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Anush Sheikh KH, Haokip SW, Hazarika BN, Devi OB, Lian HN, Yumkhaibam T, Ningombam L, Singh YD. Phyto-chemistry and Therapeutic Potential of Natural Flavonoid Naringin: A Consolidated Review. Chin J Integr Med 2025:10.1007/s11655-025-3826-9. [PMID: 39994136 DOI: 10.1007/s11655-025-3826-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2024] [Indexed: 02/26/2025]
Affiliation(s)
- K H Anush Sheikh
- Department of Fruit Science, College of Horticulture and Forestry, Central Agricultural University, Pasighat, Arunachal Pradesh, 791102, India
| | - Songthat William Haokip
- Department of Fruit Science, College of Horticulture and Forestry, Central Agricultural University, Pasighat, Arunachal Pradesh, 791102, India
| | - B N Hazarika
- Department of Fruit Science, College of Horticulture and Forestry, Central Agricultural University, Pasighat, Arunachal Pradesh, 791102, India
| | - Oinam Bidyalaxmi Devi
- Department of Vegetable Science, College of Horticulture and Forestry, Central Agricultural University, Pasighat, Arunachal Pradesh, 791102, India
| | - Hau Ngaih Lian
- Department of Fruit Science, College of Horticulture and Forestry, Central Agricultural University, Pasighat, Arunachal Pradesh, 791102, India
| | - Tabalique Yumkhaibam
- Department of Vegetable Science, College of Horticulture and Forestry, Central Agricultural University, Pasighat, Arunachal Pradesh, 791102, India
| | - Linthoingambi Ningombam
- Department of Fruit Science, College of Horticulture and Forestry, Central Agricultural University, Pasighat, Arunachal Pradesh, 791102, India
| | - Yengkhom Disco Singh
- Department of Post-Harvest Technology, College of Horticulture and Forestry, Central Agricultural University, Pasighat, Arunachal Pradesh, 791102, India.
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Gu M, Su W, Dai J, Wang J, Jia X, Yao J, Zhang G, Zhu Q, Pang Z. Jingfang granule alleviates Pseudomonas aeruginosa-induced acute lung inflammation through suppression of STAT3/IL-17/NF-κB pathway based on network pharmacology analysis and experimental validation. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:116899. [PMID: 37454750 DOI: 10.1016/j.jep.2023.116899] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/11/2023] [Accepted: 07/08/2023] [Indexed: 07/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pseudomonas aeruginosa is an opportunistic bacterial pathogen which is the second leading cause of hospital-acquired pneumonia. Jingfang granule (JFG) is an herbal formula of Traditional Chinese medicine (TCM) widely used in treatment of acute respiratory tract infections in China. However, the molecular mechanisms of JFG in treatment of P. aeruginosa-induced acute pneumonia are not clear. AIM OF STUDY This study aimed to investigate the mechanisms underlying the effects of JFG on P. aeruginosa-induced acute inflammation using a mouse model of bacterial acute pneumonia. MATERIALS AND METHODS The chemical components and targets of JFG were retrieved from Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and the P. aeruginosa pneumonia-related targets were obtained from the disease databases, including Online Mendelian Inheritance in Man (OMIM), GeneCards and DisGeNet. The protein-protein interaction (PPI) network was constructed using STRING database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Molecular docking was performed using AutoDockTools 1.5.6. Further in vivo experiments employed a mouse model of P. aeruginosa acute pneumonia to verify the target proteins and signaling pathways affected by JFG, which were predicted by the network pharmacology analysis. RESULTS A total of 218 active components and 257 targets of JFG were retrieved from TCMSP database. Moreover, 99 intersectant targets were obtained between the 257 JFG targets and 694 disease targets. Among the intersectant targets, STAT3, IL-6, AKT1, TNF, MAPK1, MAPK3 and EGFR were identified to be the key therapeutic targets through PPI network analysis, and STAT3 was in the center of the network, which is a key regulator of IL-17 expression. KEGG pathway enrichment analysis suggested that IL-17 signaling pathway was one of the crucial inflammatory pathways affected by JFG in treatment of P. aeruginosa pneumonia. Furthermore, the in vivo experiments demonstrated that the JFG-treated mice displayed reduced proinflammatory cytokine production (IL-17, IL-1β, IL-6 and TNF), diminished neutrophil infiltration and decreased mortality, compared with the non-drug-treated mice during P. aeruginosa lung infection. Moreover, the expression or phosphorylation levels of the key regulators in STAT3/IL-17/NF-κB axis including STAT3, ERK1/2 (MAPK3/1), AKT, NF-κB p65 and RORγt were significantly reduced in the lung tissues of the JFG-treated mice. CONCLUSION JFG was effective in treatment of P. aeruginosa acute lung infection, which reduced inflammatory responses through suppressing STAT3/IL-17/NF-κB pathway.
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Affiliation(s)
- Mengdi Gu
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
| | - Wen Su
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
| | - Jiangqin Dai
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
| | - Jue Wang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
| | - Xiaolei Jia
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
| | - Jingchun Yao
- State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, 276005, China.
| | - Guimin Zhang
- State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, 276005, China.
| | - Qingjun Zhu
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
| | - Zheng Pang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
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Hu X, Liu W, He M, Qiu Q, Zhou B, Liu R, Wu F, Huang Z. Comparison of the molecular mechanisms of Fuzi Lizhong Pill and Huangqin decoction in the treatment of the cold and heat syndromes of ulcerative colitis based on network pharmacology. Comput Biol Med 2023; 159:106870. [PMID: 37084637 DOI: 10.1016/j.compbiomed.2023.106870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 02/21/2023] [Accepted: 03/30/2023] [Indexed: 04/23/2023]
Abstract
OBJECTIVE The aim of this study was to illuminate the similarities and differences of two prescriptions as "cold" and "heat" drugs for treating ulcerative colitis (UC) with the simultaneous occurrence of heat and cold syndrome via network pharmacology. METHODS (1) Active compounds of Fuzi-Lizhong Pill (FLP) and Huangqin Decoction (HQT) were retrieved from the TCMSP database, and their common active compounds were compared using the Venn diagram. (2) Potential proteins targeted to three sets of compounds either (i) shared by FLP and HQT, (ii) unique to FLP or (iii) unique to HQT were screened from the STP, STITCH and TCMSP databases, and three corresponding core compound sets were identified in Herb-Compound-Target (H-C-T) networks. (3) Targets related to UC were identified from the DisGeNET and GeneCards databases and compared with the FLP-HQT common targets to identify potential targets of FLP-HQT compounds related to UC. (4) Three potential target sets were imported into the STRING database for protein‒protein interaction (PPI) analysis, and three core target sets were defined. (5) The binding capabilities and interacting modes between core compounds and key targets were verified by molecular docking via Discovery Studio 2019 and molecular dynamics (MD) simulations via Amber 2018. (6) The target sets were enriched for KEGG pathways using the DAVID database. RESULTS (1) FLP and HQT included 95 and 113 active compounds, respectively, with 46 common compounds, 49 FLP-specific compounds and 67 HQT-specific compounds. (2) 174 targets of FLP-HQT common compounds, 168 targets of FLP-specific compounds, and 369 targets of HQT-specific compounds were predicted from the STP, STITCH and TCMSP databases; six core compounds specific to FLP and HQT were screened in the FLP-specific and HQT-specific H-C-T networks, respectively. (3) 103 targets overlapped from the 174 predicted targets and the 4749 UC-related targets; two core compounds for FLP-HQT were identified from the FLP-HQT H-C-T network. (4) 103 FLP-HQT-UC common targets, 168 of FLP-specific targets and 369 of HQT-specific targets had shared core targets (AKT1, MAPK3, TNF, JUN and CASP3) based on the PPI network analysis. (5) Molecular docking demonstrated that naringenin, formononetin, luteolin, glycitein, quercetin, kaempferol and baicalein of FLP and HQT play a critical role in treating UC; meanwhile, MD simulations revealed the stability of protein‒ligand interactions. (6) The enriched pathways indicated that most targets were related to anti-inflammatory, immunomodulatory and other pathways. Compared with the pathways identified using traditional methods, FLP-specific pathways included the PPAR signaling pathway and the bile secretion pathway, and HQT-specific pathways included the vascular smooth muscle contraction pathway and the natural killer cell-mediated cytotoxicity pathway etc. CONCLUSION: In this study, we clarified the common mechanisms of FLP and HQT in treating UC and their specific mechanisms in treating cold and heat syndrome in UC through compound, target and pathway distinction and a literature comparison based on network pharmacology; these results provide a new perspective on the detailed mechanism of "multidrugs and single-disease" thought in traditional Chinese medicine.
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Affiliation(s)
- Xiyun Hu
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Dongguan, 523808, China
| | - Weidong Liu
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Dongguan, 523808, China
| | - Meiqi He
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Dongguan, 523808, China
| | - Qimiao Qiu
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Dongguan, 523808, China
| | - Bingjie Zhou
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Dongguan, 523808, China
| | - Ruining Liu
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Dongguan, 523808, China
| | - Fengxu Wu
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, 442000, China.
| | - Zunnan Huang
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Dongguan, 523808, China; Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, 524023, China.
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Dayal S, Broekelmann T, Mecham RP, Ramamurthi A. Targeting Epidermal Growth Factor Receptor to Stimulate Elastic Matrix Regenerative Repair. Tissue Eng Part A 2023; 29:187-199. [PMID: 36641641 PMCID: PMC10122231 DOI: 10.1089/ten.tea.2022.0170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/15/2022] [Indexed: 01/16/2023] Open
Abstract
Abdominal aortic aneurysms (AAAs) represent a multifactorial, proteolytic disorder involving disintegration of the matrix structure within the AAA wall. Intrinsic deficiency of adult vascular cells to regenerate and repair the wall elastic matrix, which contributes to vessel stretch and recoil, is a major clinical challenge to therapeutic reversal of AAA growth. In this study, we investigate the involvement of epidermal growth factor receptor-mitogen activated protein kinase (EGFR-MAPK) pathway in the activation of aneurysmal smooth muscle cells (SMCs) by neutrophil elastase, and how EGFR can be targeted for elastic matrix regeneration. We have demonstrated that neutrophil elastase activates EGFR and downregulates expression level of key elastin homeostasis genes (elastin, crosslinking enzyme-lysyl oxidase, and fibulin4) between a dose range of 1-10 μg/mL (p < 0.05). It also incites downstream proteolytic outcomes by upregulating p-extracellular signal-regulated kinase (ERK)1/2 (p < 0.0001) and matrix metalloprotease 2 (MMP2) at a protein level, which is significantly downregulated upon EGFR-specific inhibition by tyrosine kinase inhibitor AG1478 (p-ERK1/2 and MMP2 [p < 0.05]). Moreover, we have shown that EGFR inhibition suppresses collagen amounts in aneurysmal SMCs (p < 0.05) and promotes robust formation of elastic fibers by enhancing its deposition in the extracellular space. Hence, the EGFR-MAPK pathway in aneurysmal cells can be targeted to provide therapeutic effects toward stimulating vascular matrix regeneration. Impact statement Proteolytic disorders such as aortal expansions, called abdominal aortic aneurysms (AAAs), are characterized by naturally irreversible enzymatic breakdown and loss of elastic fibers, a problem that has not yet been surmounted by existing tissue engineering approaches. In this work, we show, for the first time, how epidermal growth factor receptor (EGFR) inhibition provides downstream benefits in elastic fiber assembly and deposition in aneurysmal smooth muscle cell cultures. This work can open future possibilities for development of EGFR-targeted drug-based therapies not only for vessel wall repair in AAAs but also other proteolytically compromised elastic tissues.
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Affiliation(s)
- Simran Dayal
- Department of Bioengineering, Lehigh University, Bethlehem, Pennsylvania, USA
| | - Thomas Broekelmann
- Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA
| | - Robert P. Mecham
- Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA
| | - Anand Ramamurthi
- Department of Bioengineering, Lehigh University, Bethlehem, Pennsylvania, USA
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Lu R, Yu RJ, Yang C, Wang Q, Xuan Y, Wang Z, He Z, Xu Y, Kou L, Zhao YZ, Yao Q, Xu SH. Evaluation of the hepatoprotective effect of naringenin loaded nanoparticles against acetaminophen overdose toxicity. Drug Deliv 2022; 29:3256-3269. [PMID: 36321805 PMCID: PMC9635473 DOI: 10.1080/10717544.2022.2139431] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Acute liver injury is a common clinical disease, which easily leads to liver failure and endangers life, seriously threatening human health. Naringenin is a natural flavonoid that holds therapeutic potential against various liver injuries; however it has poor water solubility and bioavailability. In this study, we aimed to develop naringenin-loaded bovine serum albumin nanoparticles (NGNPs) and to evaluate their hepatoprotective effect and underlying mechanisms against acetaminophen overdose toxicity. In vitro data indicated that NGNPs significantly increased the drug solubility and also more effectively protected the hepatocyte cells from oxidative damage during hydrogen peroxide exposure or lipopolysaccharide (LPS) stimulation. In vivo results confirmed that NGNPs showed an enhanced accumulation in the liver tissue. In the murine model of acetaminophen-induced hepatotoxicity, NGNPs could effectively alleviate the progression of acute liver injury by reducing drug overdose-induced levels of oxidative stress, inflammation and apoptosis in hepatocytes. In conclusion, NGNPs has strong hepatoprotective effects against acetaminophen induced acute liver injury.
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Affiliation(s)
- Ruijie Lu
- Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China,The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Run-Jie Yu
- Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Chunhui Yang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qian Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yunxia Xuan
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zeqing Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zhimin He
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yan Xu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Longfa Kou
- The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Ying-Zheng Zhao
- Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qing Yao
- Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China,CONTACT Qing Yao Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, University Town, Chashan, Wenzhou 325000, Zhejiang, China
| | - Shi-Hao Xu
- Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Shi-Hao Xu Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Lin C, Zeng Z, Lin Y, Wang P, Cao D, Xie K, Luo Y, Yang H, Yang J, Wang W, Luo L, Lin H, Chen H, Zhao Y, Shi Y, Gao Z, Liu H, Liu SL. Naringenin suppresses epithelial ovarian cancer by inhibiting proliferation and modulating gut microbiota. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 106:154401. [PMID: 36029647 DOI: 10.1016/j.phymed.2022.154401] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 08/08/2022] [Accepted: 08/17/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Ovarian cancer has the highest mortality among all gynecological malignancies; currently, no effective therapeutics are available for its treatment. Naringenin has been shown to inhibit the progression of various cancers, but its inhibitory effect on ovarian cancer remains unknown. PURPOSE This study aimed to evaluate the inhibitory effects of naringenin on ovarian cancer and elucidate the underlying mechanisms. METHODS Cancer cell proliferation was detected by cell counting kit-8 and crystal violet assays, and the migration capability was determined by wound healing and transwell assays. Western blotting and immunohistochemistry assays were employed to determine the expression levels of the epidermal growth factor receptor, phosphatidylinositol 3-kinase (PI3K) and cyclin D1 in vitro and in vivo, respectively. An ES-2 xenograft nude mouse model was established for the in vivo experiments, and fecal samples were collected for intestinal microbiota analysis by 16S rDNA sequencing. RESULTS Naringenin suppressed the proliferation and migration of A2780 and ES-2 cancer cell lines and downregulated PI3K in vitro. In animal experiments, naringenin treatment significantly decreased the tumor weight and volume, and oral administration exhibited greater effects than intraperitoneal injection. Additionally, naringenin treatment ameliorated the population composition of the microbiota in animals with ovarian cancer and significantly increased the abundances of Alistipes and Lactobacillus. CONCLUSION Naringenin suppresses epithelial ovarian cancer by inhibiting PI3K pathway expression and ameliorating the gut microbiota, and the oral route is more effective than parenteral administration.
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Affiliation(s)
- Caiji Lin
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Zheng Zeng
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Yiru Lin
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Pengfei Wang
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Danli Cao
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Kaihong Xie
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Yao Luo
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Hao Yang
- Department of Pathology, Harbin Chest Hospital, Harbin 150056, China
| | - Jiaming Yang
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Wenxue Wang
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - LingJie Luo
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Huihui Lin
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Hang Chen
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Yufan Zhao
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Yongwei Shi
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Zixiang Gao
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Huidi Liu
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary T2N 4N1, Canada.
| | - Shu-Lin Liu
- Genomics Research Center (State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin 150081, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China; Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary T2N 4N1, Canada.
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Picos-Salas MA, Cabanillas-Bojórquez LÁ, Elizalde-Romero CA, Leyva-López N, Montoya-Inzunza LA, Heredia JB, Gutiérrez-Grijalva EP. Naringenin as a Natural Agent Against Oxidative Stress and Inflammation, and Its Bioavailability. FOOD REVIEWS INTERNATIONAL 2022. [DOI: 10.1080/87559129.2022.2123502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Manuel Adrian Picos-Salas
- Functional Foods and Nutraceuticals Laboratory, Centro de Investigación en Alimentación y Desarrollo A.C., Sinalora, México
| | | | | | - Nayely Leyva-López
- Functional Foods and Nutraceuticals Laboratory, Centro de Investigación en Alimentación y Desarrollo A.C., Sinalora, México
| | - Luis Aurelio Montoya-Inzunza
- Functional Foods and Nutraceuticals Laboratory, Centro de Investigación en Alimentación y Desarrollo A.C., Sinalora, México
| | - J. Basilio Heredia
- Functional Foods and Nutraceuticals Laboratory, Centro de Investigación en Alimentación y Desarrollo A.C., Sinalora, México
| | - Erick P. Gutiérrez-Grijalva
- Functional Foods and Nutraceuticals Laboratory, Centro de Investigación en Alimentación y Desarrollo A.C., Sinalora, México
- Functional Foods and Nutraceuticals Laboratory, Cátedras CONACYT-Centro de Investigación en Alimentación y Desarrollo A.C., Sinaloa, Mexico
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Sun Y, Miao X, Zhu L, Liu J, Lin Y, Xiang G, Wu X, Wang X, Ni Z, Li S. Autocrine TGF-alpha is associated with Benzo(a)pyrene-induced mucus production and MUC5AC expression during allergic asthma. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 241:113833. [PMID: 36068759 DOI: 10.1016/j.ecoenv.2022.113833] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 06/25/2022] [Accepted: 06/28/2022] [Indexed: 06/15/2023]
Abstract
OBJECTS Benzo(a)pyrene (BaP), an environmental pollutant, is present in high concentrations in urban smog and cigarette smoke and has been reported to promote high mucin 5AC (MUC5AC) expression. Epithelium-derived inflammatory cytokines are considered an important modulator of mucus oversecretion and MUC5AC overexpression. Here, we investigated whether the effect of BaP on MUC5AC overexpression was associated with cytokine autocrine activity in vivo and in vitro. METHODS In vivo, BALB/c mice were treated with ovalbumin (OVA) in the presence or absence of BaP. Allergy-induced mucus production was assessed by Alcian Blue Periodic acid Schiff (AB-PAS) staining. The human airway epithelial cell line NCI-H292 was used in vitro. MUC5AC and transforming growth factor (TGF)-α mRNA levels were assessed with real-time quantitative PCR. The concentration of cytokines was measured by ELISA. The MUC5AC, p-ERK, ERK, p-EGFR and EGFR proteins were detected by Western blotting in cells or by immunohistochemistry in mouse lungs. Small-interfering RNAs were used for gene silencing. RESULTS TGF-α was overproduced in the supernatant of NCI-H292 cells treated with BaP. Knockdown of TGF-α expression inhibited the BaP-induced increase in MUC5AC expression and subsequent activation of the EGFR-ERK signalling pathway. Knocking down aryl hydrocarbon receptor (AhR) expression or treatment with an ROS inhibitor (N-acetyl-L-cysteine) could relieve the TGF-α secretion induced by BaP in epithelial cells. In an animal study, coexposure to BaP with OVA increased mucus production, MUC5AC expression and ROS-EGFR-ERK activation in the lung as well as TGF-α levels in bronchoalveolar lavage fluid (BALF). Furthermore, the concentration of TGF-α in BALF was correlated with MUC5AC mRNA levels. Additionally, TGF-α expression was found to be positively correlated with MUC5AC expression in the airway epithelial cells of smokers. Compared with non-smoker asthma patients, TGF-α serum levels were also elevated in smoker asthma patients. CONCLUSION Autocrine TGF-α was associated with BaP-induced MUC5AC expression in vitro and in vivo. BaP induced TGF-α secretion by activating AhR and producing ROS, which led to activation of the EGFR-ERK pathway.
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Affiliation(s)
- Yipeng Sun
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Xiayi Miao
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China
| | - Linyun Zhu
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China
| | - Jinjin Liu
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China
| | - Yuhua Lin
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China
| | - Guiling Xiang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Xiaodan Wu
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Xiaobiao Wang
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China.
| | - Zhenhua Ni
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China; Central lab, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China.
| | - Shanqun Li
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
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García-Burgos M, Moreno-Fernandez J, Díaz-Castro J, M Alférez MJ, López-Aliaga I. Fermented goat's milk modulates immune response during iron deficiency anemia recovery. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2022; 102:1114-1123. [PMID: 34329496 DOI: 10.1002/jsfa.11448] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 06/24/2021] [Accepted: 07/30/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Iron deficiency and iron overload can affect the normal functioning of the innate and adaptive immune responses. Fermented milk products may enhance immune functions, but little is known about the effect of fermented milks on modulation of the immune response during iron deficiency anemia and recovery with normal or high dietary iron intake. Eighty male Wistar rats were randomly assigned to a control group fed a standard diet or to an anemic group fed a diet deficit in iron. Control and anemic groups were fed for 30 days with diets based on a fermented goat's or cow's milk product, with normal iron content or iron overload. RESULTS In general, during anemia recovery lectin and alternative complement pathway activity and lactoferrin decreased, because it improves iron homeostasis, which is critically important in immune system functions. Fermented goat's milk diet enhanced immune function during iron deficiency recovery, suppressed oxidant-induced eotaxin and fractalkine expression due to the concurrent reduction of free radical production and pro-inflammatory cytokines, and decreased monocyte chemoattractant protein-1 and monocyte migration and adhesion. The increase in interferon-γ can confer immunological colonization of gut microbiota and downregulate inflammation. CONCLUSION Fermented goat's milk consumption enhances immune function, modifying complement pathway activity and decreasing pro-inflammatory cytokines as well as lactoferrin concentration, due to the improvement of iron homeostasis, which is critically important in the normal function of the immune system. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
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Affiliation(s)
- María García-Burgos
- Department of Physiology, University of Granada, Granada, Spain
- Institute of Nutrition and Food Technology 'José Mataix Verdú', University of Granada, Granada, Spain
| | - Jorge Moreno-Fernandez
- Department of Physiology, University of Granada, Granada, Spain
- Institute of Nutrition and Food Technology 'José Mataix Verdú', University of Granada, Granada, Spain
| | - Javier Díaz-Castro
- Department of Physiology, University of Granada, Granada, Spain
- Institute of Nutrition and Food Technology 'José Mataix Verdú', University of Granada, Granada, Spain
| | - María José M Alférez
- Department of Physiology, University of Granada, Granada, Spain
- Institute of Nutrition and Food Technology 'José Mataix Verdú', University of Granada, Granada, Spain
| | - Inmaculada López-Aliaga
- Department of Physiology, University of Granada, Granada, Spain
- Institute of Nutrition and Food Technology 'José Mataix Verdú', University of Granada, Granada, Spain
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10
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Zhou W, Dong M, Wu H, Li HL, Xie JL, Ma RY, Su WW, Dai JY. Common mechanism of Citrus Grandis Exocarpium in treatment of chronic obstructive pulmonary disease and lung cancer. CHINESE HERBAL MEDICINES 2021; 13:525-533. [PMID: 36119362 PMCID: PMC9476385 DOI: 10.1016/j.chmed.2021.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 02/07/2021] [Accepted: 06/07/2021] [Indexed: 11/28/2022] Open
Abstract
Objective “Same treatment for different diseases” is a unique treatment strategy in traditional Chinese medicine. Two kinds of malignant respiratory diseases endanger human health-chronic obstructive pulmonary disease (COPD) and lung cancer. Citrus Grandis Exocarpium (Huajuhong in Chinese, HJH), a famous herbal, is always applied by Chinese medicine practitioners to dispersion the lung to resolve phlegm based on “syndrome differentiation and treatment” theory. However, the common mechanism for HJH’s treatment of COPD and lung cancer is not clear. Methods In this study, based on network pharmacology and molecular docking technology, the common mechanism of HJH in the treatment of COPD and lung cancer was studied. The active ingredients and related targets of HJH were integrated from TCMSP, BATMAN-TAM, STP, and Pubchem databases. The standard names of these targets were united by UniProt database. Targets of COPD and lung cancer were enriched through GeneCards, NCBI (Gene), Therapeutic Target Database, and DisGeNET (v7.0) databases. Then the intersection targets of HJH and diseases were obtained. The STRING network and the Cytoscape 3.7.2 were used to construct PPI network, the DAVID database was used to perform GO and KEGG analysis. Then Cytoscape 3.6.1 was used to build “ingredient-target-signal pathway” network. Finally, AutoDock 1.5.6 software was used to perform molecular docking of key proteins and molecules. Results Eleven active ingredients in HJH were obtained by searching the database, corresponding to 184 HJH-COPD-lung cancer targets intersection. The results of biological network analysis showed that naringenin, the active component in HJH, could mainly act on target proteins such as AKT1, EGFR. Then through positive regulation of vasoconstriction and other biological processes, naringenin could regulate estrogen signaling pathway, VEGF signaling pathway, HIF-1 signaling pathway, ErbB signaling pathway, PI3K-Akt signaling pathway to play an important role in the treatment of both COPD and lung cancer. Conclusion Network pharmacology was employed to systematically investigate the active ingredients and targets of HJH in treatment of COPD and lung cancer. And then, the common pharmacodynamic network of HJH for the two malignant respiratory diseases was firstly described. Furthermore, naringenin was proved to strongly bind with AKT1 and EGFR. It may provide the scientific basis for understanding the “Same treatment for different diseases” strategy in traditional Chinese medicine and inspirit subsequent drug discovery for COPD, lung cancer and other malignant lung diseases.
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Affiliation(s)
- Wei Zhou
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Min Dong
- Department of Pulmonology, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou 730000, China
| | - Hao Wu
- Guangdong Engineering and Technology Research Center for Quality and Efficacy Re-evaluation of Post-marketed TCM, Guangdong Key Laboratory of Plant Resources, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
| | - Hui-lin Li
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Jia-le Xie
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Ru-yun Ma
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Wei-wei Su
- Guangdong Engineering and Technology Research Center for Quality and Efficacy Re-evaluation of Post-marketed TCM, Guangdong Key Laboratory of Plant Resources, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
- Corresponding authors.
| | - Jian-ye Dai
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
- Corresponding authors.
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11
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Naringenin Regulates Lipopolysaccharide-Induced Abnormal Airway Surface Liquid Secretion. Nat Prod Commun 2021. [DOI: 10.1177/1934578x211040356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Airway surface liquid (ASL) is one of the key factors affecting the respiratory system's physiological function. Abnormal ASL secretion can increase the incidence of various respiratory diseases. Lipopolysaccharide (LPS) stimulation can damage the airway epithelial barrier, affect the concentration of ASL contents, and down-regulate ion channel expression, which in turn causes abnormal ASL secretion. Naringenin, which exists in many Citrus foods, has the ability to promote airway surface liquid secretion. This work is designed to investigate the regulatory mechanism of naringenin on LPS-induced abnormal ASL secretion. The effects of naringenin and LPS on the viability of Calu-3 cells were measured by CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS). ASL secretion volume was measured by a micropipette on air–liquid interface cultured cells. The concentration of Cl−, Na+, lysozyme, and total protein in ASL were respectively measured by assay kits. The mRNA expressions were determined by quantitative real-time polymerase chain reaction, and proteins were measured by enzyme-linked immunosorbent assay. The results indicated that LPS could affect ASL secretion and regulate cystic fibrosis transmembrane conductance regulator (CFTR), aquaporin 1 (AQP1) and aquaporin 5 (AQP5) expression. Naringenin had the ability to regulate the ASL secretion by increasing secretion volume, and Cl− and Na+ concentrations, reducing lysozyme and total protein content, and regulating CFTR, AQP1, and AQP5 expression. This study indicated that naringenin had regulating effects to attenuate LPS-induced abnormal ASL secretion.
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12
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Qiu JF, Ma N, He ZY, Zhong XN, Zhang JQ, Bai J, Deng JM, Tang XJ, Luo ZL, Huang M, Liang Q, Wei YL, Tang MJ, Li MH. Erythromycin inhibits cigarette smoke-induced inflammation through regulating the PPARγ/NF-κB signaling pathway in macrophages. Int Immunopharmacol 2021; 96:107775. [PMID: 34162143 DOI: 10.1016/j.intimp.2021.107775] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 04/22/2021] [Accepted: 05/05/2021] [Indexed: 11/18/2022]
Abstract
Chronic obstructive pulmonary disease is characterized by chronic inflammation of the airway and lungs. Accumulating evidence has suggested that erythromycin (EM) plays a protective role against cigarette smoke-induced oxidative stress and the inflammatory response. However, the underlying mechanisms remain relatively unclear. The present study aimed to investigate the role of EM in inhibiting cigarette smoke-induced inflammation in human macrophages and its potential mechanism. A Cell Counting Kit-8 assay was used to determine the optimum concentration of EM and cigarette smoke extract (CSE) and it was found that 0.1 and 1% CSE and 0.1, 1.0 and 10 μg/ml EM exerted no significant effect on the cell proliferation activity, whereas 2 and 3% CSE exerted a significant inhibitory effect over the cell proliferation activity. We observed that 10 μmol/ml GW9662 (A PPARγ antagonist) and the presence of 1% CSE could promote the expression and activation of NF-κB p65. And this increased the expression of IL-6, IL-8 and reactive oxygen species (ROS). At the same time, 10 μmol/ml GW9662 and 1% CSE was found to inhibit the expression and activation of peroxisome proliferator activated receptors γ (PPARγ); However, 1 μg/ml EM was discovered to reverse these effects. Co-immunoprecipitation subsequently discovered an interaction between PPARγ and NF-κB p65. In conclusion, the present study suggested that EM may reduce the damage of PPARγ by inhibiting oxidative stress and reducing the expression of ROS and finally relieving cigarette smoke-induced inflammation through the PPARγ/NF-κB signaling pathway in macrophages.
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Affiliation(s)
- Ju-Feng Qiu
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China; Department of critical care medicine, First Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Nan Ma
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhi-Yi He
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiao-Ning Zhong
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jian-Quan Zhang
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jing Bai
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jing-Min Deng
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiao-Juan Tang
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhou-Ling Luo
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Mei Huang
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Quan Liang
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yan-Ling Wei
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ming-Jiao Tang
- Department of rehabilitation medicine, First Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Mei-Hua Li
- Department of Respiratory medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China.
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Aesculetin Inhibits Airway Thickening and Mucus Overproduction Induced by Urban Particulate Matter through Blocking Inflammation and Oxidative Stress Involving TLR4 and EGFR. Antioxidants (Basel) 2021; 10:antiox10030494. [PMID: 33809902 PMCID: PMC8004275 DOI: 10.3390/antiox10030494] [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: 03/01/2021] [Revised: 03/14/2021] [Accepted: 03/17/2021] [Indexed: 12/28/2022] Open
Abstract
Particulate matter (PM) is a mixture of solid and liquid air pollutant particles suspended in the air, varying in composition, size, and physical features. PM is the most harmful form of air pollution due to its ability to penetrate deep into the lungs and blood streams, causing diverse respiratory diseases. Aesculetin, a coumarin derivative present in the Sancho tree and chicory, is known to have antioxidant and anti-inflammatory effects in the vascular and immune system. However, its effect on PM-induced airway thickening and mucus hypersecretion is poorly understood. The current study examined whether naturally-occurring aesculetin inhibited airway thickening and mucus hypersecretion caused by urban PM10 (uPM10, particles less than 10 μm). Mice were orally administrated with 10 mg/kg aesculetin and exposed to 6 μg/mL uPM10 for 8 weeks. To further explore the mechanism(s) involved in inhibition of uPM10-induced mucus hypersecretion by aesculetin, bronchial epithelial BEAS-2B cells were treated with 1–20 µM aesculetin in the presence of 2 μg/mL uPM10. Oral administration of aesculetin attenuated collagen accumulation and mucus hypersecretion in the small airways inflamed by uPM10. In addition, aesculetin inhibited uPM10-evoked inflammation and oxidant production in lung tissues. Further, aesculetin accompanied the inhibition of induction of bronchial epithelial toll-like receptor 4 (TLR4) and epidermal growth factor receptor (EFGR) elevated by uPM10. The inhibition of TLR4 and EGFR accompanied bronchial mucus hypersecretion in the presence of uPM10. Oxidative stress was responsible for the epithelial induction of TLR4 and EGFR, which was disrupted by aesculetin. These results demonstrated that aesculetin ameliorated airway thickening and mucus hypersecretion by uPM10 inhalation by inhibiting pulmonary inflammation via oxidative stress-stimulated TLR4 and EGFR. Therefore, aesculetin may be a promising agent for treating airway mucosa-associated disorders elicited by urban coarse particulates.
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Yang F, Xu W, Pei Y. Amphiregulin induces interleukin-8 production and cell proliferation in lung epithelial cells through PI3K-Akt/ ERK pathways. EUR J INFLAMM 2021. [DOI: 10.1177/2058739221998202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Amphiregulin (AR), belongs to the epidermal growth factor (EGF) family, is able to induce a series of pathological and physiological responses by binding and activating epidermal growth factor receptor (EGFR). Interleukin-8 (IL-8) or CXCL8, a pro-inflammatory chemokine, has been suggested to be involved in tumor cell proliferation and inflammatory microenvironment via transactivation of the EGFR. However, whether there is a crosstalk between AR with IL-8 during inflammatory response remain to be fully understood. The current study was designed to investigate the possible mechanism of the interactions between AR and IL-8 production in human lung epithelial cells in vitro. Lung epithelial A549 cells were stimulated with lipopolysaccharide (LPS) to generate ALI model. LPS-induced AR and IL-8 production by A549 cells was measured by real-time PCR, Western Blot, and ELISA. The AR neutralizing antibody, PI3K specific inhibitor LY294002, JNK specific inhibitor SP60012, ERK specific inhibitor PD98089, and p38 inhibitor SB203580 were used to investigate the role of these signal pathways in LPS-induced cell proliferation, AR and IL-8 expression. LPS could induce AR through PI3K/Akt and ERK signal pathways. Furthermore, LPS induced AR promoted the production of IL-8 requires activation of EGFR, PI3K/Akt, and ERK signal pathways. The neutralizing antibody to AR prevented production of IL-8 induced by LPS. Treatment with Erlotinib, PI3K inhibitors, ERK inhibitor significantly inhibited AR-induced IL-8 production and cell proliferation. Our data indicate that a distinct role of EGFR–PI3K–Akt/ERK pathway as a bridge of interaction between AR and IL-8 production, as one of potential mechanisms to regulate inflammation and cell proliferation in human lung epithelial cells.
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Affiliation(s)
- Fangfang Yang
- Respiratory and Critical Care Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China
| | - Wei Xu
- Respiratory and Critical Care Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China
| | - Yanli Pei
- Respiratory and Critical Care Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China
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15
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Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin. MOLECULAR THERAPY-ONCOLYTICS 2021; 20:277-289. [PMID: 33614911 PMCID: PMC7873580 DOI: 10.1016/j.omto.2021.01.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 01/13/2021] [Indexed: 12/24/2022]
Abstract
Transforming growth factor β (TGF-β) has been shown to promote tumor invasion and metastasis by activating the matrix metalloproteinases (MMPs); however, signaling mechanisms remain controversial and therapies targeting MMPs are still suboptimal. In the present study, we found that combined therapy with Asiatic acid (AA), a Smad7 agonist, and Naringenin (NG), a Smad3 inhibitor, effectively retrieved the balance between Smad3 and Smad7 signaling in the TGF-β-rich tumor microenvironment and thus significantly suppressed tumor invasion and metastasis in mouse models of melanoma and lung carcinoma. Mechanistically, we unraveled that Smad3 acted as a transcriptional activator of MMP2 and as a transcriptional suppressor of tissue inhibitors of metalloproteinase-2 (TIMP2) via binding to 5′ UTR of MMP2 and 3′ UTR of TIMP2, respectively. Treatment with NG inhibited Smad3-mediated MMP2 transcription while increasing TIMP, whereas treatment with AA enhanced Smad7 to suppress TGF-β/Smad3 signaling, as well as the activation of MMP2 by targeting the nuclear factor-κB (NF-κB)-membrane-type-1 MMP (MT1-MMP) axis. Therefore, the combination of AA and NG additively suppressed invasion and metastasis of melanoma and lung carcinoma by targeting TGF-β/Smad-dependent MMP2 transcription, post-translational activation, and function.
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Multi-Therapeutic Potential of Naringenin (4',5,7-Trihydroxyflavonone): Experimental Evidence and Mechanisms. PLANTS 2020; 9:plants9121784. [PMID: 33339267 PMCID: PMC7766900 DOI: 10.3390/plants9121784] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/26/2020] [Accepted: 11/26/2020] [Indexed: 12/12/2022]
Abstract
Extensive research has been carried out during the last few decades, providing a detailed account of thousands of discovered phytochemicals and their biological activities that have the potential to be exploited for a wide variety of medicinal purposes. These phytochemicals, which are pharmacologically important for clinical use, primarily consist of polyphenols, followed by terpenoids and alkaloids. There are numerous published reports indicating the primary role of phytochemicals proven to possess therapeutic potential against several diseases. However, not all phytochemicals possess significant medicinal properties, and only some of them exhibit viable biological effects. Naringenin, a flavanone found in citrus fruits, is known to improve immunity, repair DNA damage, and scavenge free radicals. Despite the very low bioavailability of naringenin, it is known to exhibit various promising biological properties of medicinal importance, including anti-inflammatory and antioxidant activities. This review focuses on the various aspects related to naringenin, particularly its physicochemical, pharmacokinetic, and pharmacodynamic properties. Furthermore, various pharmacological activities of naringenin, such as anticancer, antidiabetic, hepatoprotective, neuroprotective, cardioprotective, nephroprotective, and gastroprotective effects, have been discussed along with their mechanisms of action.
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17
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Evaluation of Naringenin as a Promising Treatment Option for COPD Based on Literature Review and Network Pharmacology. Biomolecules 2020; 10:biom10121644. [PMID: 33302350 PMCID: PMC7762561 DOI: 10.3390/biom10121644] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/01/2020] [Accepted: 12/03/2020] [Indexed: 12/14/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by incompletely reversible airflow limitation and seriously threatens the health of humans due to its high morbidity and mortality. Naringenin, as a natural flavanone, has shown various potential pharmacological activities against multiple pathological stages of COPD, but available studies are scattered and unsystematic. Thus, we combined literature review with network pharmacology analysis to evaluate the potential therapeutic effects of naringenin on COPD and predict its underlying mechanisms, expecting to provide a promising tactic for clinical treatment of COPD.
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Wadhwa R, Paudel KR, Chin LH, Hon CM, Madheswaran T, Gupta G, Panneerselvam J, Lakshmi T, Singh SK, Gulati M, Dureja H, Hsu A, Mehta M, Anand K, Devkota HP, Chellian J, Chellappan DK, Hansbro PM, Dua K. Anti-inflammatory and anticancer activities of Naringenin-loaded liquid crystalline nanoparticles in vitro. J Food Biochem 2020; 45:e13572. [PMID: 33249629 DOI: 10.1111/jfbc.13572] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/23/2020] [Accepted: 11/02/2020] [Indexed: 12/24/2022]
Abstract
In this study, we had developed Naringenin-loaded liquid crystalline nanoparticles (LCNs) and investigated the anti-inflammatory and anticancer activities of Naringenin-LCNs against human airway epithelium-derived basal cells (BCi-NS1.1) and human lung epithelial carcinoma (A549) cell lines, respectively. The anti-inflammatory potential of Naringenin-LCNs evaluated by qPCR revealed a decreased expression of IL-6, IL-8, IL-1β, and TNF-α in lipopolysaccharide-induced BCi-NS1.1 cells. The activity of LCNs was comparable to the positive control drug Fluticasone propionate (10 nM). The anticancer activity was studied by evaluating the antiproliferative (MTT and trypan blue assays), antimigratory (scratch wound healing assay, modified Boyden chamber assay, and immunoblot), and anticolony formation activity in A549 cells. Naringenin LCNs showed promising antiproliferative, antimigratory, and anticolony formation activities in A549 cells, in vitro. Therefore, based on our observations and results, we conclude that Naringenin-LCNs may be employed as a potential therapy-based intervention to ameliorate airway inflammation and to inhibit the progression of lung cancer. PRACTICAL APPLICATIONS: Naringenin was encapsulated into liquid crystalline nanoparticles, thus, attributing to their sustained-release nature. In addition, Naringenin-loaded LCNs efficiently reduced the levels of pro-inflammatory markers, namely, IL-1β, IL-6, TNF-α, and IL-8. In addition, the Naringenin-loaded LCNs also possess potent anticancer activity, when tested in the A549 cell line, as revealed by the inhibition of proliferation and migration of cells. They also attenuated colony formation and induced apoptosis in the A549 cells. The findings from our study could form the basis for future research that may be translated into an in vivo model to validate the possible therapeutic alternative for lung cancer using Naringenin-loaded LCNs. In addition, the applications of Naringenin-loaded LCNs as an intervention would be of great interest to biological, formulation and respiratory scientists and clinicians.
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Affiliation(s)
- Ridhima Wadhwa
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia.,Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia
| | - Keshav Raj Paudel
- Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
| | - Li Hian Chin
- School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Chian Ming Hon
- School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Thiagarajan Madheswaran
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jaipur, India
| | - Jithendra Panneerselvam
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Thangavelu Lakshmi
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Monica Gulati
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Harish Dureja
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India
| | - Alan Hsu
- Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute & School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
| | - Meenu Mehta
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia.,Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia
| | - Krishnan Anand
- Department of Chemical Pathology, School of Pathology, Faculty of Health Sciences and National Health Laboratory Service, University of the Free State, Bloemfontein, South Africa
| | - Hari Prasad Devkota
- Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Jestin Chellian
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Philip M Hansbro
- Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.,Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute & School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia.,Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute & School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
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Sharma P, Kumar V, Khosla R, Guleria P. Exogenous naringenin improved digestible protein accumulation and altered morphology via VrPIN and auxin redistribution in Vigna radiata. 3 Biotech 2020; 10:431. [PMID: 32999809 PMCID: PMC7492357 DOI: 10.1007/s13205-020-02428-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 09/05/2020] [Indexed: 01/15/2023] Open
Abstract
Naringenin exposure altered auxin redistribution via VrPIN1 leading to morphological alterations and significantly reduced the protein precipitable tannins that further enhanced the protein accumulation and bioavailability. Flavonoid exposure is known to affect the antioxidant profile of legumes. However, a detailed study evaluating the effect of flavonoid naringenin on morphology and biochemical profile of legume is lacking. The present study is a novel report of improved in planta protein bioavailability and antioxidant potential of legume mungbean on naringenin exposure. The quantitative evaluation revealed significant protein accumulation (64-122 μg/g FW) on naringenin exposure. Further, an increase in protein solubility and digestibility compared to control was evident. Naringenin mediated altered α-amylase activity improved the mungbean seed germination rate. Naringenin induced auxin redistribution and altered PIN formed transcript expression reduced lateral root density and increased stem length that was subsequently reverted on exogenous indole acetic acid application. Naringenin enhanced polyphenolic accumulation and improved the antioxidant potential of mungbean. Additionally, the responsiveness of the early gene of the flavonoid biosynthetic pathway, Chalcone isomerase to naringenin concentration was revealed indicating a probable feedback regulation. Further, the presence of alternate liquiritigenin biosynthesis was also evident. The present study, thus reveals the probable potential of phytochemical naringenin towards agricultural sustainability in the changing environmental conditions.
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Affiliation(s)
- Priya Sharma
- Plant Biotechnology and Genetic Engineering Lab, Department of Biotechnology, DAV University, Jalandhar, Punjab 144012 India
| | - Vineet Kumar
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab 144111 India
| | - Rajiv Khosla
- Department of Biotechnology, Doaba College, Jalandhar, Punjab 144001 India
| | - Praveen Guleria
- Plant Biotechnology and Genetic Engineering Lab, Department of Biotechnology, DAV University, Jalandhar, Punjab 144012 India
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20
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Gopallawa I, Lee RJ. Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity. World J Biol Chem 2020; 11:30-51. [PMID: 33024516 PMCID: PMC7520643 DOI: 10.4331/wjbc.v11.i2.30] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/24/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
The airway innate immune system maintains the first line of defense against respiratory infections. The airway epithelium and associated immune cells protect the respiratory system from inhaled foreign organisms. These cells sense pathogens via activation of receptors like toll-like receptors and taste family 2 receptors (T2Rs) and respond by producing antimicrobials, inflammatory cytokines, and chemokines. Coordinated regulation of fluid secretion and ciliary beating facilitates clearance of pathogens via mucociliary transport. Airway cells also secrete antimicrobial peptides and radicals to directly kill microorganisms and inactivate viruses. The phosphoinositide-3-kinase/protein kinase B (Akt) kinase pathway regulates multiple cellular targets that modulate cell survival and proliferation. Akt also regulates proteins involved in innate immune pathways. Akt phosphorylates endothelial nitric oxide synthase (eNOS) enzymes expressed in airway epithelial cells. Activation of eNOS can have anti-inflammatory, anti-bacterial, and anti-viral roles. Moreover, Akt can increase the activity of the transcription factor nuclear factor erythroid 2 related factor-2 that protects cells from oxidative stress and may limit inflammation. In this review, we summarize the recent findings of non-cancerous functions of Akt signaling in airway innate host defense mechanisms, including an overview of several known downstream targets of Akt involved in innate immunity.
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Affiliation(s)
- Indiwari Gopallawa
- Department of Otorhinolaryngology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Robert J Lee
- Department of Otorhinolaryngology and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
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21
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Park JW, Kim SM, Min JH, Kim MG, Kwon OK, Hwang D, Oh JH, Park MW, Chun W, Lee HJ, Kim DY, Kim JH, Hwang J, Kim MO, Oh SR, Ahn KS, Lee JW. 3,4,5-Trihydroxycinnamic acid exerts anti-asthmatic effects in vitro and in vivo. Int Immunopharmacol 2020; 88:107002. [PMID: 33182035 DOI: 10.1016/j.intimp.2020.107002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 09/09/2020] [Accepted: 09/09/2020] [Indexed: 12/29/2022]
Abstract
3,4,5-Trihydroxycinnamic acid (THCA) has been reported to possess anti-inflammatory activity. However, the effect of THCA for treating allergic asthma was unknown. Therefore, in the present study, the anti-asthmatic effects of THCA were studied in both in vitro and in vivo studies. In phorbol 12-myristate 13-acetate (PMA)-stimulated A549 airway epithelial cells, THCA pretreatment decreased the mRNA expression and secretion of interleukin (IL)-8, monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecules 1 (ICAM-1), and reduced the mRNA expression of matrix metalloproteinase 9 (MMP-9). THCA also inhibited PMA-induced protein kinase B (AKT), mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) activation in A549 cells. In lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, THCA pretreatment suppressed the mRNA expression of ICAM-1 and MMP-9. In addition, THCA suppressed the adhesion of EOL and A549 cells. In ovalbumin (OVA)-administered asthmatic mice, THCA exerted inhibitory activity on IL-5, IL-13, and MCP-1 in bronchoalveolar lavage fluid (BALF) and on OVA-specific immunoglobulin E (IgE) in serum. THCA attenuated the numbers of inflammatory cells in BALF and the influx of inflammatory cell in lung tissues. Furthermore, THCA downregulated the levels of inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2), and leukotriene B4 (LTB4) expression, mucus production and CREB phosphorylation as well as Penh value. These effects were accompanied by suppression of AKT, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-κB activation. Therefore, the results of the current study suggest that THCA may be a valuable adjuvant or therapeutic in the prevention or treatment of allergic asthma.
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Affiliation(s)
- Ji-Won Park
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea
| | - Seong-Man Kim
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea; College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea
| | - Jae-Hong Min
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea; College of Pharmacy, Chungbuk National University, Cheongju-si, Chungcheongbuk-do 28160, Republic of Korea
| | - Min-Gu Kim
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea; College of Pharmacy, Chungbuk National University, Cheongju-si, Chungcheongbuk-do 28160, Republic of Korea
| | - Ok-Kyoung Kwon
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea
| | - Daseul Hwang
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea; College of Pharmacy, Chungbuk National University, Cheongju-si, Chungcheongbuk-do 28160, Republic of Korea
| | - Jae-Hoon Oh
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea; College of Pharmacy, Chungbuk National University, Cheongju-si, Chungcheongbuk-do 28160, Republic of Korea
| | - Min-Woo Park
- SciTech Korea Inc., Seoul 01138, Republic of Korea
| | - Wanjoo Chun
- Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, Kangwon 24341, Republic of Korea
| | - Hee Jae Lee
- Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, Kangwon 24341, Republic of Korea
| | - Doo-Young Kim
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea
| | - Jung Hee Kim
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea
| | - Joonsung Hwang
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, (KRIBB), Chungbuk 28116, Republic of Korea
| | - Mun Ock Kim
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea
| | - Sei-Ryang Oh
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea
| | - Kyung-Seop Ahn
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea.
| | - Jae-Won Lee
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea.
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An L, Zhao J, Sun X, Zhou Y, Zhao Z. S-allylmercaptocysteine inhibits mucin overexpression and inflammation via MAPKs and PI3K-Akt signaling pathways in acute respiratory distress syndrome. Pharmacol Res 2020; 159:105032. [PMID: 32574825 PMCID: PMC7305891 DOI: 10.1016/j.phrs.2020.105032] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/04/2020] [Accepted: 06/11/2020] [Indexed: 11/17/2022]
Abstract
Cytokine storm is an important cause of acute respiratory distress syndrome and multiple organ failure. Excessive secretion and accumulation of mucins on the surface of airway cause airway obstruction and exacerbate lung infections. MUC5AC and MUC5B are the main secreted mucins and overexpressed in various inflammatory responses. S-allylmercaptocysteine, a water-soluble organic sulfur compound extracted from garlic, has anti-inflammatory and anti-oxidative effects for various pulmonary diseases. The aim of this work was to investigate the therapeutic effects of SAMC on mucin overproduction and inflammation in 16HBE cells and LPS-induced ARDS mice. Results show that SAMC treatment ameliorated inflammatory cell infiltration and lung histopathological changes in the LPS-induced ARDS mice. SAMC also inhibited the expressions of MUC5AC and MUC5B, decreased the production of pro-inflammatory markers (IL-6, TNF-α, CD86 and IL-12) and increased the production of anti-inflammatory markers (IL-10, CD206 and TGF-β). These results confirm that SAMC had potential beneficial effects on suppressed hyperinflammation and mucin overexpression. Furthermore, SAMC exerted the therapeutic effects through the inhibition of phosphorylation of MAPKs and PI3K-Akt signaling pathways in the 16HBE cells and mice. Overall, our results demonstrate the effects of SAMC on the LPS-induced mucin overproduction and inflammation both in the 16HBE cells and mice.
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Affiliation(s)
- Lulu An
- School of Pharmaceutical Sciences, Cheelloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Jianxiong Zhao
- School of Basic Medical Sciences, Cheelloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, PR China
| | - Xiao Sun
- School of Pharmaceutical Sciences, Cheelloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Yingying Zhou
- School of Pharmaceutical Sciences, Cheelloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Zhongxi Zhao
- School of Pharmaceutical Sciences, Cheelloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China; Shandong Key University Laboratory of Pharmaceutics & Drug Delivery Systems, 44 West Wenhua Road, Jinan, Shandong 250012, PR China; Shandong Engineering & Technology Research Center for Jujube Food and Drug, 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
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23
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Molecular mechanisms of action of naringenin in chronic airway diseases. Eur J Pharmacol 2020; 879:173139. [PMID: 32343971 DOI: 10.1016/j.ejphar.2020.173139] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 04/19/2020] [Accepted: 04/21/2020] [Indexed: 12/19/2022]
Abstract
Chronic airway inflammatory diseases are characterized by persistent proinflammatory responses in the respiratory tract. Although, several treatment strategies are currently available, lifelong therapy is necessary for most of these diseases. In recent years, phytophenols, namely, flavonoids, derived from fruits and vegetables have been gaining tremendous interest and have been extensively studied due to their low toxicological profile. Naringenin is a bioflavonoid abundantly found in citrus fruits. This substance has shown notable therapeutic potential in various diseases due to its promising diverse biological activities. In this review, we have attempted to review the published studies from the available literature, discussing the molecular level mechanisms of naringenin in different experimental models of airway inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, pulmonary fibrosis and cystic fibrosis. Current evidences have proposed that the anti-inflammatory properties of naringenin play a major role in ameliorating inflammatory disease states. In addition, naringenin also possesses several other biological properties. Despite the proposed mechanisms suggesting remarkable therapeutic benefits, the clinical use of naringenin is, however, hampered by its low solubility and bioavailability. Furthermore, this review also discusses on the studies that utilise nanocarriers as a drug delivery system to address the issue of poor solubility.
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The Nrf2/HO-1 Axis as Targets for Flavanones: Neuroprotection by Pinocembrin, Naringenin, and Eriodictyol. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:4724920. [PMID: 31814878 PMCID: PMC6878820 DOI: 10.1155/2019/4724920] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/20/2019] [Accepted: 09/25/2019] [Indexed: 12/16/2022]
Abstract
Flavanones are a group of flavonoids that derive from their immediate chalcone precursors through the action of chalcone isomerase enzymes. The Aromatic A and B rings, C4-keto group, and the 15-carbon flavonoid skeleton are all evident in flavanones, but a notable absence of C2-C3 double bond and a lack of oxygenation at C-3 position of the C-ring makes them distinctively different from other groups such as flavonols (e.g., quercetin). On the basis of oxygenation level in the B ring, flavanones can vary from each other as exemplified by pinocembrin (no oxygenation), naringenin (4′-hydroxyl), or eriodictyol (3′,4′-dihydroxyl substitution). These groups are generally weaker free radical scavengers as compared to quercetin and derivatives though eriodictyol has a better free radical scavenging profile within the group due to the presence of the catechol functional moiety. In this communication, their antioxidant potential through the induction of antioxidant defenses is scrutinized. These compounds as exemplified by pinocembrin could induce the nuclear factor erythroid 2-related factor 2- (Nrf2-) heme oxygenase-1 (HO-1) axis leading to amelioration of oxidative stress in cellular and animal models. Their neuroprotective effect through such mechanism is discussed.
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Shi R, Su WW, Zhu ZT, Guan MY, Cheng KL, Fan WY, Wei GY, Li PB, Yang ZY, Yao HL. Regulation effects of naringin on diesel particulate matter-induced abnormal airway surface liquid secretion. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 63:153004. [PMID: 31301536 DOI: 10.1016/j.phymed.2019.153004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 06/05/2019] [Accepted: 06/29/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND PM2.5 is closely related to the incidence and mortality of respiratory diseases. Diesel particulate matter (DPM) is the main component of particulate air pollution and an important source of PM2.5. HYPOTHESIS/PURPOSE This study mainly explored the effect of DPM on airway surface liquid (ASL) secretion and the regulation of naringin in this process, to evaluate therapeutic potentials of naringin for the treatment of abnormal secretion of the respiratory tract caused by PM2.5. METHODS The concentration of lysozyme was measured by Lysozyme Assay Kit. Total protein content was determined by the BCA Protein Assay Kit. The concentration of cAMP and MUC5AC, expressions of CFTR, AQP1, and AQP5 proteins were measured by ELISA. Expressions of CFTR, AQP1 and AQP5 mRNA were determined by qPCR. Amount of CFTR on the cell membrane was determined by immunofluorescence. RESULTS The in vitro and in vivo studies had indicated that DPM could inhibit ASL secretion and increased the viscosity of the liquid. Naringin had the functions to attenuate DPM-induced injury, reduce liquid viscosity by reducing MUC5AC and total protein secretion, increase DPM-induced CFTR, AQP1, and AQP5 mRNA and protein expression, positively regulate apical CFTR insertion and promote CFTR activation by increasing intracellular cAMP. CONCLUSION These results demonstrated that naringin had regulating effects on the DPM-induced abnormal secretion of the respiratory tract.
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Affiliation(s)
- Rui Shi
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, Guangdong Engineering & Technology Research Center for Quality and Efficacy Re-evaluation of Post-market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Wei-Wei Su
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, Guangdong Engineering & Technology Research Center for Quality and Efficacy Re-evaluation of Post-market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Ting Zhu
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, Guangdong Engineering & Technology Research Center for Quality and Efficacy Re-evaluation of Post-market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Min-Yi Guan
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, Guangdong Engineering & Technology Research Center for Quality and Efficacy Re-evaluation of Post-market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Ke-Ling Cheng
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, Guangdong Engineering & Technology Research Center for Quality and Efficacy Re-evaluation of Post-market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Wei-Yang Fan
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, Guangdong Engineering & Technology Research Center for Quality and Efficacy Re-evaluation of Post-market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Gu-Yi Wei
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, Guangdong Engineering & Technology Research Center for Quality and Efficacy Re-evaluation of Post-market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Pei-Bo Li
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, Guangdong Engineering & Technology Research Center for Quality and Efficacy Re-evaluation of Post-market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Zhong-Yi Yang
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, Guangdong Engineering & Technology Research Center for Quality and Efficacy Re-evaluation of Post-market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Hong-Liang Yao
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, Guangdong Engineering & Technology Research Center for Quality and Efficacy Re-evaluation of Post-market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
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Bio-mediated synthesis of 5-FU based nanoparticles employing orange fruit juice: a novel drug delivery system to treat skin fibrosarcoma in model animals. Sci Rep 2019; 9:12288. [PMID: 31444363 PMCID: PMC6707153 DOI: 10.1038/s41598-019-48180-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 02/19/2019] [Indexed: 01/10/2023] Open
Abstract
Nano-sized drug delivery systems (NDDS) have been widely exploited to achieve targeted delivery of pharmaco-materials. Traditional pharmaceutical approaches, implied in the synthesis of nano-formulations, are obscure owing to the incompatible physico-chemical properties of the core drug as well as some other factors crucial in development of NDDS. Infact, most of the existing methods used in development of NDDS rely on usage of additives or excipients, a special class of chemicals. Barring few exceptions, the usage of synthetic excipients ought to be curtailed because of several associated undesirable features. Such issues necessitate strategies that lead to development of the synthetic excipient free drug delivery system. Plant based extracts have great potential to induce synthesis of nano-sized particles. Considering this fact, here we propose a prototype employing orange fruit juice (OJ) to facilitate bio-mediated synthesis of nano-sized supra-molecular assemblies of 5-fluorouracil (5-FU), a potent anticancer drug. The as-synthesized 5-FU Nanoparticles (NPs) retained the anti-neoplastic efficacy of the parent compound and induced apoptosis in cancer cells. The novel 5-FU NPs formulation demonstrated enhanced efficacy against DMBA induced experimental fibrosarcoma in the mouse model when compared to the micro-sized crystals of parent 5-FU drug.
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Ahmad A, Fauzia E, Kumar M, Mishra RK, Kumar A, Khan MA, Raza SS, Khan R. Gelatin-Coated Polycaprolactone Nanoparticle-Mediated Naringenin Delivery Rescue Human Mesenchymal Stem Cells from Oxygen Glucose Deprivation-Induced Inflammatory Stress. ACS Biomater Sci Eng 2018; 5:683-695. [PMID: 33405831 DOI: 10.1021/acsbiomaterials.8b01081] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Ischemic stroke involves pro-inflammatory species, which implicates inflammation in the disease mechanism. Recent studies indicate that the prevalence of therapeutic choice such as stem cell transplantation has seen an upsurge in ischemic stroke. However, after transplantation the fate of transplanted cells is largely unknown. Human mesenchymal stem cells (MSCs), due to their robust survival rate upon transplantation in brain tissue, are being widely employed to treat ischemic stroke. In the present study, we have evaluated naringenin-loaded gelatin-coated polycaprolactone nanoparticles (nar-gel-c-PCL NPs) to rescue MSCs against oxygen glucose deprived insult. Naringenin, due to its strong anti-inflammatory effects, remains a therapeutic choice in neurological disorders. Though, the low solubility and inefficient delivery remain challenges in using naringenin as a therapeutic drug. The present study showed that inflammation occurred in MSCs during their treatment with oxygen glucose deprivation (OGD) and was well overturned by treatment with nar-gel-c-PCL NPs. In brief, the results indicated that nar-gel-c-PCL NPs were able to protect the loss of cell membrane integrity and restored neuronal morphology. Then nar-gel-c-PCL NPs successfully protected the human MSCs against OGD-induced inflammation as evident by reduced level of pro-inflammatory cytokine (TNF-α, IFN-γ, and IL-1β) and other inflammatory biomarkers (COX2, iNOS, and MPO activity). Therefore, the modulation of inflammation by treatment with nar-gel-c-PCL NPs in MSCs could provide a novel strategy to improve MSC-based therapy, and thus, our nanoformulation may find a wide therapeutic application in ischemic stroke and other neuro-inflammatory diseases.
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Affiliation(s)
- Anas Ahmad
- Department of Nano-Therapeutics, Institute of Nano Science and Technology, Habitat Centre, Phase 10, Sector 64, Mohali, Punjab 160062, India
| | - Eram Fauzia
- Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College Hospital, Sarfarazganj, Lucknow-226003, India
| | - Manish Kumar
- Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College Hospital, Sarfarazganj, Lucknow-226003, India
| | - Rakesh Kumar Mishra
- Department of Nano-Therapeutics, Institute of Nano Science and Technology, Habitat Centre, Phase 10, Sector 64, Mohali, Punjab 160062, India
| | - Ajay Kumar
- Department of Nano-Therapeutics, Institute of Nano Science and Technology, Habitat Centre, Phase 10, Sector 64, Mohali, Punjab 160062, India
| | - Mohsin Ali Khan
- Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College Hospital, Sarfarazganj, Lucknow-226003, India
| | - Syed Shadab Raza
- Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College Hospital, Sarfarazganj, Lucknow-226003, India.,Department of Stem Cell Biology and Regenerative Medicine, Era's Lucknow Medical College Hospital, Sarfarazganj, Lucknow-226003, India
| | - Rehan Khan
- Department of Nano-Therapeutics, Institute of Nano Science and Technology, Habitat Centre, Phase 10, Sector 64, Mohali, Punjab 160062, India
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Teng J, Li Y, Yu W, Zhao Y, Hu X, Tao NP, Wang M. Naringenin, a common flavanone, inhibits the formation of AGEs in bread and attenuates AGEs-induced oxidative stress and inflammation in RAW264.7 cells. Food Chem 2018; 269:35-42. [DOI: 10.1016/j.foodchem.2018.06.126] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 06/24/2018] [Accepted: 06/25/2018] [Indexed: 12/13/2022]
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Intranasal curcumin protects against LPS-induced airway remodeling by modulating toll-like receptor-4 (TLR-4) and matrixmetalloproteinase-9 (MMP-9) expression via affecting MAP kinases in mouse model. Inflammopharmacology 2018; 27:731-748. [PMID: 30470954 DOI: 10.1007/s10787-018-0544-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 11/02/2018] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Bacterial infections can exacerbate asthmatic inflammation depending on lipopolysaccharide (LPS) composition, the outermost component of cell wall, its exposure timings as well as host's immune status. In present study, Balb/c mice were exposed to antigen (ovalbumin) and LPS simultaneously to establish an asthmatic model. Curcumin (diferuloylmethane), well known for its anti-inflammatory potential, was administered through intranasal route 1 h before LPS and OVA (ovalbumin) exposure to evaluate its efficacy against airway structural changes. METHODS Inflammatory cell infiltration in lungs was measured by flow cytometry and further eosinophils were especially measured by immunofluorescence detection of major basic protein (MBP) as marker of eosinophilc granule protein. We also measured reactive oxygen species (ROS) in BALF by spectrofluorometry. MMP-9 activity was evaluated by gelatin zymography and mRNA expressions of MMP-9, TIMP-1, TGF-β1, IL-13, Collagen-1 and TLR-4 were measured in lungs. Protein expression of MAP kinases (P-ERK, P-JNK, P-p38), TLR-4, Cox-2, Lox-5 and Eotaxin was measured by western blotting. Hydroxyproline level and masson's trichrome staining were used to evaluate collagen deposition in lung. RESULTS Exposure to LPS (0.1 µg) exacerbates airway inflammation and induces structural changes in lungs by enhanced ROS production, collagen deposition, expression of genes involved in airway remodeling and activation of MAP kinases pathway enzymes. Intranasal curcumin pretreatment had significantly suppressed inflammatory mediators and airway remodeling proteins. CONCLUSION Our results strongly suggest that intranasal curcumin effectively protects LPS-induced airway inflammation and structural changes by modulating genes involved in airway remodeling in safer way; hence, it can be considered as supplementary alternative towards asthma treatments.
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Dong X, Zhong N, Fang Y, Cai Q, Lu M, Lu Q. MicroRNA 27b-3p Modulates SYK in Pediatric Asthma Induced by Dust Mites. Front Pediatr 2018; 6:301. [PMID: 30406061 PMCID: PMC6204538 DOI: 10.3389/fped.2018.00301] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 09/25/2018] [Indexed: 01/09/2023] Open
Abstract
The PI3K-AKT pathway is known to regulate cytokines in dust mite-induced pediatric asthma. However, the underlying molecular steps involved are not clear. In order to clarify further the molecular steps, this study investigated the expression of certain genes and the involvement of miRNAs in the PI3K-AKT pathway, which might affect the resultant cytokine-secretion. in-vivo and in-vitro ELISA, qRT-PCR and microarrays analyses were used in this study. A down-expression of miRNA-27b-3p in dust mite induced asthma group (group D) was found by microarray analysis. This was confirmed by qRT-PCR that found the miRNA-27b-3p transcripts that regulated the expression of SYK and EGFR were also significantly decreased (p < 0.01) in group D. The transcript levels of the SYK and PI3K genes were higher, while those of EGFR were lower in the former group. Meanwhile, we found significant differences in plasma concentrations of some cytokines between the dust mite-induced asthma subjects and the healthy controls. On the other hand, this correlated with the finding that the transcripts of SYK and its downstream PI3K were decreased in HBE transfected with miRNA-27b-3p, but were increased in HBE transfected with the inhibitor in vitro. Our results indicate that the differential expression of the miRNAs in dust mite-induced pediatric asthma may regulate their target gene SYK and may have an impact on the PI3K-AKT pathway associated with the production of cytokines. These findings should add new insight into the pathogenesis of pediatric asthma.
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Affiliation(s)
- Xiaoyan Dong
- Department of Pulmonary, Shanghai Children's Hospital, Shanghai, China
- Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai, China
- Shanghai Children's Hospital, Shanghai, China
| | - Nanbert Zhong
- Shanghai Children's Hospital, Shanghai, China
- Department of Human Genetics, Institute for Basic Research in Developmental Disabilities, Staten Island, NY, United States
- Chinese Alliance of Translational Medicine for Maternal and Children's Health, Beijing, China
- Peking University Center of Medical Genetics, Peking University Health Science Centre, Beijing, China
| | - Yudan Fang
- Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai, China
- Shanghai Children's Hospital, Shanghai, China
| | - Qin Cai
- Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai, China
- Shanghai Children's Hospital, Shanghai, China
| | - Min Lu
- Department of Pulmonary, Shanghai Children's Hospital, Shanghai, China
- Shanghai Children's Hospital, Shanghai, China
| | - Quan Lu
- Department of Pulmonary, Shanghai Children's Hospital, Shanghai, China
- Shanghai Children's Hospital, Shanghai, China
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Tang L, Chen Q, Sun L, Zhu L, Liu J, Meng Z, Ni Z, Wang X. Curcumin suppresses MUC5AC production via interfering with the EGFR signaling pathway. Int J Mol Med 2018; 42:497-504. [PMID: 29620257 DOI: 10.3892/ijmm.2018.3609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 03/23/2018] [Indexed: 11/06/2022] Open
Abstract
Excessive mucin production in the airway may contribute to airway inflammatory diseases. Curcumin has been reported to prevent mucin 5AC (MUC5AC) production in human airway epithelial cells; however, the molecular targets of curcumin involved in regulating MUC5AC expression have remained elusive. The present study aimed to elucidate the molecular mechanisms by which curcumin regulates MUC5AC production, utilizing the NCI‑H292 human airway epithelial cell line featuring MUC5AC hypersecretion. Curcumin was able to counteract the endothelial growth factor (EGF)‑stimulated mRNA and protein expression of MUC5AC. In addition, curcumin treatment prevented EGF‑induced phosphorylation of EGF receptor (EGFR) as well as the downstream AKT and signal transducer and activator of transcription 3 (STAT3), while inhibition of PI3K and STAT3 signaling significantly attenuated the expression of MUC5AC that was induced by EGF. Furthermore, EGF‑induced increases in the levels of phosphorylated STAT3 in the nuclear fraction were inhibited by curcumin and PI3K inhibitors. In addition, treatment with curcumin significantly decreased MUC5AC and EGFR expression in a time‑dependent manner under basal conditions. These results demonstrated that curcumin inhibited MUC5AC protein expression in NCI‑H292 cells under basal conditions as well under EGF stimulation. This inhibition was accompanied by decreased activation of the EGFR/AKT/STAT3 pathway and reduced EGFR expression, which indicated that curcumin may have a dual role in interfering with the EGFR signaling pathway and inhibiting mucin expression in human airway epithelial cells.
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Affiliation(s)
- Lingling Tang
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Qingge Chen
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Li Sun
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Linyun Zhu
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Jinjin Liu
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Ziyu Meng
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Zhenhua Ni
- Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Xiongbiao Wang
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
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Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis. Oncotarget 2018; 7:83951-83963. [PMID: 27924062 PMCID: PMC5356637 DOI: 10.18632/oncotarget.13796] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 11/22/2016] [Indexed: 12/20/2022] Open
Abstract
Accumulation of hydrophobic bile acids in the liver contributes to cholestatic liver injury. Inflammation induced by excessive bile acids is believed to play a crucial role, however, the mechanisms of bile acids triggered inflammatory response remain unclear. Recent studies have highlighted the effect of NLRP3 inflammasome in mediating liver inflammation and fibrosis. In this study, we for the first time showed that chenodeoxycholic acid (CDCA), the major hydrophobic primary bile acid involved in cholestatic liver injury, could dose-dependently induce NLRP3 inflammasome activation and secretion of pro-inflammatory cytokine-IL-1β in macrophages by promoting ROS production and K+ efflux. Mechanistically, CDCA triggered ROS formation in part through TGR5/EGFR downstream signaling, including protein kinase B, extracellular regulated protein kinases and c-Jun N-terminal kinase pathways. Meanwhile, CDCA also induced ATP release from macrophages which subsequently causes K+ efflux via P2X7 receptor. Furthermore, in vivo inhibition of NLRP3 inflammasome with caspase-1 inhibitor dramatically decreased mature IL-1β level of liver tissue and ameliorated liver fibrosis in bile duct ligation (BDL) mouse model. In conclusion, excessive CDCA may represent an endogenous danger signal to activate NLRP3 inflammasome and initiate liver inflammation during cholestasis. Our finding offers a mechanistic basis to ameliorate cholestatic liver fibrosis by targeting inflammasome activation.
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de Oliveira MR, Andrade CMB, Fürstenau CR. Naringenin Exerts Anti-inflammatory Effects in Paraquat-Treated SH-SY5Y Cells Through a Mechanism Associated with the Nrf2/HO-1 Axis. Neurochem Res 2018; 43:894-903. [DOI: 10.1007/s11064-018-2495-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 01/27/2018] [Accepted: 02/02/2018] [Indexed: 12/16/2022]
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Lee S, She J, Deng B, Kim J, de Andrade M, Na J, Sun Z, Wampfler JA, Cunningham JM, Wu Y, Limper AH, Aubry MC, Wendt C, Biterman P, Yang P, Lou Z. Multiple-level validation identifies PARK2 in the development of lung cancer and chronic obstructive pulmonary disease. Oncotarget 2018; 7:44211-44223. [PMID: 27329585 PMCID: PMC5190090 DOI: 10.18632/oncotarget.9954] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 05/09/2016] [Indexed: 12/31/2022] Open
Abstract
An important precursor to lung cancer development is chronic obstructive pulmonary disease (COPD), independent of exposure to tobacco smoke. Both diseases are associated with increased host susceptibility, inflammation, and genomic instability. However, validation of the candidate genes and functional confirmation to test shared genetic contribution and cellular mechanisms to the development of lung cancer in patients with COPD remains underexplored. Here, we show that loss of PARK2 (encoding Parkin) increases the expression of proinflammation factors as well as nuclear NF-κB localization, suggesting a role of PARK2 loss in inflammation. Additional exploration showed that PARK2 deficiency promotes genomic instability and cell transformation. This role of PARK2 in inflammation and chromosome instability provides a potential link among Parkin, COPD and lung cancer. A further comprehensive validation of 114 informative single nucleotide polymorphism (SNP) variants of PARK2, in 2,484 cases and controls with well-defined lung cancer and COPD phenotypes, found rs577876, rs6455728 and rs9346917 (p<0.01) to be significantly associated with lung cancer development in people with COPD. Our findings support the evidence that PARK2 might have a tumor suppressor role in the development of COPD and lung cancer.
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Affiliation(s)
- SeungBaek Lee
- Division of Oncology Research, Mayo Clinic, Rochester, MN, USA
| | - Jun She
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Bo Deng
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.,Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China
| | - JungJin Kim
- Division of Oncology Research, Mayo Clinic, Rochester, MN, USA
| | - Mariza de Andrade
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Jie Na
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Zhifu Sun
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Jason A Wampfler
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | | | - Yanhong Wu
- Genomics Shared Resource, Mayo Clinic, Rochester, MN, USA
| | - Andrew H Limper
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Chris Wendt
- Department of Medicine, Pulmonary Division, University of Minnesota, Minneapolis, MN, USA.,Department of Medicine, Pulmonary Section, Minneapolis VA Medical Center, Minneapolis, MN, USA
| | - Peter Biterman
- Department of Medicine, Pulmonary Division, University of Minnesota, Minneapolis, MN, USA
| | - Ping Yang
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Zhenkun Lou
- Division of Oncology Research, Mayo Clinic, Rochester, MN, USA
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Wang L, Huang Z, Huang W, Chen X, Shan P, Zhong P, Khan Z, Wang J, Fang Q, Liang G, Wang Y. Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress. Sci Rep 2017; 8:45917. [PMID: 28374780 PMCID: PMC5379239 DOI: 10.1038/srep45917] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 03/06/2017] [Indexed: 12/31/2022] Open
Abstract
Atherosclerosis is a progressive disease leading to loss of vascular homeostasis and entails fibrosis, macrophage foam cell formation, and smooth muscle cell proliferation. Recent studies have reported that epidermal growth factor receptor (EGFR) is involved vascular pathophysiology and in the regulation of oxidative stress in macrophages. Although, oxidative stress and inflammation play a critical role in the development of atherosclerosis, the underlying mechanisms are complex and not completely understood. In the present study, we have elucidated the role of EGFR in high-fat diet-induced atherosclerosis in apolipoprotein E null mice. We show increased EGFR phosphorylation and activity in atherosclerotic lesion development. EGFR inhibition prevented oxidative stress, macrophage infiltration, induction of pro-inflammatory cytokines, and SMC proliferation within the lesions. We further show that EGFR is activated through toll-like receptor 4. Disruption of toll-like receptor 4 or the EGFR pathway led to reduced inflammatory activity and foam cell formation. These studies provide evidence that EGFR plays a key role on the pathogenesis of atherosclerosis, and suggests that EGFR may be a potential therapeutic target in the prevention of atherosclerosis development.
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Affiliation(s)
- Lintao Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Zhouqing Huang
- Department of Cardiology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Weijian Huang
- Department of Cardiology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xuemei Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Peiren Shan
- Department of Cardiology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Peng Zhong
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Zia Khan
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A5C1, Canada
| | - Jingying Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Qilu Fang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Yi Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
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Hu D, Zhang Z, Ke X, Kang H, Hong S. A functional variant of miRNA-149 confers risk for allergic rhinitis and comorbid asthma in Chinese children. Int J Immunogenet 2017; 44:62-70. [PMID: 28181414 DOI: 10.1111/iji.12307] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 12/15/2016] [Accepted: 01/14/2017] [Indexed: 12/18/2022]
Abstract
The prevalence of allergic rhinitis (AR) and asthma has been increasing, and the comorbidity rates of these diseases are very high. Here, 176 AR patients, 124 patients with comorbid AR and asthma (AR-A) and 206 healthy Chinese children as controls were included in a case-control study. Six single-nucleotide polymorphisms (SNPs), miR-146a (rs2910164, rs57095329 and rs6864584), miR-196a2 (rs11614913), miR-499 (rs3746444) and miR-149 (rs2292832), were genotyped. The prevalence of homozygous miR-149 (rs2292832) CC genotype and C allele were considerably increased in AR and AR-A patients, compared with the controls. AR-A group showed higher frequencies of CC genotype and C allele of rs2292832 than AR group. No significant difference in the genotypic and allelic frequencies of other miRNA SNPs was found between the groups. MiR-149 levels in peripheral blood mononuclear cells (PBMCs) were significantly lower in CC (variant type) cases compared with TT (wild-type) cases. In further experiments, PBMCs obtained from the healthy controls with CC, CT and TT genotypes were stimulated by house dust mite extracts, which led to a significant decrease in the levels of miR-149 in PBMCs obtained from CC and TT individuals. This decrease was more pronounced in CC compared with TT cases. Our results demonstrate that miR-149 rs2292832 variant is not only strongly associated with AR and AR-A, but it may lead to an increase in the susceptibility to allergies following the stimulation with an allergen, through the changes in miR149 expression. Additionally, AR patients with CC genotypes were shown to be more susceptible to asthma.
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Affiliation(s)
- D Hu
- Department of Otorhinolaryngology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Z Zhang
- Department of Otorhinolaryngology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - X Ke
- Department of Otorhinolaryngology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - H Kang
- Department of Otorhinolaryngology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - S Hong
- Department of Otorhinolaryngology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway. Sci Rep 2016; 6:39735. [PMID: 28004841 PMCID: PMC5177915 DOI: 10.1038/srep39735] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 11/28/2016] [Indexed: 12/13/2022] Open
Abstract
Excessive activation of the TLR4 signalling pathway is critical for inflammation-associated disorders, while negative regulators play key roles in restraining TLR4 from over-activation. Naringenin is a citrus flavonoid with remarkable anti-inflammatory activity, but the mechanisms underlying its inhibition of LPS/TLR4 signalling are less clear. This study investigated the molecular targets and therapeutic effects of naringenin in vitro and in vivo. In LPS-stimulated murine macrophages, naringenin suppressed the expression of TNF-α, IL-6, TLR4, inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX2) and NADPH oxidase-2 (NOX2). Naringenin also inhibited NF-κB and mitogen-activated protein kinase (MAPK) activation. However, it did not affect the IRF3 signalling pathway or interferon production, which upregulate activating transcription factor 3 (ATF3), an inducible negative regulator of TLR4 signalling. Naringenin was demonstrated to directly increase ATF3 expression. Inhibition of AMPK and its upstream calcium-dependent signalling reduced ATF3 expression and dampened the anti-inflammatory activity of naringenin. In murine endotoxaemia models, naringenin ameliorated pro-inflammatory reactions and improved survival. Furthermore, it induced AMPK activation in lung tissues, which was required for ATF3 upregulation and the enhanced anti-inflammatory activity. Overall, this study reveals a novel mechanism of naringenin through AMPK-ATF3-dependent negative regulation of the LPS/TLR4 signalling pathway, which thereby confers protection against murine endotoxaemia.
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Yang D, Jin M, Bai C, Zhou J, Shen Y. Peroxiredoxin 6 suppresses Muc5ac overproduction in LPS-induced airway inflammation through H 2O 2-EGFR-MAPK signaling pathway. Respir Physiol Neurobiol 2016; 236:84-90. [PMID: 27884794 DOI: 10.1016/j.resp.2016.11.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 11/20/2016] [Accepted: 11/20/2016] [Indexed: 12/22/2022]
Abstract
Mucus hypersecretion is a prominent mechanism in airway inflammation. Muc5ac is a major component of mucus and can be activated by reactive oxygen species (ROS). Peroxiredoxin 6 (Prdx6) highly expresses in airway epithelium and protects the airway from oxidative stress. In this study, we investigated the roles of Prdx6 in lipopolysaccharide (LPS)-induced mucin production in mice. We found that the levels of H2O2 and the Muc5ac mRNA were significantly increased in Prdx6 (-/-) mice compared to those in C57BL/6J mice after LPS instillation, which were markedly inhibited by epithelial growth factor receptor (EGFR) inhibitor Elrotinib. In vitro studies showed that mRNA levels of Prdx6 were decreased while H2O2 and Muc5ac were increased in a dose-dependent manner after LPS exposure, with significant increase in Prdx6 knockdown bronchial epithelial cells compared with those in normal epithelial cells. LPS-induced Muc5ac release was significantly inhibited by EGFR inhibitor, p38 inhibitor and JNK inhibitor, but not ERK1/2 inhibitor, indicating that the H2O2-EGFR-MAPK pathway is likely involved in the responses. This study indicated that Prdx6 decreased LPS-induced Muc5ac increase and played important roles in mucin hypersecretion after LPS exposure.
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Affiliation(s)
- Dong Yang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Meiling Jin
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chunxue Bai
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Yao Shen
- Department of Pulmonary Medicine, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
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Lim W, Song G. Naringenin-induced migration of embrynoic trophectoderm cells is mediated via PI3K/AKT and ERK1/2 MAPK signaling cascades. Mol Cell Endocrinol 2016; 428:28-37. [PMID: 26994515 DOI: 10.1016/j.mce.2016.03.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 03/13/2016] [Accepted: 03/15/2016] [Indexed: 12/23/2022]
Abstract
For successful pregnancy, a well-coordinated network of growth factors, nutrients and hormones is required for fetal-maternal interactions. Naringenin, as a weak phytoestrogen, improves diabetes, inflammation, neuronal diseases, cardiovascular diseases and cancers. However, the role of naringenin in migration mechanism(s) of peri-implantation conceptuses is unknown. Therefore, in the present study, we determined the effects of naringenin on migration of porcine trophectoderm (pTr) cells, which is a known in vitro model for research on trophectoderm cell biology and placental-fetal developmental biology, in order to assess intracellular signal transduction pathways activated by naringenin. Migration of pTr cells increased in a dose-dependent manner in response to naringenin. Also, naringenin activated the phosphorylation of AKT and ERK1/2 proteins in a dose-dependent manner and those proteins were abundant mainly in the cytoplasm of naringenin-treated pTr cells. Within 30 min after treatment with 20 μM naringenin, the abundance of phosphorylated EKR1/2, P70S6K, P90RSK and S6K proteins increased, and then returned to basal levels by 120 min whereas the abundance of AKT increased gradually to 120 min post-treatment. However, the phosphorylation of AKT, P70S6K, P90RSK and S6K was reduced in naringenin-induced pTr cells pre-treated with a PI3K inhibitor (LY294002). Also, a MEK1/2 inhibitor (U0126) significantly decreased naringenin-induced phosphorylation of ERK1/2, P70S6K and S6K proteins in pTr cells. Moreover, the naringenin-stimulated migration of pTr cells was suppressed by LY294002 and U0126. Collectively, results of the present study suggest that naringenin supports migration of pTr cells through PI3K/AKT and ERK1/2 MAPK signaling pathways crucial for orchestrating conceptus-uterine interactions.
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Affiliation(s)
- Whasun Lim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea
| | - Gwonhwa Song
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea.
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40
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Manchope MF, Calixto-Campos C, Coelho-Silva L, Zarpelon AC, Pinho-Ribeiro FA, Georgetti SR, Baracat MM, Casagrande R, Verri WA. Naringenin Inhibits Superoxide Anion-Induced Inflammatory Pain: Role of Oxidative Stress, Cytokines, Nrf-2 and the NO-cGMP-PKG-KATP Channel Signaling Pathway. PLoS One 2016; 11:e0153015. [PMID: 27045367 PMCID: PMC4821586 DOI: 10.1371/journal.pone.0153015] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 03/22/2016] [Indexed: 12/11/2022] Open
Abstract
In the present study, the effect and mechanism of action of the flavonoid naringenin were evaluated in superoxide anion donor (KO2)-induced inflammatory pain in mice. Naringenin reduced KO2-induced overt-pain like behavior, mechanical hyperalgesia, and thermal hyperalgesia. The analgesic effect of naringenin depended on the activation of the NO−cGMP−PKG−ATP-sensitive potassium channel (KATP) signaling pathway. Naringenin also reduced KO2-induced neutrophil recruitment (myeloperoxidase activity), tissue oxidative stress, and cytokine production. Furthermore, naringenin downregulated KO2-induced mRNA expression of gp91phox, cyclooxygenase (COX)-2, and preproendothelin-1. Besides, naringenin upregulated KO2-reduced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mRNA expression coupled with enhanced heme oxygenase (HO-1) mRNA expression. In conclusion, the present study demonstrates that the use of naringenin represents a potential therapeutic approach reducing superoxide anion-driven inflammatory pain. The antinociceptive, anti-inflammatory and antioxidant effects are mediated via activation of the NO−cGMP−PKG−KATP channel signaling involving the induction of Nrf2/HO-1 pathway.
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Affiliation(s)
- Marília F. Manchope
- Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil
| | - Cássia Calixto-Campos
- Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil
| | - Letícia Coelho-Silva
- Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil
| | - Ana C. Zarpelon
- Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil
| | - Felipe A. Pinho-Ribeiro
- Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil
| | - Sandra R. Georgetti
- Departamento de Ciências Farmacêuticas, Centro de Ciências de Saúde, Universidade Estadual de Londrina, Londrina, Brazil
| | - Marcela M. Baracat
- Departamento de Ciências Farmacêuticas, Centro de Ciências de Saúde, Universidade Estadual de Londrina, Londrina, Brazil
| | - Rúbia Casagrande
- Departamento de Ciências Farmacêuticas, Centro de Ciências de Saúde, Universidade Estadual de Londrina, Londrina, Brazil
| | - Waldiceu A. Verri
- Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil
- * E-mail:
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Lanciotti A, Brignone MS, Visentin S, De Nuccio C, Catacuzzeno L, Mallozzi C, Petrini S, Caramia M, Veroni C, Minnone G, Bernardo A, Franciolini F, Pessia M, Bertini E, Petrucci TC, Ambrosini E. Megalencephalic leukoencephalopathy with subcortical cysts protein-1 regulates epidermal growth factor receptor signaling in astrocytes. Hum Mol Genet 2016; 25:1543-58. [DOI: 10.1093/hmg/ddw032] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 02/03/2016] [Indexed: 01/13/2023] Open
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Martinez RM, Pinho-Ribeiro FA, Steffen VS, Silva TCC, Caviglione CV, Bottura C, Fonseca MJV, Vicentini FTMC, Vignoli JA, Baracat MM, Georgetti SR, Verri WA, Casagrande R. Topical Formulation Containing Naringenin: Efficacy against Ultraviolet B Irradiation-Induced Skin Inflammation and Oxidative Stress in Mice. PLoS One 2016; 11:e0146296. [PMID: 26741806 PMCID: PMC4704734 DOI: 10.1371/journal.pone.0146296] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 12/15/2015] [Indexed: 12/23/2022] Open
Abstract
Naringenin (NGN) exhibits anti-inflammatory and antioxidant activities, but it remains undetermined its topical actions against ultraviolet B (UVB)-induced inflammation and oxidative stress in vivo. The purpose of this study was to evaluate the physicochemical and functional antioxidant stability of NGN containing formulations, and the effects of selected NGN containing formulation on UVB irradiation-induced skin inflammation and oxidative damage in hairless mice. NGN presented ferric reducing power, ability to scavenge 2,2′-azinobis (3-ethylbenzothiazoline- 6-sulfonic acid) (ABTS) and hydroxyl radical, and inhibited iron-independent and dependent lipid peroxidation. Among the three formulations containing NGN, only the F3 kept its physicochemical and functional stability over 180 days. Topical application of F3 in mice protected from UVB-induced skin damage by inhibiting edema and cytokine production (TNF-α, IL-1β, IL-6, and IL-10). Furthermore, F3 inhibited superoxide anion and lipid hydroperoxides production and maintained ferric reducing and ABTS scavenging abilities, catalase activity, and reduced glutathione levels. In addition, F3 maintained mRNA expression of cellular antioxidants glutathione peroxidase 1, glutathione reductase and transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), and induced mRNA expression of heme oxygenase-1. In conclusion, a formulation containing NGN may be a promising approach to protecting the skin from the deleterious effects of UVB irradiation.
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Affiliation(s)
- Renata M. Martinez
- Departamento de Ciências Farmacêuticas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039–440 Londrina, Paraná, Brasil
| | - Felipe A. Pinho-Ribeiro
- Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057–970 Londrina, Paraná, Brasil
| | - Vinicius S. Steffen
- Departamento de Ciências Farmacêuticas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039–440 Londrina, Paraná, Brasil
| | - Thais C. C. Silva
- Departamento de Ciências Farmacêuticas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039–440 Londrina, Paraná, Brasil
| | - Carla V. Caviglione
- Departamento de Ciências Farmacêuticas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039–440 Londrina, Paraná, Brasil
| | - Carolina Bottura
- Departamento de Ciências Farmacêuticas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039–440 Londrina, Paraná, Brasil
| | - Maria J. V. Fonseca
- Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Av. do Café s/n, 14049–903 Ribeirão Preto, São Paulo, Brasil
| | - Fabiana T. M. C. Vicentini
- Farmacore Biotecnologia LTDA, Rua Edson Souto, 738—Anexo I, Lagoinha, 14095–250 Ribeirão Preto, São Paulo, Brasil
| | - Josiane A. Vignoli
- Departamento de Bioquímica e Biotecnologia, Centro de Ciências Exatas, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057–970 Londrina, Paraná, Brazil
| | - Marcela M. Baracat
- Departamento de Ciências Farmacêuticas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039–440 Londrina, Paraná, Brasil
| | - Sandra R. Georgetti
- Departamento de Ciências Farmacêuticas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039–440 Londrina, Paraná, Brasil
| | - Waldiceu A. Verri
- Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057–970 Londrina, Paraná, Brasil
- * E-mail: (RC); (WAV)
| | - Rubia Casagrande
- Departamento de Ciências Farmacêuticas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039–440 Londrina, Paraná, Brasil
- * E-mail: (RC); (WAV)
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Seaweed (Eucheuma cottonii) reduced inflammation, mucin synthesis, eosinophil infiltration and MMP-9 expressions in asthma-induced rats compared to Loratadine. J Funct Foods 2015. [DOI: 10.1016/j.jff.2015.10.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Hsia TC, Yin MC. s-Ethyl Cysteine ands-Methyl Cysteine Protect Human Bronchial Epithelial Cells Against Hydrogen Peroxide Induced Injury. J Food Sci 2015; 80:H2094-101. [DOI: 10.1111/1750-3841.12973] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 06/15/2015] [Indexed: 12/15/2022]
Affiliation(s)
- Te-chun Hsia
- Dept. of Respiratory Therapy; China Medical Univ; Taichung City Taiwan
- Dept. of Internal Medicine; China Medical Univ. Hospital; Taichung City Taiwan
| | - Mei-chin Yin
- Dept. of Health and Nutrition Biotechnology; Asia Univ; Taichung City Taiwan
- Dept. of Nutrition; China Medical Univ; Taichung City Taiwan
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Tsao SM, Yin MC. Antioxidative and antiinflammatory activities of asiatic acid, glycyrrhizic acid, and oleanolic acid in human bronchial epithelial cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:3196-3204. [PMID: 25779760 DOI: 10.1021/acs.jafc.5b00102] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Protective effects of triterpenic acids, asiatic acid (AA), glycyrrhizic acid (GA), or oleanolic acid (OA), for two human bronchial epithelial cells, 16HBE and BEAS-2B cells, against hydrogen peroxide (H2O2) induced injury were examined. Cells were pretreated by triterpenic acid at 4 or 8 μmol/L and followed by H2O2 treatment. Results showed that H2O2 significantly upregulated both Bax and cleaved caspase-3 expression, and also downregulated Bcl-2 expression in test cells. AA at these doses retained Bcl-2 expression, but GA and OA only at 8 μmol/L reserved Bcl-2 expression. Test triterpenic acids lowered cleaved caspase-3 expression dose-dependently. H2O2 treatment lowered Na(+)-K(+)-ATPase activity and mitochondrial membrane potential in cells. Triterpenic acid pretreatments significantly maintained mitochondrial membrane potential and Na(+)-K(+)-ATPase activity. H2O2 enhanced reactive oxygen species, interleukin-6, tumor necrosis factor-α, and prostaglandin E2 levels in test cells. Three triterpenic acid treatments dose-dependently reversed these changes. H2O2 promoted the protein expression of p47(phox), gp91(phox), cyclooxygenase-2 (COX-2), mitogen-activated protein kinase, and nuclear factor-κB (NF-κB). AA, GA, or OA pretreatments dose-dependently downregulated the expression of p47(phox), COX-2, NF-κB p65, and p-p38 but only at 8 μmol/L decreased gp91(phox) expression. These results support that these triterpenic acids could protect bronchial epithelial cells to attenuate apoptotic, oxidative, and inflammatory stress.
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Affiliation(s)
- Shih-Ming Tsao
- †Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan
- ‡Sections of Infectious Diseases and Chest Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung City, Taiwan
| | - Mei-Chin Yin
- §Department of Health and Nutrition Biotechnology, Asia University, Taichung City, Taiwan
- ∥Department of Nutrition, China Medical University, Taichung City, Taiwan
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Liang D, Zhong P, Hu J, Lin F, Qian Y, Xu Z, Wang J, Zeng C, Li X, Liang G. EGFR inhibition protects cardiac damage and remodeling through attenuating oxidative stress in STZ-induced diabetic mouse model. J Mol Cell Cardiol 2015; 82:63-74. [PMID: 25758431 DOI: 10.1016/j.yjmcc.2015.02.029] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 02/14/2015] [Accepted: 02/27/2015] [Indexed: 12/30/2022]
Abstract
Diabetes mellitus is strongly associated with cardiomyopathy. The underlying mechanisms for the development of diabetic cardiomyopathy are complex and not completely understood. Recent studies showed that epidermal growth factor receptors (EGFRs) are involved in diabetes-induced cardiac injury. However, the role of EGFR in the diabetic heart has yet to be confirmed. The aim of the present study is to further determine the role of EGRF in the pathogenesis of diabetic heart injury. The type 1 diabetic mice induced by streptozotocin were treated with EGFR inhibitors (AG1478 and 451) for 8 weeks, respectively. It was observed that diabetes induced phospohorylation of EGFR and AKT, increased cardiac ROS levels, and ultimately led to cardiac remodeling including cardiac hypertrophy, disorganization, apoptosis, and fibrosis, while all these molecular and pathological alterations were attenuated by the treatment with EGFR inhibitors. In vitro, either pharmacological inhibition of EGFR/AKT or sh-RNA silencing of EGFR significantly inhibited high concentration glucose (HG)-induced ROS generation and subsequently cell apoptosis in both cardiac H9C2 cells and primary rat cardiomyocytes, respectively. The ROS reduction by EGFR inhibitor was associated with the decreased NADPH oxidase activity and expression in H9c2 cells. HG-induced cardiomyocyte injuries were also reduced by NAC, an inhibitor of ROS. This study provides evidence that EGFR has a key role in the pathogenesis of STZ-induced diabetic cardiac damage and remodeling via ROS generation, and suggests that EGFR may be a potential target in treating diabetic cardiomyopathy.
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Affiliation(s)
- Dandan Liang
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Peng Zhong
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Cardiology, The 5th Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Jie Hu
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Feng Lin
- Department of Gynaecology, The 1st Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yuanyuan Qian
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zheng Xu
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jingying Wang
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chunlai Zeng
- Department of Cardiology, The 5th Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Xiaokun Li
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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Choi JH, Jin SW, Kim HG, Choi CY, Lee HS, Ryu SY, Chung YC, Hwang YJ, Um YJ, Jeong TC, Jeong HG. Saponins, especially platyconic acid A, from Platycodon grandiflorum reduce airway inflammation in ovalbumin-induced mice and PMA-exposed A549 cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:1468-1476. [PMID: 25590691 DOI: 10.1021/jf5043954] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
We investigated the inhibitory effects of Platycodon grandiflorum root-derived saponins (Changkil saponins: CKS) on ovalbumin-induced airway inflammation in mice. CKS suppressed leukocytes number, IgE, Th1/Th2 cytokines, and MCP-1 chemokine secretion in bronchoalveolar lavage fluid. Also, ovalbumin-increased MUC5AC, MMP-2/9, and TIMP-1/-2 mRNA expression, NF-κB activation, leukocytes recruitment, and mucus secretion were inhibited by CKS treatment. Moreover, the active component of CKS, platyconic acid A (PA), suppressed PMA-induced MUC5AC mRNA expression (from 2.1 ± 0.2 to 1.1 ± 0.1) by inhibiting NF-κB activation (from 2.3 ± 0.2 to 1.2 ± 0.1) via Akt (from 3.7 ± 0.3 to 2.1 ± 0.2) (p < 0.01) in A549 cells. Therefore, we demonstrate that CKS or PA suppressed the development of respiratory inflammation, hyperresponsiveness, and remodeling by reducing allergic responses, and they may be potential herbal drugs for allergen-induced respiratory disease prevention.
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Affiliation(s)
- Jae Ho Choi
- Department of Toxicology, College of Pharmacy, Chungnam National University , Daejeon 305-764, Republic of Korea
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Chen CY, Li ZL, Chung KT, Lu FJ, Chen CH. Liriodenine enhances the apoptosis effect of valproic acid in human colon cancer cells through oxidative stress upregulation and Akt inhibition. Process Biochem 2014. [DOI: 10.1016/j.procbio.2014.07.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Mycoplasma pneumoniae modulates STAT3-STAT6/EGFR-FOXA2 signaling to induce overexpression of airway mucins. Infect Immun 2014; 82:5246-55. [PMID: 25287927 DOI: 10.1128/iai.01989-14] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Aberrant mucin secretion and accumulation in the airway lumen are clinical hallmarks associated with various lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Mycoplasma pneumoniae, long appreciated as one of the triggers of acute exacerbations of chronic pulmonary diseases, has recently been reported to promote excessive mucus secretion. However, the mechanism of mucin overproduction induced by M. pneumoniae remains unclear. This study aimed to determine the mechanism by which M. pneumoniae induces mucus hypersecretion by using M. pneumoniae infection of mouse lungs, human primary bronchial epithelial (NHBE) cells cultured at the air-liquid interface, and the conventionally cultured airway epithelial NCI-H292 cell line. We demonstrated that M. pneumoniae induced the expression of mucins MUC5AC and MUC5B by activating the STAT6-STAT3 and epidermal growth factor receptor (EGFR) signal pathways, which in turn downregulated FOXA2, a transcriptional repressor of mucin biosynthesis. The upstream stimuli of these pathways, including interleukin-4 (IL-4), IL-6, and IL-13, increased dramatically upon exposure to M. pneumoniae. Inhibition of the STAT6, STAT3, and EGFR signaling pathways significantly restored the expression of FOXA2 and attenuated the expression of airway mucins MUC5AC and MUC5B. Collectively, these studies demonstrated that M. pneumoniae induces airway mucus hypersecretion by modulating the STAT/EGFR-FOXA2 signaling pathways.
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Cho IH, Gong JH, Kang MK, Lee EJ, Park JHY, Park SJ, Kang YH. Astragalin inhibits airway eotaxin-1 induction and epithelial apoptosis through modulating oxidative stress-responsive MAPK signaling. BMC Pulm Med 2014; 14:122. [PMID: 25069610 PMCID: PMC4118077 DOI: 10.1186/1471-2466-14-122] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2013] [Accepted: 07/23/2014] [Indexed: 08/30/2023] Open
Abstract
BACKGROUND Eotaxin proteins are a potential therapeutic target in treating the peribronchial eosinophilia associated with allergic airway diseases. Since inflammation is often associated with an increased generation of reactive oxygen species (ROS), oxidative stress is a mechanistically imperative factor in asthma. Astragalin (kaempferol-3-O-glucoside) is a flavonoid with anti-inflammatory activity and newly found in persimmon leaves and green tea seeds. This study elucidated that astragalin inhibited endotoxin-induced oxidative stress leading to eosinophilia and epithelial apoptosis in airways. METHODS Airway epithelial BEAS-2B cells were exposed to lipopolysaccharide (LPS) in the absence and presence of 1-20 μM astragalin. Western blot and immunocytochemical analyses were conducted to determine induction of target proteins. Cell and nuclear staining was also performed for ROS production and epithelial apoptosis. RESULTS When airway epithelial cells were exposed to 2 μg/ml LPS, astragalin nontoxic at ≤ 20 μM suppressed cellular induction of Toll-like receptor 4 (TLR4) and ROS production enhanced by LPS. Both LPS and H2O2 induced epithelial eotaxin-1 expression, which was blocked by astragalin. LPS activated and induced PLCγ1, PKCβ2, and NADPH oxidase subunits of p22phox and p47phox in epithelial cells and such activation and induction were demoted by astragalin or TLR4 inhibition antagonizing eotaxin-1 induction. H2O2-upregulated phosphorylation of JNK and p38 MAPK was dampened by adding astragalin to epithelial cells, while this compound enhanced epithelial activation of Akt and ERK. H2O2 and LPS promoted epithelial apoptosis concomitant with nuclear condensation or caspase-3 activation, which was blunted by astragalin. CONCLUSIONS Astragalin ameliorated oxidative stress-associated epithelial eosinophilia and apoptosis through disturbing TLR4-PKCβ2-NADPH oxidase-responsive signaling. Therefore, astragalin may be a potent agent antagonizing endotoxin-induced oxidative stress leading to airway dysfunction and inflammation.
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Affiliation(s)
| | | | | | | | | | | | - Young-Hee Kang
- Department of Food and Nutrition, Hallym University, Chuncheon, South Korea.
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