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1
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Pawlędzio S, Ziemniak M, Wang X, Woźniak K, Malinska M. Understanding the selectivity of nonsteroidal anti-inflammatory drugs for cyclooxygenases using quantum crystallography and electrostatic interaction energy. IUCRJ 2025; 12:208-222. [PMID: 39882676 DOI: 10.1107/s2052252525000053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 01/03/2025] [Indexed: 01/31/2025]
Abstract
Quantum crystallography methods have been employed to investigate complex formation between nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX) enzymes, with particular focus on the COX-1 and COX-2 isoforms. This study analyzed the electrostatic interaction energies of selected NSAIDs (flurbiprofen, ibuprofen, meloxicam and celecoxib) with the active sites of COX-1 and COX-2, revealing significant differences in binding profiles. Flurbiprofen exhibited the strongest interactions with both COX-1 and COX-2, indicating its potent binding affinity. Celecoxib and meloxicam showed a preference for COX-2, consistent with their known selectivity for this isoform, while ibuprofen showed comparable interaction energies with both isoforms, reflecting its nonselective inhibition pattern. Key amino-acid residues, including Arg120, Arg/His513 and Tyr355, were identified as critical determinants of NSAID selectivity and binding affinity. The findings highlight the complex interplay between interaction energy and selectivity, suggesting that while electrostatic interactions play a fundamental role, additional factors such as enzyme dynamics and the hydrophobic effect also contribute to the therapeutic efficacy and safety profiles of NSAIDs. These insights provide valuable guidance for the rational design of NSAIDs with enhanced therapeutic benefits and minimized adverse effects.
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Affiliation(s)
- S Pawlędzio
- Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
| | - M Ziemniak
- Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 02-093 Warsaw, Poland
| | - X Wang
- Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
| | - K Woźniak
- Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 02-093 Warsaw, Poland
| | - M Malinska
- Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 02-093 Warsaw, Poland
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2
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Borowiec K, Szwajgier D, Stachniuk A, Mielniczuk J, Trzpil A. Investigation of Changes in the Polyphenol Profile Verified by LC-MS/MS and the Pro-Health Activities of Fruit Smoothie. Mol Nutr Food Res 2024; 68:e2300426. [PMID: 38924345 DOI: 10.1002/mnfr.202300426] [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: 06/22/2023] [Revised: 04/30/2024] [Indexed: 06/28/2024]
Abstract
SCOPE Bilberry, bananas, and apples are used for smoothie production because the health-promoting activities and to prevent human diseases including neurodegenerative disorders. The smoothie is prepared to promote a promising practice for increasing the intake of fruit in the diet. METHODS AND RESULTS The smoothie is packed into dark glass jars, pasteurized, and stored for up to 4 months at 4 or 22 °C. Then, it is analyzed for the polyphenols profile using liquid chromatography-high resolution mass spectometry (LC-HRMS) Polyphenols content and the antiinflammatory, anticholinesterase, and antioxidant activities, and the impact on catalase activity are controlled using biochemical analyses. A significant decrease in the flavanol content (p < 0.05) is investigated, while there are lower decreases or no changes in the other polyphenols content in the smoothies stored at 4 °C. The changes in the anticholinesterase and antioxidant activities of the smoothie are correlated with the total polyphenols, anthocyanins, flavonols, and tannins content. CONCLUSION The proposed preservation of the smoothie and its storage at refrigeration temperature is adequate to maintain the smoothie's nutritional and functional effect for a 4-month shelf life. Even significant changes in the content of individual subgroups of polyphenols are not drastically reflected in the decrease of the smoothie biological activities.
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Affiliation(s)
- Kamila Borowiec
- Department of Biotechnology, Microbiology and Human Nutrition, University of Life Sciences in Lublin, ul. Skromna 8, Lublin, 20-704, Poland
- Department of Bioanalytics, Medical University of Lublin, ul. Jaczewskiego 8b, Lublin, 20-090, Poland
| | - Dominik Szwajgier
- Department of Biotechnology, Microbiology and Human Nutrition, University of Life Sciences in Lublin, ul. Skromna 8, Lublin, 20-704, Poland
| | - Anna Stachniuk
- Department of Bioanalytics, Medical University of Lublin, ul. Jaczewskiego 8b, Lublin, 20-090, Poland
| | - Jacek Mielniczuk
- Department of Applied Mathematics and Computer Science, University of Life Sciences in Lublin, ul. Głęboka 28, Lublin, 20-612, Poland
| | - Alicja Trzpil
- Department of Bioanalytics, Medical University of Lublin, ul. Jaczewskiego 8b, Lublin, 20-090, Poland
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Bernoud-Hubac N, Lo Van A, Lazar AN, Lagarde M. Ischemic Brain Injury: Involvement of Lipids in the Pathophysiology of Stroke and Therapeutic Strategies. Antioxidants (Basel) 2024; 13:634. [PMID: 38929073 PMCID: PMC11200865 DOI: 10.3390/antiox13060634] [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: 04/06/2024] [Revised: 05/14/2024] [Accepted: 05/21/2024] [Indexed: 06/28/2024] Open
Abstract
Stroke is a devastating neurological disorder that is characterized by the sudden disruption of blood flow to the brain. Lipids are essential components of brain structure and function and play pivotal roles in stroke pathophysiology. Dysregulation of lipid signaling pathways modulates key cellular processes such as apoptosis, inflammation, and oxidative stress, exacerbating ischemic brain injury. In the present review, we summarize the roles of lipids in stroke pathology in different models (cell cultures, animal, and human studies). Additionally, the potential of lipids, especially polyunsaturated fatty acids, to promote neuroprotection and their use as biomarkers in stroke are discussed.
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Affiliation(s)
- Nathalie Bernoud-Hubac
- Univ Lyon, INSA Lyon, CNRS, LAMCOS, UMR5259, 69621 Villeurbanne, France; (A.L.V.); (A.-N.L.); (M.L.)
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Ahmadi N, Khoramjouy M, Movahed MA, Amidi S, Faizi M, Zarghi A. Design, Synthesis, In vitro and In vivo Evaluation of New Imidazo[1,2- a]pyridine Derivatives as Cyclooxygenase-2 Inhibitors. Anticancer Agents Med Chem 2024; 24:504-513. [PMID: 38275051 DOI: 10.2174/0118715206269563231220104846] [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: 08/27/2023] [Revised: 10/15/2023] [Accepted: 10/19/2023] [Indexed: 01/27/2024]
Abstract
BACKGROUND Cyclooxygenase-2 (COX-2), the key enzyme in the arachidonic acid conversion to prostaglandins, is one of the enzymes associated with different pathophysiological conditions, such as inflammation, cancers, Alzheimer's, and Parkinson's disease. Therefore, COX-2 inhibitors have emerged as potential therapeutic agents in these diseases. OBJECTIVE The objective of this study was to design and synthesize novel imidazo[1,2-a]pyridine derivatives utilizing rational design methods with the specific aim of developing new potent COX-2 inhibitors. Additionally, we sought to investigate the biological activities of these compounds, focusing on their COX-2 inhibitory effects, analgesic activity, and antiplatelet potential. We aimed to contribute to the development of selective COX-2 inhibitors with enhanced therapeutic benefits. METHODS Docking investigations were carried out using AutoDock Vina software to analyze the interaction of designed compounds. A total of 15 synthesized derivatives were obtained through a series of five reaction steps. The COX-2 inhibitory activities were assessed using the fluorescent Cayman kit, while analgesic effects were determined through writing tests, and Born's method was employed to evaluate antiplatelet activities. RESULTS The findings indicated that the majority of the tested compounds exhibited significant and specific inhibitory effects on COX-2, with a selectivity index ranging from 51.3 to 897.1 and IC50 values of 0.13 to 0.05 μM. Among the studied compounds, derivatives 5e, 5f, and 5j demonstrated the highest potency with IC50 value of 0.05 μM, while compound 5i exhibited the highest selectivity with a selectivity index of 897.19. In vivo analgesic activity of the most potent COX-2 inhibitors revealed that 3-(4-chlorophenoxy)-2-[4-(methylsulfonyl) phenyl] imidazo[1,2-a]pyridine (5j) possessed the most notable analgesic activity with ED50 value of 12.38 mg/kg. Moreover, evaluating the antiplatelet activity showed compound 5a as the most potent for inhibiting arachidonic acidinduced platelet aggregation. In molecular modeling studies, methylsulfonyl pharmacophore was found to be inserted in the secondary pocket of the COX-2 active site, where it formed hydrogen bonds with Arg-513 and His-90. CONCLUSION The majority of the compounds examined demonstrated selectivity and potency as inhibitors of COX-2. Furthermore, the analgesic effects observed of potent compounds can be attributed to the inhibition of the cyclooxygenase enzyme.
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Affiliation(s)
- Nahid Ahmadi
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mona Khoramjouy
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Azami Movahed
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Salimeh Amidi
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrdad Faizi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Zarghi
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Bettadj FZY, Benchouk W. Computer-aided analysis for identification of novel analogues of ketoprofen based on molecular docking, ADMET, drug-likeness and DFT studies for the treatment of inflammation. J Biomol Struct Dyn 2023; 41:9915-9930. [PMID: 36444967 DOI: 10.1080/07391102.2022.2148750] [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: 08/11/2022] [Accepted: 11/12/2022] [Indexed: 11/30/2022]
Abstract
Computer-based drug design is increasingly used in strategies for discovering new molecules for therapeutic purposes. The targeted drug is ketoprofen (KTP), which belongs to the family of non-steroidal anti-inflammatory drugs, which are widely used for the treatment of pain, fever, inflammation and certain types of cancers. In an attempt to rationalize the search for 72 new potential anti-inflammatory compounds on the COX-2 enzyme, we carried out an in silico protocol that successfully combines molecular docking towards COX-2 receptor (5F1A), ADMET pharmacokinetic parameters, drug-likeness rules and molecular electrostatic potential (MEP). It was found that six of the compounds analyzed satisfy with the associated values to physico-chemical properties as key evaluation parameters for the drug-likeness and demonstrate a hydrophobic character which makes their solubility in aqueous media difficult and easy in lipids. All the compounds presented good ADMET profile and they showed an interaction with the amino acids responsible for anti-inflammatory activity of the COX-2 isoenzyme. The calculation of the MEP of the six analogues reveals new preferential sites involving the formation of new bonds. Consequently, this result allowed us to understand the origin of the potential increase in the anti-inflammatory activity of the candidates. Finally, it was obtained that six compounds have a binding mode, binding energy, and stability in the active site of COX-2 like the reference drug ketoprofen, suggesting that these compounds could become a powerful candidate in the inhibition of the COX-2 enzyme.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Fatima Zohra Yasmine Bettadj
- Laboratory of Applied Thermodynamics and Molecular Modeling, Department of Chemistry, Faculty of Science, University of Tlemcen, Tlemcen, Algeria
| | - Wafaa Benchouk
- Laboratory of Applied Thermodynamics and Molecular Modeling, Department of Chemistry, Faculty of Science, University of Tlemcen, Tlemcen, Algeria
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Yuan L, Chu Q, Yang B, Zhang W, Sun Q, Gao R. Purification and identification of anti-inflammatory peptides from sturgeon (Acipenser schrenckii) cartilage. FOOD SCIENCE AND HUMAN WELLNESS 2023. [DOI: 10.1016/j.fshw.2023.03.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
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Patel M, Avashthi G, Gacem A, Alqahtani MS, Park HK, Jeon BH. A Review of Approaches to the Metallic and Non-Metallic Synthesis of Benzimidazole (BnZ) and Their Derivatives for Biological Efficacy. Molecules 2023; 28:5490. [PMID: 37513362 PMCID: PMC10384041 DOI: 10.3390/molecules28145490] [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: 06/01/2023] [Revised: 07/08/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Heterocyclic compounds are significant lead drug candidates based on their various structure-activity relationships (SAR), and their use in pharmaceutics is constantly developing. Benzimidazole (BnZ) is synthesized by a condensation reaction between benzene and imidazole. The BnZ structure consists of two nitrogen atoms embedded in a five-membered imide ring which is fused with a benzene ring. This review examines the conventional and green synthesis of metallic and non-metallic BnZ and their derivatives, which have several potential SARs, along with a wide range of pharmacological properties, including anti-cancer, anti-inflammatory, anti-microbial, anti-tubercular, and anti-protozoal properties. These compounds have been proven by pharmacological investigations to be efficient against different strains of microbes. Therefore, in this review, the structural variations of BnZ are listed along with various applications, predominantly related to their biological activities.
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Affiliation(s)
- Muhammad Patel
- School of Sciences, P P Savani University, NH 8, GETCO, Near Biltech, Dhamdod, Kosamba, Surat 394125, Gujarat, India
| | - Gopal Avashthi
- School of Sciences, P P Savani University, NH 8, GETCO, Near Biltech, Dhamdod, Kosamba, Surat 394125, Gujarat, India
| | - Amel Gacem
- Department of Physics, Faculty of Sciences, University 20 Août 1955 Skikda, Skikda 21000, Algeria;
| | - Mohammed S. Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia;
- Bioimaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, UK
| | - Hyun-Kyung Park
- Department of Pediatrics, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea;
| | - Byong-Hun Jeon
- Department of Earth Resources and Environmental Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea
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Kim GB, Seo K, Youn JU, Kwon IK, Park J, Park KH, Kim JS. Unsaturated Fatty Acids Complex Regulates Inflammatory Cytokine Production through the Hyaluronic Acid Pathway. Molecules 2023; 28:3554. [PMID: 37110788 PMCID: PMC10142694 DOI: 10.3390/molecules28083554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 04/14/2023] [Accepted: 04/15/2023] [Indexed: 04/29/2023] Open
Abstract
In this study, we aimed to develop natural and/or functional materials with antioxidant and anti-inflammatory effects. We obtained extracts from natural plants through an oil and hot-water extraction process and prepared an extract composite of an effective unsaturated fatty acid complex (EUFOC). Furthermore, the antioxidant effect of the extract complex was evaluated, and the anti-inflammatory effect was explored by assessing its inhibitory effect on nitric oxide production through its HA-promoting effect. We conducted a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay to evaluate the cell viability of the EUFOC, and the results showed that EUFOC was not cytotoxic at the test concentrations. In addition, it showed no endogenous cytotoxicity in HaCaT (human keratinocyte) cells. The EUFOC showed excellent 1,1-diphenyl-2-picrylhydrazyl- and superoxide-scavenging abilities. Moreover, it exerted an inhibitory effect on NO production at concentrations that did not inhibit cell viability. The secretion of all the cytokines was increased by lipopolysaccharide (LPS) treatment; however, this was inhibited by the EUFOC in a concentration-dependent manner. In addition, hyaluronic acid content was markedly increased by the EUFOC in a dose-dependent manner. These results suggest that the EUFOC has excellent anti-inflammatory and antioxidant properties, and hence, it can be used as a functional material in various fields.
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Affiliation(s)
- Gi-Beum Kim
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju 54907, Republic of Korea
| | - Kwansung Seo
- Department of Dental Materials, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jong-Ung Youn
- Eouidang Agricultural Company, Wanju, Jeonbuk 55360, Republic of Korea
| | - Il Keun Kwon
- Department of Dental Materials, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jinny Park
- Division of Hematology, Gacheon University Gil Medical Center, Incheon 21565, Republic of Korea
| | - Kwang-Hyun Park
- Department of Emergency Medicine and BioMedical Science Graduate Program (BMSGP), Chonnam National University, Gwangju 61469, Republic of Korea
| | - Jong-Suk Kim
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju 54907, Republic of Korea
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Jeffrey A, Gardhouse S, Kleinhenz M, Hocker SE, Weeder M, Montgomery SR, Zhang Y, Porting A, Rooney T. Examination of the pharmacokinetics and differential inhibition of cyclooxygenase isoenzymes in New Zealand white rabbits (Oryctolagus cuniculus) by the Non-Steroidal anti-inflammatory Robenacoxib. J Vet Pharmacol Ther 2023; 46:103-111. [PMID: 36478376 DOI: 10.1111/jvp.13105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/10/2022] [Accepted: 11/19/2022] [Indexed: 12/12/2022]
Abstract
Effective rabbit analgesia is challenging, and there are few studies available on the newer COX-2 selective NSAIDs, such as robenacoxib. This study aimed to establish the pharmacokinetics of oral and subcutaneous robenacoxib, describe its inhibitory actions on COX enzymes, and develop dosing, using six healthy New Zealand white rabbits. Pharmacokinetics were determined from plasma concentrations after oral administration of robenacoxib (0.83-0.96 mg/kg) and also after subcutaneous administration (2 mg/kg). The inhibitory actions of robenacoxib were evaluated by measuring plasma concentrations of thromboxane B2 (TBX2 ) and prostaglandin E2 (PGE2 ) as surrogate markers of cyclooxygenase enzyme isoform inhibition. The mean maximum concentration for oral and subcutaneous administration was 0.23 μg/ml and 5.82 μg/ml, respectively. Oral robenacoxib administration did not demonstrate a significant difference between any time point for PGE2 or TBX2 , though subcutaneous administration did for both. There was no significant difference in PGE2 or TBX2 concentrations at any time point when comparing subcutaneous versus oral routes. Although the results support that plasma robenacoxib exceeds the therapeutic levels compared to dogs and cats, there was little significance in the difference in the changes associated with COX-1 and COX-2 inhibition. Further studies are warranted to determine appropriate dosing, safety, and efficacy in rabbits.
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Affiliation(s)
- Alison Jeffrey
- Department of Clinical Science, Kansas State University, College of Veterinary Medicine, Kansas, Manhattan, USA
| | - Sara Gardhouse
- Evolution Veterinary Specialists, Colorado, Lakewood, USA
| | - Michael Kleinhenz
- Department of Clinical Science, Kansas State University, College of Veterinary Medicine, Kansas, Manhattan, USA
| | | | - Mikaela Weeder
- Department of Clinical Science, Kansas State University, College of Veterinary Medicine, Kansas, Manhattan, USA
| | - Shawnee R Montgomery
- Department of Anatomy and Physiology, Kansas State University, Kansas, Manhattan, USA
| | - Yuntao Zhang
- Veterinary Diagnostic Laboratory, Kansas State University, Kansas, Manhattan, USA
| | - Anna Porting
- Veterinary Diagnostic Laboratory, Kansas State University, Kansas, Manhattan, USA
| | - Tess Rooney
- Department of Medicine & Epidemiology, University of California, Davis, School of Veterinary Medicine, California, Davis, USA
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Zhai Z, Zhu Z, Kong F, Xie D, Cai J, Dai J, Zhong Y, Gan Y, Zheng S, Xu Y, Sun T. Distinguish the Characteristic Mechanism of 3 Drug Pairs of Corydalis Rhizome in Ameliorating Angina Pectoris: Network Pharmacology and Meta-Analysis. Nat Prod Commun 2023. [DOI: 10.1177/1934578x231152309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Objective: Angina pectoris (AP), affecting over 523 million people, can be alleviated by corydalis rhizome (CR), usually combined with chuanxiong rhizome (CXR), angelica dahuricae radix (ADR), or astragali radix (AR) to enhance the effect. This study aims to distinguish the different mechanisms among 3 drug pairs to treat AP. Methods: The drug pair-disease intersection targets, compound targets, protein–protein interaction (PPI), and herb-compound-target-pathway network were obtained by Cytoscape, STRING, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses ( http://www.kegg.jp/ or http://www.genome.jp/kegg/ ). Importantly, with principal component analysis (PCA), the key point of KEGG and GO were explored and supported, while by meta-analysis, the different mechanisms of the drug pairs on AP were discovered. Results: JUN, SRC, PIK3CA, and MAPK1 as PPI core network of CR-AP, (CR-CXR)-AP, (CR-ADR)-AP, and (CR-AR)-AP. (highest confidence > 0.9). 10, 45, 35, and 21 key compounds, and 68, 123, 117, and 97 core targets were obtained from CR-AP, (CR-CXR)-AP, (CR-ADR)-AP, and (CR-AR)-AP based on more than 2-fold median value for degree and betweenness centrality, more than the median of closeness centrality. The core pathways of (CR-CXR)-AP and (CR-AR)-AP cover “fluid shear stress and atherosclerosis” and the “pathways in cancer”, while (CR-ADR)-AP was found as the “pathways in cancer” by PCA and KEGG ( P < .01). The core biological processes of (BP) (CR-CXR)-AP, (CR-ADR)-AP, and (CR-AR)-AP were all enriched in the “circulatory system process” by PCA and GO ( P < .01). Moreover, meta-analysis indicated the significant differences ( P < .05) of the 3 drug pairs. Conclusion: CR-CXR, CR-ADR, or CR-AR outperformed CR-AP in AP mitigation. Furthermore, meta-analysis revealed, CR-CXR was superior to alleviating AP by affecting “circulatory system process” and “fluid shear stress and atherosclerosis”, particularly the targets PTGS1, PTGS2, ADRB2, ADRA2C, and NOS, when compared with the drug pair of CR-ADR and the CR-AR.
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Affiliation(s)
- Zhenwei Zhai
- School of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhishan Zhu
- School of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fanjing Kong
- School of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Danni Xie
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jie Cai
- School of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jingyi Dai
- School of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanmei Zhong
- School of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanxiong Gan
- School of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shichao Zheng
- School of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ying Xu
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tao Sun
- School of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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11
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Golpour-Hamedani S, Pourmasoumi M, Askari G, Bagherniya M, Majeed M, Guest PC, Sahebkar A. Antiviral Mechanisms of Curcumin and Its Derivatives in Prevention and Treatment of COVID-19: A Review. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1412:397-411. [PMID: 37378779 DOI: 10.1007/978-3-031-28012-2_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 06/29/2023]
Abstract
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now plagued the world for almost 3 years. Although vaccines are now available, the severity of the pandemic and the current dearth of approved effective medications have prompted the need for novel treatment approaches. Curcumin, as a food nutraceutical with anti-inflammatory and antioxidant effects, is now under consideration for the prevention and treatment of COVID-19. Curcumin has been demonstrated to retard the entrance of SARS-CoV-2 into cells, interfere with its proliferation inside cells, and curb the hyperinflammatory state caused by the virus by modulating immune system regulators, minimizing the cytokine storm effect, and modulating the renin-angiotensin system. This chapter discusses the role of curcumin and its derivatives in the prevention and treatment of COVID-19 infection, considering the molecular mechanisms involved. It will also focus on the molecular and cellular profiling techniques as essential tools in this research, as these can be used in the identification and development of new biomarkers, drug targets, and therapeutic approaches for improved patient care.
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Affiliation(s)
- Sahar Golpour-Hamedani
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Science, Isfahan, Iran
| | - Makan Pourmasoumi
- Gastrointestinal & Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Gholamreza Askari
- Nutrition and Food Security Research Center and Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
- Anesthesia and Critical Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Mohammad Bagherniya
- Nutrition and Food Security Research Center and Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
- Anesthesia and Critical Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Paul C Guest
- Department of Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
- Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Medicine, The University of Western Australia, Perth, Australia
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El-Malah AA, Gineinah MM, Deb PK, Khayyat AN, Bansal M, Venugopala KN, Aljahdali AS. Selective COX-2 Inhibitors: Road from Success to Controversy and the Quest for Repurposing. Pharmaceuticals (Basel) 2022; 15:827. [PMID: 35890126 PMCID: PMC9318302 DOI: 10.3390/ph15070827] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/23/2022] [Accepted: 06/28/2022] [Indexed: 01/27/2023] Open
Abstract
The introduction of selective COX-2 inhibitors (so-called 'coxibs') has demonstrated tremendous commercial success due to their claimed lower potential of serious gastrointestinal adverse effects than traditional NSAIDs. However, following the repeated questioning on safety concerns, the coxibs 'controversial me-too' saga increased substantially, inferring to the risk of cardiovascular complications, subsequently leading to the voluntary withdrawal of coxibs (e.g., rofecoxib and valdecoxib) from the market. For instance, the makers (Pfizer and Merck) had to allegedly settle individual claims of cardiovascular hazards from celecoxib and valdecoxib. Undoubtedly, the lessons drawn from this saga revealed the flaws in drug surveillance and regulation, and taught science to pursue a more integrated translational approach for data acquisition and interpretation, prompting science-based strategies of risk avoidance in order to sustain the value of such drugs, rather than their withdrawal. Looking forward, coxibs are now being studied for repurposing, given their possible implications in the management of a myriad of diseases, including cancer, epilepsy, psychiatric disorders, obesity, Alzheimer's disease, and so on. This article briefly summarizes the development of COX-2 inhibitors to their market impression, followed by the controversy related to their toxicity. In addition, the events recollected in hindsight (the past lessons), the optimistic step towards drug repurposing (the present), and the potential for forthcoming success (the future) are also discussed.
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Affiliation(s)
- Afaf A. El-Malah
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.A.E.-M.); (M.M.G.); (A.N.K.); (A.S.A.)
| | - Magdy M. Gineinah
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.A.E.-M.); (M.M.G.); (A.N.K.); (A.S.A.)
| | - Pran Kishore Deb
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, Amman 19392, Jordan
| | - Ahdab N. Khayyat
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.A.E.-M.); (M.M.G.); (A.N.K.); (A.S.A.)
| | - Monika Bansal
- Department of Neuroscience Technology, College of Applied Medical Sciences in Jubail, Imam Abdul Rahman Bin Faisal University, Dammam 31441, Saudi Arabia;
| | - Katharigatta N. Venugopala
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
- Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, Durban 4001, South Africa
| | - Anfal S. Aljahdali
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.A.E.-M.); (M.M.G.); (A.N.K.); (A.S.A.)
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13
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Borowiec K, Stachniuk A, Szwajgier D, Trzpil A. Polyphenols composition and the biological effects of six selected small dark fruits. Food Chem 2022; 391:133281. [PMID: 35617757 DOI: 10.1016/j.foodchem.2022.133281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/25/2022] [Accepted: 05/19/2022] [Indexed: 12/17/2022]
Abstract
The health-promoting activities of fruits are in the limelight in view of the growing risks posed by civilisational diseases and are connected with polyphenols. The present study examined bilberry, blueberry, blackcurrant, redcurrant, cherry and plum for their polyphenolic content and biological activities. The contents of total polyphenolic compounds and their subclasses were determined. Liquid chromatography high-resolution mass spectrometry was used to characterise the polyphenolic profiles. Small dark fruits' antioxidant, anti-inflammatory, and anti-cholinesterase activities were also extensively determined. Significant qualitative and quantitative differences in the analysed fruits' polyphenols composition and biological activities were demonstrated. The highest polyphenolic contents and antioxidant activities were established in blackcurrant fruit, but bilberry also had our attention due to an additional mild influence on antioxidant enzymes. The condensed tannin content in small dark fruits is developed. All tested fruits exhibit anti-inflammatory and anti-cholinesterase activities.
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Affiliation(s)
- Kamila Borowiec
- Department of Biotechnology, Microbiology and Human Nutrition, University of Life Sciences in Lublin, ul. Skromna 8, 20-704 Lublin, Poland.
| | - Anna Stachniuk
- Department of Bioanalytics, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland
| | - Dominik Szwajgier
- Department of Biotechnology, Microbiology and Human Nutrition, University of Life Sciences in Lublin, ul. Skromna 8, 20-704 Lublin, Poland
| | - Alicja Trzpil
- Department of Bioanalytics, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland
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Hassan MSA, Ahmed EM, El-Malah AA, Kassab AE. Anti-inflammatory activity of pyridazinones: A review. Arch Pharm (Weinheim) 2022; 355:e2200067. [PMID: 35532263 DOI: 10.1002/ardp.202200067] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/05/2022] [Accepted: 04/07/2022] [Indexed: 11/06/2022]
Abstract
The pyridazinone core has emerged as a leading structure for fighting inflammation, with low ulcerogenic effects. Moreover, easy functionalization of various ring positions of the pyridazinone core structure makes it an attractive synthetic and therapeutic target for the design and synthesis of anti-inflammatory agents. The present review surveys the recent advances of pyridazinone derivatives as potential anti-inflammatory agents to provide insights into the rational design of more effective anti-inflammatory pyridazinones.
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Affiliation(s)
- Marwa S A Hassan
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Eman M Ahmed
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Afaf A El-Malah
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Asmaa E Kassab
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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15
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Zhou Y, Dou F, Song H, Liu T. Anti-ulcerative effects of wogonin on ulcerative colitis induced by dextran sulfate sodium via Nrf2/TLR4/NF-κB signaling pathway in BALB/c mice. ENVIRONMENTAL TOXICOLOGY 2022; 37:954-963. [PMID: 35044701 DOI: 10.1002/tox.23457] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 12/02/2021] [Accepted: 12/27/2021] [Indexed: 06/14/2023]
Abstract
Ulcerative colitis (UC) is an inflammatory disease on the deepest lining of the colon and rectum. Wogonin is an antitumor flavonoid, which possesses various therapeutic properties. Even if the anti-colitis effect of wogonin was documented earlier, but the wogonin effect on inflammation underlying mechanism is not fully elucidated. In this present study, we hypothesized to study the oxidative damage, anti-inflammatory, and molecular action of wogonin on dextran sulfate sodium (DSS)-induced UC mice model. In methods, mice were categorized into four groups: that is, normal control, DSS alone, DSS + wogonin (30 mg/kg/day), and DSS + sulfasalazine (50 mg/kg/day). We determined the biochemical markers, inflammatory cytokines, histopathology of colon tissue, and western blot analysis. DSS significantly reduced body weight, colon length, and increased inflammation in the colon. Wogonin treatment prevented colonic ulceration, neutrophil infiltration, oxidative stress, pro-inflammatory cytokines, and histological changes. Oxidative damage and inflammatory mediators' elevation were also dramatically diminished by wogonin. Wogonin activates apoptosis via inhibiting Bcl-2 and augmenting Bax, caspase-3, and -9 expressions. Wogonin downregulated the COX-2 and iNOS, thereby repressing NF-κB. Wogonin regulated the Nrf2 signaling pathway and decreased TLR-4/NF-κB triggering. Taken together our study exposed that wogonin has a promising anti-ulcerative agent and recommended for good anti-inflammatory drug in the colon.
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Affiliation(s)
- Yadong Zhou
- Department of Gastrointestinal Surgery, 3201 Hospital, Hanzhong, China
| | - Fafu Dou
- Department of Gastrointestinal Surgery, 3201 Hospital, Hanzhong, China
| | - Huwei Song
- Department of General Surgery 2, Xi'an Children's Hospital, Xi'an, China
| | - Tao Liu
- Department of General Surgery 2, Xi'an Children's Hospital, Xi'an, China
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16
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Nanoparticles Carrying NF-κB p65-Specific siRNA Alleviate Colitis in Mice by Attenuating NF-κB-Related Protein Expression and Pro-Inflammatory Cellular Mediator Secretion. Pharmaceutics 2022; 14:pharmaceutics14020419. [PMID: 35214151 PMCID: PMC8874689 DOI: 10.3390/pharmaceutics14020419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 12/22/2022] Open
Abstract
Ulcerative colitis is a disease that causes inflammation and ulcers in the colon and which is typically recurrent, and NF-κB proteins are important players during disease progression. Here, we assess the impact of silica-coated calcium phosphate nanoparticles carrying encapsulated siRNA against NF-κB p65 on a murine model of colitis. To this end, nanoparticles were injected intravenously (2.0 mg siRNA/kg body weight) into mice after colitis induction with dextran sulfate sodium or healthy ones. The disease activity index, the histopathological impact on the colon, the protein expression of several NF-κB-associated players, and the mediator secretion (colon tissue, blood) were analyzed. We found that the nanoparticles effectively alleviated the clinical and histopathological features of colitis. They further suppressed the expression of NF-κB proteins (e.g., p65, p50, p52, p100, etc.) in the colon. They finally attenuated the local (colon) or systemic (blood) pro-inflammatory mediator secretion (e.g., TNF-α, IFN-β, MCP-1, interleukins, etc.) as well as the leucocyte load of the spleen and mesenteric lymph nodes. The nanoparticle biodistribution in diseased animals was seen to pinpoint organs containing lymphoid entities (appendix, intestine, lung, etc.). Taken together, the nanoparticle-related silencing of p65 NF-κB protein expression could well be used for the treatment of ulcerative colitis in the future.
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17
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Polo-Cuadrado E, Acosta-Quiroga K, Rojas-Peña C, Rodriguez-Nuñez YA, Duarte Y, Brito I, Cisterna J, Gutiérrez M. Molecular modeling and structural analysis of some tetrahydroindazole and cyclopentanepyrazole derivatives as COX-2 inhibitors. ARAB J CHEM 2022. [DOI: 10.1016/j.arabjc.2021.103540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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18
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Majumder R, Dhara M, Adhikari L, Panigrahi A. Comparative evaluation of anti-inflammatory activity between n-butanol fraction, leaf and stem methanolic extract obtained from Olaxpsittacorum. JOURNAL OF ETHNOPHARMACOLOGY 2022; 283:114697. [PMID: 34626778 DOI: 10.1016/j.jep.2021.114697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/14/2021] [Accepted: 09/27/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Olax psittacorum (Lam.) Vahl. traditionally used by the tribal communities of 'INDIA' to heal conditions such as pain, psoriasis, mouthulcer, anemia, constipation as well as diabetes followed by scientific evidences like antipyretic, anti-inflammatory, antimicrobial, anti-viral, and anti-cancer property too. AIM OF THE EXPERIMENT Solvent fractionation process by using chloroform, distilled water and n-butanol has been developed to get the precipitate as a fraction (encrypted as FrAE-ISO) of leaf methanolic extract (LME) and established GC-MS and antiinflammatory evaluation. The aim was to enumerate the potency against inflammation of FrAE-ISO comparing with LME, SME (Stem methanolic extract) and Diclofenac. TLC of LME extract has been developed too for separation & evaluation of the compounds appeared as bands obtained by scraping process. The motive of the experiment was to acquire an isolate from LME that can able to show an emense anti-inflammatory action compared to LME and SME. MATERIALS AND METHODS Priliminary phytochemical screening upon LME, SME and FrAE-ISO preformed by the standard methods of literatures. Scrapped portions of developed TLC plate (G-254 graded silica) of LME (n-Hexane:Ethylacetate; 7.5:2.5) were introduced to GC-MS evaluation. FrAE-ISO has introduced at a minute quantity (5 and 10 mg/kg/bw) within Wister albino rats (per os) against inflammation (model: carrageenan-induced paw edema) to evaluate its potency as compared to LME (25 mg/kg/bw), SME (25 mg/kg/bw) and Diclofenac (100 mg/kg). GC-MS evaluation has been conducted in both FrAE-ISO and scrapped sections to evaluate the presence of compounds qualitatively. RESULTS LME and SME, qualitatively through different screening processes confirm the presence of glycosides, flavonoids, amino acids, tannins, and saponins respectively. According to the quantitative study of the extracts concerning total phenolic, flavonoid, tannin, and saponin content equivalent to gallic acid, quercetin, tannic acid, and diosgenin respectively have shown less amount of phenolic, flavonoid, and saponin content in SME (30.95, 205.33 and 30.82 mg/g extract respectively) as compared to LME (95.68, 713.33 and 66.41 mg/g extract respectively). Quantitative estimation has shown the presence of 825.27 mg of saponin equivalent to diosgenin per gram of FrAE-ISO. The GC-MS study has revealed that every section of the leaf extract has " Hexadecanoic acid, methyl ester " in common with other important compounds responsible for its potent contribution towards the anti-inflammatory property. The scrapped portions of the TLC plate having mixture of compounds but FrAE-ISO has shown a sharp peak in GC-MS (up to 34 min of run time) as well as few crystals like structures under the binocular microscope. Compact doses of FrAEISO (yield = 1.645%) i.e. 5 and 10 mg/kg body weight was able to compete with 100 mg/kg Diclofenac portraying 88%-95% inhibition respectively throughout all phases of inflammation with no-significant differences compared to standard evaluated by ANOVA (in SPSS). CONCLUSION Olax psittacorum (Lam.) Vahl. could be a good choice to explore its importance within the pharmacognostic field of drug development and might be a better source of herbal-derived lead compounds which can help to treat other various activities like ulcer healing or anti-anemic property etc.
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Affiliation(s)
- Raja Majumder
- Department of Pharmaceutics, Bengal School of Technology, A College of Pharmacy, Delhi-Road, Sugandha, Hooghly, West-Bengal, 712102, India.
| | - Moonmun Dhara
- Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Siksha 'O' Anusandhan (SOA) Deemed to be University, Bhubaneswar, Odisha, 751003, India.
| | - Lopamudra Adhikari
- Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Siksha 'O' Anusandhan (SOA) Deemed to be University, Bhubaneswar, Odisha, 751003, India.
| | - Amitav Panigrahi
- Hi-Tech Hospital Road, Pandra, Rasulgarh, Bhubaneswar, Odisha, 751025, India.
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19
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Lee JA, Shin JY, Hong SS, Cho YR, Park JH, Seo DW, Oh JS, Kang JS, Lee JH, Ahn EK. Tetracera loureiri Extract Regulates Lipopolysaccharide-Induced Inflammatory Response Via Nuclear Factor-κB and Mitogen Activated Protein Kinase Signaling Pathways. PLANTS (BASEL, SWITZERLAND) 2022; 11:284. [PMID: 35161266 PMCID: PMC8839383 DOI: 10.3390/plants11030284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/16/2022] [Accepted: 01/19/2022] [Indexed: 06/14/2023]
Abstract
Tetracera loureiri (T. loureiri) is a woody climber inhabiting open deciduous or evergreen forests in Southeast Asia. A decoction comprising its stem and other herbs is a traditional Thai remedy for fatigue and jaundice, as well as to promote overall health. Anti-inflammatory effects induced by T. loureiri extract have not been reported. In this study, we investigated the anti-inflammatory effect of an ethanol extract of T. loureiri (ETL) on lipopolysaccharide (LPS)-induced inflammatory response in RAW264.7 macrophages. We found that ETL treatment inhibited the production of nitric oxide (NO) in LPS-stimulated RAW264.7 cells, without affecting cell viability. The effect of ETL on the expression of various pro-inflammatory mediators was analyzed using reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). We observed that ETL inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the mRNA and protein levels and decreased the production of prostaglandin E2 (PGE2) by COX-2 in RAW264.7 macrophages. ETL dose-dependently reduced the production of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in LPS-induced RAW264.7 cells, in a dose-dependent manner. Furthermore, ETL suppressed the LPS-induced nuclear translocation of the nuclear factor, NF-κB. Additionally, ETL was found to inhibit the activation of mitogen-activated protein kinases (MAPK), such as extracellular signal-regulated kinase, c-Jun-N-terminal kinase, and p38 MAPK. In conclusion, our findings demonstrate that ETL inhibits the expression of pro-inflammatory mediators and cytokines, thereby downregulating NF-κB and MAPK signaling pathways in LPS-stimulated macrophages, Consequently, ETL is a potential therapeutic agent for the treatment of inflammatory diseases.
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Affiliation(s)
- Jung A Lee
- Bio-Center, Gyeonggido Business and Science Accelerator (GBSA), Suwon 16229, Korea; (J.A.L.); (S.S.H.); (Y.-R.C.)
| | - Ju Young Shin
- College of Pharmacy, Dankook University, Cheonan 31116, Korea; (J.Y.S.); (J.-H.P.); (D.-W.S.); (J.S.O.)
| | - Seong Su Hong
- Bio-Center, Gyeonggido Business and Science Accelerator (GBSA), Suwon 16229, Korea; (J.A.L.); (S.S.H.); (Y.-R.C.)
| | - Young-Rak Cho
- Bio-Center, Gyeonggido Business and Science Accelerator (GBSA), Suwon 16229, Korea; (J.A.L.); (S.S.H.); (Y.-R.C.)
| | - Ju-Hyoung Park
- College of Pharmacy, Dankook University, Cheonan 31116, Korea; (J.Y.S.); (J.-H.P.); (D.-W.S.); (J.S.O.)
| | - Dong-Wan Seo
- College of Pharmacy, Dankook University, Cheonan 31116, Korea; (J.Y.S.); (J.-H.P.); (D.-W.S.); (J.S.O.)
| | - Joa Sub Oh
- College of Pharmacy, Dankook University, Cheonan 31116, Korea; (J.Y.S.); (J.-H.P.); (D.-W.S.); (J.S.O.)
| | - Jae-Shin Kang
- Biological Genetic Resources Utilization Division, National Institute of Biological Resources, Incheon 22689, Korea; (J.-S.K.); (J.H.L.)
| | - Jae Ho Lee
- Biological Genetic Resources Utilization Division, National Institute of Biological Resources, Incheon 22689, Korea; (J.-S.K.); (J.H.L.)
| | - Eun-Kyung Ahn
- Bio-Center, Gyeonggido Business and Science Accelerator (GBSA), Suwon 16229, Korea; (J.A.L.); (S.S.H.); (Y.-R.C.)
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Park G, Eo H, Kim D. Rhamnus crenata leaf extracts exhibit anti-inflammatory activity via modulating the Nrf2/HO-1 and NF-κB/MAPK signaling pathways. Asian Pac J Trop Biomed 2022. [DOI: 10.4103/2221-1691.357742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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21
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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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22
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Lee J, Lim S. Anti-inflammatory, and anti-arthritic effects by the twigs of Cinnamomum cassia on complete Freund's adjuvant-induced arthritis in rats. JOURNAL OF ETHNOPHARMACOLOGY 2021; 278:114209. [PMID: 34015366 DOI: 10.1016/j.jep.2021.114209] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 04/29/2021] [Accepted: 05/12/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The young branches of C. cassia Blume (Cinnamomi Ramulus; Guizhi; ; C. cassia twigs) have long been used as an anti-pyretic, anti-rheumatic, anti-spasmodic and stomachic in traditional medicine. AIM OF THE STUDY The aim of this study was to test the anti-inflammatory, anti-nociceptive, and anti-arthritic effects of Cinnamomum cassia twigs in acute and chronic arthritis rats. MATERIALS AND METHODS Subcutaneous injection of carrageenan for acute inflammation and complete Freund's adjuvant (CFA) for chronic arthritis was carried out in the hind paw of SD rats. The paw volume was measured by a plethysmometer; thermal hyperalgesia was tested using a thermal plantar tester; hyperalgesia was evaluated by ankle flexion evoked vocalizations. The c-Fos expression in the lumbar spinal cord was measured with the avidin-biotin-peroxidase technique. The nitric oxide (NO) generation in lipopolysaccharide (LPS)-induced RAW 264.7 cells was tested by Griess assay. RESULTS AND DISCUSSION An 80% ethanoic extract of the C. cassia twigs exhibited chronic anti-inflammatory and anti-arthritic activities by reducing the edema volume in the paws of CFA-induced chronic arthritis in rats. In addition, it showed analgesic effects through the recovery of the paw withdrawal latency stimulated by thermal hyperalgesia, and suppressing the vocalization scores evoked by ankle flexion in the hind paws of the arthritis rats. It also controlled c-Fos expression in the lumbar spinal cord of the arthritis rats. Moreover, the addition its 80%-ethanoic extract, specifically, its ethyl acetate fraction, powerfully suppressed the paw swelling in carrageenan-stimulated arthritis and the NO production in LPS-induced murine immune cells. CONCLUSION C. cassia twigs may act as a viably sufficient therapeutic or preventive candidate for osteoarthritis and rheumatoid arthritis; additionally, it could prevent gastrointestinal damage with its gastric protection.
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Affiliation(s)
- JiSuk Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, South Korea.
| | - Sabina Lim
- Research Group of Pain and Neuroscience, East-West Medical Research Institute, WHO Collaborating Center, Kyung Hee University, Seoul, 02447, South Korea.
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Endo S, Nishiyama T, Matuoka T, Miura T, Nishinaka T, Matsunaga T, Ikari A. Loxoprofen enhances intestinal barrier function via generation of its active metabolite by carbonyl reductase 1 in differentiated Caco-2 cells. Chem Biol Interact 2021; 348:109634. [PMID: 34506768 DOI: 10.1016/j.cbi.2021.109634] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/31/2021] [Accepted: 09/05/2021] [Indexed: 02/06/2023]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used worldwide as antipyretic analgesics and agents for rheumatoid arthritis and osteoarthritis, but known to cause damage to the gastrointestinal mucosae as their serious adverse effects. Few studies showed the impairment of intestinal epithelial barrier function (EBF) by high concentrations (0.5-1 mM) of NSAIDs, but the underlying mechanism is not fully understood. This study is aimed at clarifying effects at a low concentration (50 μM) of three NSAIDs, loxoprofen (Lox), ibuprofen and indomethacin, on intestinal EBF using human intestinal epithelial-like Caco-2 cells. Among those NSAIDs, Lox increased the transepithelial electric resistance (TER) value, decreased the paracellular Lucifer yellow CH (LYCH) permeability, and upregulated claudin (CLDN)-1, -3 and -5, indicating that low doses of Lox enhanced EBF through increasing expression of CLDNs. Lox is known to be metabolized to a pharmacologically active metabolite, (2S,1'R,2'S)-loxoprofen alcohol (Lox-RS), by carbonyl reductase 1 (CBR1), which is highly expressed in human intestine. CBR1 was expressed in the Caco-2 cells, and the pretreatment with a CBR1 inhibitor suppressed both the Lox-evoked CLDN upregulation and EBF enhancement. In addition, the treatment of the cells with Lox-RS resulted in higher TER value and lower LYCH permeability than those with Lox. Thus, Lox-RS synthesized by CBR1 may greatly contribute to the improving efficacy of Lox on the barrier function. Since EBF is decreased in inflammatory bowel disease, we finally examined the effect of Lox on EBF using the Caco-2/THP-1 co-culture system, which is used as an in vitro inflammatory bowel disease model. Lox significantly recovered EBF which was impaired by inflammatory cytokines secreted from THP-1 macrophages. These in vitro observations suggest that Lox enhances intestinal EBF, for which the metabolism of Lox to Lox-RS by CBR1 has an important role.
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Affiliation(s)
- Satoshi Endo
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, 501-1196, Gifu, Japan
| | - Tsubasa Nishiyama
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, 501-1196, Gifu, Japan
| | - Tomoe Matuoka
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, 501-1196, Gifu, Japan
| | - Takeshi Miura
- Pharmaceutical Education Support Center, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, 663-8184, Japan
| | - Toru Nishinaka
- Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, 584-8540, Japan
| | - Toshiyuki Matsunaga
- Education Center of Green Pharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, 502-8585, Japan
| | - Akira Ikari
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, 501-1196, Gifu, Japan.
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Abstract
The subcutaneous air pouch is an in vivo model that can be used to study the components of acute and chronic inflammation, the resolution of the inflammatory response, the oxidative stress response, and potential therapeutic targets for treating inflammation. Injection of irritants into an air pouch in rats or mice induces an inflammatory response that can be quantified by the volume of exudate produced, the infiltration of cells, and the release of inflammatory mediators. The model presented in this article has been extensively used to identify potential anti-inflammatory drugs. © 2021 Wiley Periodicals LLC. Basic Protocol: Air pouch model in the rat Alternate Protocol: Air pouch model in the mouse.
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Affiliation(s)
- Jill C Fehrenbacher
- Department of Pharmacology and Toxicology and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kenneth E McCarson
- Kansas Intellectual and Developmental Disabilities Research Center (KIDDRC), Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
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Badawy MAS, Abdelall EKA, El-Nahass ES, Abdellatif KRA, Abdel-Rahman HM. Design, synthesis, biological assessment and in silico ADME prediction of new 2-(4-(methylsulfonyl) phenyl) benzimidazoles as selective cyclooxygenase-2 inhibitors. RSC Adv 2021; 11:27659-27673. [PMID: 35480694 PMCID: PMC9037807 DOI: 10.1039/d1ra04756f] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 07/30/2021] [Indexed: 11/22/2022] Open
Abstract
A novel series of benzimidazole derivatives wherein 4-(methylsulfonyl) phenyl pharmacophore attached via its C-2 position was designed and synthesized. These compounds were evaluated in vitro as cyclooxygenase-1(COX-1)/cyclooxygenese-2(COX-2) inhibitors. Furthermore, the synthesized compounds were also in vivo evaluated for their anti-inflammatory activity and ulcerogenic liability. Examination of histopathological lesions was also performed to evaluate the cariogenic effect of most active compounds. In silico prediction of physicochemical properties, ADME, and drug-likeness profiles were also studied. Several compounds as 11b, 11k, 12b, and 12d showed selective inhibition to (COX-2) isozyme. Compound 11b showed the most potent (COX-2) inhibitory activity with (IC50 = 0.10 μM) and selectivity index (SI = 134); the tested compounds also have shown good anti-inflammatory activity. Regarding the ulcerogenic liability, compound 11b was also safest one (Ulcer Index) (UI = 0.83). The results of the molecular docking studies is closely related to the results of the in vitro COX-2 inhibitory activities. A novel series of benzimidazole derivatives wherein 4-(methylsulfonyl) phenyl pharmacophore attached via its C-2 position was designed and synthesized.![]()
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Affiliation(s)
- Mohamed A S Badawy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Nahda University (NUB) Beni-Suef 62513 Egypt +2001066394559
| | - Eman K A Abdelall
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University Beni-Suef 62514 Egypt
| | - El-Shaymaa El-Nahass
- Department of Pathology, Faculty of Veterinary Medicine, Beni-Suef University Beni-Suef 62511 Egypt
| | - Khaled R A Abdellatif
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University Beni-Suef 62514 Egypt.,Pharmaceutical Sciences Department, IbnSina National College for Medical Studies Jeddah Kingdom of Saudi Arabia
| | - Hamdy M Abdel-Rahman
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Nahda University (NUB) Beni-Suef 62513 Egypt +2001066394559.,Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University Assiut 71526 Egypt
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Min SY, Park CH, Yu HW, Park YJ. Anti-Inflammatory and Anti-Allergic Effects of Saponarin and Its Impact on Signaling Pathways of RAW 264.7, RBL-2H3, and HaCaT Cells. Int J Mol Sci 2021; 22:ijms22168431. [PMID: 34445132 PMCID: PMC8395081 DOI: 10.3390/ijms22168431] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/02/2021] [Accepted: 08/03/2021] [Indexed: 12/27/2022] Open
Abstract
Saponarin{5-hydroxy-2-(4-hydroxyphenyl)-6-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]-7-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxychromen-4-one}, a flavone found in young green barley leaves, is known to possess antioxidant, antidiabetic, and hepatoprotective effects. In the present study, the anti-inflammatory, anti-allergic, and skin-protective effects of saponarin were investigated to evaluate its usefulness as a functional ingredient in cosmetics. In lipopolysaccharide-induced RAW264.7 (murine macrophage) cells, saponarin (80 μM) significantly inhibited cytokine expression, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, inducible nitric oxide synthase, and cyclooxygenase (COX)-2. Saponarin (80 μM) also inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 involved in the mitogen-activated protein kinase signaling pathway in RAW264.7 cells. Saponarin (40 μM) significantly inhibited β-hexosaminidase degranulation as well as the phosphorylation of signaling effectors (Syk, phospholipase Cγ1, ERK, JNK, and p38) and the expression of inflammatory mediators (tumor necrosis factor [TNF]-α, IL-4, IL-5, IL-6, IL-13, COX-2, and FcεRIα/γ) in DNP-IgE- and DNP-BSA-stimulated RBL-2H3 (rat basophilic leukemia) cells. In addition, saponarin (100 μM) significantly inhibited the expression of macrophage-derived chemokine, thymus and activation-regulated chemokine, IL-33, thymic stromal lymphopoietin, and the phosphorylation of signaling molecules (ERK, p38 and signal transducer and activator of transcription 1 [STAT1]) in TNF-α- and interferon (IFN)-γ-stimulated HaCaT (human immortalized keratinocyte) cells. Saponarin (100 μM) also significantly induced the expression of hyaluronan synthase-3, aquaporin 3, and cathelicidin antimicrobial peptide (LL-37) in HaCaT cells, which play an important role as skin barriers. Saponarin remarkably inhibited the essential factors involved in the inflammatory and allergic responses of RAW264.7, RBL-2H3, and HaCaT cells, and induced the expression of factors that function as physical and chemical skin barriers in HaCaT cells. Therefore, saponarin could potentially be used to prevent and relieve immune-related skin diseases, including atopic dermatitis.
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Sunil MA, Sunitha VS, Santhakumaran P, Mohan MC, Jose MS, Radhakrishnan EK, Mathew J. Protective effect of (+)-catechin against lipopolysaccharide-induced inflammatory response in RAW 264.7 cells through downregulation of NF-κB and p38 MAPK. Inflammopharmacology 2021; 29:1139-1155. [PMID: 34115226 DOI: 10.1007/s10787-021-00827-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/29/2021] [Indexed: 12/26/2022]
Abstract
Catechin, a flavonol belonging to the flavonoid group of polyphenols is present in many plant foods. The present study was done to evaluate the effect of catechin on various inflammatory mediators using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The effect of catechin on total cyclooxygenase (COX) activity, 5-lipoxygenase (5-LOX), myeloperoxidase, nitrite and inducible nitric oxide synthase (iNOS) level, secretion of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were assessed in LPS-stimulated RAW 264.7 cells. The expression of COX-2, iNOS, TNF-α, nuclear factor-ĸB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) genes were also investigated. The effect was further analyzed using human PBMCs by assessing the level of TNF-α and IL-10. The study demonstrated that the inflammatory mediators such as COX, 5-LOX, nitrite, iNOS, and TNF-α were significantly inhibited by catechin in a concentration-dependent manner whereas IL-10 production was up-regulated in RAW 264.7 cells. Moreover, catechin down-regulated the mRNA level expression of COX-2, iNOS, TNF-α, NF-κB and p38 MAPK. The current study ratifies the beneficial effect of catechin as a dietary component in plant foods to provide protection against inflammatory diseases.
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Affiliation(s)
- M A Sunil
- School of Biosciences, Mahatma Gandhi University Kottayam, Kerala, 686560, India
| | - V S Sunitha
- School of Biosciences, Mahatma Gandhi University Kottayam, Kerala, 686560, India
| | | | - Mohind C Mohan
- School of Biosciences, Mahatma Gandhi University Kottayam, Kerala, 686560, India
| | | | - E K Radhakrishnan
- School of Biosciences, Mahatma Gandhi University Kottayam, Kerala, 686560, India
| | - Jyothis Mathew
- School of Biosciences, Mahatma Gandhi University Kottayam, Kerala, 686560, India.
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Bai HW, Yang C, Wang P, Rao S, Zhu BT. Inhibition of cyclooxygenase by blocking the reducing cosubstrate at the peroxidase site: Discovery of galangin as a novel cyclooxygenase inhibitor. Eur J Pharmacol 2021; 899:174036. [PMID: 33737009 DOI: 10.1016/j.ejphar.2021.174036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 12/01/2022]
Abstract
Earlier we have shown that certain flavonoids (e.g., quercetin) are high-affinity reducing cosubstrates for cyclooxygenase (COX) 1 and 2. These compounds can bind inside the peroxidase active sites of COXs and donate an electron from one of their B-ring hydroxyl groups to hematin. Based on these earlier findings, it is postulated that some of the natural flavonoids such as galangin that are structural analogs of quercetin but lack the proper B-ring hydroxyl groups might function as novel inhibitors of COXs by blocking the effect of the reducing cosubstrates. This idea is tested in the present study. Computational docking analysis together with quantum chemistry calculation shows that galangin can bind inside the peroxidase active sites of COX-1 and COX-2 in a similar manner as quercetin, but it has little ability to effectively donate its electrons, thereby blocking the effect of the reducing cosubstrates like quercetin. Further experimental studies confirm that galangin can inhibit, both in vitro and in vivo, quercetin-mediated activation of the peroxidase activity of the COX-1/2 enzymes. The results of the present study demonstrate that galangin is a novel naturally-occurring inhibitor of COX-1 and COX-2, acting by blocking the function of the reducing cosubstrates at the peroxidase sites.
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Affiliation(s)
- Hyoung-Woo Bai
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China; Present Address: Advanced Radiation Technology Institute (ARTI), Korea Atomic Energy Research Institute (KAERI), Jeongeup-si, Jeollabuk-do 580-185, Republic of Korea
| | - Chengxi Yang
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China
| | - Pan Wang
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China
| | - Shun Rao
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China
| | - Bao Ting Zhu
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China; Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
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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: 24] [Impact Index Per Article: 6.0] [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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Zhao X, Wang H, Yang Y, Gou Y, Wang Z, Yang D, Li C. Protective Effects of Silymarin Against D-Gal/LPS-Induced Organ Damage and Inflammation in Mice. Drug Des Devel Ther 2021; 15:1903-1914. [PMID: 33976540 PMCID: PMC8106468 DOI: 10.2147/dddt.s305033] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/10/2021] [Indexed: 01/26/2023] Open
Abstract
AIM Silymarin contains various flavonoids and exhibits antioxidative, anti-inflammatory, and anticancer effects, in addition to other pharmacological properties. This study explored the alleviating effect of silymarin on multiple-organ damage induced by D-galactose/lipopolysaccharide in Kunming mice. METHODS Kunming mice were injected intraperitoneally with D-galactose (30 mg/kg·BW)/LPS (3 μg/kg·BW) and then treated using silymarin with different doses (75 mg/kg·bw and 150 mg/kg·bw) via intragastric administration. Changes in organ indexes, pathological changes, liver-function index, biochemical indexes, molecular biological indexes, and genes related to the oxidation and inflammation of main organs were evaluated. RESULTS After the mice were treated with silymarin, their body weight showed no significant change, and the liver, kidney, and lung indexes of the treated mice were higher than those of the model group; meanwhile, the corresponding histopathological formation was reduced. Compared with the model group, the silymarin-treated group showed reductions in ALT, AST, and liver function indexes in the mouse serum. Silymarin treatment also increased the SOD, CAT, GSH, GSH-Px, T-AOC, IL-10, and IL-12 levels, as well as reduced the MDA, NO, IL-6, IL-1β, TNF-α, IFN-γ levels in the mouse serum and liver tissues. In addition, quantitative polymerase chain reaction analysis indicated that the mRNA expression levels of SOD1, SOD2, CAT, GSH-Px, IL-10, Nrf2, HO-1, NQO1, Trx, and IκB-α were higher in the liver tissue of the silymarin-treated mice than in those of the model group; meanwhile, the mRNA expression levels of IL-6, IL-1β, TNF-α, IFN-γ, NF-κB, NLRP3, COX2, and p38 were lower than those in the model group. CONCLUSION Silymarin, which exhibits antioxidative and anti-inflammatory effects, can alleviate the liver, lung, and kidney damage induced by D-galactose/lipopolysaccharide. High-dose (150 mg/kg·bw) silymarin can more effectively inhibit organ damage, compared with low-dose silymarin (75 mg/kg·bw) in Kunming mice.
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Affiliation(s)
- Xin Zhao
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing, 400067, People’s Republic of China
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing, 400067, People’s Republic of China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, 400067, People’s Republic of China
| | - Haoxiang Wang
- Department of Neurology, Second Affiliated Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
| | - Yue Yang
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing, 400067, People’s Republic of China
- College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People’s Republic of China
| | - Yuting Gou
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing, 400067, People’s Republic of China
- College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People’s Republic of China
| | - Zhiying Wang
- School of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, People’s Republic of China
| | - Dingyi Yang
- Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, 400044, People’s Republic of China
| | - Chong Li
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing, 400067, People’s Republic of China
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing, 400067, People’s Republic of China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, 400067, People’s Republic of China
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Wangdi JT, Sabou V, O’Leary MF, Kelly VG, Bowtell JL. Use, Practices and Attitudes of Elite and Sub-Elite Athletes towards Tart Cherry Supplementation. Sports (Basel) 2021; 9:sports9040049. [PMID: 33807198 PMCID: PMC8066185 DOI: 10.3390/sports9040049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/18/2021] [Accepted: 03/29/2021] [Indexed: 11/16/2022] Open
Abstract
Tart cherry (TC) supplementation can improve exercise recovery and performance; and may also improve sleep duration and quality. This study investigated the use and knowledge of TC supplementation by athletes of all competitive levels. Eighty participants (52.5% elite (international, national, professional), 47.5% sub-elite (semi-professional, state/regional, county level, club level, recreational)) completed an online questionnaire investigating their attitudes towards and use of TC supplementation. Overall, 22.6% of participants were using or had previously used TC supplements, and 12.5% of participants planned to used TC supplements. Improved recovery (71.4%), sleep (32.1%) and immunity and general health (32.1%) were the most frequently indicated goals by respondents using TC supplements. In total, 32.1% of respondents were supplemented with TC chronically, 39.3% acutely and 28.6% used a combination of chronic and acute supplementation. The majority of those employing TC supplementation chronically used TC either over 2-3 days (37.0%) or continuously (37.0%). The most popular TC pre- and post-loading period was one day (34.3% and 41.5%, respectively). There were no significant differences between elite and sub-elite athletes in any parameters assessed (p > 0.05). TC supplementation is not widely used by the athletes surveyed, and athletes using TC supplements showed poor awareness of an evidence-led dosing strategy, regardless of competitive level.
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Affiliation(s)
- Jimmy T. Wangdi
- School of Human Movement and Nutrition Sciences, University of Queensland, Brisbane, QLD 4072, Australia; (J.T.W.); (V.G.K.)
- Sport and Health Sciences, St Luke’s Campus, University of Exeter, Heavitree Road, Exeter EX1 2LU, UK; (V.S.); (M.F.O.)
| | - Vlad Sabou
- Sport and Health Sciences, St Luke’s Campus, University of Exeter, Heavitree Road, Exeter EX1 2LU, UK; (V.S.); (M.F.O.)
| | - Mary F. O’Leary
- Sport and Health Sciences, St Luke’s Campus, University of Exeter, Heavitree Road, Exeter EX1 2LU, UK; (V.S.); (M.F.O.)
| | - Vincent G. Kelly
- School of Human Movement and Nutrition Sciences, University of Queensland, Brisbane, QLD 4072, Australia; (J.T.W.); (V.G.K.)
- School of Exercise and Nutrition Sciences, Queensland University of Technology, Brisbane, QLD 4000, Australia
| | - Joanna L. Bowtell
- Sport and Health Sciences, St Luke’s Campus, University of Exeter, Heavitree Road, Exeter EX1 2LU, UK; (V.S.); (M.F.O.)
- Correspondence:
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Ayoub SS. Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action. Temperature (Austin) 2021; 8:351-371. [PMID: 34901318 PMCID: PMC8654482 DOI: 10.1080/23328940.2021.1886392] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/26/2021] [Accepted: 02/01/2021] [Indexed: 02/02/2023] Open
Abstract
Paracetamol (acetaminophen) is undoubtedly one of the most widely used drugs worldwide. As an over-the-counter medication, paracetamol is the standard and first-line treatment for fever and acute pain and is believed to remain so for many years to come. Despite being in clinical use for over a century, the precise mechanism of action of this familiar drug remains a mystery. The oldest and most prevailing theory on the mechanism of analgesic and antipyretic actions of paracetamol relates to the inhibition of CNS cyclooxygenase (COX) enzyme activities, with conflicting views on the COX isoenzyme/variant targeted by paracetamol and on the nature of the molecular interactions with these enzymes. Paracetamol has been proposed to selectively inhibit COX-2 by working as a reducing agent, despite the fact that in vitro screens demonstrate low potency on the inhibition of COX-1 and COX-2. In vivo data from COX-1 transgenic mice suggest that paracetamol works through inhibition of a COX-1 variant enzyme to mediate its analgesic and particularly thermoregulatory actions (antipyresis and hypothermia). A separate line of research provides evidence on potentiation of the descending inhibitory serotonergic pathway to mediate the analgesic action of paracetamol, but with no evidence of binding to serotonergic molecules. AM404 as a metabolite for paracetamol has been proposed to activate the endocannabinoid and the transient receptor potential vanilloid-1 (TRPV1) systems. The current review gives an update and in some cases challenges the different theories on the pharmacology of paracetamol and raises questions on some of the inadequately explored actions of paracetamol. List of Abbreviations: AM404, N-(4-hydroxyphenyl)-arachidonamide; CB1R, Cannabinoid receptor-1; Cmax, Maximum concentration; CNS, Central nervous system; COX, Cyclooxygenase; CSF, Cerebrospinal fluid; ED50, 50% of maximal effective dose; FAAH, Fatty acid amidohydrolase; IC50, 50% of the maximal inhibitor concentration; LPS, Lipopolysaccharide; NSAIDs, Non-steroidal anti-inflammatory drugs; PGE2, Prostaglandin E2; TRPV1, Transient receptor potential vanilloid-1.
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Affiliation(s)
- Samir S Ayoub
- School of Health, Sport and Bioscience, Medicines Research Group, University of East London, London, UK
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Cai M, Ni WJ, Han L, Chen WD, Peng DY. Research Progress of Therapeutic Enzymes and Their Derivatives: Based on Herbal Medicinal Products in Rheumatoid Arthritis. Front Pharmacol 2021; 12:626342. [PMID: 33796022 PMCID: PMC8008143 DOI: 10.3389/fphar.2021.626342] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 01/07/2021] [Indexed: 12/19/2022] Open
Abstract
Rheumatoid arthritis (RA) acts as one of the most common, agnogenic and chronic inflammatory-autoimmune disorder which is characterized by persistent synovitis, cartilage destruction, and joint deformities, leads to a wide range of disabilities, and increased mortality, thus imposing enormous burdens. Several drugs with anti-inflammatory and immunomodulatory properties such as celecoxib, diclofenac and methotrexate are being selected as conventional drugs in the allopathic system of medicine for the treatment of RA in clinic. However, there are some serious side effects more or less when using these drugs because of their short poor bioavailability and biological half-life for a long time. These shortcomings greatly promote the exploration and application of new low- or no-toxicity drugs for treating the RA. Meanwhile, a growing number of studies demonstrate that several herbs present certain anti-inflammatory and anti-arthritic activities through different enzymes and their derivatives, which indicate that they are promising therapeutic strategies when targeting these mediators based on herbal medicinal products in RA research. This review article summarizes the roles of the main enzymes and their derivatives during the pathogenesis of RA, and clearly clarifies the explicit and potential targeted actions of herbal medicinal products that have anti-RA activity. Our review provides timely and critical reference for the scientific rationale use of herbal medicinal products, with the increasing basic research and clinical application of herbal medicinal products by patients with RA.
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Affiliation(s)
- Ming Cai
- Department of Pharmacy, The Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,Anhui University of Chinese Medicine, Hefei, China.,Key Laboratory of Chinese Medicinal Formula Research, Anhui University of Chinese Medicine, Hefei, China
| | - Wei-Jian Ni
- School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.,Department of Pharmacy, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Lan Han
- Anhui University of Chinese Medicine, Hefei, China.,Key Laboratory of Chinese Medicinal Formula Research, Anhui University of Chinese Medicine, Hefei, China
| | - Wei-Dong Chen
- Anhui University of Chinese Medicine, Hefei, China.,Key Laboratory of Chinese Medicinal Formula Research, Anhui University of Chinese Medicine, Hefei, China
| | - Dai-Yin Peng
- Anhui University of Chinese Medicine, Hefei, China.,Key Laboratory of Chinese Medicinal Formula Research, Anhui University of Chinese Medicine, Hefei, 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: 41] [Impact Index Per Article: 8.2] [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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Pratima Yadav, Kumar R, Tewari AK. Docking Simulation and Anti-Inflammatory Profile of Some Synthesized Heterodimer of Pyrazole. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2020. [DOI: 10.1134/s1068162020060370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Wei W, Chen Y, Ma J, Xie D, Zhou Y. Computational determination of binding modes of 2-acetoxyphenylhept-2-ynyl sulfide to cyclooxygenase-2. J Biomol Struct Dyn 2020; 38:3648-3658. [DOI: 10.1080/07391102.2019.1666033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Wanqing Wei
- Institute of Theoretical and Computational Chemistry, Key Laboratory of Mesoscopic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Yani Chen
- Institute of Theoretical and Computational Chemistry, Key Laboratory of Mesoscopic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Jing Ma
- Institute of Theoretical and Computational Chemistry, Key Laboratory of Mesoscopic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Daiqian Xie
- Institute of Theoretical and Computational Chemistry, Key Laboratory of Mesoscopic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Yanzi Zhou
- Institute of Theoretical and Computational Chemistry, Key Laboratory of Mesoscopic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
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5-(4 H)-Oxazolones and Their Benzamides as Potential Bioactive Small Molecules. Molecules 2020; 25:molecules25143173. [PMID: 32664550 PMCID: PMC7397336 DOI: 10.3390/molecules25143173] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/09/2020] [Accepted: 07/10/2020] [Indexed: 11/21/2022] Open
Abstract
The five membered heterocyclic oxazole group plays an important role in drug discovery. Oxazolones present a wide range of biological activities. In this article the synthesis of 4-substituted-2-phenyloxazol-5(4H)-ones from the appropriate substituted aldehydes via an Erlenmeyer–Plochl reaction is reported. Subsequently, the corresponding benzamides were produced via a nucleophilic attack of a secondary amine on the oxazolone ring applying microwave irradiation. The compounds are obtained in good yields up to 94% and their structures were confirmed using IR, 1H-NMR, 13C-NMR and LC/MS data. The in vitro anti-lipid peroxidation activity and inhibitory activity against lipoxygenase and trypsin induced proteolysis of the novel derivatives were studied. Inhibition of carrageenin-induced paw edema (CPE) and nociception was also determined for compounds 4a and 4c. Oxazolones 2a and 2c strongly inhibit lipid peroxidation, followed by oxazolones 2b and 2d with an average inhibition of 86.5%. The most potent lipoxygenase inhibitor was the bisbenzamide derivative 4c, with IC50 41 μM. The benzamides 3c, 4a–4e and 5c were strong inhibitors of proteolysis. The replacement of the thienyl moiety by a phenyl group does not favor the protection. Compound 4c inhibited nociception higher than 4a. The replacement of thienyl groups by phenyl ring led to reduced biological activity. Docking studies of the most potent LOX inhibitor highlight interactions through allosteric mechanism. All the potent derivatives present good oral bioavailability.
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7-Acetoxycoumarin Inhibits LPS-Induced Inflammatory Cytokine Synthesis by IκBα Degradation and MAPK Activation in Macrophage Cells. Molecules 2020; 25:molecules25143124. [PMID: 32650550 PMCID: PMC7397006 DOI: 10.3390/molecules25143124] [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: 06/01/2020] [Revised: 07/01/2020] [Accepted: 07/07/2020] [Indexed: 11/25/2022] Open
Abstract
Acetylation involves the chemical introduction of an acetyl group in place of an active hydrogen group into a compound. In this study, we synthesized 7-acetoxycoumarin (7AC) from acetylation of umbelliferone (UMB). We examined the anti-inflammatory properties of 7AC in lipopolysaccharide (LPS)-treated RAW 264.7 macrophage cells. The anti-inflammatory activity of 7AC on viability of treated cells was assessed by measuring the level of expression of NO, PGE2 and pro-inflammatory cytokines, namely interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in 7AC-treated RAW 264.7 macrophages. The 7AC was nontoxic to cells and inhibited the production of cytokines in a concentration-dependent manner. In addition, its treatment suppressed the production of pro-inflammatory cytokines in a dose-dependent manner and concomitantly decreased the protein and mRNA expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, the levels of the phosphorylation of mitogen-activated protein kinase (MAPK) family proteins such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 and nuclear factor kappa B (NF-κB) were reduced by 7AC. In conclusion, we generated an anti-inflammatory compound through acetylation and demonstrated its efficacy in cell-based in vitro assays.
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Park CH, Min SY, Yu HW, Kim K, Kim S, Lee HJ, Kim JH, Park YJ. Effects of Apigenin on RBL-2H3, RAW264.7, and HaCaT Cells: Anti-Allergic, Anti-Inflammatory, and Skin-Protective Activities. Int J Mol Sci 2020; 21:ijms21134620. [PMID: 32610574 PMCID: PMC7370139 DOI: 10.3390/ijms21134620] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/19/2020] [Accepted: 06/28/2020] [Indexed: 12/31/2022] Open
Abstract
Apigenin (4',5,7-trihydroxyflavone, flavonoid) is a phenolic compound that is known to reduce the risk of chronic disease owing to its low toxicity. The first study on apigenin analyzed its effect on histamine release in the 1950s. Since then, anti-mutation and antitumor properties of apigenin have been widely reported. In the present study, we evaluated the apigenin-mediated amelioration of skin disease and investigated its applicability as a functional ingredient, especially in cosmetics. The effect of apigenin on RAW264.7 (murine macrophage), RBL-2H3 (rat basophilic leukemia), and HaCaT (human immortalized keratinocyte) cells were analyzed. Apigenin (100 μM) significantly inhibited nitric oxide (NO) production, cytokine expression (interleukin (IL)-1β, IL6, cyclooxygenase (COX)-2, and inducible nitric oxide synthase [iNOS]), and phosphorylation of mitogen-activated protein kinase (MAPK) signal molecules, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal protein kinase (JNK) in RAW264.7 cells. Apigenin (30 M) also inhibited the phosphorylation of signaling molecules (Lyn, Syk, phospholipase Cγ1, ERK, and JNK) and the expression of high-affinity IgE receptor FcεRIα and cytokines (tumor necrosis factor (TNF)-α, IL-4, IL-5, IL-6, IL-13, and COX-2) that are known to induce inflammation and allergic responses in RBL-2H3 cells. Further, apigenin (20 μM) significantly induced the expression of filaggrin, loricrin, aquaporin-3, hyaluronic acid, hyaluronic acid synthase (HAS)-1, HAS-2, and HAS-3 in HaCaT cells that are the main components of the physical barrier of the skin. Moreover, it promoted the expression of human β-defensin (HBD)-1, HBD-2, HBD-3, and cathelicidin (LL-37) in HaCaT cells. These antimicrobial peptides are known to play an important role in the skin as chemical barriers. Apigenin significantly suppressed the inflammatory and allergic responses of RAW264.7 and RBL cells, respectively, and would, therefore, serve as a potential prophylactic and therapeutic agent for immune-related diseases. Apigenin could also be used to improve the functions of the physical and chemical skin barriers and to alleviate psoriasis, acne, and atopic dermatitis.
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Affiliation(s)
- Che-Hwon Park
- Department of Medicinal Biosciences, Research Institute for Biomedical & Health Science, College of Biomedical and Health Science, Konkuk University, 268 Chungwon-daero, Chungju-si 27478, Korea; (C.-H.P.); (S.-Y.M.); (H.-W.Y.)
| | - Seon-Young Min
- Department of Medicinal Biosciences, Research Institute for Biomedical & Health Science, College of Biomedical and Health Science, Konkuk University, 268 Chungwon-daero, Chungju-si 27478, Korea; (C.-H.P.); (S.-Y.M.); (H.-W.Y.)
| | - Hye-Won Yu
- Department of Medicinal Biosciences, Research Institute for Biomedical & Health Science, College of Biomedical and Health Science, Konkuk University, 268 Chungwon-daero, Chungju-si 27478, Korea; (C.-H.P.); (S.-Y.M.); (H.-W.Y.)
| | - Kyungmin Kim
- Jeju R&D Center, AMI Cosmetics Co., Ltd., 16, Sancheondandong-gil, Jeju-si 63359, Korea; (K.K.); (S.K.)
| | - Suyeong Kim
- Jeju R&D Center, AMI Cosmetics Co., Ltd., 16, Sancheondandong-gil, Jeju-si 63359, Korea; (K.K.); (S.K.)
| | - Hye-Ja Lee
- Natural Products Laboratory, DAEBONG Life Science Co., Ltd., 213-4, Chumdan-Ro, Jeju-si 63309, Korea; (H.-J.L.); (J.-H.K.)
| | - Ji-Hye Kim
- Natural Products Laboratory, DAEBONG Life Science Co., Ltd., 213-4, Chumdan-Ro, Jeju-si 63309, Korea; (H.-J.L.); (J.-H.K.)
| | - Young-Jin Park
- Department of Medicinal Biosciences, Research Institute for Biomedical & Health Science, College of Biomedical and Health Science, Konkuk University, 268 Chungwon-daero, Chungju-si 27478, Korea; (C.-H.P.); (S.-Y.M.); (H.-W.Y.)
- Correspondence: ; Tel.: +82-43-840-3601
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Nabiyeva T, Marschner C, Blom B. Synthesis, structure and anti-cancer activity of osmium complexes bearing π-bound arene substituents and phosphane Co-Ligands: A review. Eur J Med Chem 2020; 201:112483. [PMID: 32592914 DOI: 10.1016/j.ejmech.2020.112483] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 05/17/2020] [Accepted: 05/17/2020] [Indexed: 12/24/2022]
Abstract
While many examples of osmium complexes, as anti-cancer agents, have been reported and some reviews have been devoted to this topic, a particularly interesting and synthetically accessible sub-class of these compounds namely those bearing a π- bound arene and phosphane co-ligand have escaped review. These complexes have made a surprisingly late entry in the literature (2005) in terms of anti-cancer investigations. This is somewhat surprising considering the plethora of analogous complexes that have been reported for the lighter analogue, ruthenium. Herein we review all complexes, neutral and ionic, bearing the "(ƞ6-arene)Os(PR3)" moiety focusing on their synthesis, reactivity, structural features (by X-ray diffraction analysis) as well as anti-cancer biological activity. An attempt is made throughout the article to contrast these to each other and to analogous Ru systems, and a full summary of all existing in vitro biological data is presented.
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Affiliation(s)
- Tomiris Nabiyeva
- Maastricht Science Programme, Faculty of Science and Engineering, Maastricht University, Kapoenstraat 2, PO Box 616, 6200, MD, Maastricht, the Netherlands
| | - Christoph Marschner
- Institut für Anorganische Chemie, Technische Universität Graz, Stremayrgasse 9, A-8010, Graz, Austria
| | - Burgert Blom
- Maastricht Science Programme, Faculty of Science and Engineering, Maastricht University, Kapoenstraat 2, PO Box 616, 6200, MD, Maastricht, the Netherlands.
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Li H, Jiang W, Ye S, Zhou M, Liu C, Yang X, Hao K, Hu Q. P2Y 14 receptor has a critical role in acute gouty arthritis by regulating pyroptosis of macrophages. Cell Death Dis 2020; 11:394. [PMID: 32457291 PMCID: PMC7250907 DOI: 10.1038/s41419-020-2609-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/11/2020] [Accepted: 05/14/2020] [Indexed: 12/11/2022]
Abstract
Nod-like receptor protein 3 (NLRP3)-mediated pyroptosis has a causal role in the pathogenesis of gout. P2Y14 receptor (P2Y14R) distributed in immune cells including macrophages is a Gi-coupled receptor that inhibits the synthesis of cAMP, which has been regarded as a potential regulator of inflammatory response. Nevertheless, the role of P2Y14R in MSU-induced pyroptosis of macrophages involved in acute gouty arthritis is still unclear. In our present study, P2Y14R knockout (P2Y14R-KO) disrupted MSU-induced histopathologic changes in rat synoviums, accompanied with a significant inhibition of pyroptotic cell death characterized by Caspase-1/PI double-positive and blockade of NLRP3 inflammasome activation in synovial tissues, which was consistent with that observed in in vitro studies. Owing to the interaction of NLRP3 inflammasome and cAMP, we then investigated the effect of adenylate cyclase activator (Forskolin) on macrophage pyroptosis and gout flare caused by MSU stimulation. The reversal effect of Forskolin verified the negative regulatory role of cAMP in MSU-induced pyroptosis. More importantly, adenylate cyclase inhibitor (SQ22536) intervention led to a reversal of protection attributed to P2Y14R deficiency. Findings in air pouch animal models also verified aforementioned experimental results. Our study first identified the role of P2Y14R/cAMP/NLRP3 signaling pathway in acute gouty arthritis, which provides a novel insight into the pathological mechanisms of pyroptosis-related diseases.
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Affiliation(s)
- Hanwen Li
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, PR China.,Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Wenjiao Jiang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, PR China
| | - Shumin Ye
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, PR China.,Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Mengze Zhou
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, PR China
| | - Chunxiao Liu
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, PR China.,Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Xiping Yang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, PR China.,Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Kun Hao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, PR China.
| | - Qinghua Hu
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, PR China. .,Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.
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The quest for effective pharmacological suppression of neointimal hyperplasia. Curr Probl Surg 2020; 57:100807. [PMID: 32771085 DOI: 10.1016/j.cpsurg.2020.100807] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 04/22/2020] [Indexed: 12/15/2022]
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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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Kantrong N, Jit-Armart P, Arayatrakoollikit U. Melatonin antagonizes lipopolysaccharide-induced pulpal fibroblast responses. BMC Oral Health 2020; 20:91. [PMID: 32223750 PMCID: PMC7104493 DOI: 10.1186/s12903-020-1055-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 02/27/2020] [Indexed: 01/13/2023] Open
Abstract
Background Pulpal inflammation is known to be mediated by multiple signaling pathways. However, whether melatonin plays regulatory roles in pulpal inflammation remains unclear. This study aimed at elucidating an in situ expression of melatonin and its receptors in human pulpal tissues, and the contribution of melatonin on the antagonism of lipopolysaccharide (LPS)-infected pulpal fibroblasts. Methods Melatonin expression in pulpal tissues harvested from healthy teeth was investigated by immunohistochemical staining. Its receptors, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2), were also immunostained in pulpal tissues isolated from healthy teeth and inflamed teeth diagnosed with irreversible pulpitis. Morphometric analysis was subsequently performed. After LPS infection of cultured pulpal fibroblasts, cyclo-oxygenase (COX) and interleukin-1 β (IL-1 β) transcripts were examined by using reverse transcription-polymerase chain reaction (RT-PCR). Analysis of mRNA expression was performed to investigate an antagonism of LPS stimulation by melatonin via COX and IL-1 β induction. Mann-Whitney U test and One-way ANOVA were used for statistical analysis to determine a significance level. Results Melatonin was expressed in healthy pulpal tissue within the odontoblastic zone, cell-rich zone, and in the pulpal connective tissue. Furthermore, in health, strong MT1 and MT2 expression was distributed similarly in all 3 pulpal zones. In contrast, during disease, expression of MT2 was reduced in inflamed pulpal tissues (P-value< 0.001), but not MT1 (P-value = 0.559). Co-culturing of melatonin with LPS resulted in the reduction of COX-2 and IL-1 β expression in primary pulpal fibroblasts, indicating that melatonin may play an antagonistic role to LPS infection in pulpal fibroblasts. Conclusions Human dental pulp abundantly expressed melatonin and its receptors MT1 and MT2 in the odontoblastic layers and pulpal connective tissue layers. Melatonin exerted antagonistic activity against LPS-mediated COX-2 and IL-1 β induction in pulpal fibroblasts, suggesting its therapeutic potential for pulpal inflammation and a possible role of pulpal melatonin in an immunomodulation via functional melatonin receptors expressed in dental pulp.
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Affiliation(s)
- Nutthapong Kantrong
- Department of Restorative Dentistry, Faculty of Dentistry, Khon Kaen University, Mittraphap road, Nai Mueang, Mueang, Khon Kaen, 40002, Thailand.,Oral Biology Research Unit, Faculty of Dentistry, Khon Kaen University, Khon Kaen, Thailand.,Research Group of Chronic Inflammatory Oral Diseases and Systemic Diseases Associated with Oral Health, Faculty of Dentistry, Khon Kaen University, Khon Kaen, Thailand
| | - Piyabhorn Jit-Armart
- Research Group of Chronic Inflammatory Oral Diseases and Systemic Diseases Associated with Oral Health, Faculty of Dentistry, Khon Kaen University, Khon Kaen, Thailand.,Wanon-Niwat Hospital, Wanon-Niwat, Sakon Nakhon, Thailand
| | - Uthaiwan Arayatrakoollikit
- Department of Restorative Dentistry, Faculty of Dentistry, Khon Kaen University, Mittraphap road, Nai Mueang, Mueang, Khon Kaen, 40002, Thailand. .,Research Group of Chronic Inflammatory Oral Diseases and Systemic Diseases Associated with Oral Health, Faculty of Dentistry, Khon Kaen University, Khon Kaen, Thailand.
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Ajayi AM, Badaki VB, Ariyo OO, Ben-Azu B, Asejeje FO, Adedapo ADA. Chrysophyllum albidum fruit peel attenuates nociceptive pain and inflammatory response in rodents by inhibition of pro-inflammatory cytokines and COX-2 expression through suppression of NF-κB activation. Nutr Res 2020; 77:73-84. [PMID: 32375072 DOI: 10.1016/j.nutres.2020.03.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 02/23/2020] [Accepted: 03/17/2020] [Indexed: 11/18/2022]
Abstract
Chrysophyllum abidum fruit is a seasonal fruit commonly eaten as snacks with abundant health promoting phytochemicals in the fruit peels. The fruit peels have been reported to be rich in anti-inflammatory eleagnine, myricetin rhamnoside, quercetin, linoleic acid and oleic acid. We hypothesized that the anti-inflammatory effect of the peel extract involve suppression of pro-inflammatory cytokines, cyclooxygenase-2 and nuclear factor-kappa B (NF-κB). Hence, this study was designed to assess the anti-nociceptive and anti-inflammatory effects of fruit peel extract of Chrysophyllum albidum in animal models of nociception and inflammation. The anti-nociceptive activity of CAPEE (100 and 400 mg/kg) was evaluated in acetic acid-induced writhing and formalin-induced paw licking in mice. Formalin-induced paw edema and carrageenan-induced air pouch models of inflammation were used to evaluate the anti-inflammatory activity. CAPEE (100 and 400 mg/kg) significantly reduced abdominal writhing and paw licking in acetic acid and formalin tests in mice, respectively. CAPEE demonstrated significant inhibition of paw edema at 24 h (41.0% and 55.7%) and 72 h (52.3% and 86.6%) after formalin injection. CAPEE suppressed inflammatory responses in carrageenan-induced air pouch by reducing exudates, inflammatory cells infiltration, nitrites and myeloperoxidase activity. There was significant inhibition of tumor necrosis factor-alpha, interleukin-6 levels and reduced immunopositive expression of COX-2 and NF-κB. In conclusion, CAPEE has anti-nociceptive and anti-inflammatory potentials via mechanisms associated with inhibition of pro-inflammatory cytokines and cyclooxygenase-2 (COX-2) expression through suppression of nuclear factor kappa B (NF-κB) activation, and has potential as a functional food ingredient.
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Affiliation(s)
- Abayomi M Ajayi
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo-State, Nigeria.
| | - Victoria B Badaki
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo-State, Nigeria
| | - Oluwakemi O Ariyo
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo-State, Nigeria
| | - Benneth Ben-Azu
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo-State, Nigeria; Department of Pharmacology, Faculty of Basic Medical Sciences, PAMO University of Medical Sciences, Port Harcourt, Rivers State, Nigeria
| | - Folake O Asejeje
- Department of Biological Sciences, KolaDaisi University, Ibadan, Oyo-State, Nigeria
| | - Aduragbenro D A Adedapo
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo-State, Nigeria
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Rong R, Zhang QL, Zhang RZ, Dan YH, Wang X, Zhao YL, Yu ZG. Exploring stereoselective excretion and metabolism studies of novel 2-(2-hydroxypropanamido)-5-trifluoromethyl benzoic acid enantiomers. RSC Adv 2020; 10:27267-27279. [PMID: 35516918 PMCID: PMC9055496 DOI: 10.1039/d0ra03500a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 06/28/2020] [Indexed: 11/21/2022] Open
Abstract
R-/S-2-(2-Hydroxypropanamido)-5-trifluoromethyl benzoic acid (R-/S-HFBA), as a novel COX inhibitor, was firstly reported to have remarkable anti-inflammatory and antiplatelet aggregation activities by our group. In our previous study, stereoselective differences in pharmacokinetics were found between HFBA enantiomers after oral and intravenous administration of each enantiomer to rats. The discrepancies might be associated with the excretion and metabolism of the two enantiomers. In this research, an UHPLC-MS/MS method was established and validated for quantification of R-/S-HFBA in rats urine, feces and bile samples in excretion study. Moreover, an ultra high performance liquid chromatography coupled with Fourier transform ion cyclotron resonance mass spectrometry (UHPLC-FT-ICR-MS) method was employed to understand the metabolism of R-/S-HFBA in rats. Results showed that the total cumulative excretion of R-/S-HFBA in three routes were 65.8% and 58.5% of the dose, respectively. The urinary excretion of R-/S-HFBA was the main route, which accounted for 40.2% and 31.7% respectively; the cumulative biliary excretion of R-/S-HFBA were 11.3% and 7.4%; the cumulative amounts of R-/S-HFBA excreted directly via feces without absorption from the gastrointestinal tract were 14.3% and 19.4%, respectively. R-/S-HFBA existed stereoselective discrepancy in excretion. In addition, 8 metabolites of S-HFBA were detected and tentatively identified including glucuronidation, glycine and N-acetyl conjugation while R-HFBA existed 7 metabolites without glycine conjugation. Formation of metabolites of R-/S-HFBA also exhibited stereoselectivity. In summary, these new findings on excretion and metabolism of R-/S-HFBA provided valuable information for stereoselective pharmacokinetics and were greatly helpful for further investigation, such as safety and mechanism of action. R-/S-2-(2-Hydroxypropanamido)-5-trifluoromethyl benzoic acid (R-/S-HFBA), as a novel COX inhibitor, was firstly reported to have remarkable anti-inflammatory and antiplatelet aggregation activities by our group.![]()
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Affiliation(s)
- Rong Rong
- Department of Pharmaceutical Analysis
- School of Pharmacy
- Shenyang Pharmaceutical University
- Shenyang
- China
| | - Qi-li Zhang
- Department of Pharmaceutical Engineering
- College of Life Science
- Shandong University of Technology
- Zibo
- China
| | - Rui-zhen Zhang
- Department of Pharmaceutical Analysis
- School of Pharmacy
- Shenyang Pharmaceutical University
- Shenyang
- China
| | - Yu-han Dan
- Department of Pharmaceutical Analysis
- School of Pharmacy
- Shenyang Pharmaceutical University
- Shenyang
- China
| | - Xin Wang
- Department of Pharmaceutical Analysis
- School of Pharmacy
- Shenyang Pharmaceutical University
- Shenyang
- China
| | - Yun-li Zhao
- Department of Pharmaceutical Analysis
- School of Pharmacy
- Shenyang Pharmaceutical University
- Shenyang
- China
| | - Zhi-guo Yu
- Department of Pharmaceutical Analysis
- School of Pharmacy
- Shenyang Pharmaceutical University
- Shenyang
- China
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Maseda D, Ricciotti E. NSAID-Gut Microbiota Interactions. Front Pharmacol 2020; 11:1153. [PMID: 32848762 PMCID: PMC7426480 DOI: 10.3389/fphar.2020.01153] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 07/15/2020] [Indexed: 12/21/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAID)s relieve pain, inflammation, and fever by inhibiting the activity of cyclooxygenase isozymes (COX-1 and COX-2). Despite their clinical efficacy, NSAIDs can cause gastrointestinal (GI) and cardiovascular (CV) complications. Moreover, NSAID use is characterized by a remarkable individual variability in the extent of COX isozyme inhibition, therapeutic efficacy, and incidence of adverse effects. The interaction between the gut microbiota and host has emerged as a key player in modulating host physiology, gut microbiota-related disorders, and metabolism of xenobiotics. Indeed, host-gut microbiota dynamic interactions influence NSAID disposition, therapeutic efficacy, and toxicity. The gut microbiota can directly cause chemical modifications of the NSAID or can indirectly influence its absorption or metabolism by regulating host metabolic enzymes or processes, which may have consequences for drug pharmacokinetic and pharmacodynamic properties. NSAID itself can directly impact the composition and function of the gut microbiota or indirectly alter the physiological properties or functions of the host which may, in turn, precipitate in dysbiosis. Thus, the complex interconnectedness between host-gut microbiota and drug may contribute to the variability in NSAID response and ultimately influence the outcome of NSAID therapy. Herein, we review the interplay between host-gut microbiota and NSAID and its consequences for both drug efficacy and toxicity, mainly in the GI tract. In addition, we highlight progress towards microbiota-based intervention to reduce NSAID-induced enteropathy.
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Affiliation(s)
- Damian Maseda
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, United States
| | - Emanuela Ricciotti
- Department of Systems Pharmacology and Translational Therapeutics, and Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States
- *Correspondence: Emanuela Ricciotti,
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Cebrián-Prats A, González-Lafont À, Lluch JM. Understanding the Molecular Details of the Mechanism That Governs the Oxidation of Arachidonic Acid Catalyzed by Aspirin-Acetylated Cyclooxygenase-2. ACS Catal 2019. [DOI: 10.1021/acscatal.9b04223] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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LEE IC, LEE JS, LEE JH, KIM Y, SO WY. Anti-Oxidative and Anti-Inflammatory Activity of Kenya Grade AA Green Coffee Bean Extracts. IRANIAN JOURNAL OF PUBLIC HEALTH 2019; 48:2025-2034. [PMID: 31970101 PMCID: PMC6961199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Kenya AA green coffee bean extracts were tested for natural ingredients used for anti-oxidative and anti-inflammatory purposes in cosmetic products. METHODS Anti-oxidative activities were measured by total polyphenol, 1,1-diphenyl-2-picrylhydrazyl (DPPH), and the 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. Anti-inflammatory activities were evaluated via nitric oxide (NO) assays, and through quantification of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) protein expression by western blotting. Data analyses were performed using independent Student's t-tests, with statistical significance set at P < 0.05. RESULTS Total polyphenol content of water and ethanol extract was 169.0 ± 3.1 mg and 300.34 ± 16.6 mg tannic acid/g dry weight, respectively. The DPPH and ABTS radical scavenging activities of all the extracts were significantly increased in a concentration-dependent manner. Kenya AA green coffee bean extracts were toxic at a concentration of 1,000 μg/mL in RAW 264.7 cells. Anti-inflammatory activity as determined by NO assay showed that lipopolysaccharide (LPS)-induced NO was significantly inhibited following treatment with Kenya AA green coffee bean extracts in a concentration-dependent manner. iNOS and COX-2 protein expression was also significantly inhibited following treatment. CONCLUSION These results highlight the potential of Kenya AA green coffee bean extracts as a naturally active anti-inflammatory agent in cosmetic products.
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Affiliation(s)
- In-Chul LEE
- Department of Bio-Cosmetic Science, Seowon University, Cheongju, Korea
| | - Jae-Sook LEE
- Department of Beauty Science, Kwangju Women’s University, Kwangju, Korea
| | - Jeong-Hyun LEE
- Department of Beauty Art, Youngsan University, Busan, Korea
| | - Yeona KIM
- Department of Beauty Art, Youngsan University, Busan, Korea
| | - Wi-Young SO
- Sports and Health Care Major, College of Humanities and Arts, Korea National University of Transportation, Chungju-si, Korea,Corresponding Author:
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50
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Mohammed A, Janakiram NB, Madka V, Zhang Y, Singh A, Biddick L, Li Q, Lightfoot S, Steele VE, Lubet RA, Suen CS, Miller MS, Sei S, Rao CV. Intermittent Dosing Regimens of Aspirin and Naproxen Inhibit Azoxymethane-Induced Colon Adenoma Progression to Adenocarcinoma and Invasive Carcinoma. Cancer Prev Res (Phila) 2019; 12:751-762. [PMID: 31530543 PMCID: PMC6849393 DOI: 10.1158/1940-6207.capr-19-0312] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 07/17/2019] [Accepted: 09/10/2019] [Indexed: 12/24/2022]
Abstract
Chronic use of aspirin and related drugs to reduce cancer risk is limited by unwanted side effects. Thus, we assessed the efficacy associated with different dosing regimens of aspirin and naproxen. Azoxymethane (AOM)-rat colon cancer model was used to establish the pharmacodynamic efficacy of aspirin and naproxen under different dosing regimens. Colon tumors were induced in rats (36/group) by two weekly doses of AOM. At the early adenoma stage, rats were fed diets containing aspirin (700 and 1,400 ppm) or naproxen (200 and 400 ppm), either continuously, 1 week on/1 week off, or 3 weeks on/3 weeks off, or aspirin (2,800 ppm) 3 weeks on/3 weeks off. All rats were euthanized 48 weeks after AOM treatment and assessed for efficacy and biomarkers in tumor tissues. Administration of aspirin and naproxen produced no overt toxicities. Administration of different treatment regimens of both agents had significant inhibitory effects with clear dose-response effects. Aspirin suppressed colon adenocarcinoma multiplicity (both invasive and noninvasive) by 41% (P < 0.003) to 72% (P < 0.0001) and invasive colon adenocarcinomas by 67%-91% (P < 0.0001), depending on the treatment regimen. Naproxen doses of 200 and 400 ppm inhibited invasive adenocarcinoma multiplicity by 53%-88% (P < 0.0001), depending on the dosing regimen. Colonic tumor biomarker analysis revealed that proliferation (proliferating cell nuclear antigen and p21), apoptosis (p53 and Caspase-3), and proinflammatory mediators (IL1β and prostaglandin E2) were significantly correlated with the tumor inhibitory effects of aspirin and naproxen. Overall, our results suggest that intermittent dosing regimens with aspirin or naproxen demonstrated significant efficacy on the progression of adenomas to adenocarcinomas, without gastrointestinal toxicities.
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Affiliation(s)
- Altaf Mohammed
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, Rockville, Maryland
| | - Naveena B Janakiram
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- DoD/VA, Extremity Trauma & Amputation Center of Excellence, WRNMMC, Bethesda, Maryland
| | - Venkateshwar Madka
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Yuting Zhang
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Anil Singh
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- VA Medical Center, Oklahoma City, Oklahoma
| | - Laura Biddick
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Qian Li
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Stanley Lightfoot
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Vernon E Steele
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, Rockville, Maryland
| | - Ronald A Lubet
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, Rockville, Maryland
| | - Chen S Suen
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, Rockville, Maryland
| | - Mark Steven Miller
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, Rockville, Maryland
| | - Shizuko Sei
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, Rockville, Maryland
| | - Chinthalapally V Rao
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
- VA Medical Center, Oklahoma City, Oklahoma
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