|
1
|
Wróbel-Biedrawa D, Kubacka M, Kotańska M, Bednarski M, Grabowska K, Podolak I. Comparative Evaluation of Vasorelaxant and Antiplatelet Activity of Two Plant-Derived Benzoquinones: Rapanone and Embelin. Molecules 2025; 30:845. [PMID: 40005155 PMCID: PMC11858406 DOI: 10.3390/molecules30040845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 02/07/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Vasorelaxant and antiplatelet agents play an important role in preventing and combating endothelial dysfunction, atherosclerosis and a plethora of associated cardiovascular diseases (CVDs). CVDs are the leading cause of death worldwide and nowadays occur not only in developed but also in developing societies. They include, among others, coronary heart disease, cerebrovascular disease and peripheral artery disease. Due to their high prevalence, it is important to seek efficient preventive measures, such as lifestyle changes and the implementation of appropriate herbal dietary supplementation and treatment alternatives. Plant-derived quinones have recently drawn researchers' attention due to their interesting biological potential. Embelin and rapanone are two plant-derived benzoquinones with anti-inflammatory and antioxidant properties. Embelin has already been shown to have vasorelaxant and antiplatelet activity, but little is known about rapanone in the context of CVDs. Therefore, we decided to comparatively evaluate their activity in a specially designed experimental protocol. Following the isolation of both benzoquinones from plant sources (rapanone from Ardisia crenata leaves; embelin from Lysimachia punctata roots), their effects were comparatively assessed in a biofunctional study on isolated rat aorta (precontracted with phenylephrine) and in vitro on platelet aggregation. Both benzoquinones showed 50% vasorelaxation in an NO-dependent manner. Interestingly, rapanone was slightly more effective as an antiplatelet agent than embelin. The antiplatelet effect of both benzoquinones was specific, as no cytotoxicity towards platelets was observed at the concentrations tested. This is the first report on the vasorelaxant and antiplatelet activity of rapanone.
Collapse
Affiliation(s)
- Dagmara Wróbel-Biedrawa
- Department of Pharmacognosy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland; (D.W.-B.); (K.G.)
| | - Monika Kubacka
- Department of Pharmacodynamics, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland;
| | - Magdalena Kotańska
- Department of Pharmacological Screening, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland; (M.K.); (M.B.)
| | - Marek Bednarski
- Department of Pharmacological Screening, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland; (M.K.); (M.B.)
| | - Karolina Grabowska
- Department of Pharmacognosy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland; (D.W.-B.); (K.G.)
| | - Irma Podolak
- Department of Pharmacognosy, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland; (D.W.-B.); (K.G.)
| |
Collapse
|
|
2
|
Noor L, Hafeez A, Rahman MA, Vishwakarma KK, Kapoor A, Ara N, Aqeel R. Demystifying the Potential of Embelin-Loaded Nanoformulations: a Comprehensive Review. AAPS PharmSciTech 2024; 25:249. [PMID: 39433611 DOI: 10.1208/s12249-024-02968-7] [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: 07/05/2024] [Accepted: 10/01/2024] [Indexed: 10/23/2024] Open
Abstract
Phytoconstituent based therapies have the potential to reduce the adverse effects and enhance overall patient compliance for different diseased conditions. Embelin (EMB) is a natural compound extracted from Embelia ribes that has demonstrated high therapeutic potential, particularly as anti-inflammatory and anticancer therapeutic applications. However, its poor water solubility and low oral bioavailability limitations make it challenging to use in biomedical applications. Nanostructure-based novel formulations have shown the potential to improve physicochemical and biological characteristics of active pharmaceutical ingredients obtained from plants. Different nanoformulations that have been utilized to encapsulate/entrap EMB for various therapeutic applications are nanoliposomes, nanostructured lipid carriers, niosomes, polymeric nanoparticles, nanosuspensions, phytosomes, self nanoemulsifying drug delivery system, silver nanoparticles, microparticles, solid lipid nanoparticle, gold nanoparticles and nanomicelles. The common methods reported for the preparation of EMB nanoformulations are thin film hydration, nanoprecipitation, ethanol injection, emulsification followed by sonication. The size of nanoformulations ranged in between 50 and 345 nm. In this review, the mentioned EMB loaded nanocarriers are methodically discussed for size, shape, drug entrapment, zeta potential, in vitro release & permeation and in vivo studies. Potential of EMB with other drugs (dual drug approach) incorporated in nanocarriers are also discussed (physicochemical and preclinical characteristics). Patents related to EMB nanoformulations are also presented which showed the clinical translation of this bioactive for future utilization in different indications.
Collapse
Affiliation(s)
- Layba Noor
- Faculty of Pharmacy, Integral University, Lucknow, 226026, India
| | - Abdul Hafeez
- Faculty of Pharmacy, Integral University, Lucknow, 226026, India.
| | - Md Azizur Rahman
- Faculty of Pharmacy, Integral University, Lucknow, 226026, India
| | | | - Archita Kapoor
- Faculty of Pharmacy, Integral University, Lucknow, 226026, India
| | - Nargis Ara
- Faculty of Pharmacy, Integral University, Lucknow, 226026, India
| | - Rabia Aqeel
- Faculty of Pharmacy, Integral University, Lucknow, 226026, India
| |
Collapse
|
|
3
|
Kang M, Kang M, Lee J, Yoo J, Lee S, Oh S. Allium tuberosum-derived nanovesicles with anti-inflammatory properties prevent DSS-induced colitis and modify the gut microbiome. Food Funct 2024; 15:7641-7657. [PMID: 38953279 DOI: 10.1039/d4fo01366b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
Edible plant-derived nanovesicles (ePDNs) have shown potential as a non-pharmacological option for inflammatory bowel disease (IBD) by maintaining gut health and showing anti-inflammatory effects. However, the effects of Allium tuberosum-derived nanovesicles (ADNs) on colitis have not been studied to date. Here, we extracted exosome-like nanovesicles from Allium tuberosum and investigated whether they have an anti-inflammatory effect in RAW 264.7 cells and colitis mice. The results showed that ADNs reduced the elevated levels of inflammatory factors such as IL-1β, IL-6, TNF-α, and NF-κB pathway-related proteins as a consequence of lipopolysaccharide (LPS) stimulation in RAW 264.7 cells. Furthermore, our mouse experiments demonstrated that ADNs could ameliorate dextran sulfate sodium (DSS)-induced colitis symptoms (e.g., increased disease activity index score, intestinal permeability, and histological appearance). Additionally, ADNs counteracted DSS-induced colitis by downregulating the expression of serum amyloid A (SAA), IL-1β, IL-6, and TNF-α and increasing the expression of tight junction proteins (ZO-1 and occludin) and the anti-inflammatory cytokine IL-10. 16S rRNA gene sequencing showed that ADN intervention restored the gut microbial composition, which was similar to that of the DSS non-treated group, by decreasing the ratio of Firmicutes to Bacteroidetes and the relative abundance of Proteobacteria. Furthermore, ADNs induced acetic acid production along with an increase in the abundance of Lactobacillus. Overall, our findings suggest that ADN supplementation has a crucial role in maintaining gut health and is a novel preventive therapy for IBD.
Collapse
Affiliation(s)
- Minkyoung Kang
- Department of Environmental Science and Biotechnology, Jeonju University, Jeonju 55069, Republic of Korea.
| | - Minji Kang
- Department of Environmental Science and Biotechnology, Jeonju University, Jeonju 55069, Republic of Korea.
| | - Juyeon Lee
- Department of Environmental Science and Biotechnology, Jeonju University, Jeonju 55069, Republic of Korea.
| | - Jiseon Yoo
- Department of Environmental Science and Biotechnology, Jeonju University, Jeonju 55069, Republic of Korea.
| | - Sujeong Lee
- Department of Environmental Science and Biotechnology, Jeonju University, Jeonju 55069, Republic of Korea.
| | - Sangnam Oh
- Department of Environmental Science and Biotechnology, Jeonju University, Jeonju 55069, Republic of Korea.
- Department of Food and Nutrition, Jeonju University, Jeonju 55069, Republic of Korea
| |
Collapse
|
|
4
|
Prakash AN, Prasad N, Puppala ER, Panda SR, Jain S, Ravichandiran V, Singh M, Naidu VGM. Loganic acid protects against ulcerative colitis by inhibiting TLR4/NF-κB mediated inflammation and activating the SIRT1/Nrf2 anti-oxidant responses in-vitro and in-vivo. Int Immunopharmacol 2023; 122:110585. [PMID: 37421777 DOI: 10.1016/j.intimp.2023.110585] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 05/27/2023] [Accepted: 06/28/2023] [Indexed: 07/10/2023]
Abstract
Ulcerative colitis (UC) is an idiopathic, chronic disorder of the intestines characterized by excessive inflammation and oxidative stress. Loganic acid (LA) is an iridoid glycoside reported to have antioxidant and anti-inflammatory properties. However, the beneficial effects of LA on UC are unexplored yet. Thus, this study aims to explore the potential protective effects of LA and its possible mechanisms. In-vitro models were employed using LPS-stimulated RAW 264.7 macrophage cells, and Caco-2 cells, whereas an in-vivo model of ulcerative colitis was employed using 2.5% DSS in BALB/c mice. Results indicated that LA significantly suppressed the intracellular ROS levels and inhibited the phosphorylation of NF-κB in both RAW 264.7 and Caco-2 cells, contrarily LA activated the Nrf2 pathway in RAW 264.7 cells. In DSS-induced colitis mice, LA significantly alleviated the inflammation and colonic damage by decreasing the pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IFN-γ), oxidative stress markers (MDA, and NO), and also expression levels of various inflammatory proteins (TLR4 and NF-кB) which was evidenced by immunoblotting. On the contrary, the release of GSH, SOD, HO-1, and Nrf2 were profoundly increased upon LA treatment.Subsequently, molecular docking studies showed that LA interacts with active site regions of target proteins (TLR4, NF-κB, SIRT1, and Nrf2) through hydrogen bonding and salt bridge interaction. The current findings demonstrated that LA could exhibit a protective effect in DSS-induced ulcerative colitis through its anti-inflammatory and anti-oxidant effects via inactivating the TLR4/NF-κB signaling pathway and activating the SIRT1/Nrf2 pathways.
Collapse
Affiliation(s)
- Arun N Prakash
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Assam 781101, India
| | - Neethu Prasad
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Assam 781101, India
| | - Eswara Rao Puppala
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Assam 781101, India
| | - Samir Ranjan Panda
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Assam 781101, India
| | - Siddhi Jain
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Assam 781101, India
| | - V Ravichandiran
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER)-Kolkata, West Bengal 700054, India
| | - Meenakshi Singh
- Centre for GMP Extraction Facility, Sponsored by Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Assam 781101, India.
| | - V G M Naidu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Assam 781101, India; Centre for GMP Extraction Facility, Sponsored by Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Assam 781101, India.
| |
Collapse
|
|
5
|
Bai X, Wang J, Ding S, Yang S, Pei B, Yao M, Zhu X, Jiang M, Zhang M, Mu W, Guo S. Embelin protects against apoptosis and inflammation by regulating PI3K/Akt signaling in IL-1β-stimulated human nucleus pulposus cells. Tissue Cell 2023; 82:102089. [PMID: 37075678 DOI: 10.1016/j.tice.2023.102089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 02/20/2023] [Accepted: 04/10/2023] [Indexed: 04/21/2023]
Abstract
Embelin is a natural benzoquinone compound that displays a beneficial effect in various inflammatory-related diseases. However, the effect of embelin on degeneration of intervertebral disc (IDD), a chronic inflammatory disorder, has not been reported. This study was attempted to explore the therapeutic action of embelin on IDD in vitro. Network pharmacology analysis was performed for evaluating the link between embelin and IDD. The human nucleus pulposus cells (NPCs) were stimulated with IL-1β to induce inflammation. Cell viability of NPCs was assessed by CCK-8 assay. Western blotting was conducted to detect the expression levels of PI3K, p-PI3K, Akt, p-Akt, cleaved caspase-3, caspase-3, Bax, Bcl-2, p65 and p-p65. Apoptotic deaths of NPCs were examined by TUNEL assay. The production of COX-2, IL-6, IL-8, and TNF-α was examined by ELISA. It can be seen that 16 overlapping genes were selected from 109 possible targets of embelin and 342 possible targets of IDD. KEGG pathway enrichment analysis showed that the PI3K/Akt signaling pathway was a close link between embelin and IDD. We found that embelin dose-dependently improved the cell viability in IL-1β-stimulated NPCs. Embelin elevated the relative levels of p-PI3K/PI3K and p-Akt/Akt in IL-1β-stimulated NPCs. IL-1β induced a significant increase in apoptotic deaths of NPCs, which was attenuated by embelin treatment. IL-1β-induced alternations in expression levels of apoptotic-related proteins including cleaved caspase-3, Bax and Bcl-2 were prevented by embelin treatment. Pretreatment with LY294002 (an inhibitor of PI3K) reversed the inhibitory effect of embelin on IL-1β-induced apoptosis in NPCs. Embelin treatment caused inhibitory effects on the IL-1β-stimulated production of COX-2, IL-6, IL-8, and TNF-α, which were abolished by LY294002 treatment. Furthermore, embelin treatment prevented IL-1β-induced phosphorylation of p65 in NPCs, while LY294002 elevated the embelin-caused decrease in p-p65/p65 level. Overall, embelin protected human NPCs against IL-1β-stimulated apoptosis and inflammation by regulating the PI3K/Akt signaling pathway. These findings provided new ideas for the clinical usage of embelin in the prevention and treatment of IDD.
Collapse
Affiliation(s)
- Xiaoliang Bai
- The Fifth Department of Orthopedics, Baoding NO.1 Central Hospital, Baoding, Hebei 071000, China
| | - Jie Wang
- The Fifth Department of Orthopedics, Baoding NO.1 Central Hospital, Baoding, Hebei 071000, China
| | - Siguang Ding
- The Fifth Department of Orthopedics, Baoding NO.1 Central Hospital, Baoding, Hebei 071000, China
| | - Shuai Yang
- The Fifth Department of Orthopedics, Baoding NO.1 Central Hospital, Baoding, Hebei 071000, China
| | - Bo Pei
- The Fifth Department of Orthopedics, Baoding NO.1 Central Hospital, Baoding, Hebei 071000, China
| | - Mingyan Yao
- Department of Endocrinology, Baoding NO.1 Central Hospital, Baoding, Hebei 071000, China
| | - Xiaojuan Zhu
- Department of Geriatrics, Baoding NO.1 Central Hospital, Baoding, Hebei 071000, China
| | - Meichao Jiang
- The Fifth Department of Orthopedics, Baoding NO.1 Central Hospital, Baoding, Hebei 071000, China
| | - Mingyuan Zhang
- Department of Orthopedics, Laishui County TCM Hospital, Baoding, Hebei 074199, China
| | - Weina Mu
- Department of Ultrasonography, Baoding NO.1 Central Hospital, Baoding, Hebei 071000, China
| | - Shuqin Guo
- Department of Endocrinology, Baoding NO.1 Central Hospital, Baoding, Hebei 071000, China.
| |
Collapse
|
|
6
|
Li N, Wang M, Lyu Z, Shan K, Chen Z, Chen B, Chen Y, Hu X, Dou B, Zhang J, Wang L, Zhao T, Li H. Medicinal plant-based drug delivery system for inflammatory bowel disease. Front Pharmacol 2023; 14:1158945. [PMID: 37033644 PMCID: PMC10076537 DOI: 10.3389/fphar.2023.1158945] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 03/14/2023] [Indexed: 04/11/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic recurrent intestinal disease. The incidence rate of IBD is increasing year by year, which seriously endangers human health worldwide. More and more studies have shown that medicinal plants or their main phytochemicals have great potential in the treatment of intestinal diseases. However, the disadvantages of low oral absorption rate, low biological distribution and low systemic bioavailability limit their clinical application to a certain extent. In recent years, the application of nanotechnology has made it possible to treat IBD. Nanoparticles (NPs) drug delivery system has attracted special attention in the treatment of IBD due to its small size, low immunogenicity, surface modification diversity, targeting and other advantages. Synthetic nanoparticles and extracellular vehicles (EVs) can deliver drug components to colon, and play a role in anti-inflammation, regulation of oxidative stress, improvement of intestinal flora, etc. In addition, some medicinal plants can secrete EVs by themselves, and carry biological molecules with therapeutic effects to act on the intestine. Some clinical trials to evaluate the safety, tolerance, toxicity and effectiveness of EVs-loaded drugs in IBD are also progressing steadily. This review introduces that synthetic nanoparticles and medicinal plants derived EVs can play an important role in the treatment of IBD by carrying the effective active phytochemicals of medicinal plants, and discuss the limitations of current research and future research needs, providing a scientific and reliable basis and perspective for further clinical application and promotion.
Collapse
Affiliation(s)
- Ningcen Li
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Meijuan Wang
- Qingdao Hospital of Traditional Chinese Medicine (Qingdao Hiser Hospital), Qingdao, Shandong, China
| | - Zhongxi Lyu
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Kai Shan
- Qingdao Hospital of Traditional Chinese Medicine (Qingdao Hiser Hospital), Qingdao, Shandong, China
| | - Zelin Chen
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Bo Chen
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Binhai New Area Hospital of TCM, Fourth Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yong Chen
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiyou Hu
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Baomin Dou
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jingyu Zhang
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lifen Wang
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Tianyi Zhao
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Tianyi Zhao, ; Hongjiao Li,
| | - Hongjiao Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Tianyi Zhao, ; Hongjiao Li,
| |
Collapse
|
|
7
|
Zhang Y, Feng X, Lin H, Chen X, He P, Wang Y, Chu Q. Tieguanyin extracts ameliorated DSS-induced mouse colitis by suppressing inflammation and regulating intestinal microbiota. Food Funct 2022; 13:13040-13051. [PMID: 36453715 DOI: 10.1039/d2fo02781j] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Previous studies have shown that a typical kind of oolong tea, Tieguanyin, has multiple health benefits, while there is no research investigating its effects on inflammatory bowel disease (IBD). In this study, we aimed to explore the alleviation effects of Tieguanyin water (TWE) and ethanol (TES) extracts on IBD. Physiological activity status, colitis severity (disease activity index (DAI), colon and spleen weight), inflammatory cytokines (interleukin (IL)-4, interferon-γ (IFN-γ), IL-17, transforming growth factor-β (TGF-β), and IL-10) and microbiota composition were measured in experimental colitis mice induced by dextran sulfate sodium (DSS). TWE and TES exerted remarkable protective effects against experimental colitis, showing decreased colitis severity and improved colon morphology. TES also suppressed colonic inflammation via downregulation of pro-inflammatory cytokines (IL-4, IFN-γ, IL-17, and TGF-β) and upregulation of the anti-inflammatory cytokine IL-10. In addition, TWE and TES treatment caused significant alterations in the gut microbiota. Oolong tea extract treatment reduced the community abundance of pernicious bacteria Escherichia-Shigella from 21.6% (DSS) to 0.9% (TES) and 1.2% (TWE), and elevated that of probiotics Lachnospiraceae_NK4A136_group from 2.2% to 15.2% (TES) and 11.9% (TWE). Therefore, TWE and TES both remarkably ameliorated DSS-induced colitis, which suggested oolong extracts could be a candidate for IBD treatment.
Collapse
Affiliation(s)
- Yuxi Zhang
- Institute of Tea Science, Zhejiang University, Hangzhou 310058, China. .,Key Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Ministry of Agriculture, Hangzhou 310058, China
| | - Xinyu Feng
- Institute of Tea Science, Zhejiang University, Hangzhou 310058, China. .,Key Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Ministry of Agriculture, Hangzhou 310058, China.,Department of Food Science and Nutrition, Zhejiang University, Hangzhou 310058, China
| | - Haiyu Lin
- Institute of Tea Science, Zhejiang University, Hangzhou 310058, China. .,Key Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Ministry of Agriculture, Hangzhou 310058, China
| | - Xue Chen
- Institute of Tea Science, Zhejiang University, Hangzhou 310058, China. .,Key Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Ministry of Agriculture, Hangzhou 310058, China
| | - Puming He
- Institute of Tea Science, Zhejiang University, Hangzhou 310058, China. .,Key Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Ministry of Agriculture, Hangzhou 310058, China
| | - Yuefei Wang
- Institute of Tea Science, Zhejiang University, Hangzhou 310058, China. .,Key Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Ministry of Agriculture, Hangzhou 310058, China
| | - Qiang Chu
- Institute of Tea Science, Zhejiang University, Hangzhou 310058, China. .,Key Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Ministry of Agriculture, Hangzhou 310058, China
| |
Collapse
|
|
8
|
Wan C, Qian WW, Liu W, Pi X, Tang MT, Wang XL, Gu Q, Li P, Zhou T. Exopolysaccharide from Lactobacillus rhamnosus ZFM231 alleviates DSS-induced colitis in mice by regulating gut microbiota. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2022; 102:7087-7097. [PMID: 35707876 DOI: 10.1002/jsfa.12070] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 06/01/2022] [Accepted: 06/16/2022] [Indexed: 05/26/2023]
Abstract
BACKGROUND The exopolysaccharides (EPS) produced by Lactobacillus and other probiotics are associated with many benefits, such as immune regulation, antioxidant properties, antitumor effect, and regulation of intestinal microbe homeostasis. In the present study, the modulatory effect of EPS produced by Lactobacillus rhamnosus ZFM231 on the intestinal flora of mice with inflammatory bowel disease induced by dextran sulfate solution was investigated. RESULTS Results indicated that weight loss, colonic length, the disease activity index score and colonic tissue damage in mice were significantly improved by EPS treatment. Compared with the model group, in the EPS-treated group, the diversity of and the composition of gut microbiota at both phylum and genus levels were found to recover to the levels of normal group, indicating the effective modulation on gut microbiota by EPS; short-chain fatty acids, including acetic acid, propionic acid and butyric acid produced by intestinal microbial metabolism, increased significantly; the level of anti-inflammatory factor transforning growth factor-β significantly increased and the level of pro-inflammatory factor tumor necrosis factor-α significantly decreased in the colonic cells of EPS-treated mice. CONCLUSION It is clear that EPS produced by L. rhamnosus ZFM231 could find application in functional foods with the property of anti-ulcerative colitis. The experimental results provide new insights into the probiotic effect of EPS. © 2022 Society of Chemical Industry.
Collapse
Affiliation(s)
- Cheng Wan
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, China
| | - Wen-Wen Qian
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, China
| | - Wei Liu
- Institute of Plant Protection and Microbiology, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, China
| | - Xionge Pi
- Institute of Plant Protection and Microbiology, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, China
| | - Meng-Ting Tang
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, China
| | - Xiao-Lin Wang
- Faulty of Food Science, Zhejiang Pharmaceutical College, Ningbo, Zhejiang, China
| | - Qing Gu
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, China
| | - Ping Li
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, China
| | - Tao Zhou
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, China
| |
Collapse
|
|
9
|
Sun Y, Koyama Y, Shimada S. Measurement of intraluminal pH changes in the gastrointestinal tract of mice with gastrointestinal diseases. Biochem Biophys Res Commun 2022; 620:129-134. [DOI: 10.1016/j.bbrc.2022.06.061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 06/21/2022] [Indexed: 11/02/2022]
|
|
10
|
Devi Daimary U, Girisa S, Parama D, Verma E, Kumar A, Kunnumakkara AB. Embelin: A novel XIAP inhibitor for the prevention and treatment of chronic diseases. J Biochem Mol Toxicol 2021; 36:e22950. [PMID: 34842329 DOI: 10.1002/jbt.22950] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 09/28/2021] [Accepted: 11/01/2021] [Indexed: 12/19/2022]
Abstract
Chronic diseases are a serious health concern worldwide, especially in the elderly population. Most chronic diseases like cancer, cardiovascular ailments, neurodegenerative disorders, and autoimmune diseases are caused due to the abnormal functioning of multiple signaling pathways that give rise to critical anomalies in the body. Although a lot of advanced therapies are available, these have failed to entirely cure the disease due to their less efficacy. Apart from this, they have been shown to manifest disturbing side effects which hamper the patient's quality of life to the extreme. Since the last few decades, extensive studies have been done on natural herbs due to their excellent medicinal benefits. Components present in natural herbs target multiple signaling pathways involved in diseases and therefore hold high potential in the prevention and treatment of various chronic diseases. Embelin, a benzoquinone, is one such agent isolated from Embelia ribes, which has shown excellent biological activities toward several chronic ailments by upregulating a number of antioxidant enzymes (e.g., SOD, CAT, GSH, etc.), inhibiting anti-apoptotic genes (e.g., TRAIL, XIAP, survivin, etc.), modulating transcription factors (e.g., NF-κB, STAT3, etc.) blocking inflammatory biomarkers (e.g., NO, IL-1β, IL-6, TNF-α, etc.), monitoring cell cycle synchronizing genes (e.g., p53, cyclins, CDKs, etc.), and so forth. Several preclinical studies have confirmed its excellent therapeutic activities against malicious diseases like cancer, obesity, heart diseases, Alzheimer's, and so forth. This review presents an overview of embelin, its therapeutic prospective, and the molecular targets in different chronic diseases.
Collapse
Affiliation(s)
- Uzini Devi Daimary
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Dey Parama
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Elika Verma
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| |
Collapse
|
|
11
|
Khare T, Palakurthi SS, Shah BM, Palakurthi S, Khare S. Natural Product-Based Nanomedicine in Treatment of Inflammatory Bowel Disease. Int J Mol Sci 2020; 21:E3956. [PMID: 32486445 PMCID: PMC7312938 DOI: 10.3390/ijms21113956] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/26/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
: Many synthetic drugs and monoclonal antibodies are currently in use to treat Inflammatory Bowel Disease (IBD). However, they all are implicated in causing severe side effects and long-term use results in many complications. Numerous in vitro and in vivo experiments demonstrate that phytochemicals and natural macromolecules from plants and animals reduce IBD-related complications with encouraging results. Additionally, many of them modify enzymatic activity, alleviate oxidative stress, and downregulate pro-inflammatory transcriptional factors and cytokine secretion. Translational significance of natural nanomedicine and strategies to investigate future natural product-based nanomedicine is discussed. Our focus in this review is to summarize the use of phytochemicals and macromolecules encapsulated in nanoparticles for the treatment of IBD and IBD-associated colorectal cancer.
Collapse
Affiliation(s)
- Tripti Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA;
| | - Sushesh Srivatsa Palakurthi
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA; (S.S.P.); (B.M.S.); (S.P.)
| | - Brijesh M. Shah
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA; (S.S.P.); (B.M.S.); (S.P.)
| | - Srinath Palakurthi
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA; (S.S.P.); (B.M.S.); (S.P.)
| | - Sharad Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA;
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| |
Collapse
|
|
12
|
Lee PS, Chiou YS, Nagabhushanam K, Ho CT, Pan MH. 3'-Hydroxypterostilbene Potently Alleviates Obesity Exacerbated Colitis in Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:5365-5374. [PMID: 32316726 DOI: 10.1021/acs.jafc.0c01782] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Epidemiological surveys show that obesity and the western diet increase the risk of colitis. Studies have also confirmed that the high-fat-diet (HFD) promoted the deterioration of colitis-related indicators in mice. Compared with stilbenoids, the results showed that 3'-hydroxypterostilbene (HPSB) was found to be the most effective inhibitor for the antiadipogenesis and anti-inflammation. However, its role in ameliorating obesity-promoted colitis is still unknown. We intend to investigate the protective effect and related molecular mechanisms of HPSB on HFD promoted dextran sodium sulfate (DSS)-induced colitis in mice. The results indicate that colitis in the HFD+DSS group tends to be more apparent in the DSS-only group, while feeding 0.025% of HPSB at different stages can improve the colitis induced by HFD+DSS. HPSB significantly reduced the levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) induced by HFD+DSS in mice. Furthermore, the Western blotting revealed that the administration of HPSB significantly downregulated cyclooxygenase-2 (COX-2), plasmalemma vesicle-associated protein-1 (PV-1), and phospho-signal transducer and activator of transcription 3 (p-STAT3) expressions in HFD+DSS treated mice. Presented results reveal that HPSB is a novel functional agent capable of preventing HFD exacerbated colitis.
Collapse
Affiliation(s)
- Pei-Sheng Lee
- Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan
| | - Yi-Shiou Chiou
- Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan
- Tsinghua Berkeley Shenzhen Institute (TBSI), Tsinghua University, Shenzhen, China
| | | | - Chi-Tang Ho
- Department of Food Science, Rutgers University, New Brunswick, New Jersey 08901, United States
| | - Min-Hsiung Pan
- Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
| |
Collapse
|
|
13
|
Sheng Z, Ge S, Gao M, Jian R, Chen X, Xu X, Li D, Zhang K, Chen WH. Synthesis and Biological Activity of Embelin and its Derivatives: An Overview. Mini Rev Med Chem 2020; 20:396-407. [DOI: 10.2174/1389557519666191015202723] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/24/2019] [Accepted: 06/27/2019] [Indexed: 02/04/2023]
Abstract
Embelin is a naturally occurring para-benzoquinone isolated from Embelia ribes (Burm. f.)
of the Myrsinaceae family, and contains two carbonyl groups, a methine group and two hydroxyl
groups. With embelin as the lead compound, more than one hundred derivatives have been reported.
Embelin is well known for its ability to antagonize the X-linked inhibitor of apoptosis protein (XIAP)
with an IC50 value of 4.1 μM. The potential of embelin and its derivatives in the treatment of various
cancers has been extensively studied. In addition, these compounds display a variety of other biological
effects: antimicrobial, antioxidant, analgesic, anti-inflammatory, anxiolytic and antifertility activity.
This paper reviews the recent progress in the synthesis and biological activity of embelin and its derivatives.
Their cellular mechanisms of action and prospects in the research and development of new
drugs are also discussed.
Collapse
Affiliation(s)
- Zhaojun Sheng
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China
| | - Siyuan Ge
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China
| | - Min Gao
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China
| | - Rongchao Jian
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China
| | - Xiaole Chen
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China
| | - Xuetao Xu
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China
| | - Dongli Li
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China
| | - Kun Zhang
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China
| | - Wen-Hua Chen
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China
| |
Collapse
|
|
14
|
Wróbel-Biedrawa D, Grabowska K, Galanty A, Sobolewska D, Żmudzki P, Podolak I. Anti-melanoma potential of two benzoquinone homologues embelin and rapanone - a comparative in vitro study. Toxicol In Vitro 2020; 65:104826. [PMID: 32169436 DOI: 10.1016/j.tiv.2020.104826] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/29/2020] [Accepted: 03/09/2020] [Indexed: 11/30/2022]
Abstract
Rapanone and embelin are simple alkyl benzoquinone derivatives, mainly distributed in the Primulaceae. They have an interesting scope of biological activities including cytotoxicity. As melanoma is one of the most common types of cancer, in many cases resistant to current treatment regimens, the aim of this study was to assess and compare anti-melanoma activity of the two benzoquinones. Cytotoxicity of both compounds towards different melanoma cell lines (A375, HTB140, WM793) and selectivity with respect to normal keratinocytes (HaCaT) were investigated. Furthermore, interactions with a reference chemotherapeutic, doxorubicine, were assessed. Finally, analysis of anti-inflammatory, antioxidant and anti-tyrosinase activities of both benzoquinones was conducted as well. Rapanone showed selective and higher than doxorubicine cytotoxic potential against primary melanoma cell line, WM793. Although embelin was also highly cytotoxic, its selectivity was much poorer. Interestingly, in case of HTB140 and HaCaT cell lines a combination of each benzoquinone with doxorubicine potentiated the cytotoxic potential in a synergistic manner. Embelin revealed higher albumin anti-denaturation potential than rapanone but lower than diclofenac sodium. Anti-hyaluronidase effect of both benzoquinones was higher than quercetin. Both compounds showed antioxidant potential although significantly lower as compared to vitamin C. Finally, neither embelin nor rapanone had any inhibitory effect on tyrosinase.
Collapse
Affiliation(s)
- Dagmara Wróbel-Biedrawa
- Department of Pharmacognosy, Pharmaceutical Faculty, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland.
| | - Karolina Grabowska
- Department of Pharmacognosy, Pharmaceutical Faculty, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland.
| | - Agnieszka Galanty
- Department of Pharmacognosy, Pharmaceutical Faculty, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland.
| | - Danuta Sobolewska
- Department of Pharmacognosy, Pharmaceutical Faculty, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland.
| | - Paweł Żmudzki
- Department of Medicinal Chemistry, Pharmaceutical Faculty, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland.
| | - Irma Podolak
- Department of Pharmacognosy, Pharmaceutical Faculty, Medical College, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland.
| |
Collapse
|
|
15
|
Rao SP, Sharma N, Kalivendi SV. Embelin averts MPTP-induced dysfunction in mitochondrial bioenergetics and biogenesis via activation of SIRT1. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2020; 1861:148157. [PMID: 31987812 DOI: 10.1016/j.bbabio.2020.148157] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 12/17/2019] [Accepted: 01/23/2020] [Indexed: 11/18/2022]
Abstract
Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by the death of dopamine neurons of Substantia nigra pars compacta (SNpc) leading to motor deficits. Amongst the mechanisms proposed, mitochondrial dysfunction, reduced complex-I and PGC1α levels were found to correlate with the pathology of PD. As embelin is a natural product with structural resemblance to ubiquinone, exhibits mitochondrial uncoupling and antioxidant effects, in the present study, we sought to examine its role in the mechanisms mediating PD. Results indicate that embelin protects from MPP+-induced oxidative stress and apoptosis in a time and dose-dependent manner in N27 dopaminergic cells. Cells treated with embelin exhibited increased levels of pAMPK, SIRT1 and PGC1α leading to enhanced mitochondrial biogenesis. Though treatment of cells with MPP+ also increased pAMPK levels, but, SIRT1 and PGC1α levels decreased substantially, possibly due to the block in the mitochondrial electron transport chain and reduced NAD/NADH levels. The mitochondrial uncoupling effects of embelin leading to increased NAD/NADH levels followed by enhanced SIRT1, PGC1α and mitochondrial biogenesis were found to confer embelin mediated protection as treatment of cells with SIRT1 inhibitor or siRNA nullified this effect. Embelin (10 mg/kg) also conferred protection in vivo in MPTP mouse model of PD, wherein, MPTP-induced loss of TH staining, reduced striatal dopamine and markers of mitochondrial biogenesis pathway were averted by embelin.
Collapse
Affiliation(s)
- Swetha Pavani Rao
- Department of Applied Biology and Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India
| | - Neelam Sharma
- Department of Applied Biology and Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India
| | - Shasi V Kalivendi
- Department of Applied Biology and Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India.
| |
Collapse
|
|
16
|
Borges D, Guzman-Novoa E, Goodwin PH. Control of the microsporidian parasite Nosema ceranae in honey bees (Apis mellifera) using nutraceutical and immuno-stimulatory compounds. PLoS One 2020; 15:e0227484. [PMID: 31923212 PMCID: PMC6953808 DOI: 10.1371/journal.pone.0227484] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 12/19/2019] [Indexed: 11/18/2022] Open
Abstract
Nosema ceranae is a microsporidian parasite that causes nosemosis in the honey bee (Apis mellifera). As alternatives to the antibiotic fumagillin, ten nutraceuticals (oregano oil, thymol, carvacrol, trans-cinnmaldehyde, tetrahydrocurcumin, sulforaphane, naringenin, embelin, allyl sulfide, hydroxytyrosol) and two immuno-stimulatory compounds (chitosan, poly I:C) were examined for controlling N. ceranae infections. Caged bees were inoculated with N. ceranae spores, and treatments were administered in sugar syrup. Only two compounds did not significantly reduce N. ceranae spore counts compared to the infected positive control, but the most effective were sulforaphane from cruciferous vegetables, carvacrol from oregano oil, and naringenin from citrus fruit. When tested at several concentrations, the highest sulforaphane concentration reduced spore counts by 100%, but also caused 100% bee mortality. For carvacrol, the maximum reduction in spore counts was 57% with an intermediate concentration and the maximum bee mortality was 23% with the highest concentration. For naringenin, the maximum reduction in spore counts was 64% with the highest concentration, and the maximum bee mortality was only 15% with an intermediate concentration. In the longevity experiment, naringenin-fed bees lived as long as Nosema-free control bees, both of which lived significantly longer than infected positive control bees. While its antimicrobial properties may be promising, reducing sulforaphane toxicity to bees is necessary before it can be considered as a candidate for controlling N. ceranae. Although further work on formulation is needed with naringenin, its effect on extending longevity in infected bees may give it an additional value as a potential additive for bee feed in honey bee colonies.
Collapse
Affiliation(s)
- Daniel Borges
- School of Environmental Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Ernesto Guzman-Novoa
- School of Environmental Sciences, University of Guelph, Guelph, Ontario, Canada
- * E-mail:
| | - Paul H. Goodwin
- School of Environmental Sciences, University of Guelph, Guelph, Ontario, Canada
| |
Collapse
|
|
17
|
Discovery of small-molecule candidates against inflammatory bowel disease. Eur J Med Chem 2020; 185:111805. [DOI: 10.1016/j.ejmech.2019.111805] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 10/19/2019] [Accepted: 10/20/2019] [Indexed: 12/12/2022]
|
|
18
|
Lee Y, Lee J, Ju J. Perilla frutescens Britton var. frutescens leaves attenuate dextran sulfate sodium-induced acute colitis in mice and lipopolysaccharide-stimulated angiogenic processes in human umbilical vein endothelial cells. Food Sci Biotechnol 2019; 29:131-140. [PMID: 31976135 DOI: 10.1007/s10068-019-00711-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 02/08/2023] Open
Abstract
The aim of the current study was to investigate whether the leaves of Perilla frutescens Britton var. frutescens (PL), a frequently consumed vegetable in Korea, attenuate dextran sulfate sodium (DSS)-induced acute colitis in mice and lipopolysaccharide (LPS)-stimulated angiogenic processes in human umbilical vein endothelial cells (HUVEC). In DSS-treated mice, dietary supplementation with PL mitigated DAI and colon shortening. The dietary PL also reduced colonic levels of inflammatory and angiogenic mediators, such as interleukin-1β, interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, leukotriene B4, inducible nitric oxide synthase, cyclooxygenase-2, basic fibroblast growth factor, and intercellular adhesion molecule-1 (ICAM-1). Treatment of HUVEC with ethanol extract of PL attenuated LPS-stimulated increases in ICAM-1 levels, monocyte adhesion, invasion, and tube formation. This study suggests that dietary PL effectively inhibited DSS-induced acute colitis in mice, and its anti-angiogenic activities may partially contribute to the inhibition.
Collapse
Affiliation(s)
- Yuna Lee
- Department of Food and Nutrition, Chungbuk National University, 1 Chungdae-ro, Seowon-gu, Cheongju, 362-763 Korea
| | - Jungjae Lee
- Department of Food and Nutrition, Chungbuk National University, 1 Chungdae-ro, Seowon-gu, Cheongju, 362-763 Korea
| | - Jihyeung Ju
- Department of Food and Nutrition, Chungbuk National University, 1 Chungdae-ro, Seowon-gu, Cheongju, 362-763 Korea
| |
Collapse
|
|
19
|
He Z, Zhou Q, Wen K, Wu B, Sun X, Wang X, Chen Y. Huangkui Lianchang Decoction Ameliorates DSS-Induced Ulcerative Colitis in Mice by Inhibiting the NF-kappaB Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2019; 2019:1040847. [PMID: 31093294 PMCID: PMC6481129 DOI: 10.1155/2019/1040847] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 03/20/2019] [Accepted: 03/26/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND The nuclear factor kappa beta (NF-κB) signaling pathway plays an important role in ulcerative colitis (UC). Huangkui Lianchang decoction (HLD) is an effective traditional Chinese medicinal compound used in the treatment of UC. HLD has good effects in the clinic, but the mechanism by which HLD acts is unclear. This study aims to reveal the exact molecular mechanism of HLD in the treatment of UC. METHODS Mouse ulcerative colitis was induced by dextran sulfate sodium (DSS) and treated with HLD. Intestinal damage was assessed by disease activity index (DAI), colon macroscopic lesion scores, and histological scores. Interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β were detected in colon tissue using ELISA. Myeloperoxidase (MPO) and superoxide dismutase (SOD) activities in the colonic mucosa were measured. The levels of IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in the colon were determined by real-time quantitative polymerase chain reaction (qPCR). The expression of NF-κB, IκBα, and p-IκBα in the colon was measured by Western blot. RESULTS After treatment with HLD, the DAI scores, macroscopic lesion scores, and histological scores decreased, and the levels of inflammatory cytokines related to the NF-κB signaling pathway, such as IL-6, TNF-α, and IL-1β, as well as those of iNOS and COX-2, were reduced; at the same time, colonic pathological damage was alleviated, and the MPO and SOD activities decreased. Western blot confirmed that HLD can inhibit the NF-κB signaling pathway in DSS-induced ulcerative colitis. CONCLUSION HLD can alleviate the inflammation caused by ulcerative colitis. In particular, high doses of HLD can significantly alleviate intestinal inflammation and have comparable efficacy to Mesalazine. We propose that the anti-inflammatory activity of HLD on DSS-induced colitis in mice may involve the inhibition of the NF-κB pathway.
Collapse
Affiliation(s)
- Zongqi He
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210046, China
- Department of Colorectal Surgery, Suzhou Hospital Affiliated with Nanjing University of Chinese Medicine, Suzhou 215009, China
| | - Qing Zhou
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210046, China
| | - Ke Wen
- Department of Colorectal Surgery, Suzhou Hospital Affiliated with Nanjing University of Chinese Medicine, Suzhou 215009, China
| | - Bensheng Wu
- Department of Colorectal Surgery, Suzhou Hospital Affiliated with Nanjing University of Chinese Medicine, Suzhou 215009, China
| | - Xueliang Sun
- Department of Colorectal Surgery, Suzhou Hospital Affiliated with Nanjing University of Chinese Medicine, Suzhou 215009, China
| | - Xiaopeng Wang
- Department of Colorectal Surgery, Suzhou Hospital Affiliated with Nanjing University of Chinese Medicine, Suzhou 215009, China
| | - Yugen Chen
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210046, China
| |
Collapse
|
|
20
|
Li Z, Chen SJ, Yu XA, Li J, Gao XM, He J, Chang YX. Pharmacokinetic and Bioavailability Studies of Embelin after Intravenous and Oral Administration to Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2019; 2019:9682495. [PMID: 31015855 PMCID: PMC6446108 DOI: 10.1155/2019/9682495] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/08/2019] [Accepted: 03/13/2019] [Indexed: 12/22/2022]
Abstract
Embelin exhibits the broad bioactivities such as antitumor, antifertility, antidiabetic, anti-inflammatory, antioxidant, anticonvulsant, anxiolytic, antimicrobial, and hepatoprotective activity. In order to further understand the pharmacokinetic characteristics and oral bioavailability of embelin in vivo, the concentration of embelin in rat plasma was determined by a sensitive high-performance liquid chromatography with diode array detector (HPLC-DAD). The preparation of samples was accomplished by a simple precipitating protein with methanol. Emodin was selected as the internal standard (IS). Embelin and IS were completely separated on an analytical column (Extend-C18, 4.6 × 250 mm, 5 μm) using 0.1% phosphoric acid in methanol and 0.1% phosphoric acid in aqueous solution (90:10, v/v) as the mobile phase. The lower limit of quantification was 0.15 μg/mL. Oral bioavailability of embelin was 30.2 ± 11.9%. This study could provide the information about pharmacokinetics and oral bioavailability of embelin, which was useful to assess the clinic efficacy and safety and promote further development of embelin.
Collapse
Affiliation(s)
- Zhen Li
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Shu-jing Chen
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Xie-an Yu
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Jin Li
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Xiu-mei Gao
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
- Tianjin Key Laboratory of Phytochemistry and Pharmaceutical Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Jun He
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
- Tianjin Key Laboratory of Phytochemistry and Pharmaceutical Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Yan-xu Chang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
- Tianjin Key Laboratory of Phytochemistry and Pharmaceutical Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| |
Collapse
|
|
21
|
Hossen I, Hua W, Ting L, Mehmood A, Jingyi S, Duoxia X, Yanping C, Hongqing W, Zhipeng G, Kaiqi Z, Fang Y, Junsong X. Phytochemicals and inflammatory bowel disease: a review. Crit Rev Food Sci Nutr 2019; 60:1321-1345. [PMID: 30729797 DOI: 10.1080/10408398.2019.1570913] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Gastrointestinal tract is the second largest organ in the body that mainly functions in nutrients and minerals intake through the intestinal barrier. Intestinal permeability maintains the circulation of minerals and nutrients from digested foods. Life and all the metabolic processes depend either directly or indirectly on proper functioning of GI tract. Compromised intestinal permeability and related disorders are common among all the patients with inflammatory bowel disease (IBD), which is a collective term of inflammatory diseases including Crohn's disease and ulcerative colitis. Many synthetic drugs are currently in use to treat IBD such as 5-aminosalicylic acid corticosteroids. However, they all have some drawbacks as long-term use result in many complications. These problems encourage us to look out for alternative medicine. Numerous in vitro and in vivo experiments showed that the plant-derived secondary metabolites including phenolic compounds, glucosinolates, alkaloids, terpenoids, oligosaccharides, and quinones could reduce permeability, ameliorate-related dysfunctions with promising results. In addition, many of them could modulate enzymatic activity, suppress the inflammatory transcriptional factors, ease oxidative stress, and reduce pro-inflammatory cytokines secretion. In this review, we summarized the phytochemicals, which were proven potent in treating increased intestinal permeability and related complication along with their mechanism of action.
Collapse
Affiliation(s)
- Imam Hossen
- School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China
| | - Wu Hua
- School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China
| | - Luo Ting
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Arshad Mehmood
- School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China
| | - Song Jingyi
- School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China
| | - Xu Duoxia
- School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China
| | - Cao Yanping
- School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China
| | - Wu Hongqing
- School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China
| | - Gao Zhipeng
- School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China
| | - Zhang Kaiqi
- School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China
| | - Yang Fang
- School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China
| | - Xiao Junsong
- School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China.,Beijing Engineering and Technology Research Center of Food Additives, Beijing, China
| |
Collapse
|
|
22
|
Yoon DW, Kim YS, Hwang S, Khalmuratova R, Lee M, Kim JH, Lee GY, Koh SJ, Park JW, Shin HW. Intermittent hypoxia promotes carcinogenesis in azoxymethane and dextran sodium sulfate-induced colon cancer model. Mol Carcinog 2019; 58:654-665. [PMID: 30575123 DOI: 10.1002/mc.22957] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 10/30/2018] [Accepted: 12/15/2018] [Indexed: 02/06/2023]
Abstract
Intermittent hypoxia (IH), a characteristic of obstructive sleep apnea, is known to promote cancer progression and aggressiveness in mouse models. However, little is known regarding the effect of IH on cancer initiation. Here, the effect of IH on carcinogenesis was explored in azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced colon cancer models with three different protocols. In the first protocol, two other application time points (early or late initiation of IH) were applied. In the second protocol, mice were divided into only two groups, and then exposed to either N or IH conditions for 14 days. In the third protocol, a pharmacological inhibition study for anti-inflammation (5-aminosalicylate) or anti-oxidative stress (N-acetylcysteine [NAC]) was performed. The number of tumors was significantly higher in the IH-1 than in the N or IH-2 groups. 8-oxo-2'-deoxyguanosine (8-OHdG) levels were higher in tumors of the IH-1 group than in that of the N and IH-2 groups. Gene expression related to reactive oxygen species production was higher in the IH-1 group than in the N and IH-2 groups, and it showed a positive correlation with 8-OHdG levels. Prior to cancer development 8-OHdG levels were already elevated in colonic epithelial regions in the IH group, possibly due to an imbalance between oxidative stress and antioxidant systems. NAC treatment resulted in a significant reduction in the number of tumors in mice exposed to IH. In conclusion, IH promotes carcinogenesis in a chemically-induced colon cancer model where elevated 8-OHdG may contribute to the increased tumor induction.
Collapse
Affiliation(s)
- Dae Wui Yoon
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea
| | - Yi-Sook Kim
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.,Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea
| | - Soyoung Hwang
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.,Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea
| | - Roza Khalmuratova
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea
| | - Mingyu Lee
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.,Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea
| | - Jee Hyun Kim
- Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Gah Young Lee
- Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Seong-Joon Koh
- Division of Gastroenterology, Department of Internal Medicine, Seoul National University Boramae Hospital, Seoul, Korea
| | - Jong-Wan Park
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.,Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea.,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun-Woo Shin
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.,Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea.,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea
| |
Collapse
|
|
23
|
Taghipour YD, Bahramsoltani R, Marques AM, Naseri R, Rahimi R, Haratipour P, Panah AI, Farzaei MH, Abdollahi M. A systematic review of nano formulation of natural products for the treatment of inflammatory bowel disease: drug delivery and pharmacological targets. Daru 2018; 26:229-239. [PMID: 30382546 PMCID: PMC6279665 DOI: 10.1007/s40199-018-0222-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 10/10/2018] [Indexed: 12/17/2022] Open
Abstract
Inflammatory bowel diseases (IBD), which is classified into Crohn's disease and ulcerative colitis, are among chronic gastrointestinal diseases with unknown pathogenesis. Diverse strategies have been applied for the treatment of this chronic disease. However, selective and site-specific routes of drug delivery to the inflamed location of the colon remain of high importance. Consequently, the application and effects of natural products in the form of nanoformulation and stimuli responsive nanoparticles as a novel strategy for the treatment of IBD are discussed in this review article. This approach may potentially overcome some complications that are associated with conventional means of colon drug delivery. Meanwhile, in vitro and in vivo studies pave the way for understanding of the mechanism that lies behind this chronic relapsing disease and potentially more effective treatment. Graphical abstract ᅟ.
Collapse
Affiliation(s)
- Yasamin Davatgaran Taghipour
- Department of Medical Nanotechnology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Roodabeh Bahramsoltani
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Pharmacy in Persian Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - André M. Marques
- Oswaldo Cruz Foundation (FIOCRUZ), Institute of Technology in Pharmaceuticals (Farmanguinhos), Rio de Janeiro, RJ Brazil
| | - Rozita Naseri
- Internal Medicine Department, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Roja Rahimi
- Department of Pharmacy in Persian Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Pouya Haratipour
- Department of Chemistry, Sharif University of Technology, Tehran, Iran
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Los Angeles, CA USA
| | - Amin Iran Panah
- Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
24
|
Wu T, Wang C, Wang W, Hui Y, Zhang R, Qiao L, Dai Y. Embelin impairs the accumulation and activation of MDSCs in colitis-associated tumorigenesis. Oncoimmunology 2018; 7:e1498437. [PMID: 30377563 PMCID: PMC6205065 DOI: 10.1080/2162402x.2018.1498437] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 06/30/2018] [Accepted: 07/03/2018] [Indexed: 01/01/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a major component of the immunosuppressive tumor microenvironment and has been recognized as a contributing factor for inflammation-related cancers. We previously showed that embelin has potent anti-inflammatory and anti-tumor effects in a colitis-associated cancer (CAC) model. Here, by using this model, we assessed the effect of embelin on the accumulation and suppressive function of MDSCs. We have demonstrated that embelin substantially reduced accumulation of MDSCs in the peripheral lymphoid organ and tumor tissue of CAC-bearing mice. Embelin impaired immunosuppressive activity of MDSCs by reducing the generation of reactive oxygen species (ROS) and arginase 1 level, leading to restored T cell responses. In tumor milieu, embelin increased the infiltration of CD8+ T cells, NK cells and mature dendritic cells whilst depleted the regulatory T cells. Moreover, embelin could directly interfere with the generation and function of MDSCs in vitro. These effects of embelin on MDSCs were mediated largely via limiting C/EBPβ and STAT3 signaling. Our findings support the hypothesis that embelin may be a promising pharmacologic agent in regulating MDSC-mediated immune tolerance in colorectal cancer.
Collapse
Affiliation(s)
- Ting Wu
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Chaohui Wang
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Weihong Wang
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Yuhang Hui
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Rongxin Zhang
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Liang Qiao
- Storr Liver Centre, The Westmead Institute for Medical Research, Department of Medicine and Western Clinical School, The University of Sydney, Westmead, NSW, Australia
| | - Yun Dai
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| |
Collapse
|
|
25
|
Williams B, Dharmapatni A, Crotti T. Intracellular apoptotic pathways: a potential target for reducing joint damage in rheumatoid arthritis. Inflamm Res 2017; 67:219-231. [DOI: 10.1007/s00011-017-1116-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 10/19/2017] [Accepted: 11/13/2017] [Indexed: 12/24/2022] Open
|
|
26
|
Cha JY, Jeon YD, Xin M, Kim DK, Lee HY, Kim BR, Hwang SW, Kim DK, Jin JS, Lee YM. Anti-inflammatory effect of Euphorbia supina extract in dextran sulfate sodium-induced colitis mice. Biosci Biotechnol Biochem 2017; 81:2178-2185. [PMID: 28958181 DOI: 10.1080/09168451.2017.1373590] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The aim of this study is to examine the anti-inflammatory effect of Euphorbia supina (ES) ethanol extract in dextran sulfate sodium (DSS)-induced experimental colitis model. ES was per orally administered at different doses of 4 or 20 mg/kg body weight with 5% DSS in drinking water for 7 days. Twenty mg/kg of ES administration regulated body weight decrease, recovered colon length shortening, and increased disease activity index score and myeloperoxidase level in DSS-induced colitis. Histological features showed that 20 mg/kg of ES administration suppressed edema, mucosal damage, and the loss of crypts induced by DSS. Furthermore, ES suppressed the expressions of COX-2, iNOS, NF-kB, IkBα, pIkBα in colon tissue. These findings demonstrated a possible effect of amelioration of ulcerative colitis and could be clinically applied.
Collapse
Affiliation(s)
- Ji-Yun Cha
- a Department of Oriental Pharmacy, College of Pharmacy , Wonkwang Oriental Medicine Research Institute, Wonkwang University , Iksan , Jeollabuk-do , Republic of Korea
| | - Yong-Deok Jeon
- b Department of Oriental Medicine Resources , Chonbuk National University , Iksan , Jeollabuk-do , Republic of Korea
| | - Mingjie Xin
- c EastHill Co ., Gwonseon-gu, Suwon , Gyoenggi-do , Republic of Korea
| | - Do-Kuk Kim
- d National Institute of Horticultural and Herbal Science , RDA , Jeonju , Jeollabuk-do , Republic of Korea
| | - Hoon-Yeon Lee
- a Department of Oriental Pharmacy, College of Pharmacy , Wonkwang Oriental Medicine Research Institute, Wonkwang University , Iksan , Jeollabuk-do , Republic of Korea
| | - Bo-Ram Kim
- a Department of Oriental Pharmacy, College of Pharmacy , Wonkwang Oriental Medicine Research Institute, Wonkwang University , Iksan , Jeollabuk-do , Republic of Korea
| | - Sung-Woo Hwang
- a Department of Oriental Pharmacy, College of Pharmacy , Wonkwang Oriental Medicine Research Institute, Wonkwang University , Iksan , Jeollabuk-do , Republic of Korea
| | - Dae-Ki Kim
- e Department of Immunology and Institute of Medical Science , Chonbuk National University , Jeonju , Jeollabuk-do , Republic of Korea
| | - Jong-Sik Jin
- b Department of Oriental Medicine Resources , Chonbuk National University , Iksan , Jeollabuk-do , Republic of Korea
| | - Young-Mi Lee
- a Department of Oriental Pharmacy, College of Pharmacy , Wonkwang Oriental Medicine Research Institute, Wonkwang University , Iksan , Jeollabuk-do , Republic of Korea
| |
Collapse
|
|
27
|
Khelifi L, Soufli I, Labsi M, Touil-Boukoffa C. Immune-protective effect of echinococcosis on colitis experimental model is dependent of down regulation of TNF-α and NO production. Acta Trop 2017; 166:7-15. [PMID: 27983971 DOI: 10.1016/j.actatropica.2016.10.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 10/24/2016] [Accepted: 10/26/2016] [Indexed: 12/26/2022]
Abstract
Hydatid disease (echinococcosis) is a chronic, endemic helminthic disease caused by the larval stage of the tapeworm, Echinococcus granulosus. This disease is endemic in many parts of the world, such as the Mediterranean area, and in particular in Algeria. Helminth parasites have developed complex strategies to modulate the immune responses of their hosts through versatile immune-regulatory mechanisms. These mechanisms may regulate immune responses associated with inflammatory diseases such as inflammatory bowel diseases (IBD). the goal of this study was to investigate the effect of Echinococcus granulosus infection on the development of dextran sulfate sodium (DSS)-induced colitis. Our results demonstrated that E. granulosus infection significantly improved the clinical symptoms and histological scores observed during DSS-induced colitis, and also maintained mucus production by goblet cells. Interestingly, this infection reduced Nitric oxide (NO) and tumor necrosis factor α (TNF-α) production and attenuated inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB) expression in colonic tissues. Collectively, our data support the hygiene hypothesis and indicate that prior infection with E. granulosus can effectively protect mice from DSS-induced colitis by enhancing immune-regulatory mechanisms.
Collapse
Affiliation(s)
- Lila Khelifi
- Laboratory of Cellular and Molecular Biology, Department of Biology, University of Sciences and Technology Houari Boumediene, Algiers, Algeria.
| | - Imene Soufli
- Laboratory of Cellular and Molecular Biology, Department of Biology, University of Sciences and Technology Houari Boumediene, Algiers, Algeria.
| | - Moussa Labsi
- Laboratory of Cellular and Molecular Biology, Department of Biology, University of Sciences and Technology Houari Boumediene, Algiers, Algeria.
| | - Chafia Touil-Boukoffa
- Laboratory of Cellular and Molecular Biology, Department of Biology, University of Sciences and Technology Houari Boumediene, Algiers, Algeria.
| |
Collapse
|
|
28
|
Xu J, Tian G, Ma C, Gao H, Chen C, Yang W, Deng Q, Huang Q, Ma Z, Huang F. Flaxseed lignan secoisolariciresinol diglucoside ameliorates experimental colitis induced by dextran sulphate sodium in mice. J Funct Foods 2016. [DOI: 10.1016/j.jff.2016.07.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
|
|
29
|
Importance of the Evaluation of N-Acetyltransferase Enzyme Activity Prior to 5-Aminosalicylic Acid Medication for Ulcerative Colitis. Inflamm Bowel Dis 2016; 22:1793-802. [PMID: 27416043 PMCID: PMC4956520 DOI: 10.1097/mib.0000000000000823] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND 5-aminosalicylic acid (5-ASA) is a classic anti-inflammatory drug for the treatment of ulcerative colitis. N-acetyltransferase (NAT) enzymes convert 5-ASA to its metabolite N-acetyl-5-ASA, and it is unresolved whether 5-ASA or N-acetyl-5-ASA is the effective therapeutic molecule. We previously demonstrated that colonic production of N-acetyl-5-ASA (NAT activity) is decreased in dextran sulfate sodium-induced colitis. Our hypothesis is that 5-ASA is the therapeutic molecule to improve colitis, with the corollary that altered NAT activity affects drug efficacy. Since varying clinical effectiveness of 5-ASA has been reported, we also ask if NAT activity varies with inflammation in pediatric or adult patients. METHODS Acute colonic inflammation was induced in C57BL/6 NAT wild-type (WT) or knockout mice, using 3.5% dextran sulfate sodium (w/v) concurrent with 5-ASA treatment. Adult and pediatric rectosigmoid biopsies were collected from control or patients with ulcerative colitis. Tissue was analyzed for NAT and myeloperoxidase activity. RESULTS Dextran sulfate sodium-induced colitis was of similar severity in both NAT WT and knockout mice, and NAT activity was significantly decreased in NAT WT mice. In the setting of colitis, 5-ASA significantly restored colon length and decreased myeloperoxidase activity in NAT knockout but not in WT mice. Myeloperoxidase activity negatively correlated with NAT activity in pediatric patients, but correlation was not observed in adult patients. CONCLUSIONS Inflammation decreases NAT activity in the colon of mice and human pediatric patients. Decreased NAT activity enhances the therapeutic effect of 5-ASA in mice. A NAT activity assay could be useful to help predict the efficacy of 5-ASA therapy.
Collapse
|
|
30
|
Nidhi, Dadwal A, Hallan SS, Sharma S, Mishra N. Development of enteric-coated microspheres of embelin for their beneficial pharmacological potential in ulcerative colitis. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2016; 45:1-9. [PMID: 27388946 DOI: 10.1080/21691401.2016.1202258] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The aim of the present study is to develop embelin-loaded enteric-coated microspheres and investigate their pharmacological potential in acetic acid induced ulcerative colitis. The optimized formulation of embelin-loaded microspheres has shown significant sustained release of embelin. Further this formulation significantly reduced the ulcer activity score and oxidative stress, and attenuated the inflammatory changes. Thus it may be concluded that embelin-loaded enteric-coated microspheres have shown delayed release capacity than plain embelin and exerts colon ulcer protective effect in rats.
Collapse
Affiliation(s)
- Nidhi
- a Department of Pharmaceutics , I.S.F. College of Pharmacy , Moga , Punjab , India
| | - Ankita Dadwal
- a Department of Pharmaceutics , I.S.F. College of Pharmacy , Moga , Punjab , India
| | | | - Saurabh Sharma
- b Department of Pharmacology , I.S.F. College of Pharmacy , Moga , Punjab , India
| | - Neeraj Mishra
- a Department of Pharmaceutics , I.S.F. College of Pharmacy , Moga , Punjab , India
| |
Collapse
|
|
31
|
Triantafillidis JK, Triantafyllidi A, Vagianos C, Papalois A. Favorable results from the use of herbal and plant products in inflammatory bowel disease: evidence from experimental animal studies. Ann Gastroenterol 2016; 29:268-281. [PMID: 27366027 PMCID: PMC4923812 DOI: 10.20524/aog.2016.0059] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 02/01/2016] [Indexed: 12/14/2022] Open
Abstract
The use of herbal therapy for inflammatory bowel disease is increasing worldwide. The aim of this study was to review the available literature on the efficacy of herbal therapy in experimental colitis. All relevant studies published in Medline and Embase up to June 2015 have been reviewed. The results of bowel histology and serum parameters have been recorded. A satisfactory number of published experimental studies, and a quite large one of both herbal and plant products tested in different studies have been reported. The results showed that in the majority of the studies, herbal therapy reduced the inflammatory activity of experimental colitis and diminished the levels of many inflammatory indices, including serum cytokines and indices of oxidative stress. The most promising plant and herbal products were tormentil extracts, wormwoodherb, Aloe vera, germinated barley foodstuff, curcumin, Boswellia serrata, Panax notoginseng, Ixeris dentata, green tea, Cordia dichotoma, Plantago lanceolata, Iridoidglycosides, and mastic gum. Herbal therapies exert their therapeutic benefit via various mechanisms, including immune regulation, anti-oxidant activity, inhibition of leukotriene B4 and nuclear factor-κB, and antiplatelet activity. Large, double-blind clinical studies assessing these natural substances should be urgently conducted.
Collapse
Affiliation(s)
- John K. Triantafillidis
- Inflammatory Bowel Disease Unit, “IASO General” Hospital (John K. Triantafillidis, Aikaterini Triantafyllidi), Athens, Greece
| | - Aikaterini Triantafyllidi
- Inflammatory Bowel Disease Unit, “IASO General” Hospital (John K. Triantafillidis, Aikaterini Triantafyllidi), Athens, Greece
| | - Constantinos Vagianos
- 2 Surgical Department, “Laikon” Hospital, University of Athens (Constantinos Vagianos), Athens, Greece
| | - Apostolos Papalois
- Experimental-Research Center, ELPEN (Apostolos Papalois), Athens, Greece
| |
Collapse
|
|
32
|
Zhou XL, Huang L, Cao J. Embelin Reduces Systemic Inflammation and Ameliorates Organ Injuries in Septic Rats Through Downregulating STAT3 and NF-κB Pathways. Inflammation 2016; 38:1556-62. [PMID: 25682469 DOI: 10.1007/s10753-015-0130-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Current evidence shows that the majority of the damage induced during sepsis is pursuant to induction and overproduction of endogenous cytokines. Embelin has been reported to suppress cytokine expressions in inflammatory disorders. The present study was designed to investigate the effects of embelin on cecal and ligation and puncture (CLP)-induced rat sepsis. Single-dose administration of embelin 1 h after surgery significantly improved survival of rats with CLP-induced sepsis. In addition, embelin treatment reduced the serum levels of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 and decreased organ inflammation and injuries. Moreover, embelin suppressed the activation of p65 subunit of nuclear factor-kappa B (NF-κB) and signal transducers and activators of transcription 3 (STAT3). Collectively, these results indicated that embelin ameliorates sepsis in rats through suppressing STAT3 and NF-κB pathways.
Collapse
Affiliation(s)
- Xian-Long Zhou
- Emergency Center, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, Hubei, China
| | | | | |
Collapse
|
|
33
|
Lu H, Wang J, Wang Y, Qiao L, Zhou Y. Embelin and Its Role in Chronic Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016:397-418. [DOI: 10.1007/978-3-319-41334-1_16] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
|
|
34
|
Pervin M, Hasnat MA, Lim JH, Lee YM, Kim EO, Um BH, Lim BO. Preventive and therapeutic effects of blueberry (Vaccinium corymbosum) extract against DSS-induced ulcerative colitis by regulation of antioxidant and inflammatory mediators. J Nutr Biochem 2015; 28:103-13. [PMID: 26878787 DOI: 10.1016/j.jnutbio.2015.10.006] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 10/06/2015] [Accepted: 10/12/2015] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disorder caused by hyperactivation of effector immune cells that produce high levels of proinflammatory cytokines. The aims of our study were to determine whether orally administered blueberry extract (BE) could attenuate or prevent the development of experimental colitis in mice and to elucidate the mechanism of action. Female Balb/C mice (n=7) were randomized into groups differing in treatment conditions (prevention and treatment) and dose of BE (50 mg/kg body weight). Acute ulcerative colitis was induced by oral administration of 3% dextran sodium sulfate for 7 days in drinking water. Colonic mucosal injury was assessed by clinical, macroscopic, biochemical and histopathological examinations. BE significantly decreased disease activity index and improved the macroscopic and histological score of colons when compared to the colitis group (P<.05). BE markedly attenuated myeloperoxidase accumulation (colitis group 54.97±2.78 nmol/mg, treatment group 30.78±1.33 nmol/mg) and malondialdehyde in colon and prostaglandin E2 level in serum while increasing the levels of superoxide dismutase and catalase (colitis group 11.94±1.16 U/ml, BE treatment group 16.49±0.39 U/ml) compared with the colitis group (P<.05). mRNA levels of the cyclooxygenase (COX)-2, interferon-γ, interleukin (IL)-1β and inducible nitric oxide synthase cytokines were determined by reverse transcriptase polymerase chain reaction. Immunohistochemical analysis showed that BE attenuates the expression of COX-2 and IL-1β in colonic tissue. Moreover, BE reduced the nuclear translocation of nuclear transcription factor kappa B (NF-κB) by immunofluorescence analysis. Thus, the anti-inflammatory effect of BE at colorectal sites is a result of a number of mechanisms: antioxidation, down-regulation of the expression of inflammatory mediators and inhibition of the nuclear translocation of NF-κB.
Collapse
Affiliation(s)
- Mehnaz Pervin
- College of Biomedical & Health Science, Department of Life Science, Konkuk University, Chungju, 380-701, Republic of Korea
| | - Md Abul Hasnat
- College of Biomedical & Health Science, Department of Life Science, Konkuk University, Chungju, 380-701, Republic of Korea
| | - Ji-Hong Lim
- College of Biomedical & Health Science, Department of Life Science, Konkuk University, Chungju, 380-701, Republic of Korea
| | - Yoon-Mi Lee
- College of Biomedical & Health Science, Department of Life Science, Konkuk University, Chungju, 380-701, Republic of Korea
| | - Eun Ok Kim
- Functional Food Center, KIST Gangneung Institute, 290, Daejeon-dong, Gangneung, Gangwon, 210-340, Republic of Korea
| | - Byung-Hun Um
- Functional Food Center, KIST Gangneung Institute, 290, Daejeon-dong, Gangneung, Gangwon, 210-340, Republic of Korea
| | - Beong Ou Lim
- College of Biomedical & Health Science, Department of Life Science, Konkuk University, Chungju, 380-701, Republic of Korea.
| |
Collapse
|
|
35
|
Antioxidant therapy for treatment of inflammatory bowel disease: Does it work? Redox Biol 2015; 6:617-639. [PMID: 26520808 PMCID: PMC4637335 DOI: 10.1016/j.redox.2015.10.006] [Citation(s) in RCA: 269] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 10/18/2015] [Accepted: 10/20/2015] [Indexed: 12/13/2022] Open
Abstract
Oxidative stress (OS) is considered as one of the etiologic factors involved in several signals and symptoms of inflammatory bowel diseases (IBD) that include diarrhea, toxic megacolon and abdominal pain. This systematic review discusses approaches, challenges and perspectives into the use of nontraditional antioxidant therapy on IBD, including natural and synthetic compounds in both human and animal models. One hundred and thirty four papers were identified, of which only four were evaluated in humans. Some of the challenges identified in this review can shed light on this fact: lack of standardization of OS biomarkers, absence of safety data and clinical trials for the chemicals and biological molecules, as well as the fact that most of the compounds were not repeatedly tested in several situations, including acute and chronic colitis. This review hopes to stimulate researchers to become more involved in this fruitful area, to warrant investigation of novel, alternative and efficacious antioxidant-based therapies.
Major biomarkers used for evaluation of antioxidant therapy were MPO, TBARS/MDA and glutathione levels. Challenges were identified for the yet poor use of antioxidant therapy in IBD. This review stimulates the investigation of alternative and efficacious antioxidant therapies.
Collapse
|
|
36
|
The X-Linked Inhibitor of Apoptosis Protein Inhibitor Embelin Suppresses Inflammation and Bone Erosion in Collagen Antibody Induced Arthritis Mice. Mediators Inflamm 2015; 2015:564042. [PMID: 26347311 PMCID: PMC4539506 DOI: 10.1155/2015/564042] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 09/27/2014] [Accepted: 09/28/2014] [Indexed: 01/04/2023] Open
Abstract
Objective. To investigate the effect of Embelin, an inhibitor of X-Linked Inhibitor of Apoptosis Protein (XIAP), on inflammation and bone erosion in a collagen antibody induced arthritis (CAIA) in mice. Methods. Four groups of mice (n = 6 per group) were allocated: CAIA untreated mice, CAIA treated with Prednisolone (10 mg/kg/day), CAIA treated with low dose Embelin (30 mg/kg/day), and CAIA treated with high dose Embelin (50 mg/kg/day). Joint inflammation was evaluated using clinical paw score and histological assessments. Bone erosion was assessed using micro-CT, tartrate resistant acid phosphatase (TRAP) staining, and serum carboxy-terminal collagen crosslinks (CTX-1) ELISA. Immunohistochemistry was used to detect XIAP protein. TUNEL was performed to identify apoptotic cells. Results. Low dose, but not high dose Embelin, suppressed inflammation as reflected by lower paw scores (P < 0.05) and lower histological scores for inflammation. Low dose Embelin reduced serum CTX-1 (P < 0.05) and demonstrated lower histological score and TRAP counting, and slightly higher bone volume as compared to CAIA untreated mice. XIAP expression was not reduced but TUNEL positive cells were more abundant in Embelin treated CAIA mice. Conclusion. Low dose Embelin suppressed inflammation and serum CTX-1 in CAIA mice, indicating a potential use for Embelin to treat pathological bone loss.
Collapse
|
|
37
|
Shirole RL, Shirole NL, Saraf MN. Embelia ribes ameliorates lipopolysaccharide-induced acute respiratory distress syndrome. JOURNAL OF ETHNOPHARMACOLOGY 2015; 168:356-63. [PMID: 25818695 DOI: 10.1016/j.jep.2015.03.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 02/17/2015] [Accepted: 03/04/2015] [Indexed: 05/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Embelia ribes Burm. f. (Fam. Myrsinaceae) locally known as Vidanga have been used for treating tumors, ascites, bronchitis, jaundice, diseases of the heart and brain in traditional Indian medicine. However, no scientific studies providing new insights in its pharmacological properties with respect to acute respiratory distress syndrome have been investigated. AIM The present investigation aimed to elucidate the effectiveness of Embelin isolated from Embelia ribes seeds on attenuation of LPS-induced acute respiratory distress syndrome in murine models. METHODS Embelin (5, 10 and 20 mg/kg/day, i.p.) and Roflumilast (1 mg/kg/day, p.o.) were administered for four days and prior to LPS in rats (i.t.). Four hour after LPS challenge animals were anesthesized and bronchoalveolar lavage was done with ice-cold phosphate buffer. Assessment of BAL fluid was done for albumin, total protein, total cell and neutrophil count, TNF-α levels, nitrosoative stress. Superior lobe of right lung was used for histopathologic evaluation. Inferior lobe of right lung was used to obtain lung edema. Left lung was used for myeloperoxidase estimation. Arterial blood was collected immediately and analyzed for pH, pO2 and pCO2 were estimated. RESULTS Pretreatment with embelin (5, 10 and 20 mg/kg, i.p.) decreased lung edema, mononucleated cellular infiltration, nitrate/nitrite, total protein, albumin concentrations, TNF-α in the bronchoalveolar lavage fluid and myeloperoxidase activity in lung homogenate. Embelin markedly prevented pO2 down-regulation and pCO2 augmentation. Additionally, it attenuated lung histopathological changes in acute respiratory distress syndrome model. CONCLUSION The study demonstrates the effectiveness of Embelia ribes Burm. f. (Fam. Myrsinaceae) seeds in acute respiratory distress syndrome possibly related to its anti-inflammatory and protective effect against LPS induced airway inflammation by reducing nitrosative stress, reducing physiological parameters of blood gas change, TNF-α and mononucleated cellular infiltration indicating it as a potential therapeutic agent for acute respiratory distress syndrome.
Collapse
Affiliation(s)
- R L Shirole
- Department of Pharmacology, A. R. A. College of Pharmacy, Dhule, Maharashtra, India.
| | - N L Shirole
- Department of Pharmaceutical Chemistry, A. R. A. College of Pharmacy, Dhule, Maharashtra, India
| | - M N Saraf
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, Maharashtra, India
| |
Collapse
|
|
38
|
Hasnat MA, Pervin M, Cha KM, Kim SK, Lim BO. Anti-inflammatory activity on mice of extract of Ganoderma lucidum grown on rice via modulation of MAPK and NF-κB pathways. PHYTOCHEMISTRY 2015; 114:125-136. [PMID: 25457483 DOI: 10.1016/j.phytochem.2014.10.019] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 08/19/2014] [Accepted: 08/21/2014] [Indexed: 06/04/2023]
Abstract
Ganoderma lucidum is a popular medicinal mushroom with anti-inflammatory potential. In the present study, the aim was to determine the anti-inflammatory effect and mode of action of G. lucidum grown on germinated brown rice (GLBR) in a mouse model of colitis. It was shown that GLBR suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated macrophages and decreased the expression of COX-2, TNF-α, iNOS, IL-1β, IL-6, and IL-10 mRNAs. GLBR also inhibited activation of p38, ERK, JNK, MAPKs, and nuclear factor kappa-B (NF-κB). In a mouse model of colitis, colonic mucosal injury was evaluated using macroscopic, biochemical, and histopathological testing. Disease activity index (DAI), macroscopic score, and histological score significantly decreased upon GLBR treatment. Moreover, immunofluorescence studies indicated that DSS activates nuclear translocation of NF-κB in colon tissue, which is attenuated by GLBR extract. These findings suggest that GLBR is protective against colitis via inhibition of MAPK phosphorylation and NF-κB activation.
Collapse
Affiliation(s)
- Md Abul Hasnat
- Department of Applied Biochemistry, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - Mehnaz Pervin
- Department of Applied Biochemistry, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - Kyu Min Cha
- Department of Applied Biochemistry, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - Si Kwan Kim
- Department of Applied Biochemistry, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - Beong Ou Lim
- Department of Applied Biochemistry, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea.
| |
Collapse
|
|
39
|
Embelin lipid nanospheres for enhanced treatment of ulcerative colitis - Preparation, characterization and in vivo evaluation. Eur J Pharm Sci 2015; 76:73-82. [PMID: 25957524 DOI: 10.1016/j.ejps.2015.05.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 04/11/2015] [Accepted: 05/05/2015] [Indexed: 12/21/2022]
Abstract
Aim of the present study is to develop embelin lipid nanospheres (LNE) for better treatment of ulcerative colitis. Embelin LNs were developed using soya bean oil/virgin coconut oil as liquid lipid carrier and soya/egg lecithin as stabilizer by hot homogenization followed by ultrasonication technique. The particle size of LNEs ranged from 196.1±3.57 to 269.2±1.05nm with narrow polydispersity index values whereas zeta potential was from -36.6 to -62.0mV. Embelin was successfully incorporated into lipid nanospheres with entrapment efficiency about 99%. There was no interaction between embelin and selected liquid lipids which was confirmed by FTIR studies. In vitro drug release studies performed using Franz diffusion cell and results showed sustained release of embelin. Embelin LNs were stabilized with egg and soya lecithin, embelin release from these LNs followed Higuchi model and first order model, respectively, however mechanism of drug release in both LNs was non-Fickian. In vivo studies were carried out using acetic acid induced ulcerative colitis rat model and results revealed that treatment with embelin LNs significantly reduced clinical activity and macroscopic scores compared to embelin conventional suspension. Treatment with embelin LNs decreased MPO, LDH and LPO levels, increased reduced GSH levels which indicated better treatment of ulcerative colitis was achieved. This was also confirmed by improved histopathological conditions. Thus embelin LNs could be favourably used for treatment of ulcerative colitis.
Collapse
|
|
40
|
Allicin Alleviates Dextran Sodium Sulfate- (DSS-) Induced Ulcerative Colitis in BALB/c Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:605208. [PMID: 26075036 PMCID: PMC4436474 DOI: 10.1155/2015/605208] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 04/23/2015] [Indexed: 12/20/2022]
Abstract
The objective of this study is to evaluate the effect of allicin (10 mg/kg body weight, orally) in an experimental murine model of UC by administering 2.5% dextran sodium sulfate (DSS) in drinking water to BALB/c mice. DSS-induced mice presented reduced body weight, which was improved by allicin administration. We noted increases in CD68 expression, myeloperoxidase (MPO) activities, and Malonaldehyde (MDA) and mRNA levels of proinflammatory cytokines, such as tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-17, and decrease in the activities of enzymic antioxidants such as superoxide dismutase (SOD), Catalase (CAT), Glutathione reductase (GR), and Glutathione peroxidase (GPx) in DSS-induced mice. However, allicin treatment significantly decreased CD68, MPO, MDA, and proinflammatory cytokines and increased the enzymic antioxidants significantly (P < 0.05). In addition, allicin was capable of reducing the activation and nuclear accumulation of signal transducer and activator of transcription 3 (STAT3), thereby preventing degradation of the inhibitory protein IκB and inducing inhibition of the nuclear translocation of nuclear factor (NF)-κB-p65 in the colonic mucosa. These findings suggest that allicin exerts clinically useful anti-inflammatory effects mediated through the suppression of the NF-κB and IL-6/p-STAT3Y705 pathways.
Collapse
|
|
41
|
Zhao ZG, Tang ZZ, Zhang WK, Li JG. Protective effects of embelin on myocardial ischemia-reperfusion injury following cardiac arrest in a rabbit model. Inflammation 2015; 38:527-33. [PMID: 24962644 DOI: 10.1007/s10753-014-9959-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Embelin has been used to treat fever and inflammatory diseases for thousands of years. Although reports indicate that embelin has antiinflammatory effects, its effects on myocardial injury following cardiac arrest (CA) have not been previously explored. In this study, we aim to investigate the protective effects of embelin on myocardial ischemia-reperfusion injury (IRI) following CA in a rabbit model. Pro-inflammatory (TNF-α, IL-1β, and IL-6) cytokines, cardiac troponin I (cTnI), necrosis ratio, apoptotic index (AI), hemodynamics, nuclear factor-kappa B (NF-κB) p65, and histological damage have been measured or evaluated. Embelin reverts TNF-α, IL-1β, and IL-6 to basal levels and reduces the serum level of cTnI, the necrosis ratio, the AI, and the expression of NF-κB p65. Meanwhile, it improves the hemodynamics and myocardial function. Moreover, embelin-treated groups also showed improved myocardial morphology. Our results indicate that embelin may protect the heart against myocardial IRI following CA via its antiinflammatory abilities.
Collapse
Affiliation(s)
- Zhi-Gang Zhao
- Intensive Care Unit, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | | | | | | |
Collapse
|
|
42
|
Um MY, Park JH, Gwon SY, Ahn J, Jung CH, Ha TY. Agaricus bisporusAttenuates Dextran Sulfate Sodium-Induced Colitis. J Med Food 2014; 17:1383-5. [DOI: 10.1089/jmf.2014.3191] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Min Young Um
- Metabolism and Nutrition Research Group, Korea Food Research Institute, Seongnam, South Korea
| | - Jae Ho Park
- Metabolism and Nutrition Research Group, Korea Food Research Institute, Seongnam, South Korea
| | - So Young Gwon
- Metabolism and Nutrition Research Group, Korea Food Research Institute, Seongnam, South Korea
| | - Jiyun Ahn
- Metabolism and Nutrition Research Group, Korea Food Research Institute, Seongnam, South Korea
| | - Chang Hwa Jung
- Metabolism and Nutrition Research Group, Korea Food Research Institute, Seongnam, South Korea
| | - Tae Youl Ha
- Metabolism and Nutrition Research Group, Korea Food Research Institute, Seongnam, South Korea
| |
Collapse
|
|
43
|
Randhawa PK, Singh K, Singh N, Jaggi AS. A review on chemical-induced inflammatory bowel disease models in rodents. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2014; 18:279-88. [PMID: 25177159 PMCID: PMC4146629 DOI: 10.4196/kjpp.2014.18.4.279] [Citation(s) in RCA: 325] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 06/09/2014] [Accepted: 06/14/2014] [Indexed: 12/14/2022]
Abstract
Ulcerative colitis and Crohn's disease are a set of chronic, idiopathic, immunological and relapsing inflammatory disorders of the gastrointestinal tract referred to as inflammatory bowel disorder (IBD). Although the etiological factors involved in the perpetuation of IBD remain uncertain, development of various animal models provides new insights to unveil the onset and the progression of IBD. Various chemical-induced colitis models are widely used on laboratory scale. Furthermore, these models closely mimic morphological, histopathological and symptomatical features of human IBD. Among the chemical-induced colitis models, trinitrobenzene sulfonic acid (TNBS)-induced colitis, oxazolone induced-colitis and dextran sulphate sodium (DSS)-induced colitis models are most widely used. TNBS elicits Th-1 driven immune response, whereas oxazolone predominantly exhibits immune response of Th-2 phenotype. DSS-induced colitis model also induces changes in Th-1/Th-2 cytokine profile. The present review discusses the methodology and rationale of using various chemical-induced colitis models for evaluating the pathogenesis of IBD.
Collapse
Affiliation(s)
- Puneet Kaur Randhawa
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India
| | - Kavinder Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India
| | - Nirmal Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India
| | - Amteshwar Singh Jaggi
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India
| |
Collapse
|
|
44
|
Sahu BD, Anubolu H, Koneru M, Kumar JM, Kuncha M, Rachamalla SS, Sistla R. Cardioprotective effect of embelin on isoproterenol-induced myocardial injury in rats: possible involvement of mitochondrial dysfunction and apoptosis. Life Sci 2014; 107:59-67. [PMID: 24816332 DOI: 10.1016/j.lfs.2014.04.035] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 04/23/2014] [Accepted: 04/25/2014] [Indexed: 11/15/2022]
Abstract
AIMS Preventive and/or therapeutic interventions using natural products for ischemic heart disease have gained considerable attention worldwide. This study investigated the cardioprotective effect and possible mechanism of embelin, a major constituent of Embelia ribes Burm, using isoproterenol (ISO)-induced myocardial infarction model in rats. MATERIALS AND METHODS Rats were pretreated for three days with embelin (50mg/kg, p.o) before inducing myocardial injury by administration of ISO (85 mg/kg) subcutaneously at an interval of 24h for 2 consecutive days. Serum was analyzed for cardiac specific injury biomarkers, lipids and lipoprotein content. Heart tissues were isolated and were used for histopathology, antioxidant and mitochondrial respiratory enzyme activity assays and western blot analysis. KEY FINDINGS Results showed that pretreatment with embelin significantly decreased the elevated levels of serum specific cardiac injury biomarkers (CK-MB, LDH and AST), serum levels of lipids and lipoproteins and histopathological changes when compared to ISO-induced controls. Exploration of the underlying mechanisms of embelin action revealed that embelin pretreatment restored the myocardial mitochondrial respiratory enzyme activities (NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity), strengthened antioxidant status and attenuated ISO-induced myocardial lipid peroxidation. Immunoblot analysis revealed that embelin interrupted mitochondria dependent apoptotic damage by increasing the myocardial expression of Bcl-2 and downregulating the expression of Bax, cytochrome c, cleaved-caspase-3 & 9 and PARP. Histopathology findings further strengthened the cardioprotective findings of embelin. SIGNIFICANCE Result suggested that embelin may have a potential benefit in preventing ischemic heart disease like myocardial infarction.
Collapse
Affiliation(s)
- Bidya Dhar Sahu
- Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India
| | - Harika Anubolu
- Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India
| | - Meghana Koneru
- Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India
| | - Jerald Mahesh Kumar
- CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500 007, India
| | - Madhusudana Kuncha
- Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India
| | | | - Ramakrishna Sistla
- Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India.
| |
Collapse
|
|
45
|
Dai Y, Jiao H, Teng G, Wang W, Zhang R, Wang Y, Hebbard L, George J, Qiao L. Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling. Mol Cancer Ther 2014; 13:1206-16. [PMID: 24651526 DOI: 10.1158/1535-7163.mct-13-0378] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Yun Dai
- Authors' Affiliations: Departments of Gastroenterology, Gerontology, and Pathology, Peking University First Hospital, Beijing; Research Center of Basic Medical Sciences and Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China; and Storr Liver Unit, Westmead Millennium Institute, the University of Sydney at the Westmead Hospital, Westmead, New South Wales, Australia
| | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Koehler BC, Jäger D, Schulze-Bergkamen H. Targeting cell death signaling in colorectal cancer: Current strategies and future perspectives. World J Gastroenterol 2014; 20:1923-1934. [PMID: 24587670 PMCID: PMC3934462 DOI: 10.3748/wjg.v20.i8.1923] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 12/06/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive cancer treatment finally aims to induce cell death. However, apoptosis resistance is the major cause for insufficient therapeutic success and disease relapse in gastrointestinal oncology. Various compounds have been developed and evaluated with the aim to meet with this obstacle by triggering cell death in cancer cells. The aim of this review is to illustrate current approaches and future directions in targeting cell death signaling in colorectal cancer. The complex signaling network of apoptosis will be demonstrated and the “druggability” of targets will be identified. In detail, proteins regulating mitochondrial cell death in colorectal cancer, such as Bcl-2 and survivin, will be discussed with respect to potential therapeutic exploitation. Death receptor signaling and targeting in colorectal cancer will be outlined. Encouraging clinical trials including cell death based targeted therapies for colorectal cancer are under way and will be demonstrated. Our conceptual understanding of cell death in cancer is rapidly emerging and new types of controlled cellular death have been identified. To meet this progress in cell death research, the implication of autophagy and necroptosis for colorectal carcinogenesis and therapeutic approaches will also be depicted. The main focus of this topic highlight will be on the revelation of the complex cell death concepts in colorectal cancer and the bridging from basic research to clinical use.
Collapse
|
|
47
|
Abstract
Clinical application of anticancer drugs is limited by problems such as low water solubility, lack of tissue-specificity and toxicity. Formulation development represents an important approach to these problems. Among the many delivery systems studied, polymeric micelles have gained considerable attention owing to ease in preparation, small sizes (10-100 nm), and ability to solubilize water-insoluble anticancer drugs and accumulate specifically at the tumors. This article provides a brief review of several promising micellar systems and their applications in tumor therapy. The emphasis is placed on the discussion of the authors' recent work on several nanomicellar systems that have both a delivery function and antitumor activity, named dual-function drug carriers.
Collapse
|
|
48
|
Poojari R. Embelin – a drug of antiquity: shifting the paradigm towards modern medicine. Expert Opin Investig Drugs 2014; 23:427-44. [DOI: 10.1517/13543784.2014.867016] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
|
|
49
|
Toumi R, Abdelouhab K, Rafa H, Soufli I, Raissi-Kerboua D, Djeraba Z, Touil-Boukoffa C. Beneficial role of the probiotic mixture Ultrabiotique on maintaining the integrity of intestinal mucosal barrier in DSS-induced experimental colitis. Immunopharmacol Immunotoxicol 2013; 35:403-9. [PMID: 23638770 DOI: 10.3109/08923973.2013.790413] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The etiology of inflammatory bowel diseases which include ulcerative colitis (UC) and Crohn disease has not yet been clarified. Several hypotheses suggest a change in composition of gut microflora along with an impaired mucosal barrier that lead to excessive mucosal immunologic responses. Increased production of nitric oxide (NO) contributes greatly to the tissue injury caused by chronic inflammation. Evidence indicates that the mucus layer covering the epithelium is altered during UC and experimental colitis. Our aim in this study was to investigate the potential therapeutic effect of probiotic during DSS-induced colitis by modulating the immune system and colonic mucus production. For that purpose, the probiotic formulation Ultrabiotique(®) (Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus plantarum and Bifidobacterium breve) was administered daily for 7 d to mice with colitis. Probiotic supplementation improved clinical symptoms and histological alterations observed during DSS induced colitis. Ultrabiotique(®) treatment down regulated the NO production by peritoneal macrophages of DSS-treated mice and enhanced mucus production in both DSS-treated and healthy mice. In conclusion, the modification of microflora by the Ultrabiotique(®) played a beneficial role in maintaining the integrity of the intestinal mucosal barrier and promoted tissue repair.
Collapse
Affiliation(s)
- Ryma Toumi
- USTHB (University of Sciences and Technology), Laboratory of Cellular and Molecular Biology (LBCM), Cytokines and NO Synthases Team, Faculty of Biological Science, Algiers, Algeria
| | | | | | | | | | | | | |
Collapse
|
|
50
|
Schaible AM, Traber H, Temml V, Noha SM, Filosa R, Peduto A, Weinigel C, Barz D, Schuster D, Werz O. Potent inhibition of human 5-lipoxygenase and microsomal prostaglandin E₂ synthase-1 by the anti-carcinogenic and anti-inflammatory agent embelin. Biochem Pharmacol 2013; 86:476-86. [PMID: 23623753 DOI: 10.1016/j.bcp.2013.04.015] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2013] [Revised: 04/12/2013] [Accepted: 04/15/2013] [Indexed: 11/30/2022]
Abstract
Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) possesses anti-inflammatory and anti-carcinogenic properties in vivo, and these features have been related to interference with multiple targets including XIAPs, NFκB, STAT-3, Akt and mTOR. However, interference with these proteins requires relatively high concentrations of embelin (IC₅₀>4 μM) and cannot fully explain its bioactivity observed in several functional studies. Here we reveal human 5-lipoxygenase (5-LO) and microsomal prostaglandin E₂ synthase (mPGES)-1 as direct molecular targets of embelin. Thus, embelin potently suppressed the biosynthesis of eicosanoids by selective inhibition of 5-LO and mPGES-1 with IC₅₀=0.06 and 0.2 μM, respectively. In intact human polymorphonuclear leukocytes and monocytes, embelin consistently blocked the biosynthesis of various 5-LO products regardless of the stimulus (fMLP or A23187) with IC₅₀=0.8-2 μM. Neither the related human 12- and 15-LO nor the cyclooxygenases-1 and -2 or cytosolic phospholipase A₂ were significantly affected by 10 μM embelin. Inhibition of 5-LO and mPGES-1 by embelin was (I) essentially reversible after wash-out, (II) not impaired at higher substrate concentrations, (III) unaffected by inclusion of Triton X-100, and (IV) did not correlate to its proposed antioxidant properties. Docking simulations suggest concrete binding poses in the active sites of both 5-LO and mPGES-1. Because 5-LO- and mPGES-1-derived eicosanoids play roles in inflammation and cancer, the interference of embelin with these enzymes may contribute to its biological effects and suggests embelin as novel chemotype for development of dual 5-LO/mPGES-1 inhibitors.
Collapse
Affiliation(s)
- Anja M Schaible
- Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany
| | | | | | | | | | | | | | | | | | | |
Collapse
|