonatal safety of early-onset long-term antenatal indomethacin treatment (LIT) for short cervix.Methods: In this cohort study, women started LIT for short cervix (<25 mm) before completing 25 weeks. They followed a standardized regiment of oral indomethacin: 100 mg loading, 50 mg qid for 48 h, 25 mg qid until delivery or at 32 weeks gestational age (GA), whichever comes first. Weekly monitoring for oligohydramnios and ductus arteriosus (DA) constriction included confirmation of compliance with treatment/dose. This approach is established in our clinical practice. To identify LIT complications separate from prematurity, each neonate exposed to LIT were matched to two unexposed neonatal controls within ±3 days of GA of delivery and birth weight of ±10%. Odds ratios for neonatal variables included pulmonary hemorrhage, patent DA (PDA) requiring medical or surgical correction, necrotizing enterocolitis (NEC), spontaneous intestinal perforation (SIP), intraventricular hemorrhage (IVH) grade III-IV, other intracranial hemorrhage (ICH), neonatal mortality, calculated individually, and for total composite morbidity. Statistical determinants of neonatal morbidity were assessed using binary logistic regression. Exposure to LIT, maternal age, parity, BMI, GA at delivery, birth-weight (BW), neonatal gender, cord artery pH, and 5-min Apgar score were independent variables.Results: 166 LIT cases were matched with 332 controls. LIT median duration was 49 (3-108) days. Mean delivery GA was 34 weeks. LIT was stopped for 5 patients (2.9%) with oligohydramnios and 1 (0.6%) with DA constriction, without consequent morbidity. 71 cases (43%) completed LIT, stopping at 32 weeks. 95 stopped early for preterm premature ruptures of membranes (PPROM) (20%), active labor (11%) or patient choice (22%). Odds of any individual complication did not differ between treated cases and controls. LIT was not a statistical determinant of composite morbidity or any individual neonatal problem.Conclusion: Continuous early-onset indomethacin exposure, up to 15 weeks antenatally, did not increase fetal or neonatal complications. This level of safety is permissive to a randomized trial of indomethacin for the treatment of short cervix.
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Affiliation(s)
- Ozhan M Turan
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Colleen Driscoll
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Bilge Cetinkaya-Demir
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Rinat Gabbay-Benziv
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Sifa Turan
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jerome N Kopelman
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Chris Harman
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
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41
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Mitchell JA, Kirkby NS. Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system. Br J Pharmacol 2019; 176:1038-1050. [PMID: 29468666 PMCID: PMC6451069 DOI: 10.1111/bph.14167] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 01/19/2018] [Accepted: 01/29/2018] [Indexed: 12/30/2022] Open
Abstract
Eicosanoids represent a diverse family of lipid mediators with fundamental roles in physiology and disease. Within the eicosanoid superfamily are prostanoids, which are specifically derived from arachidonic acid by the enzyme cyclooxygenase (COX). COX has two isoforms; COX-1 and COX-2. COX-2 is the therapeutic target for the nonsteroidal anti-inflammatory drug (NSAID) class of pain medications. Of the prostanoids, prostacyclin, first discovered by Sir John Vane in 1976, remains amongst the best studied and retains an impressive pedigree as one of the fundamental cardiovascular protective pathways. Since this time, we have learnt much about how eicosanoids, COX enzymes and prostacyclin function in the cardiovascular system, knowledge that has allowed us, for example, to harness the power of prostacyclin as therapy to treat pulmonary arterial hypertension and peripheral vascular disease. However, there remain many unanswered questions in our basic understanding of the pathways, and how they can be used to improve human health. Perhaps, the most important and controversial outstanding question in the field remains; 'how do NSAIDs produce their much publicized cardiovascular side-effects?' This review summarizes the history, biology and cardiovascular function of key eicosanoids with particular focus on prostacyclin and other COX products and discusses how our knowledge of these pathways can applied in future drug discovery and be used to explain the cardiovascular side-effects of NSAIDs. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.
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Affiliation(s)
- Jane A Mitchell
- Cardiothoracic PharmacologyNational Heart and Lung InstituteLondonUK
| | - Nicholas S Kirkby
- Cardiothoracic PharmacologyNational Heart and Lung InstituteLondonUK
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Moilanen E, Vuolteenaho K. Nonsteroidal Anti-inflammatory Drugs. NIJKAMP AND PARNHAM'S PRINCIPLES OF IMMUNOPHARMACOLOGY 2019:689-707. [DOI: 10.1007/978-3-030-10811-3_33] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Ma T, Kandhare AD, Mukherjee-Kandhare AA, Bodhankar SL. Fisetin, a plant flavonoid ameliorates doxorubicin-induced cardiotoxicity in experimental rats: the decisive role of caspase-3, COX-II, cTn-I, iNOs and TNF-α. Mol Biol Rep 2018; 46:105-118. [PMID: 30362071 DOI: 10.1007/s11033-018-4450-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 10/17/2018] [Indexed: 11/25/2022]
Abstract
Doxorubicin (DOX) is a widely used anthracycline antibiotic for the management of carcinoma. However, it is associated with cardiotoxicity. Fisetin is a plant flavonoid reported to have anti-inflammatory and antiapoptotic potential. To evaluate the cardioprotective potential of fisetin in DOX-induced cardiotoxicity in experimental rats. Sprague-Dawley rats were pre-treated with either fisetin (10, 20 and 40 mg/kg) or sitagliptin (10 mg/kg, p.o.) for 7 days. Cardiac toxicity was induced in rats (except the normal group) by doxorubicin (15 mg/kg i.p.) on 8th day. Various behavioral, biochemical, molecular and histological parameters were assessed in cardiac tissue. DOX-induced alterations in electrocardiographic, hemodynamic and left ventricular function were significantly (p < 0.05) inhibited by fisetin (20 and 40 mg/kg) treatment. Fisetin significantly decrease (p < 0.05) DOX-induced elevated serum CK-MB, LDH, AST, ALT and ALP levels. DOX-induced elevated cardiac oxido-nitrosative (SOD, GSH, MDA and NO) was significantly inhibited (p < 0.05) by fisetin. Up-regulated cardiac caspase-3, COX-II, cTn-I, iNOs, TNF-α, and IL-1β mRNA, as well as protein expressions were significantly decreased (p < 0.05) by fisetin treatment. It also significantly (p < 0.05) attenuated DOX-induced histopathological alterations in cardiac tissue. In conclusion, the fisetin exerts its cardioprotective potential against DOX-induced toxicity via inhibition of multiple pathways including oxidative stress (SOD, GSH, MDA and NO), inflammation (COX-II, TNF-α, and IL-1β), and apoptosis (Caspase-3). Therefore, fisetin can be considered as a potential cardioprotective agent during the management of carcinoma using doxorubicin anthracyclines.
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Affiliation(s)
- Tao Ma
- Department of Cardiology, The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China
| | - Amit D Kandhare
- Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Erandwane, Pune, Maharashtra, 411038, India
| | - Anwesha A Mukherjee-Kandhare
- Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Erandwane, Pune, Maharashtra, 411038, India
| | - Subhash L Bodhankar
- Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Erandwane, Pune, Maharashtra, 411038, India.
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Yatam S, Jadav SS, Gundla R, Gundla KP, Reddy GM, Ahsan MJ, Chimakurthy J. Design, Synthesis and Biological Evaluation of 2 (((5-aryl-1,2,4-oxadiazol-3-yl)methyl)thio)benzo[d]oxazoles: New Antiinflammatory and Antioxidant Agents. ChemistrySelect 2018. [DOI: 10.1002/slct.201801558] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Satyanarayana Yatam
- Department of Chemistry; School of Technology; GITAM University, Hyderabad, T.S, 502 102; India
| | - Surender Singh Jadav
- Department of Chemistry; School of Technology; GITAM University, Hyderabad, T.S, 502 102; India
| | - Rambabu Gundla
- Department of Chemistry; School of Technology; GITAM University, Hyderabad, T.S, 502 102; India
| | - Krishna Prasadh Gundla
- Department of Chemistry; School of Technology; GITAM University, Hyderabad, T.S, 502 102; India
| | | | - Mohamed Jawed Ahsan
- Department of Pharmaceutical Chemistry; College of Pharmacy; King Khalid University; Abha 62529 Kingdom of Saudi Arabia
| | - Jithendra Chimakurthy
- Vignan's Foundation for Science, Technology & Research, Vadlamudi, Guntur, Andhrapradesh; India
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Tang N, Liu L, Qiu H, Shi W, Mao D. Analysis of gene expression and functional changes of adrenal gland in a rat model of kidney yang deficiency syndrome treated with Sini decoction. Exp Ther Med 2018; 16:3107-3115. [PMID: 30214533 DOI: 10.3892/etm.2018.6521] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 01/12/2018] [Indexed: 12/28/2022] Open
Abstract
Sini decoction (SND), a well-known traditional Chinese medicine, has been used to treat kidney Yang deficiency for ~1,800 years. The present study aimed to evaluate the effects of SND treatment on hypothalamic-pituitary-adrenal axis hormones in a rat model of Yang deficiency and to explore the molecular mechanisms using microarray analysis of adrenal glands and in vitro adrenocortical cell culture systems. The results indicated that SND treatment recovered circulating serum cortisol, adrenocortical hormone (ACTH) and testosterone levels in a yang deficiency model. Immunohistochemical analysis of pituitary and hypothalamic tissues confirmed increased expression of ACTH and corticotropin-releasing factor, respectively, in response to SND treatment. Microarray analysis identified a marked upregulation of genes involved in ≤metabolic and stress response pathways in rat adrenal tissues in response to SND treatment, exemplified by cyclooxygenase-2 and nuclear factor (NF)-κB. In vitro, SND exerted a protective effect on mitochondria in response to H2O2 exposure also activated NF-κB and cyclic adenosine monophosphate response element binding protein reporter gene activity. These results contributed towards an improved understanding of how SND effectively alleviates the symptoms of kidney Yang deficiency syndrome at the molecular level.
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Affiliation(s)
- Nong Tang
- Department of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R. China
| | - Lihong Liu
- Department of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R. China
| | - Hua Qiu
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R. China
| | - Wei Shi
- Department of Nephrology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R. China
| | - Dewen Mao
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R. China
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Zhu X, Wang L, Teng X, Chen Q, Pan C. N-Methyl Pyrrolidone (NMP) Alleviates Lipopolysaccharide (LPS)-Induced Inflammatory Injury in Articular Chondrocytes. Med Sci Monit 2018; 24:6480-6488. [PMID: 30218608 PMCID: PMC6151968 DOI: 10.12659/msm.910050] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Studies on the chondrocyte inflammatory injury are very important for understanding the pathogenesis and clinical treatment of osteoarthritis (OA). Evidence suggests that N-methyl pyrrolidone (NMP) may be used as an adjuvant therapy alongside established methods of OA treatment. This study investigated the effect of NMP on chondrocyte inflammatory injury and explored the underlying molecular mechanism. Material/Methods To mimic the inflammatory injury in vitro, the articular chondrocyte line ATDC5 was simulated with lipopolysaccharide (LPS). ATDC5 cells were treated with various concentrations of NMP (0, 5, and 10 nM). Cell viability was measured using CCK-8 assay; cell apoptosis was detected using FCM; related protein and mRNA expressions were determined using Western blot assay and qRT-PCR assay; and inflammatory factors (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8) productions were measured by performing ELISA assay. Results The results showed that LPS simulation repressed ATDC5 cell viability, prompted cell apoptosis, and enhanced the secretion of inflammatory factors. NMP treatment reduced inflammatory injury induced by LPS in a dose-dependent manner. Furthermore, NMP inhibited the activation of JNK and p38 pathways. In addition, inhibition of NF-κB activation was observed following NMP treatment. Conclusions NMP prevents inflammatory reaction of articular chondrocytes via repressing the MAPK/NF-κB pathway. Our findings provide a promising therapeutic agent for OA treatment.
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Affiliation(s)
- Xianping Zhu
- Department of Orthopaedics, Taizhou Central Hospital (Affiliated Hospital of Taizhou University), Taizhou, Zhejiang, China (mainland)
| | - Lin Wang
- Department of Anesthesiology, Taizhou Central Hospital (Affiliated Hospital of Taizhou University), Taizhou, Zhejiang, China (mainland)
| | - Xiao Teng
- Department of Orthopedics, Taizhou Central Hospital (Affiliated Hospital of Taizhou University), Taizhou, Zhejiang, China (mainland)
| | - Qi Chen
- Department of Laboratory Medicine, Taizhou Central Hospital (Affiliated Hospital of Taizhou University), Taizhou, Zhejiang, China (mainland)
| | - Chenshuai Pan
- Department of Orthopedics, Taizhou Central Hospital (Affiliated Hospital of Taizhou University), Taizhou, Zhejiang, China (mainland)
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Ribosomal RACK1:Protein Kinase C βII Phosphorylates Eukaryotic Initiation Factor 4G1 at S1093 To Modulate Cap-Dependent and -Independent Translation Initiation. Mol Cell Biol 2018; 38:MCB.00304-18. [PMID: 30012863 DOI: 10.1128/mcb.00304-18] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 07/09/2018] [Indexed: 11/20/2022] Open
Abstract
Eukaryotic ribosomes contain the high-affinity protein kinase C βII (PKCβII) scaffold, receptor for activated C kinase (RACK1), but its role in protein synthesis control remains unclear. We found that RACK1:PKCβII phosphorylates eukaryotic initiation factor 4G1 (eIF4G1) at S1093 and eIF3a at S1364. We showed that reversible eIF4G(S1093) phosphorylation is involved in a global protein synthesis surge upon PKC-Raf-extracellular signal-regulated kinase 1/2 (ERK1/2) activation and in induction of phorbol ester-responsive transcripts, such as cyclooxygenase 2 (Cox-2) and cyclin-dependent kinase inhibitor (p21Cip1), or in 5' 7-methylguanosine (m7G) cap-independent enterovirus translation. Comparison of mRNA and protein levels revealed that eIF4G1 or RACK1 depletion blocked phorbol ester-induced Cox-2 or p21Cip1 expression mostly at the translational level, whereas PKCβ inhibition reduced them both at the translational and transcript levels. Our findings reveal a physiological role for ribosomal RACK1 in providing the molecular scaffold for PKCβII and its role in coordinating the translational response to PKC-Raf-ERK1/2 activation.
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Kaur R, Thakur S, Rastogi P, Kaushal N. Resolution of Cox mediated inflammation by Se supplementation in mouse experimental model of colitis. PLoS One 2018; 13:e0201356. [PMID: 30063735 PMCID: PMC6067745 DOI: 10.1371/journal.pone.0201356] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 07/13/2018] [Indexed: 12/21/2022] Open
Abstract
UC a form of IBD is a chronic inflammatory disorder of large intestine, with unknown etiology. Reports suggest a critical role of COX-2 dependent prostaglandins (PGs) mediated inflammatory pathway in pathophysiology of UC. However, COX inhibition using NSAIDs exacerbate IBD and thus is not a viable solution. Currently, in DSS induced experimental colitis in mice, we have demonstrated that dietary Se supplementation (0.5ppm as sodium selenite) symptomatically resolves the signs of inflammation in a redox sensitive manner as compared to Se deficient (0.01ppm) conditions, as seen by modulation in oxidative stress markers, morphological changes, histopathological examinations, biochemical studies such as MPO activity, activity of intestinal markers enzymes as well as mRNA and expressions of various pro and anti-inflammatory factors such as, mPGES, hPGDS, TXAS, 15-PGDH, GPX-1 and GPX-2. These findings were validated and correlated with changes in the biophysical parameters such as membrane fluidity, electrical parameters (impedance), transport across the colonic tissue and FTIR. Current study not only concluded that Se at supranutritional concentrations by modulating the redox status relieves the signs of colitis by regulating COX dependent PG biosynthetic pathway, but also sheds light on the biophysical characterization of these inflammatory/resolution pathways involved in UC.
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Affiliation(s)
- Ramanpreet Kaur
- Department of Biophysics, BMS Block -II, Panjab University, South Campus, Chandigarh, India
| | - Shivani Thakur
- Department of Biophysics, BMS Block -II, Panjab University, South Campus, Chandigarh, India
| | - Pulkit Rastogi
- Department of Hematology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Naveen Kaushal
- Department of Biophysics, BMS Block -II, Panjab University, South Campus, Chandigarh, India
- * E-mail:
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Abstract
While normal angiogenesis is critical for development and tissue growth, pathological angiogenesis is important for the growth and spread of cancers by supplying nutrients and oxygen as well as providing a conduit for distant metastasis. The interaction among extracellular matrix molecules, tumor cells, endothelial cells, fibroblasts, and immune cells is critical in pathological angiogenesis, in which various angiogenic growth factors, chemokines, and lipid mediators produced from these cells as well as hypoxic microenvironment promote angiogenesis by regulating expression and/or activity of various related genes. Sphingosine 1-phosphate and lysophosphatidic acid, bioactive lipid mediators which act via specific G protein-coupled receptors, play critical roles in angiogenesis. In addition, other lipid mediators including prostaglandin E2, lipoxin, and resolvins are produced in a stimulus-dependent manner and have pro- or anti-angiogenic effects, presumably through their specific GPCRs. Dysregulated lipid mediator signaling pathways are observed in the contxt of some tumors. This review will focus on LPA and S1P, two bioactive lipid mediators in their regulation of angiogenesis and cell migration that are critical for tumor growth and spread.
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Affiliation(s)
- Yu Hisano
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States
| | - Timothy Hla
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States.
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50
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Iacona JR, Monteleone NJ, Lutz CS. miR-146a suppresses 5-lipoxygenase activating protein (FLAP) expression and Leukotriene B4 production in lung cancer cells. Oncotarget 2018; 9:26751-26769. [PMID: 29928483 PMCID: PMC6003571 DOI: 10.18632/oncotarget.25482] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 05/08/2018] [Indexed: 12/31/2022] Open
Abstract
Arachidonic acid (AA) can be converted into prostaglandins (PGs) or leukotrienes (LTs) by the enzymatic actions of cyclooxygenases (COX-1 and COX-2) or 5-lipoxygenase (5-LO), respectively. PGs and LTs are lipid signaling molecules that have been implicated in various diseases, including multiple cancers. 5-LO and its activating protein (FLAP) work together in the first two conversion steps of LT production. Previous work has suggested a role for LTs in cancer development and progression. MicroRNAs (miRNAs) are small RNA molecules that negatively regulate gene expression post-transcriptionally, and have previously been shown to be involved in cancer. Here, we show that high FLAP expression is associated with lower overall survival in lung adenocarcinoma patients, and FLAP protein is overexpressed in lung cancer cells compared to normal lung cells. Our lab has previously shown that miR-146a regulates COX-2 in lung cancer cells, and this miRNA is also predicted to target FLAP. Transient and stable transfections of miR-146a repress endogenous FLAP expression in lung cancer cells, and reporter assays show this regulation occurs through a direct interaction between the FLAP 3′ untranslated region (UTR) and miR-146a. Restoration of miR-146a also results in decreased cancer cell Leukotriene B4 (LTB4) production. Additionally, methylation analysis indicates the miR-146a promoter is hypermethylated in lung cancer cell lines. Taken together, this study and previous work from our lab suggest miR-146a is an endogenous dual inhibitor of AA metabolism in lung cancer cells by regulating both PG and LT production through direct targeting of the COX-2 and FLAP 3’ UTRs.
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Affiliation(s)
- Joseph R Iacona
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School and the School of Graduate Studies, Health Sciences Campus, Newark, NJ, USA
| | - Nicholas J Monteleone
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School and the School of Graduate Studies, Health Sciences Campus, Newark, NJ, USA
| | - Carol S Lutz
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School and the School of Graduate Studies, Health Sciences Campus, Newark, NJ, USA
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