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Hawker P, Zhang L, Liu L. Mas-related G protein-coupled receptors in gastrointestinal dysfunction and inflammatory bowel disease: A review. Br J Pharmacol 2024; 181:2197-2211. [PMID: 36787888 DOI: 10.1111/bph.16059] [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: 09/22/2022] [Revised: 12/25/2022] [Accepted: 02/04/2023] [Indexed: 02/16/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic debilitating condition, hallmarked by persistent inflammation of the gastrointestinal tract. Despite recent advances in clinical treatments, the aetiology of IBD is unknown, and a large proportion of patients are refractory to pharmacotherapy. Understanding IBD immunopathogenesis is crucial to discern the cause of IBD and optimise treatments. Mas-related G protein-coupled receptors (Mrgprs) are a family of approximately 50 G protein-coupled receptors that were first identified over 20 years ago. Originally known for their expression in skin nociceptors and their role in transmitting the sensation of itch in the periphery, new reports have described the presence of Mrgprs in the gastrointestinal tract. In this review, we consider the impact of these findings and assess the evidence that suggests that Mrgprs may be involved in the disrupted homeostatic processes that contribute to gastrointestinal disorders and IBD. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.
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Affiliation(s)
- Patrick Hawker
- School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Li Zhang
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Lu Liu
- School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
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Küpeli Akkol E, Subaş T, Özgen U, Süntar I, Ilhan M, Keleş H. Effects of Naphthoquinones from the Roots of Onosma Armeniacum Klokov on Wound Healing. Chem Biodivers 2024; 21:e202301946. [PMID: 38433095 DOI: 10.1002/cbdv.202301946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 03/01/2024] [Accepted: 03/01/2024] [Indexed: 03/05/2024]
Abstract
In Turkish folk medicine, the roots of Onosma armeniacum Klokov are used to heal wounds, burns, hemorrhoids, hoarseness, dyspnea, stomach ulcers, and abdominal aches. The objective was to evaluate the plant's ethnopharmacological applications using in vivo pharmacological experimental models. In vivo linear incision and circular excision the wound models were used to assess the wound healing activity along with histopathological investigation. The active component(s) were isolated and identified after being exposed to several chromatographic separation procedures on the primary extract. The n-hexane-dichloromethane mixture extract was subjected to chromatographic separation after the wound-healing activity was confirmed. Deoxyshikonin (1), β,β-dimethylacrylshikonin (2), α-methyl-n-butylshikonin (3), isovalerylshikonin (4), acetylshikonin (5), β-hydroxyisovalerylshikonin (6), and 5,8-O-dimethylacetylshikonin (7) were identified as the structures of the isolated compounds. The efficacy of O. armeniacum to heal wounds was investigated in this study. Shikonin derivatives were identified as the primary active components of the roots by bioassay-guided fractionation and isolation procedures.
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Affiliation(s)
- Esra Küpeli Akkol
- Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, 06330, Türkiye
| | - Tuğba Subaş
- Department of Pharmacognosy, Faculty of Pharmacy, Karadeniz Technical University, 61080, Trabzon, Türkiye
| | - Ufuk Özgen
- Department of Pharmacognosy, Faculty of Pharmacy, Karadeniz Technical University, 61080, Trabzon, Türkiye
| | - Ipek Süntar
- Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, 06330, Türkiye
| | - Mert Ilhan
- Department of Pharmacognosy, Faculty of Pharmacy, Düzce University, Düzce, 81620, Türkiye
| | - Hikmet Keleş
- Department of Pathology, Faculty of Veterinary Medicine, Afyon Kocatepe University, 03200, Afyonkarahisar, Türkiye
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Xue C, Dou J, Zhang S, Yu H, Zhang S. Shikonin potentiates skin wound healing in Sprague-Dawley rats by stimulating fibroblast and endothelial cell proliferation and angiogenesis. J Gene Med 2024; 26:e3633. [PMID: 38017625 DOI: 10.1002/jgm.3633] [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: 05/11/2023] [Revised: 09/27/2023] [Accepted: 10/28/2023] [Indexed: 11/30/2023] Open
Abstract
BACKGROUND Shikonin, a major component of Lithospermum erythrorhizon, exerts anti-inflammatory and antibacterial effects and expedites wound healing. This study aims to evaluate the anti-inflammatory and antioxidant activities of shikonin in a Sprague-Dawley rat model and cell models using fibroblast and endothelial cells. METHODS The impact of shikonin on the activity of endothelial cells and fibroblasts was examined by cell counting kit 8 and wound-healing assays. A diabetic rat model was constructed, followed by wound creation for treatment with shikonin. Hematoxylin-eosin staining was used to assess pathological changes, and Masson's trichrome method to detect collagen deposition. Immunohistochemistry using antibodies against proliferating cell nuclear antigen and CD31 was conducted to detect proliferation and vascular density. Enzyme-linked immunosorbent assay and immunohistochemistry were carried out to assess pro-inflammatory and anti-inflammatory factor concentrations. Western blot and immunofluorescence were implemented to analyze oxidative stress-related protein expression. RESULTS Shikonin induced the activity of both fibroblasts and endothelial cells. Shikonin treatment contributed to facilitated wound healing and higher healing rates in rats. It also resulted in faster lesion debulking in tissues, reduced inflammatory infiltration, increased collagen deposition, and enhanced angiogenesis. Detection of markers at the wounds showed that shikonin accelerated cell proliferation, enhanced tissue remodeling, and inhibited oxidative stress. CONCLUSION Shikonin stimulates the proliferation and migration of fibroblasts and endothelial cells to promote angiogenesis and tissue remodeling, resulting in faster wound healing.
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Affiliation(s)
- Chenhong Xue
- Department of Dermatology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
| | - Jinfa Dou
- Department of Dermatology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
| | - Shuzhen Zhang
- Department of Dermatology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
| | - Huiqian Yu
- Department of Dermatology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
| | - Shoumin Zhang
- Department of Dermatology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
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Han JH, Lee EJ, Park W, Ha KT, Chung HS. Natural compounds as lactate dehydrogenase inhibitors: potential therapeutics for lactate dehydrogenase inhibitors-related diseases. Front Pharmacol 2023; 14:1275000. [PMID: 37915411 PMCID: PMC10616500 DOI: 10.3389/fphar.2023.1275000] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 09/27/2023] [Indexed: 11/03/2023] Open
Abstract
Lactate dehydrogenase (LDH) is a crucial enzyme involved in energy metabolism and present in various cells throughout the body. Its diverse physiological functions encompass glycolysis, and its abnormal activity is associated with numerous diseases. Targeting LDH has emerged as a vital approach in drug discovery, leading to the identification of LDH inhibitors among natural compounds, such as polyphenols, alkaloids, and terpenoids. These compounds demonstrate therapeutic potential against LDH-related diseases, including anti-cancer effects. However, challenges concerning limited bioavailability, poor solubility, and potential toxicity must be addressed. Combining natural compounds with LDH inhibitors has led to promising outcomes in preclinical studies. This review highlights the promise of natural compounds as LDH inhibitors for treating cancer, cardiovascular, and neurodegenerative diseases.
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Affiliation(s)
- Jung Ho Han
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu, Republic of Korea
| | - Eun-Ji Lee
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu, Republic of Korea
| | - Wonyoung Park
- Korean Convergence Medical Science Major, KIOM Campus, University of Science and Technology (UST), Daegu, Republic of Korea
| | - Ki-Tae Ha
- Korean Convergence Medical Science Major, KIOM Campus, University of Science and Technology (UST), Daegu, Republic of Korea
| | - Hwan-Suck Chung
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu, Republic of Korea
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Republic of Korea
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Guo Y, Zhou M, Mu Z, Guo J, Hou Y, Xu Y, Geng L. Recent advances in shikonin for the treatment of immune-related diseases: Anti-inflammatory and immunomodulatory mechanisms. Biomed Pharmacother 2023; 165:115138. [PMID: 37454591 DOI: 10.1016/j.biopha.2023.115138] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/03/2023] [Accepted: 07/07/2023] [Indexed: 07/18/2023] Open
Abstract
Shikonin, the primary active compound found in the rhizome of the traditional Chinese medicinal herb known as "ZiCao", exhibits a diverse range of pharmacological effects. This drug has a wide range of uses, including as an anti-inflammatory, antioxidant, and anti-cancer agent. It is also effective in promoting wound healing and treating autoimmune diseases such as multiple sclerosis, diabetes, asthma, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. Although shikonin has a wide range of applications, its mechanisms are still not fully understood. This review article provides a comprehensive overview of the recent advancements in the use of shikonin for the treatment of immune-related diseases. The article also delves into the anti-inflammatory and immunoregulatory mechanisms of shikonin and offers insights into the inflammation and immunopathogenesis of related diseases. Overall, this article serves as a valuable resource for researchers and clinicians working in this field. These findings not only provide significant new information on the effects and mechanisms of shikonin but also establish a foundation for the development of clinical applications in treating autoimmune diseases.
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Affiliation(s)
- Yimeng Guo
- Department of Dermatology, The First Hospital of China Medical University, 155N Nanjing Street, Heping District, Shenyang, Liaoning 110000, China; National joint Engineering Research Center for Theranostics of Immunological Skin Diseases, Shenyang, China; Key Laboratory of Immunodermatology, Ministry of Education and NHC, Shenyang, China
| | - Mingming Zhou
- Department of Dermatology, The First Hospital of China Medical University, 155N Nanjing Street, Heping District, Shenyang, Liaoning 110000, China; National joint Engineering Research Center for Theranostics of Immunological Skin Diseases, Shenyang, China; Key Laboratory of Immunodermatology, Ministry of Education and NHC, Shenyang, China
| | - Zhenzhen Mu
- Department of Dermatology, Shengjing Hospital of China Medical University, 155N Nanjing Street, Heping District, Shenyang, Liaoning 110000, China
| | - Jinrong Guo
- Department of Dermatology, Jincheng People's Hospital, 456N Wenchang East Street, Jincheng, Shanxi 048000, China
| | - Yuzhu Hou
- Department of Dermatology, The First Hospital of China Medical University, 155N Nanjing Street, Heping District, Shenyang, Liaoning 110000, China; National joint Engineering Research Center for Theranostics of Immunological Skin Diseases, Shenyang, China; Key Laboratory of Immunodermatology, Ministry of Education and NHC, Shenyang, China
| | - Yuanyuan Xu
- Department of Dermatology, The First Hospital of China Medical University, 155N Nanjing Street, Heping District, Shenyang, Liaoning 110000, China; National joint Engineering Research Center for Theranostics of Immunological Skin Diseases, Shenyang, China; Key Laboratory of Immunodermatology, Ministry of Education and NHC, Shenyang, China
| | - Long Geng
- Department of Dermatology, The First Hospital of China Medical University, 155N Nanjing Street, Heping District, Shenyang, Liaoning 110000, China; National joint Engineering Research Center for Theranostics of Immunological Skin Diseases, Shenyang, China; Key Laboratory of Immunodermatology, Ministry of Education and NHC, Shenyang, China.
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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.
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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,
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7
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Khan A, Khan A, Shal B, Aziz A, Ahmad S, Amin MU, Ahmed MN, Zia-Ur-Rehman, Khan S. Ameliorative effect of two structurally divergent hydrazide derivatives against DSS-induced colitis by targeting Nrf2 and NF-κB signaling in mice. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:1167-1188. [PMID: 35851927 DOI: 10.1007/s00210-022-02272-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 07/08/2022] [Indexed: 11/27/2022]
Abstract
The environmental factors and genetic vulnerability trigger the inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease. Furthermore, the oxidative stress and inflammatory cytokines have been implicated in the aggravation of the IBDs. The aim of the present study was to investigate the effect of N-(benzylidene)-2-((2-hydroxynaphthalen-1-yl)diazenyl)benzohydrazides (NCHDH and NTHDH) compounds against the DSS-induced colitis in mice. The colitis was induced by 5% dextran sulfate sodium (DSS) dissolved in normal saline for 5 days. The effect of the NCHDH and NTHDH on the behavioral, biochemical, histological, and immunohistological parameters was assessed. The NCHDH and NTHDH treatment improved the behavioral parameters such as food intake, disease activity index, and diarrhea score significantly compared to DSS control. The NCHDH and NTHDH treatments significantly increased the antioxidant enzymes, whereas oxidative stress markers were markedly reduced. Similarly, the NCHDH and NTHDH treatments significantly suppressed the activity of nitric oxide (NO), myeloperoxidase (MPO), and eosinophil peroxidase (EPO). The histological studies showed a significant reduction in inflammation, immune cell infiltration, and fibrosis in the NCHDH- and NTHDH-treated groups. The immunohistochemical results demonstrated that NCHDH and NTHDH treatments markedly increase the expression level of Nrf2, HO-1 (hemeoxygenase-1), TRX (thioredoxin reductase), and IκB compared to the DSS-induced group. In the same way, the NCHDH and NTHDH significantly reduced the NF-κB and COX-2 (cyclooxygenase-2) expression levels. The NCHDH and NTHDH treatment significantly improved the symptoms associated with colitis via inducing antioxidants and attenuating oxidative stress markers.
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Affiliation(s)
- Ashrafullah Khan
- Pharmacological Sciences Research Laboratory, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan
- Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar, 25000, KPK, Pakistan
| | - Adnan Khan
- Pharmacological Sciences Research Laboratory, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Bushra Shal
- Pharmacological Sciences Research Laboratory, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Abdul Aziz
- Department of Chemistry, The University of Azad Jammu and Kashmir, Muzaffarabad, 13100, Pakistan
| | - Sajjad Ahmad
- Department of Health and Biological Sciences, Abasyn University, Peshawar, 25000, Pakistan
| | - Muhammad Usman Amin
- Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar, 25000, KPK, Pakistan
| | - Muhammad Naeem Ahmed
- Department of Chemistry, The University of Azad Jammu and Kashmir, Muzaffarabad, 13100, Pakistan
| | - Zia-Ur-Rehman
- Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan
| | - Salman Khan
- Pharmacological Sciences Research Laboratory, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan.
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Feng J, Wang Y, Lv Y, Fang S, Ren M, Yao M, Lan M, Zhao Y, Gao F. XA pH-Responsive and Colitis-Targeted Nanoparticle Loaded with Shikonin for the Oral Treatment of Inflammatory Bowel Disease in Mice. Mol Pharm 2022; 19:4157-4170. [DOI: 10.1021/acs.molpharmaceut.2c00550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Juewen Feng
- Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
- Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai, 200237, China
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Yanbing Wang
- Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Yingni Lv
- Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Siqi Fang
- Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Mengjiao Ren
- Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | | | - Minbo Lan
- Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai, 200237, China
| | - Yuzheng Zhao
- Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
- Optogenetics and Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
- CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Feng Gao
- Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
- Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai, 200237, China
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
- Optogenetics and Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
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Huang B, Wang Q, Jiang L, Lu S, Li C, Xu C, Wang C, Zhang E, Zhang X. Shikonin ameliorated mice colitis by inhibiting dimerization and tetramerization of PKM2 in macrophages. Front Pharmacol 2022; 13:926945. [PMID: 36059938 PMCID: PMC9428403 DOI: 10.3389/fphar.2022.926945] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 07/06/2022] [Indexed: 01/10/2023] Open
Abstract
Dysregulated immune response plays a pivotal role in Ulcerative colitis. In lamina propria of inflammatory colonic mucosa, macrophages tend to polarize into M1 type and metabolically reprogram to aerobic glycolysis. PKM2 orchestrates glucose metabolic switch in macrophages, which tetramer has high pyruvate kinase activity, while which dimer mainly works as a protein kinase to stabilize HIF-1α and mediate anabolism. Shikonin is a potent PKM2 inhibitor derived from traditional Chinese medicine Arnebiae Radix with anti-inflammatory and anticarcinogen activities. However, it is unclear which conformation of PKM2 is inhibited by Shikonin, and whether this inhibition mediates pharmacological effect of Shikonin. In this study, we examined the efficacy of Shikonin on dextran sulfate sodium-induced mice colitis and determined the states of PKM2 aggregation after Shikonin treatment. Results showed that Shikonin dose-dependently alleviated mice colitis, down-regulated expression of F4/80, iNOS and CD86, decreased IFN-γ, IL-1β, IL-6 and TNF-α, while increased IL-10 in mice colon. Furthermore, Shikonin suppressed the pyruvate, lactate production and glucose consumption, inhibited the pyruvate kinase activity and nuclear translocation of PKM2, and decreased both dimerization and tetramerization of PKM2 in macrophages. In vitro assay revealed that Shikonin bounded to PKM2 protein, inhibited the formation of both dimer and tetramer, while promoted aggregation of PKM2 macromolecular polymer. TEPP-46, an activator of PKM2 tetramerization, attenuated the ameliorative effect of Shikonin on disuccinimidyl suberate mice. In summary, Shikonin improved mice colitis, which mechanism may be mediated by inhibiting dimerization and tetramerization of PKM2, suppressing aerobic glycolysis reprogram, improving mitochondrial dynamic, and therefore alleviating inflammatory response of macrophages.
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Affiliation(s)
- Baoyuan Huang
- School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qiumei Wang
- School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lin Jiang
- International Institute of Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shuru Lu
- School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chengcheng Li
- School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chunqi Xu
- School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Caiyan Wang
- International Institute of Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Caiyan Wang, ; Enxin Zhang, ; Xiaojun Zhang,
| | - Enxin Zhang
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
- *Correspondence: Caiyan Wang, ; Enxin Zhang, ; Xiaojun Zhang,
| | - Xiaojun Zhang
- School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Caiyan Wang, ; Enxin Zhang, ; Xiaojun Zhang,
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10
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Yan BF, Chen X, Chen YF, Liu SJ, Xu CX, Chen L, Wang WB, Wen TT, Zheng X, Liu J. Aqueous extract of Paeoniae Radix Alba (Paeonia lactiflora Pall.) ameliorates DSS-induced colitis in mice by tunning the intestinal physical barrier, immune responses, and microbiota. JOURNAL OF ETHNOPHARMACOLOGY 2022; 294:115365. [PMID: 35597411 DOI: 10.1016/j.jep.2022.115365] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/05/2022] [Accepted: 05/06/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ulcerative colitis (UC) is a chronic non-specific intestinal inflammatory disease, the pathogenesis of which is strongly associated with the compromised intestinal barrier. Paeoniae Radix Alba (PRA), the root of Paeonia lactiflora Pall., is a well-known traditional Chinese medicine and an adaptogen used in Hozai, exhibiting appreciable anti-inflammatory and immunomodulatory activity. Nevertheless, the role and mechanism of PRA in UC have yet to be elucidated. AIM OF THE STUDY This study was set out to examine the ameliorative effects of the aqueous extract of PRA (i.e., PRA dispensing granule, PRADG) on dextran sulfate sodium (DSS)-induced colitis. MATERIALS AND METHODS The chemical components of PRADG was analyzed by HPLC. Colitis model mice were induced by free access to water containing 2.5% DSS for 10 consecutive days, and concurrently, PRADG (0.1025 and 0.41 g/kg) or Salazosulfapyridine (SASP, 450 mg/kg) was given orally from day 1-10. Body weight, disease activity index (DAI), colon length, histologic scoring, and inflammatory response were assessed. Additionally, IL-23/IL-17 axis and tight junction (TJ) proteins, as well as gut microbiota were also investigated under the above-mentioned regimen. RESULTS Eight main chemical constituents of CPT were revealed with HPLC analysis. Noticeably, PRADG could effectively lower body weight loss as well as DAI scores, alleviate colon shortening, and reduce the levels of proinflammatory cytokines in mice with colitis. Further exploration found that increment of TJ proteins expression (ZO-1, occludin and claudin-1) and inhibition of IL-23/IL-17 axis-modulated inflammation were observed in PRADG-treated mice. Additionally, the diversity of gut microbiota and the relative abundance of beneficial bacteria were increased following PRADG treatment. CONCLUSIONS PRADG could be sufficient to ameliorate colitis by regulating the intestinal physical barrier, immune responses, and gut microbiota in mice. Our findings highlight that PRADG might be a prospective remedy for UC.
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Affiliation(s)
- Bao-Fei Yan
- Jiangsu Health Vocational College, Nanjing, 210023, PR China; Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae, Nanjing, 210023, PR China
| | - Xi Chen
- Jiangsu College of Nursing, Huaian, 223001, PR China
| | - Ya-Fang Chen
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, 215300, PR China
| | - Sheng-Jin Liu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae, Nanjing, 210023, PR China
| | - Chen-Xin Xu
- Jiangsu Health Vocational College, Nanjing, 210023, PR China
| | - Ling Chen
- Jiangsu Health Vocational College, Nanjing, 210023, PR China
| | - Wen-Bo Wang
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, 215300, PR China
| | - Ting-Ting Wen
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, 215300, PR China
| | - Xian Zheng
- Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, 215300, PR China.
| | - Jia Liu
- Jiangsu Health Vocational College, Nanjing, 210023, PR China.
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11
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Lin H, Ma X, Yang X, Chen Q, Wen Z, Yang M, Fu J, Yin T, Lu G, Qi J, Han H, Yang Y. Natural shikonin and acetyl-shikonin improve intestinal microbial and protein composition to alleviate colitis-associated colorectal cancer. Int Immunopharmacol 2022; 111:109097. [PMID: 35952517 DOI: 10.1016/j.intimp.2022.109097] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 06/24/2022] [Accepted: 07/24/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) and inflammatory bowel disease (IBD) are the most common diseases of human digestive system. Nowadays, the influence of the inflammatory microenvironment on tumorigenesis has become a new direction, and the exploration of relative molecular mechanism will facilitate the discovery and identification of novel potential anti-cancer molecules. METHODS Natural shikonin (SK) and acetyl-shikonin (acetyl-SK) was administered to azoxymethane (AOM)/dextran sodium sulphate (DSS)-induced colitis-associated colorectal cancer (CAC) mice model by gavage to investigate their therapeutic effects. Moreover, fresh feces and colon tissues were collected for determining the function of SK and acetyl-SK on the gut microbes and protein expression, respectively. RESULTS Both SK and acetyl-SK decreased AOM/DSS-induced CAC, and regulated the intestinal flora structure in CAC mouse model. They, especially SK, improved species richness, evenness and diversity of intestinal flora, recovered the upregulated ratio of Firmicutes to Bacteroidota (F/B ratio) which symbolizes gut microbiota dysbiosis. SK and its derivative increased the beneficial bacteria g__norank_f__Muribaculaceae, Lactobacillus, Lachnospiraceae_NK4A136_Group, and reduced those harmful ones including Ileibacterium and Coriobacteriaceae UCG-002. Notably, AOM/DSS caused significant increase in the abundance of Ileibaterium valens and g__norank_f__norank_o__Clostridia_UCG-014, which were not previously reported in studies of colonic inflammation or cancer, and the disorder was reversed by 20 mg/kg of SK. In our current study, the action of SK and acetyl-SK is dose-dependent, and 20 mg/kg SK exhibited the most effective functions, even better than the positive drug mesalazine. Moreover, differential proteomics and ELISA results showed that SK could recover the increase of pro-inflammatory cytokines (including IL-1β, IL-6 and TNF-α), the upregulation of pyruvate kinase isozyme type M2 (PKM2) and some other proteins (mainly concentrated in transcriptional mis-regulation in cancer and IL-17 signaling pathways), and the downregulation of Aldh1b1-Acc3-Maoa and Μgt2b34-Aldh1a1-Aldh1a7 involved in Wnt/β-catenin signaling pathway. CONCLUSION Our study identified SK and acetyl-SK, especially SK, as potential preventive agents for CAC through regulating both gut microbes and pathways involved in inflammation and cancer such as Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Hongyan Lin
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; School of Pharmacy, Changzhou University, Changzhou 213164, China
| | - Xiaopeng Ma
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Xiaorong Yang
- School of Biology and Geography Science, Yili Normal University, Yining 835000, China
| | - Qingqing Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Zhongling Wen
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Minkai Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Jiangyan Fu
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Tongming Yin
- Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Guihua Lu
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Jinliang Qi
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Hongwei Han
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China.
| | - Yonghua Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China.
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12
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Prakash T, Janadri S. Anti-inflammatory effect of wedelolactone on DSS induced colitis in rats: IL-6/STAT3 signaling pathway. J Ayurveda Integr Med 2022:100544. [DOI: 10.1016/j.jaim.2022.100544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 12/05/2021] [Accepted: 01/11/2022] [Indexed: 11/29/2022] Open
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13
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Shastri S, Shinde T, Woolley KL, Smith JA, Gueven N, Eri R. Short-Chain Naphthoquinone Protects Against Both Acute and Spontaneous Chronic Murine Colitis by Alleviating Inflammatory Responses. Front Pharmacol 2021; 12:709973. [PMID: 34497514 PMCID: PMC8419285 DOI: 10.3389/fphar.2021.709973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/19/2021] [Indexed: 12/12/2022] Open
Abstract
Ulcerative colitis (UC) is characterised by chronic, relapsing, idiopathic, and multifactorial colon inflammation. Recent evidence suggests that mitochondrial dysfunction plays a critical role in the onset and recurrence of this disease. Previous reports highlighted the potential of short-chain quinones (SCQs) for the treatment of mitochondrial dysfunction due to their reversible redox characteristics. We hypothesised that a recently described potent mitoprotective SCQ (UTA77) could ameliorate UC symptoms and pathology. In a dextran sodium sulphate- (DSS-) induced acute colitis model in C57BL/6J mice, UTA77 substantially improved DSS-induced body weight loss, disease activity index (DAI), colon length, and histopathology. UTA77 administration also significantly increased the expression of tight junction (TJ) proteins occludin and zona-occludin 1 (ZO-1), which preserved intestinal barrier integrity. Similar responses were observed in the spontaneous Winnie model of chronic colitis, where UTA77 significantly improved DAI, colon length, and histopathology. Furthermore, UTA77 potently suppressed elevated levels of proinflammatory cytokines and chemokines in colonic explants of both DSS-treated and Winnie mice. These results strongly suggest that UTA77 or its derivatives could be a promising novel therapeutic approach for the treatment of human UC.
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Affiliation(s)
- Sonia Shastri
- Gut Health Laboratory, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
| | - Tanvi Shinde
- Gut Health Laboratory, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia.,Centre for Food Innovation, Tasmanian Institute of Agriculture, University of Tasmania, Launceston, TAS, Australia
| | - Krystel L Woolley
- School of Natural Sciences-Chemistry, College of Science and Engineering, University of Tasmania, Hobart, TAS, Australia
| | - Jason A Smith
- School of Natural Sciences-Chemistry, College of Science and Engineering, University of Tasmania, Hobart, TAS, Australia
| | - Nuri Gueven
- School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Rajaraman Eri
- Gut Health Laboratory, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
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14
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Pu Y, Li M, Xu F, Kang Y, Li J. Determination of four kinds of hydroxynaphthoquinone ingredients in the root of Arnebia euchroma (Royle) Johnst. from different batches in Xinjiang Province by using high-performance thin-layer chromatography. JPC-J PLANAR CHROMAT 2021. [DOI: 10.1007/s00764-021-00119-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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15
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Phytochemicals Targeting JAK-STAT Pathways in Inflammatory Bowel Disease: Insights from Animal Models. Molecules 2021; 26:molecules26092824. [PMID: 34068714 PMCID: PMC8126249 DOI: 10.3390/molecules26092824] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/07/2021] [Accepted: 05/07/2021] [Indexed: 12/18/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that consists of Crohn’s disease (CD) and ulcerative colitis (UC). Cytokines are thought to be key mediators of inflammation-mediated pathological processes of IBD. These cytokines play a crucial role through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways. Several small molecules inhibiting JAK have been used in clinical trials, and one of them has been approved for IBD treatment. Many anti-inflammatory phytochemicals have been shown to have potential as new drugs for IBD treatment. This review describes the significance of the JAK–STAT pathway as a current therapeutic target for IBD and discusses the recent findings that phytochemicals can ameliorate disease symptoms by affecting the JAK–STAT pathway in vivo in IBD disease models. Thus, we suggest that phytochemicals modulating JAK–STAT pathways are potential candidates for developing new therapeutic drugs, alternative medicines, and nutraceutical agents for the treatment of IBD.
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16
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Han H, Sun W, Feng L, Wen Z, Yang M, Ma Y, Fu J, Ma X, Xu X, Wang Z, Yin T, Wang XM, Lu GH, Qi JL, Lin H, Yang Y. Differential relieving effects of shikonin and its derivatives on inflammation and mucosal barrier damage caused by ulcerative colitis. PeerJ 2021; 9:e10675. [PMID: 33505807 PMCID: PMC7797173 DOI: 10.7717/peerj.10675] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 12/09/2020] [Indexed: 12/17/2022] Open
Abstract
Background Ulcerative colitis (UC) is one of the most challenging human diseases. Natural shikonin (SK) and its derivatives (with have higher accumulation) isolated from the root of Lithospermum erythrorhizon have numerous beneficial effects, such as wound healing and anti-inflammatory activities. Some researchers have reported that hydroxynaphthoquinone mixture (HM) and SK attenuate the acute UC induced by dextran sulfate sodium (DSS). However, no existing study has systemically investigated the effectiveness of SK and other hydroxynaphthoquinone natural derivative monomers on UC. Methods In this study, mice were treated with SK and its derivatives (25 mg/kg) and mesalazine (200 mg/kg) after DSS administration daily for one week. Disease progression was monitored daily by observing the changes in clinical signs and body weight. Results Intragastric administration natural single naphthoquinone attenuated the malignant symptoms induced by DSS. SK or its derivatives remarkably suppressed the serum levels of pro-inflammatory cytokines while increasing the inflammatory cytokine interleukin (IL)-10 . Additionally, both SK and alkanin restrained the activities of cyclooxygenase-2 (COX-2), myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) in serum and colonic tissues. SK and its derivatives inhibited the activation of nucleotide binding oligomerization domain-like receptors (NLRP3) inflammasome and NF-κB signaling pathway, thereby relieving the DSS-induced disruption of epithelial tight junction (TJ) in colonic tissues. Conclusions Our findings shed more lights on the pharmacological efficacy of SK and its derivatives in UC against inflammation and mucosal barrier damage.
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Affiliation(s)
- Hongwei Han
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Wenxue Sun
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Lu Feng
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Zhongling Wen
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Minkai Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Yingying Ma
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Jiangyan Fu
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Xiaopeng Ma
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Xinhong Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Zhaoyue Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Tongming Yin
- Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Xiao-Ming Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Gui-Hua Lu
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,School of Life Sciences, Huaiyin Normal University, Huaian, China
| | - Jin-Liang Qi
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Hongyan Lin
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
| | - Yonghua Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.,Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, China
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17
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Cao ZT, Gan LQ, Jiang W, Wang JL, Zhang HB, Zhang Y, Wang Y, Yang X, Xiong M, Wang J. Protein Binding Affinity of Polymeric Nanoparticles as a Direct Indicator of Their Pharmacokinetics. ACS NANO 2020; 14:3563-3575. [PMID: 32053346 DOI: 10.1021/acsnano.9b10015] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Polymeric nanoparticles (NPs) are an important category of drug delivery systems, and their in vivo fate is closely associated with delivery efficacy. Analysis of the protein corona on the surface of NPs to understand the in vivo fate of different NPs has been shown to be reliable but complicated and time-consuming. In this work, we establish a simple approach for predicting the in vivo fate of polymeric NPs. We prepared a series of poly(ethylene glycol)-block-poly(d,l-lactide) (PEG-b-PLA) NPs with different protein binding behaviors by adjusting their PEG densities, which were determined by analyzing the serum protein adsorption. We further determined the protein binding affinity, denoted as the equilibrium association constant (KA), to correlate with in vivo fate of NPs. The in vivo fate, including blood clearance and Kupffer cell uptake, was studied, and the maximum concentration (Cmax), the area under the plasma concentration-time curve (AUC), and the mean residence time (MRT) were negatively linearly dependent, while Kupffer cell uptake was positively linearly dependent on KA. Subsequently, we verified the reliability of the approach for in vivo fate prediction using poly(methoxyethyl ethylene phosphate)-block-poly(d,l-lactide) (PEEP-b-PLA) and poly(vinylpyrrolidone)-block-poly(d,l-lactide) (PVP-b-PLA) NPs, and the linear relationship between the KA value and their PK parameters further suggests that the protein binding affinity of polymeric NPs can be a direct indicator of their pharmacokinetics.
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Affiliation(s)
- Zhi-Ting Cao
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P.R. China
| | - Li-Qin Gan
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P.R. China
| | - Wei Jiang
- Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, P.R. China
| | - Ji-Long Wang
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P.R. China
| | - Hou-Bing Zhang
- Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, P.R. China
| | - Yue Zhang
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P.R. China
| | - Yucai Wang
- Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, P.R. China
| | - Xianzhu Yang
- Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou 510006, P.R. China
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, P.R. China
| | - Menghua Xiong
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P.R. China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, P.R. China
| | - Jun Wang
- Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P.R. China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P.R. China
- Key Laboratory of Biomedical Engineering of Guangdong Province and Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P.R. China
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, P.R. China
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18
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Lu PD, Zhao YH. Targeting NF-κB pathway for treating ulcerative colitis: comprehensive regulatory characteristics of Chinese medicines. Chin Med 2020; 15:15. [PMID: 32063999 PMCID: PMC7011253 DOI: 10.1186/s13020-020-0296-z] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 01/30/2020] [Indexed: 12/15/2022] Open
Abstract
Nuclear factor-kappa B (NF-κB) is a kind of multi-functional nuclear transcription factor involved in regulating gene transcription to influence pathological evolution of inflammatory and immune diseases. Numerous literature evidence that NF-κB pathway plays an essential role in pathogenic development of ulcerative colitis (UC). UC is a chronic non-specific inflammatory bowel disease, and until now, therapeutic agents for UC including aminosalicylates, corticosteroids and immune inhibitors still cannot exert satisfied effects on patients. In recent years, Chinese medicines suggest the advantages of alleviating symptoms and signs, decreasing side-effects and recurrence, whose one of mechanisms is related to regulation of NF-κB pathway. In this review, we categorize Chinese medicines according to their traditional therapeutic functions, and summarize the characteristics of Chinese medicines targeting NF-κB pathway in UC treatment. It indicates that 85 kinds of Chinese medicines’ compounds and formulae can directly act on NF-κBp65; while 58 Chinese medicines’ ingredients and formulae indirectly suppress NF-κBp65 by regulation of its upstream or other related pathways. Moreover, by the analysis of Chinese medicines’ category based on their traditional functions, we conclude the category of dampness-drying and detoxificating medicine targeting NF-κB pathway accounts for primary status for amelioration of UC. Simultaneously, this review also contributes to the choices of Chinese medicine category and provides curative potential of Chinese medicines for clinical UC treatment.
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Affiliation(s)
- Peng-De Lu
- 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yong-Hua Zhao
- 2State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, 999078 Macao, Special Administrative Region of China
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Al‐Kishali HA, Abd El Fattah MA, Mohammad WA, El‐Abhar HS. Cilostazol against 2,4,6‐trinitrobenzene sulfonic acid‐induced colitis: Effect on tight junction, inflammation, and apoptosis. JGH Open 2019; 3:281-289. [PMID: 31406920 PMCID: PMC6684512 DOI: 10.1002/jgh3.12148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 12/13/2018] [Accepted: 12/29/2018] [Indexed: 11/07/2022]
Abstract
Background Aim Methods Results Conclusion
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Affiliation(s)
- Hiba A Al‐Kishali
- Department of Pharmacology and Toxicology, Faculty of PharmacyCairo UniversityCairoEgypt
| | - Mai A Abd El Fattah
- Department of Pharmacology and Toxicology, Faculty of PharmacyCairo UniversityCairoEgypt
| | | | - Hanan S El‐Abhar
- Department of Pharmacology and Toxicology, Faculty of PharmacyCairo UniversityCairoEgypt
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Guo H, Sun J, Li D, Hu Y, Yu X, Hua H, Jing X, Chen F, Jia Z, Xu J. Shikonin attenuates acetaminophen-induced acute liver injury via inhibition of oxidative stress and inflammation. Biomed Pharmacother 2019; 112:108704. [PMID: 30818140 DOI: 10.1016/j.biopha.2019.108704] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 02/13/2019] [Accepted: 02/19/2019] [Indexed: 01/02/2023] Open
Abstract
Acetaminophen (APAP) overdose causes acute liver injury and leads to fatal liver damage. However, the therapies are quite limited. Shikonin is a natural product with antioxidant and anti-inflammatory activities. In the present study, the hepatoprotective effects and the underlying mechanisms of shikonin in APAP-induced hepatotoxicity in vivo and in vitro were investigated. APAP-induced acute liver injury and shikonin pretreatment models were established in vivo and in vitro, as evidenced by serum hepatic enzymes, histological changes, oxidative stress indicators and proinflammatory cytokines. The results revealed that shikonin pretreatment prevented the elevation of serum alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels and markedly reduced APAP-induced histological alterations in liver tissues. Additionally, shikonin restored superoxide dismutase (SOD) expression and glutathione (GSH) content in line with the blockade of oxidative stress. The changes in gene expression involved in oxidative stress including methionine sulfoxide reductase (such as MsrA and MsrB1), heme oxygenase-1 (HO-1), SOD2 and cytochrome P450 2E1 (CYP2E1), were markedly reversed after shikonin therapy. Furthermore, shikonin markedly attenuated the APAP-induced production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) and suppressed the expression of genes related to inflammation. In AML-12 cells, shikonin pretreatment decreased APAP-induced cytotoxicity as measured by CCK-8 assay and LDH release. The changes in gene expression involved in oxidative stress and the inflammatory response were consistent with those in mouse livers. This study indicated that shikonin attenuated APAP-induced acute liver injury via inhibiting oxidative stress and inflammatory responses in vivo and in vitro. These findings offer new insights into the potential therapy for APAP hepatotoxicity.
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Affiliation(s)
- Hongli Guo
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Jieyu Sun
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; China Pharmaceutical University, Nanjing, 210009, China
| | - Deyi Li
- School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110000, China
| | - Yahui Hu
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Xiaowen Yu
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Hu Hua
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Xia Jing
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Feng Chen
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Zhanjun Jia
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
| | - Jing Xu
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
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21
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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.
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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
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22
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Cao SY, Ye SJ, Wang WW, Wang B, Zhang T, Pu YQ. Progress in active compounds effective on ulcerative colitis from Chinese medicines. Chin J Nat Med 2019; 17:81-102. [PMID: 30797423 DOI: 10.1016/s1875-5364(19)30012-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Indexed: 02/09/2023]
Abstract
Ulcerative colitis (UC), a chronic inflammatory disease affecting the colon, has a rising incidence worldwide. The known pathogenesis is multifactorial and involves genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors. Nowadays, the drugs for UC include 5-aminosalicylic acid, steroids, and immunosuppressants. Long-term use of these drugs, however, may cause several side effects, such as hepatic and renal toxicity, drug resistance and allergic reactions. Moreover, the use of traditional Chinese medicine (TCM) in the treatment of UC shows significantly positive effects, low recurrence rate, few side effects and other obvious advantages. This paper summarizes several kinds of active compounds used in the experimental research of anti-UC effects extracted from TCM, mainly including flavonoids, acids, terpenoids, phenols, alkaloids, quinones, and bile acids from some animal medicines. It is found that the anti-UC activities are mainly focused on targeting inflammation or oxidative stress, which is associated with increasing the levels of anti-inflammatory cytokine (IL-4, IL-10, SOD), suppressing the levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-23, NF-κB, NO), reducing the activity of MPO, MDA, IFN-γ, and iNOS. This review may offer valuable reference for UC-related studies on the compounds from natural medicines.
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Affiliation(s)
- Si-Yu Cao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Sheng-Jie Ye
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei-Wei Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Bing Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tong Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yi-Qiong Pu
- Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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23
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Fan C, Zhang X, Upton Z. Anti-inflammatory effects of shikonin in human periodontal ligament cells. PHARMACEUTICAL BIOLOGY 2018; 56:415-421. [PMID: 30392422 PMCID: PMC7011859 DOI: 10.1080/13880209.2018.1506482] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 07/12/2018] [Accepted: 07/26/2018] [Indexed: 05/26/2023]
Abstract
CONTEXT Shikonin (SHI), an active component extracted from Radix Arnebiae, has been reported to possess anti-inflammatory properties in various cells. However, its effect on lipopolysaccharide (LPS)-stimulated human periodontal ligament cells (hPDLCs) is unknown. OBJECTIVE To investigate the effects of SHI on the expression of inflammatory related cytokines in LPS-stimulated hPDLCs. MATERIALS AND METHODS The effects of SHI (0.125, 0.25, 0.5, 1, and 2 μg/mL) on hPDLCs proliferation for 1, 3 and 7 days were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α), matrix metalloproteinase-2 (MMP-2), MMP-9 and cyclooxygenase-2 (COX-2) were detected in hPDLCs following SHI treatment (0.25 and 0.5 μg/mL) using Quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR). The signaling pathways triggered by SHI in hPDLC were evaluated using western blotting. RESULTS LD50 of SHI is 1.7 μg/mL (day 1) and 1.1 μg/mL (day 3 and 7) in hPDLCs. No morphological changes were observed when hPDLCs were treated with LPS only (1 μg/mL) or LPS with SHI (0.25 and 0.5 μg/mL). Data from qRT-PCR suggests that SHI attenuates LPS-induced increases of IL-1, IL-6, TNF-α, MMP-2, MMP-9 and COX-2 in hPDLCs. Down-regulation of phosphorylated extracellular signal-regulated kinase (ERK) and nuclear factor-κB (NF-κB), and up-regulation of I-κB, were observed in LPS-stimulated hPDLCs after exposed to SHI at 0.25 or 0.5 μg/mL. DISCUSSION AND CONCLUSIONS SHI possesses anti-inflammatory effects in LPS-stimulated hPDLCs via phospho-ERK and NF-κB/I-κB signaling pathways; this suggests that SHI may hold potential as an anti-inflammatory agent against periodontitis.
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Affiliation(s)
- Chen Fan
- Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Singapore
- Skin Research Institute of Singapore, A*STAR, Singapore
| | - Xufang Zhang
- Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
- Guangdong Province Key Laboratory of Stomatology, Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zee Upton
- Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Singapore
- Skin Research Institute of Singapore, A*STAR, Singapore
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24
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Je IG, Lee DG, Jeong DG, Hong D, Yoon JM, Moon JS, Park S. The Probiotic, ID-JPL934, Attenuates Dextran Sulfate Sodium-Induced Colitis in Mice Through Inhibition of Proinflammatory Cytokines Expression. J Med Food 2018; 21:858-865. [PMID: 30036104 DOI: 10.1089/jmf.2017.4152] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Despite the increasing prevalence of inflammatory bowel disease (IBD), classified as immune-mediated disorders, the exact biological mechanisms leading to its development are undetermined, and treatment strategies remain elusive. Probiotics have been proposed as potential alternatives for treating IBD. The purpose of this research was to find therapeutic candidates of probiotics for colitis. We adopted dextran sulfate sodium (DSS)-induced colitis model to demonstrate the therapeutic effects of ID-JPL934, a mixture of three live bacterial strains at a 1:1:1 ratio: Lactobacillus johnsonii IDCC9203, Lactobacillus plantarum IDCC3501, and Bifidobacterium animalis subspecies lactis IDCC4301, on IBD. The severity was scored according to the disease activity index (DAI) for colitis by observing body weight (BW) and stool status of each mouse once a day. BALB/c mice given 3.5% DSS in drinking water suffered from symptoms of colitis such as weight loss, diarrhea, and bloody excrement. In our study, administration of ID-JPL934 reduced the DAI scores in a dose-dependent manner, and treatments with ID-JPL934 108 and 109 colony-forming unit per mouse per day showed similar inhibition compared with those of sulfasalazine 500 mg per kg BW per day. Moreover, the contraction of colon length improved. ID-JPL934 also suppressed inflammatory lesions such as infiltration of immune cells in mucosa and submucosa, severe crypt damage, and loss of goblet and epithelial cells on the histological analysis. These results might be due to downregulation of the expression of proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. From these results, ID-JPL934 might be an effective therapeutic candidate for IBD.
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Affiliation(s)
- In-Gyu Je
- Research Laboratories, Ildong Pharmaceutical Co., Ltd. , Hwaseong, Korea
| | - Don-Gil Lee
- Research Laboratories, Ildong Pharmaceutical Co., Ltd. , Hwaseong, Korea
| | - Dong-Gu Jeong
- Research Laboratories, Ildong Pharmaceutical Co., Ltd. , Hwaseong, Korea
| | - Dahae Hong
- Research Laboratories, Ildong Pharmaceutical Co., Ltd. , Hwaseong, Korea
| | - Jong-Min Yoon
- Research Laboratories, Ildong Pharmaceutical Co., Ltd. , Hwaseong, Korea
| | - Jin Seok Moon
- Research Laboratories, Ildong Pharmaceutical Co., Ltd. , Hwaseong, Korea
| | - Soobong Park
- Research Laboratories, Ildong Pharmaceutical Co., Ltd. , Hwaseong, Korea
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25
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Kang R, Zeng L, Zhu S, Xie Y, Liu J, Wen Q, Cao L, Xie M, Ran Q, Kroemer G, Wang H, Billiar TR, Jiang J, Tang D. Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis. Cell Host Microbe 2018; 24:97-108.e4. [PMID: 29937272 PMCID: PMC6043361 DOI: 10.1016/j.chom.2018.05.009] [Citation(s) in RCA: 448] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 04/25/2018] [Accepted: 05/18/2018] [Indexed: 12/18/2022]
Abstract
Sepsis is a life-threatening condition caused by pathogen infection and associated with pyroptosis. Pyroptosis occurs upon activation of proinflammatory caspases and their subsequent cleavage of gasdermin D (GSDMD), resulting in GSDMD N-terminal fragments that form membrane pores to induce cell lysis. Here, we show that antioxidant defense enzyme glutathione peroxidase 4 (GPX4) and its ability to decrease lipid peroxidation, negatively regulate macrophage pyroptosis, and septic lethality in mice. Conditional Gpx4 knockout in myeloid lineage cells increases lipid peroxidation-dependent caspase-11 activation and GSDMD cleavage. The resultant N-terminal GSDMD fragments then trigger macrophage pyroptotic cell death in a phospholipase C gamma 1 (PLCG1)-dependent fashion. Administration of the antioxidant vitamin E that reduces lipid peroxidation, chemical inhibition of PLCG1, or genetic Caspase-11 deletion or Gsdmd inactivation prevents polymicrobial sepsis in Gpx4-/- mice. Collectively, this study suggests that lipid peroxidation drives GSDMD-mediated pyroptosis and hence constitutes a potential therapeutic target for lethal infection.
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Affiliation(s)
- Rui Kang
- The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation Laboratory of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Ling Zeng
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research Institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Shan Zhu
- The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation Laboratory of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Yangchun Xie
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410008, China
| | - Jiao Liu
- The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation Laboratory of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Qirong Wen
- The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation Laboratory of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Min Xie
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Qitao Ran
- Department of Cell Systems and Anatomy, University of Texas Health Science Center, Research Service, South Texas Veterans Health Care System, San Antonio, TX 78229, USA
| | - Guido Kroemer
- Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Equipe 11 Labellisée Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France; Institut National de La Santé et de La Recherche Médicale, U1138 Paris, France; Université Pierre et Marie Curie, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Haichao Wang
- Laboratory of Emergency Medicine, North Shore University Hospital, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Jianxin Jiang
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research Institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
| | - Daolin Tang
- The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation Laboratory of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
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26
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Deng W, Zhu S, Zeng L, Liu J, Kang R, Yang M, Cao L, Wang H, Billiar TR, Jiang J, Xie M, Tang D. The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis. Cell Rep 2018; 24:366-378. [PMID: 29996098 PMCID: PMC6094382 DOI: 10.1016/j.celrep.2018.06.026] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 02/28/2018] [Accepted: 06/05/2018] [Indexed: 12/21/2022] Open
Abstract
Sepsis and septic shock are associated with life-threatening organ dysfunction caused by an impaired host response to infections. Although circadian clock disturbance impairs the early inflammatory response, its impact on post-septic immunosuppression remains poorly elucidated. Here, we show that Bmal1, a core circadian clock gene, plays a role in the regulation of host immune responses in experimental sepsis. Mechanistically, Bmal1 deficiency in macrophages increases PKM2 expression and lactate production, which is required for expression of the immune checkpoint protein PD-L1 in a STAT1-dependent manner. Consequently, targeted ablation of Pkm2 in myeloid cells or administration of anti-PD-L1-neutralizing antibody or supplementation with recombinant interleukin-7 (IL-7) facilitates microbial clearance, inhibits T cell apoptosis, reduces multiple organ dysfunction, and reduces septic death in Bmal1-deficient mice. Collectively, these findings suggest that the circadian clock controls the immune checkpoint pathway in macrophages and therefore represents a potential therapeutic target for lethal infection.
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Affiliation(s)
- Wenjun Deng
- The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Shan Zhu
- The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Ling Zeng
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research Institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Jiao Liu
- The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Minghua Yang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Haichao Wang
- Laboratory of Emergency Medicine, North Shore University Hospital and The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Jianxin Jiang
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research Institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Min Xie
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
| | - Daolin Tang
- The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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27
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Zeng L, Kang R, Zhu S, Wang X, Cao L, Wang H, Billiar TR, Jiang J, Tang D. ALK is a therapeutic target for lethal sepsis. Sci Transl Med 2018; 9:9/412/eaan5689. [PMID: 29046432 DOI: 10.1126/scitranslmed.aan5689] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 06/30/2017] [Accepted: 09/22/2017] [Indexed: 12/13/2022]
Abstract
Sepsis, a life-threatening organ dysfunction caused by infection, is a major public health concern with limited therapeutic options. We provide evidence to support a role for anaplastic lymphoma kinase (ALK), a tumor-associated receptor tyrosine kinase, in the regulation of innate immunity during lethal sepsis. The genetic disruption of ALK expression diminishes the stimulator of interferon genes (STING)-mediated host immune response to cyclic dinucleotides in monocytes and macrophages. Mechanistically, ALK directly interacts with epidermal growth factor receptor (EGFR) to trigger serine-threonine protein kinase AKT phosphorylation and activate interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) signaling pathways, enabling STING-dependent rigorous inflammatory responses. Moreover, pharmacological or genetic inhibition of the ALK-STING pathway confers protection against lethal endotoxemia and sepsis in mice. The ALK pathway is up-regulated in patients with sepsis. These findings uncover a key role for ALK in modulating the inflammatory signaling pathway and shed light on the development of ALK-targeting therapeutics for lethal systemic inflammatory disorders.
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Affiliation(s)
- Ling Zeng
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China.,The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.,Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Shan Zhu
- The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Xiao Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Haichao Wang
- Laboratory of Emergency Medicine, North Shore University Hospital and The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Jianxin Jiang
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
| | - Daolin Tang
- The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, Guangdong 510510, China. .,Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA
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28
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Erjaee H, Nazifi S, Rajaian H. Effect of Ag‐NPs synthesised by
Chamaemelum nobile
extract on the inflammation and oxidative stress induced by carrageenan in mice paw. IET Nanobiotechnol 2017. [DOI: 10.1049/iet-nbt.2016.0245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Hoda Erjaee
- Department of PharmacologySchool of Veterinary MedicineShiraz UniversityShirazIran
| | - Saeed Nazifi
- Department of Clinical StudiesSchool of Veterinary MedicineShiraz UniversityShirazIran
| | - Hamid Rajaian
- Department of PharmacologySchool of Veterinary MedicineShiraz UniversityShirazIran
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The Impacts of Chrysanthemum indicum Extract on Oxidative Stress and Inflammatory Responses in Adjuvant-Induced Arthritic Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:3285394. [PMID: 28491105 PMCID: PMC5402234 DOI: 10.1155/2017/3285394] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 03/24/2017] [Accepted: 03/30/2017] [Indexed: 02/07/2023]
Abstract
Chrysanthemum indicum has been used as a therapeutic agent against inflammation, hypertension, and respiratory conditions for many years. This research's aim has been to examine the antioxidant impacts that Chrysanthemum indicum extract (CIE) has on the oxidative stress and inflammatory responses in adjuvant-induced arthritic (AA) rats. 40 rats were categorised into 4 groups according to a completely randomized approach: Group I involved normal control rats (CTRL) that received a basal diet; Group II involved arthritic control rats (CTRL-AA) that received the same diet; Group III involved rats that received a basal diet and 30 mg/kg CIE; and Group IV involved arthritic rats with the same diet as Group III rats (CIE-AA). After injection with complete Freund's adjuvant, body weight, arthritis score, and the serum levels of TNF-α, IL-1β, IL-6, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) were assessed. The results demonstrated that CIE delayed the onset time of arthritis and decreased the clinical arthritis severity score (P < 0.05). Observations of CIE-AA and CTRL-AA rats demonstrated that CIE alleviates oxidative stress and inflammatory responses in CIE-AA group. In conclusion, CIE alleviated oxidative stress and inflammatory responses, thereby highlighting its potential use as a candidate for clinical treatments of rheumatoid arthritis.
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Radiation Synthesis of Poly(Starch/Acrylic acid) pH Sensitive Hydrogel for Rutin Controlled Release. Int J Biol Macromol 2016; 92:957-964. [DOI: 10.1016/j.ijbiomac.2016.07.079] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 07/21/2016] [Accepted: 07/23/2016] [Indexed: 12/22/2022]
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Xie M, Yu Y, Kang R, Zhu S, Yang L, Zeng L, Sun X, Yang M, Billiar TR, Wang H, Cao L, Jiang J, Tang D. PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation. Nat Commun 2016; 7:13280. [PMID: 27779186 PMCID: PMC5093342 DOI: 10.1038/ncomms13280] [Citation(s) in RCA: 388] [Impact Index Per Article: 43.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 09/16/2016] [Indexed: 02/06/2023] Open
Abstract
Sepsis, severe sepsis and septic shock are the main cause of mortality in non-cardiac intensive care units. Immunometabolism has been linked to sepsis; however, the precise mechanism by which metabolic reprogramming regulates the inflammatory response is unclear. Here we show that aerobic glycolysis contributes to sepsis by modulating inflammasome activation in macrophages. PKM2-mediated glycolysis promotes inflammasome activation by modulating EIF2AK2 phosphorylation in macrophages. Pharmacological and genetic inhibition of PKM2 or EIF2AK2 attenuates NLRP3 and AIM2 inflammasomes activation, and consequently suppresses the release of IL-1β, IL-18 and HMGB1 by macrophages. Pharmacological inhibition of the PKM2-EIF2AK2 pathway protects mice from lethal endotoxemia and polymicrobial sepsis. Moreover, conditional knockout of PKM2 in myeloid cells protects mice from septic death induced by NLRP3 and AIM2 inflammasome activation. These findings define an important role of PKM2 in immunometabolism and guide future development of therapeutic strategies to treat sepsis.
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Affiliation(s)
- Min Xie
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yan Yu
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
| | - Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
| | - Shan Zhu
- Center of DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Liangchun Yang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Ling Zeng
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Xiaofang Sun
- Center of DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Minghua Yang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Timothy R. Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
| | - Haichao Wang
- Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Jianxin Jiang
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
- Center of DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China
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Lee HH, Shin JS, Lee WS, Ryu B, Jang DS, Lee KT. Biflorin, Isolated from the Flower Buds of Syzygium aromaticum L., Suppresses LPS-Induced Inflammatory Mediators via STAT1 Inactivation in Macrophages and Protects Mice from Endotoxin Shock. JOURNAL OF NATURAL PRODUCTS 2016; 79:711-720. [PMID: 26977531 DOI: 10.1021/acs.jnatprod.5b00609] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Two chromone C-glucosides, biflorin (1) and isobiflorin (2), were isolated from the flower buds of Syzygium aromaticum L. (Myrtaceae). Here, inhibitory effects of 1 and 2 on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7 macrophages were evaluated, and 1 (IC50 = 51.7 and 37.1 μM, respectively) was more potent than 2 (IC50 > 60 and 46.0 μM). The suppression of NO and PGE2 production by 1 correlated with inhibition of iNOS and COX-2 protein expression. Compound 1 reduced inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expression via inhibition of their promoter activities. Compound 1 inhibited the LPS-induced production and mRNA expression of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. Furthermore, 1 reduced p-STAT1 and p-p38 expression but did not affect the activity of nuclear factor κ light-chain enhancer of activated B cells (NF-κB) or activator protein 1 (AP-1). In a mouse model of LPS-induced endotoxemia, 1 reduced the mRNA levels of iNOS, COX-2, and TNF-α, and the phosphorylation-mediated activation of the signal transducer and activator of transcription 1 (STAT1), consequently improving the survival rates of mice. Compound 1 showed a significant anti-inflammatory effect on carrageenan-induced paw edema and croton-oil-induced ear edema in rats. The collective data indicate that the suppression of pro-inflammatory gene expression via p38 mitogen-activated protein kinase and STAT1 inactivation may be a mechanism for the anti-inflammatory activity of 1.
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Affiliation(s)
- Hwi-Ho Lee
- Department of Pharmaceutical Biochemistry, College of Pharmacy, ‡Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, §Reactive Oxygen Species Medical Research Center College of Pharmacy, and ⊥Department of Physiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea
| | - Ji-Sun Shin
- Department of Pharmaceutical Biochemistry, College of Pharmacy, ‡Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, §Reactive Oxygen Species Medical Research Center College of Pharmacy, and ⊥Department of Physiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea
| | - Woo-Seok Lee
- Department of Pharmaceutical Biochemistry, College of Pharmacy, ‡Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, §Reactive Oxygen Species Medical Research Center College of Pharmacy, and ⊥Department of Physiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea
| | - Byeol Ryu
- Department of Pharmaceutical Biochemistry, College of Pharmacy, ‡Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, §Reactive Oxygen Species Medical Research Center College of Pharmacy, and ⊥Department of Physiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea
| | - Dae Sik Jang
- Department of Pharmaceutical Biochemistry, College of Pharmacy, ‡Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, §Reactive Oxygen Species Medical Research Center College of Pharmacy, and ⊥Department of Physiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea
| | - Kyung-Tae Lee
- Department of Pharmaceutical Biochemistry, College of Pharmacy, ‡Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, §Reactive Oxygen Species Medical Research Center College of Pharmacy, and ⊥Department of Physiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea
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Zhang Z, Deng W, Kang R, Xie M, Billiar T, Wang H, Cao L, Tang D. Plumbagin Protects Mice from Lethal Sepsis by Modulating Immunometabolism Upstream of PKM2. Mol Med 2016; 22:162-172. [PMID: 26982513 DOI: 10.2119/molmed.2015.00250] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 02/16/2016] [Indexed: 01/14/2023] Open
Abstract
Sepsis is characterized by dysregulated systemic inflammation with release of early (for example, interleukin (IL)-1β) and late (for example, HMGB1) proinflammatory mediators from macrophages. Plumbagin, a medicinal plant-derived naphthoquinone, has been reported to exhibit antiinflammatory activity, but the underling mechanisms remain unclear. Here, we have demonstrated that plumbagin inhibits the inflammatory response through interfering with the immunometabolism pathway in activated macrophages. Remarkably, plumbagin inhibited lipopolysaccharide (LPS)-induced aerobic glycolysis by downregulating the expression of pyruvate kinase M2 (PKM2), a protein kinase responsible for the final and rate-limiting reaction step of the glycolytic pathway. Moreover, the NADPH oxidase 4 (NOX4)-mediated oxidative stress was required for LPS-induced PKM2 expression, because pharmacologic or genetic inhibition of NOX4 by plumbagin or RNA interference limited LPS-induced PKM2 expression, lactate production and subsequent proinflammatory cytokine (IL-1β and HMGB1) release in macrophages. Finally, plumbagin protected mice from lethal endotoxemia and polymicrobial sepsis induced by cecal ligation and puncture. These findings identify a new approach for inhibiting the NOX4/PKM2-dependent immunometabolism pathway in the treatment of sepsis and inflammatory diseases.
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Affiliation(s)
- Zhaoxia Zhang
- Department of Pediatrics, The Second Affiliated Hospital of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong, People's Republic of China
| | - Wenjun Deng
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Min Xie
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Timothy Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Haichao Wang
- Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.,Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China
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Widhalm JR, Rhodes D. Biosynthesis and molecular actions of specialized 1,4-naphthoquinone natural products produced by horticultural plants. HORTICULTURE RESEARCH 2016; 3:16046. [PMID: 27688890 PMCID: PMC5030760 DOI: 10.1038/hortres.2016.46] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 08/23/2016] [Indexed: 05/20/2023]
Abstract
The 1,4-naphthoquinones (1,4-NQs) are a diverse group of natural products found in every kingdom of life. Plants, including many horticultural species, collectively synthesize hundreds of specialized 1,4-NQs with ecological roles in plant-plant (allelopathy), plant-insect and plant-microbe interactions. Numerous horticultural plants producing 1,4-NQs have also served as sources of traditional medicines for hundreds of years. As a result, horticultural species have been at the forefront of many basic studies conducted to understand the metabolism and function of specialized plant 1,4-NQs. Several 1,4-NQ natural products derived from horticultural plants have also emerged as promising scaffolds for developing new drugs. In this review, the current understanding of the core metabolic pathways leading to plant 1,4-NQs is provided with additional emphasis on downstream natural products originating from horticultural species. An overview on the biochemical mechanisms of action, both from an ecological and pharmacological perspective, of 1,4-NQs derived from horticultural plants is also provided. In addition, future directions for improving basic knowledge about plant 1,4-NQ metabolism are discussed.
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Affiliation(s)
- Joshua R Widhalm
- Department of Horticulture and Landscape Architecture, Purdue University, 625 Agriculture Mall Drive, West Lafayette, IN 47907-2010, USA
- ()
| | - David Rhodes
- Department of Horticulture and Landscape Architecture, Purdue University, 625 Agriculture Mall Drive, West Lafayette, IN 47907-2010, USA
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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.
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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.
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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
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Yang L, Xie M, Yang M, Yu Y, Zhu S, Hou W, Kang R, Lotze M, Billiar TR, Wang H, Cao L, Tang D. PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat Commun 2014; 5:4436. [PMID: 25019241 PMCID: PMC4104986 DOI: 10.1038/ncomms5436] [Citation(s) in RCA: 367] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 06/18/2014] [Indexed: 12/27/2022] Open
Abstract
Increasing evidence suggests the important role of metabolic reprogramming in the regulation of the innate inflammatory response, but the underlying mechanism remains unclear. Here we provide evidence to support a novel role for the pyruvate kinase M2 (PKM2)-mediated Warburg effect, namely aerobic glycolysis, in the regulation of high-mobility group box 1 (HMGB1) release. PKM2 interacts with hypoxia-inducible factor 1α (HIF1α) and activates the HIF-1α-dependent transcription of enzymes necessary for aerobic glycolysis in macrophages. Knockdown of PKM2, HIF1α and glycolysis-related genes uniformly decreases lactate production and HMGB1 release. Similarly, a potential PKM2 inhibitor, shikonin, reduces serum lactate and HMGB1 levels, and protects mice from lethal endotoxemia and sepsis. Collectively, these findings shed light on a novel mechanism for metabolic control of inflammation by regulating HMGB1 release and highlight the importance of targeting aerobic glycolysis in the treatment of sepsis and other inflammatory diseases.
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Affiliation(s)
- Liangchun Yang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of China
| | - Min Xie
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of China
| | - Minghua Yang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of China
| | - Yan Yu
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of China
| | - Shan Zhu
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of China
| | - Wen Hou
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
| | - Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
| | - Michael Lotze
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
| | - Timothy R. Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
| | - Haichao Wang
- Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of China
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
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Xu Y, Xu X, Gao X, Chen H, Geng L. Shikonin suppresses IL-17-induced VEGF expression via blockage of JAK2/STAT3 pathway. Int Immunopharmacol 2014; 19:327-33. [DOI: 10.1016/j.intimp.2014.01.027] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 01/02/2014] [Accepted: 01/20/2014] [Indexed: 12/25/2022]
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Yang Y, Wang J, Yang Q, Wu S, Yang Z, Zhu H, Zheng M, Liu W, Wu W, He J, Chen Z. Shikonin inhibits the lipopolysaccharide-induced release of HMGB1 in RAW264.7 cells via IFN and NF-κB signaling pathways. Int Immunopharmacol 2014; 19:81-7. [PMID: 24447680 DOI: 10.1016/j.intimp.2014.01.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Revised: 12/29/2013] [Accepted: 01/06/2014] [Indexed: 11/30/2022]
Abstract
To study the anti-inflammation effect of Shikonin (Shik) and its mechanism, murine macrophage-like RAW264.7 cells (RAW264.7 cells) were divided into control group, LPS group (0.125, 0.25 and 0.5μg/ml), LPS (0.125, 0.25 and 0.5μg/ml) plus Shik (0.5, 1 and 2μM) group, and Shik (2μM) group. After exposure for 24h, the levels of Interleukin-6 (IL-6), nitric oxide (NO) and Tumor Necrosis Factor-α (TNF-α) in supernatant were measured with ELISA, the expression of high mobility group box 1(HMGB1) in supernatant and cytoplasm was assayed using qRT-PCR, western blot and immunofluorescence assays, the expression of IFN-β in cellular and supernatant was assayed by qRT-PCR and ELISA, and the ratio of nuclear to cytoplasm for NF-κB protein expression was assayed using western blot. The results of our investigation demonstrated that Shik could reduce significantly the levels of IL-6, NO and TNF-α in RAW264.7 cells exposed to LPS (P<0.05 or P<0.01). The expression of HMGB1, IFN-β and the ratio of nuclear to cytoplasm for NF-κB protein expression in LPS plus Shik group declined significantly as compared with LPS group (P<0.05 or P<0.01). The inhibitors of IFN-β signaling molecule JAK and NF-κB could attenuate significantly the expression of HMGB1 in supernatant. It was found in the present study that Shik could have the anti-inflammatory effects in RAW264.7 cells exposed to LPS, and one of the mechanisms may be the down-regulation of HMGB expression, which was associated with the IFN-β and NF-κB signaling pathways.
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Affiliation(s)
- Ying Yang
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou 310003, China
| | - Jing Wang
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou 310003, China
| | - Qiao Yang
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310016, China
| | - Shanshan Wu
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou 310003, China
| | - Zhenggang Yang
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou 310003, China
| | - Haihong Zhu
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou 310003, China
| | - Min Zheng
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou 310003, China
| | - Weixia Liu
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou 310003, China
| | - Wei Wu
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou 310003, China
| | - Jiliang He
- Department of Environmental Medicine, School of Public Health, Zhejiang University, Hangzhou 310058, China
| | - Zhi Chen
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou 310003, China.
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Anti-Inflammatory Effect of Supercritical-Carbon Dioxide Fluid Extract from Flowers and Buds of Chrysanthemum indicum Linnén. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:413237. [PMID: 24223056 PMCID: PMC3816045 DOI: 10.1155/2013/413237] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 08/19/2013] [Indexed: 11/20/2022]
Abstract
The aim of this study was to analyze the chemical composition and investigate the anti-inflammatory property of the supercritical-carbon dioxide extract from flowers and buds of C. indicum (CISCFE). The anti-inflammatory effect was evaluated in four animal models including xylene-induced mouse ear edema, acetic acid-induced mouse vascular permeability, carrageenan-induced mouse hind paw edema, and cotton pellet-induced rat granuloma formation. The results indicated that CISCFE significantly attenuated xylene-induced ear edema, decreased acetic acid-induced capillary permeability, reduced carrageenan-induced paw, and inhibited the cotton pellet-induced granuloma formation in a dose-dependent manner. Histopathologically, CISCFE abated inflammatory response of the edema paw. Preliminary mechanistic studies demonstrated that CISCFE decreased the MDA level via increasing the activities of anti-oxidant enzymes (SOD, GPx, and GRd), attenuated the productions of NF-κB, TNF-α, IL-1β, IL-6, PGE2 and NO, and suppressed the activities of iNOS and COX-2. In phytochemical study, 35 compounds were identified by GC-MS, and 5 compounds (chlorogenic acid, luteolin-7-glucoside, linarin, luteolin and acacetin) were reconfirmed and quantitatively determined by HPLC-PAD. This paper firstly analyzed the chemical composition by combining GC-MS with HPLC-PAD and explored possible mechanisms for the anti-inflammatory effect of CISCFE.
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Shikonin Suppresses Human T Lymphocyte Activation through Inhibition of IKK β Activity and JNK Phosphorylation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:379536. [PMID: 23762128 PMCID: PMC3670545 DOI: 10.1155/2013/379536] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 03/30/2013] [Indexed: 11/24/2022]
Abstract
The key role of T cells has been elaborated in mediating immune responses and pathogenesis of human inflammatory and autoimmune conditions. In the current study the effect of shikonin, a compound isolated from a medicinal plant, on inhibition of T-cell activation was firstly examined by using primary human T lymphocytes isolated from buffy coat. Results showed that shikonin dose dependently suppressed T-cell proliferation, IL-2 and IFN-γ secretion, CD69 and CD25 expression, as well as cell cycle arrest activated by costimulation of PMA/ionomycin or OKT-3/CD28 monoclonal antibodies. Moreover, these inhibitory responses mediated by shikonin were found to be associated with suppression of the NF-κB signaling pathway via inhibition of the IKKα/β phosphorylation, IκB-α phosphorylation and degradation, and NF-κB nuclear translocation by directly decreasing IKKβ activity. Moreover, shikonin suppressed JNK phosphorylation in the MAPKs pathway of T cells. In this connection, we conclude that shikonin could suppress T lymphocyte activation through suppressing IKKβ activity and JNK signaling, which suggests that shikonin is valuable for further investigation as a potential immunosuppressive agent.
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