|
1
|
Saki N, Haybar H, Maniati M, Davari N, Javan M, Moghimian-Boroujeni B. Modification macrophage to foam cells in atherosclerosis disease: some factors stimulate or inhibit this process. J Diabetes Metab Disord 2024; 23:1687-1697. [PMID: 39610485 PMCID: PMC11599683 DOI: 10.1007/s40200-024-01482-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/16/2024] [Indexed: 11/30/2024]
Abstract
Background Atherosclerosis is an arterial blood vessel disease that begins and progresses by turning macrophages into foam cells. Uptake of oxidized low-density lipoprotein (ox-LDL), cholesterol esterification and cholesterol efflux are the most important factors in the formation of foam cells and play an important role in atherosclerosis. Methods The present study is based on the data obtained from the PubMed database (1961-2024) using the MeSH search terms "Atherosclerosis", "Macrophages" and "Foam cells". Reviews for writing the main text and non-English-language articles were excluded. Result The interaction between ox-LDL and macrophages plays an important role in plaque initiation and promotion processes. Macrophages abnormally digest ox-LDL, resulting in the accumulation of lipids and formation of foam cells. This is an important step in the development of atherosclerosis. Also, several other factors such as inflammatory factors, growth factors, hormones, etc. can play an important role in the development of atherosclerotic lesions or counteract it by affecting the formation of foam cells. Conclusion Several factors can affect the progression of atherosclerosis by affecting macrophage activity or its conversion to foam cells. Also, some of these factors play a protective role against the development and atherosclerosis progression. In this paper, we reviewed some of these factors and their effect on atherosclerosis.
Collapse
Affiliation(s)
- Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Habib Haybar
- Cardiology Department, Medical College, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahmood Maniati
- School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Nader Davari
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammadreza Javan
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Iranian Blood Transfusion Organization (IBTO), Tehran, Iran
| | - Bahareh Moghimian-Boroujeni
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
2
|
Takano-Kawabe K, Matoba K, Nakamura Y, Moriyama M. Low Density Lipoprotein Receptor-related Protein 2 Expression and Function in Cultured Astrocytes and Microglia. Neurochem Res 2024; 49:199-211. [PMID: 37702891 DOI: 10.1007/s11064-023-04022-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/23/2023] [Accepted: 08/28/2023] [Indexed: 09/14/2023]
Abstract
Activation of glial cells, astrocytes and microglia, has been observed in neurodegenerative diseases including Alzheimer's disease (AD). Amyloid β (Aβ), which is aggregated and the aggregation is detected as characteristic pathology in AD brain, is known to be produced by neurons and to activate glial cells. Clearance of Aβ from the brain via active transport system is important to prevent the accumulation and aggregation. Low density lipoprotein receptor-related protein 2 (LRP2/megalin) is an Aβ transporter. However, expression and contribution of LRP2 in astrocytes and microglia remain to be clarified. In the present study, we examined the expression of LRP2 and its roles in cultured astrocytes prepared from rat embryonic brain cortex and mouse microglial cell line BV-2. Both cultured rat astrocytes and BV-2 cells expressed LRP2 mRNA detected by RT-PCR. When lipopolysaccharide (LPS) or all-trans retinoic acid (ATRA) were added to BV-2 cells, LRP2 mRNA expression and uptake of microbeads, Aβ and insulin were increased. On the other hand, LPS decreased LRP2 expression and uptake of Aβ and insulin in cultured astrocytes. Knockdown of LRP2 using siRNA attenuated the LPS- or ATRA-increased uptake of microbeads, Aβ and insulin in BV-2 cells. These results suggest that LRP2 was expressed in both astrocytes and microglia and might be involved in endocytosis activities. Adequate control of LRP2 expression and function in astrocytes and microglia might regulate Aβ and insulin levels in brain and would be a potential target in AD pathology.
Collapse
Affiliation(s)
- Katsura Takano-Kawabe
- Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Metropolitan University, 1-58, Rinku-Ourai Kita, Izumisano, Osaka, 598-8531, Japan.
| | - Kazuyuki Matoba
- Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Metropolitan University, 1-58, Rinku-Ourai Kita, Izumisano, Osaka, 598-8531, Japan
| | - Yoichi Nakamura
- Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Metropolitan University, 1-58, Rinku-Ourai Kita, Izumisano, Osaka, 598-8531, Japan
| | - Mitsuaki Moriyama
- Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Metropolitan University, 1-58, Rinku-Ourai Kita, Izumisano, Osaka, 598-8531, Japan
| |
Collapse
|
|
3
|
Miller AP, Hornero-Méndez D, Bandara S, Parra-Rivero O, Limón MC, von Lintig J, Avalos J, Amengual J. Bioavailability and provitamin A activity of neurosporaxanthin in mice. Commun Biol 2023; 6:1068. [PMID: 37864015 PMCID: PMC10589281 DOI: 10.1038/s42003-023-05446-1] [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: 05/04/2023] [Accepted: 10/11/2023] [Indexed: 10/22/2023] Open
Abstract
Various species of ascomycete fungi synthesize the carboxylic carotenoid neurosporaxanthin. The unique chemical structure of this xanthophyll reveals that: (1) Its carboxylic end and shorter length increase the polarity of neurosporaxanthin in comparison to other carotenoids, and (2) it contains an unsubstituted β-ionone ring, conferring the potential to form vitamin A. Previously, neurosporaxanthin production was optimized in Fusarium fujikuroi, which allowed us to characterize its antioxidant properties in in vitro assays. In this study, we assessed the bioavailability of neurosporaxanthin compared to other provitamin A carotenoids in mice and examined whether it can be cleaved by the two carotenoid-cleaving enzymes: β-carotene-oxygenase 1 (BCO1) and 2 (BCO2). Using Bco1-/-Bco2-/- mice, we report that neurosporaxanthin displays greater bioavailability than β-carotene and β-cryptoxanthin, as evidenced by higher accumulation and decreased fecal elimination. Enzymatic assays with purified BCO1 and BCO2, together with feeding studies in wild-type, Bco1-/-, Bco2-/-, and Bco1-/-Bco2-/- mice, revealed that neurosporaxanthin is a substrate for either carotenoid-cleaving enzyme. Wild-type mice fed neurosporaxanthin displayed comparable amounts of vitamin A to those fed β-carotene. Together, our study unveils neurosporaxanthin as a highly bioavailable fungal carotenoid with provitamin A activity, highlighting its potential as a novel food additive.
Collapse
Affiliation(s)
- Anthony P Miller
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | | | - Sepalika Bandara
- Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Obdulia Parra-Rivero
- Department of Genetics, Faculty of Biology, University of Seville, Seville, Spain
| | - M Carmen Limón
- Department of Genetics, Faculty of Biology, University of Seville, Seville, Spain
| | - Johannes von Lintig
- Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Javier Avalos
- Department of Genetics, Faculty of Biology, University of Seville, Seville, Spain.
| | - Jaume Amengual
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
| |
Collapse
|
|
4
|
Li S, Zhu Y, Wei C, Li C, Chen W, Jiang S, Yuan D, Xu R. Identification of Molecular Correlations Between DHRS4 and Progressive Neurodegeneration in Amyotrophic Lateral Sclerosis By Gene Co-Expression Network Analysis. Front Immunol 2022; 13:874978. [PMID: 35479082 PMCID: PMC9035787 DOI: 10.3389/fimmu.2022.874978] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 03/15/2022] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and its candidate biomarkers have not yet been fully elucidated in previous studies. Therefore, with the present study, we aim to define and verify effective biomarkers of ALS by bioinformatics. Here, we employed differentially expressed gene (DEG) analysis, weighted gene co-expression network analysis (WGCNA), enrichment analysis, immune infiltration analysis, and protein-protein interaction (PPI) to identify biomarkers of ALS. To validate the biomarkers, we isolated the lumbar spinal cord from mice and characterized them using Western blotting and immunofluorescence. The results showed that Dhrs4 expression in the spinal cord was upregulated with the progression of SOD1G93A mice, and the upregulation of DHRS4 and its synergistic DHRS3 might be primarily associated with the activation of the complement cascade in the immune system (C1QA, C1QB, C1QC, C3, and ITGB2), which might be a novel mechanism that induces spinal neurodegeneration in ALS. We propose that DHRS4 and its synergistic DHRS3 are promising molecular markers for detecting ALS progression.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Renshi Xu
- Department of Neurology, Jiangxi Provincial People’s Hospital, Affiliated People’s Hospital of Nanchang University, Nanchang, China
| |
Collapse
|
|
5
|
Pu J, Chen D, Tian G, He J, Huang Z, Zheng P, Mao X, Yu J, Luo J, Luo Y, Yan H, Yu B. All-Trans Retinoic Acid Attenuates Transmissible Gastroenteritis Virus-Induced Inflammation in IPEC-J2 Cells via Suppressing the RLRs/NF-κB Signaling Pathway. Front Immunol 2022; 13:734171. [PMID: 35173714 PMCID: PMC8841732 DOI: 10.3389/fimmu.2022.734171] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 01/06/2022] [Indexed: 01/03/2023] Open
Abstract
Transmissible gastroenteritis virus (TGEV) infection can cause transmissible gastroenteritis (TGE), especially in suckling piglets, resulting in a significant economic loss for the global pig industry. The pathogenesis of TGEV infection is closely related to intestinal inflammation. All-trans retinoic acid (ATRA) has anti-inflammatory activity and immunomodulatory properties, but it is unclear whether ATRA can attenuate the inflammatory response induced by TGEV. This study aimed to investigate the protective effect of ATRA on TGEV-induced inflammatory injury in intestinal porcine epithelial cells (IPEC-J2) and to explore the underlying molecular mechanism. The results showed that TGEV infection triggered inflammatory response and damaged epithelial barrier integrity in IPEC-J2 cells. However, ATRA attenuated TGEV-induced inflammatory response by inhibiting the release of pro-inflammatory cytokines, including IL-1β, IL-6, IL-8 and TNF-α. ATRA also significantly reversed the reduction of ZO-1 and Occludin protein levels induced by TGEV infection and maintained epithelial barrier integrity. Moreover, ATRA treatment significantly prevented the upregulation of IкBα and NF-κB p65 phosphorylation levels and the nuclear translocation of NF-кB p65 induced by TGEV. On the other hand, treatment of TGEV-infected IPEC-J2 cells with the NF-κB inhibitors (BAY11-7082) significantly decreased the levels of inflammatory cytokines. Furthermore, ATRA treatment significantly downregulated the mRNA abundance and protein levels of TLR3, TLR7, RIG-I and MDA5, and downregulated their downstream signaling molecules TRIF, TRAF6 and MAVS mRNA expressions in TGEV-infected IPEC-J2 cells. However, the knockdown of RIG-I and MDA5 but not TLR3 and TLR7 significantly reduced the NF-κB p65 phosphorylation level and inflammatory cytokines levels in TGEV-infected IPEC-J2 cells. Our results indicated that ATRA attenuated TGEV-induced IPEC-J2 cells damage via suppressing inflammatory response, the mechanism of which is associated with the inhibition of TGEV-mediated activation of the RLRs/NF-κB signaling pathway.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Bing Yu
- Key Laboratory for Animal Disease-Resistance Nutrition, Ministry of Education/Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China
| |
Collapse
|
|
6
|
Li S, Lei Y, Lei J, Li H. All‑trans retinoic acid promotes macrophage phagocytosis and decreases inflammation via inhibiting CD14/TLR4 in acute lung injury. Mol Med Rep 2021; 24:868. [PMID: 34676874 PMCID: PMC8554390 DOI: 10.3892/mmr.2021.12508] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 02/18/2021] [Indexed: 12/22/2022] Open
Abstract
Acute lung injury (ALI) is a common clinical emergency and all-trans retinoic acid (ATRA) can alleviate organ injury. Therefore, the present study investigated the role of ATRA in ALI. Lipopolysaccharide (LPS)-induced ALI rats were treated with ATRA and the arterial partial pressure of oxygen (PaO2), lung wet/dry weight (W/D) ratio and protein content in the bronchial alveolar lavage fluid (BALF) were measured to evaluate the effect of ATRA on ALI rats. Alveolar macrophages were isolated from the BALF. The phagocytic function of macrophages was detected using the chicken erythrocyte phagocytosis method and flow cytometry. The viability of macrophages was measured using a Cell Counting Kit-8 assay, and apoptosis was analyzed using a TUNEL assay and flow cytometry. The expression levels of Toll-like receptor 4 (TLR4) and cluster of differentiation (CD)14 on the macrophage membrane were detected by immunofluorescence staining. The protein levels of TLR4, CD14, phosphorylated (p)-65, p65, p-IκBα and IκBα were analyzed using western blotting. The concentrations of IL-6, IL-1β and macrophage inflammatory protein-2 in the plasma of rats were detected by ELISA. Macrophages were treated with IAXO-102 (TLR4 inhibitor) to verify the involvement of CD14/TLR4 in the effect of ATRA on ALI. ATRA provided protection against LPS-induced ALI, as evidenced by the increased PaO2 and reduced lung W/D ratio and protein content in the BALF. ATRA enhanced macrophage phagocytosis and viability and reduced apoptosis and inflammation in ALI rats. Mechanically, ATRA inhibited CD14 and TLR4 expression and NF-κB pathway activation. ATRA enhanced macrophage phagocytosis and reduced inflammation by inhibiting the CD14/TLR4-NF-κB pathway in LPS-induced ALI. In summary, ATRA inactivated the NF-κB pathway by inhibiting the expression of CD14/TLR4 receptor in the alveolar macrophages of rats, thus enhancing the phagocytic function of macrophages in ALI rats, improving the activity of macrophages, inhibiting apoptosis, reducing the levels of inflammatory factors, and consequently playing a protective role in ALI model rats. This study may offer novel insights for the clinical management of ALI.
Collapse
Affiliation(s)
- Shuangxue Li
- Department of Respiratory and Critical Care Medicine, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
| | - Yuansheng Lei
- Department of Neurology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Jieyun Lei
- Department of Cardiology, Taiyuan Central Hospital, Taiyuan, Shanxi 030009, P.R. China
| | - Hui Li
- Department of Gynecology, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
| |
Collapse
|
|
7
|
Chen QH, Wu BK, Pan D, Sang LX, Chang B. Beta-carotene and its protective effect on gastric cancer. World J Clin Cases 2021; 9:6591-6607. [PMID: 34447808 PMCID: PMC8362528 DOI: 10.12998/wjcc.v9.i23.6591] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 05/16/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Beta-carotene is an important natural pigment that is very beneficial to human health. It is widely found in vegetables and fruits. The three main functions are antioxidant effects, cell gap junction-related functions and immune-related functions. Because of its diverse functions, beta-carotene is believed to prevent and treat many chronic diseases. Gastric cancer is one of the most important diseases it can treat. Gastric cancer is a type of cancer with a high incidence. Its etiology varies, and the pathogenesis is complex. Gastric cancer seriously affects human health. The role of beta-carotene, a natural nutrient, in gastric cancer has been explored by many researchers, including molecular mechanisms and epidemiological studies. Molecular studies have mainly focused on oxidative stress, cell cycle, signal transduction pathways and immune-related mechanisms of beta-carotene in gastric cancer. Many epidemiological surveys and cohort studies of patients with gastric cancer have been conducted, and the results of these epidemiological studies vary due to the use of different research methods and analysis of different regions. This paper will summarize the results of these studies, mainly in terms of molecular mechanisms and epidemiological research results, which will provide a systematic basis for future studies of the treatment and prognosis of gastric cancer. This paper will help researchers identify new research directions.
Collapse
Affiliation(s)
- Qian-Hui Chen
- Department of Intensive Care Unit, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bao-Kang Wu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Dan Pan
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Li-Xuan Sang
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bing Chang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| |
Collapse
|
|
8
|
Liu Z, Dong X, Cao Z, Qiu S, Li Y, Zhong M, Xue Z, Xu Y, Xing H, Tang K, Tian Z, Wang M, Rao Q, Wang J. Mutant U2AF1-induced differential alternative splicing causes an oxidative stress in bone marrow stromal cells. Exp Biol Med (Maywood) 2021; 246:1750-1759. [PMID: 34034558 DOI: 10.1177/15353702211010130] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Alternative splicing (AS) is a critical regulatory process of gene expression. In bone marrow microenvironment, AS plays a critical role in mesenchymal stem cells fate determination by forming distinct isoforms of important regulators. As a spliceosome factor, U2AF1 is essential for the catalysis of pre-mRNA splicing, and its mutation can cause differential AS events. In the present study, by forced expression of mutant U2AF1 (U2AF1S34F) in the mouse bone marrow stroma OP9 cells, we determine AS changes in U2AF1S34F transduced OP9 cells and investigate their role in stroma cell biological functions. We find that abundant differential RNA splicing events are induced by U2AF1S34F in OP9 cells. U2AF1S34F causes increased generation of hydrogen peroxide, promotes production of cytokines and chemokines. U2AF1S34F transduced OP9 cells also exhibit dysfunction of mitochondria. RNA-seq data, gene ontology (GO), and gene set enrichment analysis reveal that differentially expressed genes downregulated in response to U2AF1S34F are enriched in peroxisome component and function. U2AF1S34F can also cause release of hydrogen peroxide from OP9 cells. Furthermore, we investigate the influence of U2AF1S34F-induced oxidative stress in stromal cells on hematopoietic cells. When co-culturing mouse bone marrow mononuclear cells with OP9 cells, the U2AF1S34F expressing OP9 cells induce phosphorylation of histone H2AX in hematopoietic cells. Collectively, our results reveal that mutant U2AF1-induced differential AS events cause oxidative stress in bone marrow stromal cells and can further lead to DNA damage and genomic instability in hematopoietic cells.
Collapse
Affiliation(s)
- Zhe Liu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Xuanjia Dong
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Zhijie Cao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Shaowei Qiu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China.,National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Yihui Li
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Mengjun Zhong
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Zhenya Xue
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Yingxi Xu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Haiyan Xing
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Kejing Tang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Zheng Tian
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Min Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Qing Rao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| | - Jianxiang Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China.,National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, P.R. China
| |
Collapse
|
|
9
|
Pan Y, Zhao X, Kim SH, Kang SA, Kim YG, Park KY. Anti-inflammatory effects of Beopje curly dock (Rumex crispus L.) in LPS-induced RAW 264.7 cells and its active compounds. J Food Biochem 2020; 44:e13291. [PMID: 32458452 DOI: 10.1111/jfbc.13291] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/20/2020] [Accepted: 05/02/2020] [Indexed: 12/21/2022]
Abstract
Inflammation is a defense response of the body to stimuli. Curly dock (CD) is an herbal food with anti-inflammatory effects. Beopje is an herbal food processing method that reduces toxicity and enhances beneficial effects. This study investigated the effects of CD and Beopje curly dock (CD-B) extracts on lipopolysaccharide (LPS)-induced inflammatory damage in RAW 264.7 cells. Cell survival rate and nitrite concentration were determined using the MTT assay and Griess method, respectively. Enzyme-linked immunosorbent assay was used to detect the inflammatory cytokine levels. The mRNA and protein expression levels of inflammatory associated genes were detected by qPCR and Western blot, respectively. CD and CD-B extracts compositions were assessed by UPLC-Q-TOF MS analysis. Our results indicate that CD-B has a more significant inhibitory effect on the LPS-induced inflammatory response in RAW 264.7 cells than CD, suggesting that the Beopje process potentially enhances the anti-inflammatory effect of CD. PRACTICAL APPLICATIONS: Long-term inflammation can cause a variety of chronic diseases. Therefore, it is necessary to suppress the occurrence of body inflammation in time. This study preliminarily clarified the mechanism of herbal foods to alleviate inflammation by regulating the immune response, and further confirms that applying the Beopje process enhances the anti-inflammatory effect. This research can serve as a significant reference for future research, prevention and treatment of inflammation-related diseases, and the development of functional foods with anti-inflammatory activity. It also provides a theoretical basis for the further reasonable application of Beopje processing method.
Collapse
Affiliation(s)
- Yanni Pan
- Department of Food Science and Biotechnology, Cha University, Seongnam, South Korea.,Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing, China.,Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing, China.,Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, China
| | - Xin Zhao
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing, China.,Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing, China.,Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, China
| | - Seung-Hee Kim
- Department of Conversing Technology, Graduate School of Venture, Hoseo University, Seoul, South Korea
| | - Soon-Ah Kang
- Department of Conversing Technology, Graduate School of Venture, Hoseo University, Seoul, South Korea
| | | | - Kun-Young Park
- Department of Food Science and Biotechnology, Cha University, Seongnam, South Korea.,Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing, China.,Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing, China.,Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, China
| |
Collapse
|
|
10
|
Takahashi N, Kake T, Hasegawa S, Imai M. Effects of Post-administration of β-Carotene on Diet-induced Atopic Dermatitis in Hairless Mice. J Oleo Sci 2019; 68:793-802. [PMID: 31292344 DOI: 10.5650/jos.ess19092] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Atopic dermatitis (AD) is a cutaneous condition characterized by itchy, swollen, and dry skin, which is mediated by T helper cell-related cytokines. β-Carotene, a natural red pigment found in plants, exhibits antioxidant activity that has been shown to promote an inflammatory response. Because it is not clear whether β-carotene suppresses inflammation in AD skin tissues, we examined the effects of oral administration of β-carotene in mice induced by a low zinc/magnesium diet (HR-AD diet). Our studies found that AD-like inflammation was remarkably reduced by β-carotene. In addition, β-carotene significantly suppressed protein expression of TNF-α, IL-1β, and MCP-1 and mRNA expression of TSLP, IL-6, IL-1β, IL-4, IL-5, and Par-2 in AD-like skin tissues. It was also found that mRNA and protein expression of filaggrin (a major structural protein in epidermis) in AD-like skin was significantly elevated by β-carotene administration. Furthermore, β-carotene treatment significantly reduced the activity and/or mRNA expression of matrix metalloproteinases (MMPs), degradation of the extracellular matrix and regulation of chemokines. These results suggest that β-carotene reduces skin inflammation through the suppressed expression of inflammatory factors or the activity of MMPs as well as the promotion of filaggrin expression in AD-like skin. β-Carotene is a potent anti-inflammatory agent, which improves AD-like skin by enhancing the skin barrier function.
Collapse
Affiliation(s)
- Noriko Takahashi
- Laboratory of Physiological Chemistry, Institute of Medicinal Chemistry, Hoshi University
| | - Takamichi Kake
- Laboratory of Physiological Chemistry, Institute of Medicinal Chemistry, Hoshi University
| | - Shinya Hasegawa
- Laboratory of Physiological Chemistry, Institute of Medicinal Chemistry, Hoshi University
| | - Masahiko Imai
- Laboratory of Physiological Chemistry, Institute of Medicinal Chemistry, Hoshi University
| |
Collapse
|
|
11
|
Terao R, Murata A, Sugamoto K, Watanabe T, Nagahama K, Nakahara K, Kondo T, Murakami N, Fukui K, Hattori H, Eto N. Immunostimulatory effect of kumquat (Fortunella crassifolia) and its constituents, β-cryptoxanthin andR-limonene. Food Funct 2019; 10:38-48. [DOI: 10.1039/c8fo01971a] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The active constituents of kumquat in NK cell activation and anti-stress effects are β-cryptoxanthin andR-limonene.
Collapse
Affiliation(s)
- Rina Terao
- Graduate School of Agriculture
- University of Miyazaki
- Miyazaki
- Japan
| | - Akira Murata
- Graduate School of Agriculture
- University of Miyazaki
- Miyazaki
- Japan
| | - Kazuhiro Sugamoto
- Interdisciplinary Graduate School of Agriculture and Engineering
- University of Miyazaki
- Miyazaki
- Japan
| | | | - Kiyoko Nagahama
- Interdisciplinary Graduate School of Agriculture and Engineering
- University of Miyazaki
- Miyazaki
- Japan
| | - Keiko Nakahara
- Department of Veterinary Physiology
- Faculty of Agriculture
- University of Miyazaki
- Miyazaki
- Japan
| | - Tomomi Kondo
- Miyazaki JA Food Research & Development Inc
- Miyazaki
- Japan
| | - Noboru Murakami
- Department of Veterinary Physiology
- Faculty of Agriculture
- University of Miyazaki
- Miyazaki
- Japan
| | - Keiichi Fukui
- Miyazaki JA Food Research & Development Inc
- Miyazaki
- Japan
| | - Hidemi Hattori
- Graduate School of Agriculture
- University of Miyazaki
- Miyazaki
- Japan
- Interdisciplinary Graduate School of Agriculture and Engineering
| | - Nozomu Eto
- Graduate School of Agriculture
- University of Miyazaki
- Miyazaki
- Japan
- Interdisciplinary Graduate School of Agriculture and Engineering
| |
Collapse
|
|
12
|
Bi W, Liu Y, Guo J, Lin Z, Liu J, Zhou M, Wismeijer D, Pathak JL, Wu G. All-trans retinoic-acid inhibits heterodimeric bone morphogenetic protein 2/7-stimulated osteoclastogenesis, and resorption activity. Cell Biosci 2018; 8:48. [PMID: 30159139 PMCID: PMC6107948 DOI: 10.1186/s13578-018-0246-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 08/20/2018] [Indexed: 11/10/2022] Open
Abstract
Background Bone regenerative heterodimeric bone morphogenetic protein 2/7 (BMP2/7) enhances but all-trans retinoic acid (ATRA) inhibits osteoclastogenesis. However, the effect of ATRA on physiological and/or BMP2/7-induced osteoclastogenesis in still unclear. In this study, we aimed to test the effect of combined treatment of BMP2/7 and ATRA on osteoclastogenesis, and resorption activity. Results All-trans retinoic acid (1 µM) ± BMP2/7 (5 or 50 ng/ml) was added in murine pre-osteoclasts cell line RAW264.7 or mouse bone marrow derived macrophages (BMM) cultures. Osteoclast marker gene expression, osteoclastogenesis, and resorption activity were analyzed. BMP2/7 robustly enhanced osteoclast maker gene expression, osteoclastogenesis, and resorption activity. Interestingly, ATRA completely inhibited osteoclast formation in presence or absence of BMP2/7. Pan-antagonist of retinoic acid receptors (RARs) and antagonist of RARα, β or γ failed to reverse the inhibitory effect of ATRA on osteoclastogenesis. ATRA strongly inhibited Rank and Nfatc1 expression. Conclusions All-trans retinoic acid inhibits BMP2/7-induced osteoclastogenesis, and resorption activity possibly via RANKL-RANK pathway. Our findings from previous and current study suggest that combination of ATRA and BMP2/7 could be a novel approach to treat hyperactive osteoclast-induced bone loss such as in inflammation-induced severe osteoporosis and bone loss caused by cancer metastasis to bone.
Collapse
Affiliation(s)
- Wenjuan Bi
- 1School of Stomatology, North China University of Science and Technology, Tangshan, China
| | - Yi Liu
- 2Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China.,3Department of Oral Implantology and Prosthetic Dentistry, Academic Centre of Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Jing Guo
- 2Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhen Lin
- 4Department of Orthopedics, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jinsong Liu
- 5School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Miao Zhou
- 2Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Daniel Wismeijer
- 3Department of Oral Implantology and Prosthetic Dentistry, Academic Centre of Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Janak L Pathak
- 2Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Gang Wu
- 3Department of Oral Implantology and Prosthetic Dentistry, Academic Centre of Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
13
|
Zhou Q, Xian M, Xiang S, Xiang D, Shao X, Wang J, Cao J, Yang X, Yang B, Ying M, He Q. All-Trans Retinoic Acid Prevents Osteosarcoma Metastasis by Inhibiting M2 Polarization of Tumor-Associated Macrophages. Cancer Immunol Res 2017; 5:547-559. [PMID: 28515123 DOI: 10.1158/2326-6066.cir-16-0259] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 02/24/2017] [Accepted: 05/12/2017] [Indexed: 12/22/2022]
Abstract
M2-polarized tumor-associated macrophages (TAM) play a critical role in cancer invasion and metastasis. Here, we report that M2 macrophages enhanced metastasis of K7M2 WT osteosarcoma cells to the lungs in mice, thus establishing M2 TAMs as a therapeutic target for blocking osteosarcoma metastasis. We found that all-trans retinoic acid (ATRA) inhibited osteosarcoma metastasis via inhibiting the M2 polarization of TAMs. ATRA suppressed IL13- or IL4-induced M2-type macrophages, and then inhibited migration of osteosarcoma cells as promoted by M2-type macrophages in vitro ATRA reduced the number of pulmonary metastatic nodes of osteosarcoma and decreased expression of M2-type macrophages in metastatic nodes both in intravenous injection and orthotopic transplantation models. ATRA's effect was independent of conventional STAT3/6 or C/EBPβ signaling, which regulate M2-like polarization of macrophages. Quantitative genomic and functional analyses revealed that MMP12, a macrophage-secreted elastase, was elevated in IL13-skewed TAM polarization, whereas ATRA treatment downregulated IL13-induced secretion of MMP12. This downregulation correlates with the antimetastasis effect of ATRA. Our results show the role of TAM polarization in osteosarcoma metastasis, identify a therapeutic opportunity for antimetastasis treatment, and indicate ATRA treatment as an approach for preventing osteosarcoma metastasis via M2-type polarization intervention. Cancer Immunol Res; 5(7); 547-59. ©2017 AACR.
Collapse
Affiliation(s)
- Qian Zhou
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Miao Xian
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Senfeng Xiang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Danyan Xiang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Xuejing Shao
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jincheng Wang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Ji Cao
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Xiaochun Yang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Bo Yang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Meidan Ying
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
| | - Qiaojun He
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
| |
Collapse
|
|
14
|
Ho VW, Hofs E, Elisia I, Lam V, Hsu BE, Lai J, Luk B, Samudio I, Krystal G. All Trans Retinoic Acid, Transforming Growth Factor β and Prostaglandin E2 in Mouse Plasma Synergize with Basophil-Secreted Interleukin-4 to M2 Polarize Murine Macrophages. PLoS One 2016; 11:e0168072. [PMID: 27977740 PMCID: PMC5158015 DOI: 10.1371/journal.pone.0168072] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 11/27/2016] [Indexed: 01/04/2023] Open
Abstract
In previous studies we found that macrophages (MФs) from SH2-containing inositol-5'-phosphatase (SHIP) deficient mice are M2 polarized while their wild type (WT) counterparts are M1 polarized and that this difference in MФ phenotype can be recapitulated during in vitro derivation from bone marrow if mouse plasma (MP), but not fetal calf serum, is added to standard M-CSF-containing cultures. In the current study we investigated the mechanism by which MP skews SHIP-/- but not +/+ MФs to an M2 phenotype. Our results suggest that SHIP-/- basophils constitutively secrete higher levels of IL-4 than SHIP+/+ basophils and this higher level of IL-4 is sufficient to skew both SHIP+/+ and SHIP-/- MФs to an M2 phenotype, but only when MP is present to increase the sensitivity of the MФs to this level of IL-4. MP increases the IL-4 sensitivity of both SHIP+/+ and -/- MФs not by increasing cell surface IL-4 or CD36 receptor levels, but by triggering the activation of Erk and Akt and the production of ROS, all of which play a critical role in sensitizing MФs to IL-4-induced M2 skewing. Studies to identify the factor(s) in MP responsible for promoting IL-4-induced M2 skewing suggests that all-trans retinoic acid (ATRA), TGFβ and prostaglandin E2 (PGE2) all play a role. Taken together, these results indicate that basophil-secreted IL-4 plays an essential role in M2 skewing and that ATRA, TGFβ and PGE2 within MP collaborate to dramatically promote M2 skewing by acting directly on MФs to increase their sensitivity to IL-4.
Collapse
Affiliation(s)
- Victor W. Ho
- The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Elyse Hofs
- The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Ingrid Elisia
- The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Vivian Lam
- The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Brian E. Hsu
- The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - June Lai
- The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Beryl Luk
- The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Ismael Samudio
- The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Gerald Krystal
- The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
- * E-mail:
| |
Collapse
|
|
15
|
9-cis β-Carotene Increased Cholesterol Efflux to HDL in Macrophages. Nutrients 2016; 8:nu8070435. [PMID: 27447665 PMCID: PMC4963911 DOI: 10.3390/nu8070435] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 05/29/2016] [Accepted: 07/14/2016] [Indexed: 12/15/2022] Open
Abstract
Cholesterol efflux from macrophages is a key process in reverse cholesterol transport and, therefore, might inhibit atherogenesis. 9-cis-β-carotene (9-cis-βc) is a precursor for 9-cis-retinoic-acid (9-cis-RA), which regulates macrophage cholesterol efflux. Our objective was to assess whether 9-cis-βc increases macrophage cholesterol efflux and induces the expression of cholesterol transporters. Enrichment of a mouse diet with βc from the alga Dunaliella led to βc accumulation in peritoneal macrophages. 9-cis-βc increased the mRNA levels of CYP26B1, an enzyme that regulates RA cellular levels, indicating the formation of RA from βc in RAW264.7 macrophages. Furthermore, 9-cis-βc, as well as all-trans-βc, significantly increased cholesterol efflux to high-density lipoprotein (HDL) by 50% in RAW264.7 macrophages. Likewise, food fortification with 9-cis-βc augmented cholesterol efflux from macrophages ex vivo. 9-cis-βc increased both the mRNA and protein levels of ABCA1 and apolipoprotein E (APOE) and the mRNA level of ABCG1. Our study shows, for the first time, that 9-cis-βc from the diet accumulates in peritoneal macrophages and increases cholesterol efflux to HDL. These effects might be ascribed to transcriptional induction of ABCA1, ABCG1, and APOE. These results highlight the beneficial effect of βc in inhibition of atherosclerosis by improving cholesterol efflux from macrophages.
Collapse
|
|
16
|
Lam L, Chin L, Halder RC, Sagong B, Famenini S, Sayre J, Montoya D, Rubbi L, Pellegrini M, Fiala M. Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients. FASEB J 2016; 30:3461-3473. [PMID: 27368295 DOI: 10.1096/fj.201600259rr] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 06/21/2016] [Indexed: 12/13/2022]
Abstract
We have investigated transcriptional and epigenetic differences in peripheral blood mononuclear cells (PBMCs) of monozygotic female twins discordant in the diagnosis of amyotrophic lateral sclerosis (ALS). Exploring DNA methylation differences by reduced representation bisulfite sequencing (RRBS), we determined that, over time, the ALS twin developed higher abundances of the CD14 macrophages and lower abundances of T cells compared to the non-ALS twin. Higher macrophage signature in the ALS twin was also shown by RNA sequencing (RNA-seq). Moreover, the twins differed in the methylome at loci near several genes, including EGFR and TNFRSF11A, and in the pathways related to the tretinoin and H3K27me3 markers. We also tested cytokine production by PBMCs. The ALS twin's PBMCs spontaneously produced IL-6 and TNF-α, whereas PBMCs of the healthy twin produced these cytokines only when stimulated by superoxide dismutase (SOD)-1. These results and flow cytometric detection of CD45 and CD127 suggest the presence of memory T cells in both twins, but effector T cells only in the ALS twin. The ALS twin's PBMC supernatants, but not the healthy twin's, were toxic to rat cortical neurons, and this toxicity was strongly inhibited by an IL-6 receptor antibody (tocilizumab) and less well by TNF-α and IL-1β antibodies. The putative neurotoxicity of IL-6 and TNF-α is in agreement with a high expression of these cytokines on infiltrating macrophages in the ALS spinal cord. We hypothesize that higher macrophage abundance and increased neurotoxic cytokines have a fundamental role in the phenotype and treatment of certain individuals with ALS.-Lam, L., Chin, L., Halder, R. C., Sagong, B., Famenini, S., Sayre, J., Montoya, D., Rubbi L., Pellegrini, M., Fiala, M. Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients.
Collapse
Affiliation(s)
- Larry Lam
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA
| | - Lydia Chin
- Department of Surgery, UCLA School of Medicine, University of California, Los Angeles, Los Angeles, California, USA; and
| | - Ramesh C Halder
- Department of Surgery, UCLA School of Medicine, University of California, Los Angeles, Los Angeles, California, USA; and
| | - Bien Sagong
- Department of Surgery, UCLA School of Medicine, University of California, Los Angeles, Los Angeles, California, USA; and
| | - Sam Famenini
- Department of Surgery, UCLA School of Medicine, University of California, Los Angeles, Los Angeles, California, USA; and
| | - James Sayre
- Department of Biostatistics, UCLA School of Public Health, University of California, Los Angeles, Los Angeles, California, USA
| | - Dennis Montoya
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA
| | - Liudmilla Rubbi
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA
| | - Matteo Pellegrini
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA
| | - Milan Fiala
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA; Department of Surgery, UCLA School of Medicine, University of California, Los Angeles, Los Angeles, California, USA; and
| |
Collapse
|
|
17
|
Penkert RR, Surman SL, Jones BG, Sealy RE, Vogel P, Neale G, Hurwitz JL. Vitamin A deficient mice exhibit increased viral antigens and enhanced cytokine/chemokine production in nasal tissues following respiratory virus infection despite the presence of FoxP3+ T cells. Int Immunol 2015; 28:139-52. [PMID: 26507129 DOI: 10.1093/intimm/dxv064] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 10/20/2015] [Indexed: 01/03/2023] Open
Abstract
The World Health Organization (WHO) estimates that 250 million children under the age of five suffer from vitamin A deficiencies (VAD). Individuals with VAD experience higher rates of mortality and increased morbidity during enteric and respiratory infections compared with those who are vitamin A sufficient. Previously, our laboratory has demonstrated that VAD mice have significantly impaired virus-specific IgA and CD8(+) T-cell responses in the airways. Here, we demonstrate that VAD mice experience enhanced cytokine/chemokine gene expression and release in the respiratory tract 10 days following virus infection compared with control vitamin A sufficient animals. Cytokines/chemokines that are reproducibly up-regulated at the gene expression and protein levels include IFNγ and IL-6. Despite previous indications that cytokine dysregulation in VAD animals might reflect low forkhead box P3 (FoxP3)-positive regulatory T-cell frequencies, we found no reduction in FoxP3(+) T cells in VAD respiratory tissues. As an alternative explanation for the high cytokine levels, we found that the extent of virus infection and the persistence of viral antigens were increased on day 10 post-infection in VAD animals compared with controls, and consequently that respiratory tract tissues had an increased potential to activate virus-specific T cells. Results encourage cautious management of viral infections in patients with VAD, as efforts to enhance FoxP3(+) T cell frequencies and quell immune effectors could potentially exacerbate disease if the virus has not been cleared.
Collapse
Affiliation(s)
- Rhiannon R Penkert
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Sherri L Surman
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Bart G Jones
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Robert E Sealy
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Peter Vogel
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Geoffrey Neale
- Hartwell Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Julia L Hurwitz
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| |
Collapse
|
|
18
|
Castillo Y, Tachibana M, Nakatsu Y, Watanabe K, Shimizu T, Watarai M. Combination of Zinc and All-Trans Retinoic Acid Promotes Protection against Listeria monocytogenes Infection. PLoS One 2015; 10:e0137463. [PMID: 26351852 PMCID: PMC4564104 DOI: 10.1371/journal.pone.0137463] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 08/17/2015] [Indexed: 11/29/2022] Open
Abstract
Zinc (Zn) is the second most abundant transition metal after iron. It plays a vital role in living organisms and affects multiple aspects of the immune system. All-trans retinoic acid (atRA) is an isomeric form of the vitamin A or retinol. It possesses the greatest biological activity of Vitamin A. Vitamin A and related retinoids influence many aspects of immunity. In this study, we demonstrated that treatment with a combination of Zn and atRA contributes to host resistance against infection by Listeria monocytogenes. Pretreatment with Zn and atRA enhanced resistance against L. monocytogenes infection in mice and treatment with both Zn and atRA showed a higher protective effect than treatment with either alone. Supplementation with Zn, atRA or their combination decreased the number of L. monocytogenes present in target organs. In vitro, supplementation increased the bacterial uptake by macrophage cells and reduced the replication of L. monocytogenes. Our results suggest that the combination of Zn and atRA has a great bacteriostatic impact on L. monocytogenes and its infection.
Collapse
Affiliation(s)
- Yussaira Castillo
- The United Graduate School of Veterinary Science, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
| | - Masato Tachibana
- The United Graduate School of Veterinary Science, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
| | - Yukiko Nakatsu
- The United Graduate School of Veterinary Science, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
| | - Kenta Watanabe
- The United Graduate School of Veterinary Science, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
| | - Takashi Shimizu
- The United Graduate School of Veterinary Science, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
| | - Masahisa Watarai
- The United Graduate School of Veterinary Science, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
- * E-mail:
| |
Collapse
|
|
19
|
The inhibition of macrophage foam cell formation by 9-cis β-carotene is driven by BCMO1 activity. PLoS One 2015; 10:e0115272. [PMID: 25629601 PMCID: PMC4309590 DOI: 10.1371/journal.pone.0115272] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 11/23/2014] [Indexed: 01/04/2023] Open
Abstract
Atherosclerosis is a major cause of morbidity and mortality in developed societies, and begins when activated endothelial cells recruit monocytes and T-cells from the bloodstream into the arterial wall. Macrophages that accumulate cholesterol and other fatty materials are transformed into foam cells. Several epidemiological studies have demonstrated that a diet rich in carotenoids is associated with a reduced risk of heart disease; while previous work in our laboratory has shown that the 9-cis β-carotene rich alga Dunaliella inhibits atherogenesis in mice. The effect of 9-cis β-carotene on macrophage foam cell formation has not yet been investigated. In the present work, we sought to study whether the 9-cis β-carotene isomer, isolated from the alga Dunaliella, can inhibit macrophage foam cell formation upon its conversion to retinoids. The 9-cis β-carotene and Dunaliella lipid extract inhibited foam cell formation in the RAW264.7 cell line, similar to 9-cis retinoic acid. Furthermore, dietary enrichment with the algal powder in mice resulted in carotenoid accumulation in the peritoneal macrophages and in the inhibition of foam cell formation ex-vivo and in-vivo. We also found that the β-carotene cleavage enzyme β-carotene 15,15’-monooxygenase (BCMO1) is expressed and active in macrophages. Finally, 9-cis β-carotene, as well as the Dunaliella extract, activated the nuclear receptor RXR in hepa1-6 cells. These results indicate that dietary carotenoids, such as 9-cis β-carotene, accumulate in macrophages and can be locally cleaved by endogenous BCMO1 to form 9-cis retinoic acid and other retinoids. Subsequently, these retinoids activate the nuclear receptor RXR that, along with additional nuclear receptors, can affect various metabolic pathways, including those involved in foam cell formation and atherosclerosis.
Collapse
|