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He Y, Huang H, Li G, Zhang Y, He J, Lin Y, Wu F, Yan J, Cai X, Liu L. Safety Profile, Toxicokinetic, and Intestinal Absorption Differences of a Naturally-Derived Anti-Rheumatic Drug, Sinomenine Hydrochloride, in Normal and Arthritic Rats. Pharmaceutics 2025; 17:484. [PMID: 40284479 PMCID: PMC12030057 DOI: 10.3390/pharmaceutics17040484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/28/2025] [Accepted: 04/03/2025] [Indexed: 04/29/2025] Open
Abstract
Background/Objective: Sinomenine hydrochloride (SH), a natural anti-rheumatic drug derived from the Chinese medicinal plant Sinomenium acutum, demonstrates disease-modifying properties but lacks comprehensive safety and toxicokinetic (TK) comparisons between physiological and pathological states. This study evaluated SH's safety profile, TK parameters, and intestinal absorption differences in adjuvant-induced arthritis (AIA) and normal rats. Methods: Safety assessments determined median lethal doses (LD50) in female Sprague Dawley rats. TK parameters were analyzed via a validated ultrahigh performance liquid chromatography-tandem mass spectrometry approach after single oral administration of 600 mg/kg SH. Plasma protein binding (PPB) were measured using equilibrium dialysis. Intestinal absorption was evaluated through everted gut sac experiments, with P-glycoprotein (P-gp) inhibition tested via verapamil co-administration. Results: LD50 values revealed AIA rats tolerated SH better than normal rats (1179 vs. 805 mg/kg). TK analysis showed that Cmax, AUC(0-t), and AUC(0-∞) of SIN in normal rats were 2.01, 1.94, and 2.14 times higher than in AIA rats, respectively, while CL/F and V/F in AIA rats were 2.24 times greater. In addition, the PPB of SIN in normal rats was 2 times greater than that in AIA rats. AIA rats exhibited significantly lower SH absorption in the jejunum and ileum compared to normal rats. Notably, verapamil co-administration markedly increased SH absorption across most intestinal segments. Conclusions: Pathological states significantly alter SH's safety and TK profiles. Enhanced tolerance in AIA rats correlates with reduced intestinal absorption via altered P-gp activity and decreased PPB. These findings emphasize the necessity of disease-specific evaluations for optimizing SH's therapeutic safety in pathological contexts.
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Affiliation(s)
- Yini He
- Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China; (Y.H.); (H.H.); (G.L.); (Y.Z.); (J.H.); (Y.L.); (J.Y.)
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Hong Huang
- Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China; (Y.H.); (H.H.); (G.L.); (Y.Z.); (J.H.); (Y.L.); (J.Y.)
| | - Gejing Li
- Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China; (Y.H.); (H.H.); (G.L.); (Y.Z.); (J.H.); (Y.L.); (J.Y.)
| | - Ye Zhang
- Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China; (Y.H.); (H.H.); (G.L.); (Y.Z.); (J.H.); (Y.L.); (J.Y.)
| | - Junjie He
- Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China; (Y.H.); (H.H.); (G.L.); (Y.Z.); (J.H.); (Y.L.); (J.Y.)
| | - Ye Lin
- Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China; (Y.H.); (H.H.); (G.L.); (Y.Z.); (J.H.); (Y.L.); (J.Y.)
| | - Feichi Wu
- Hunan ZhenQin Pharmaceutical Group Co., Ltd., Huaihua 418000, China;
| | - Jianye Yan
- Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China; (Y.H.); (H.H.); (G.L.); (Y.Z.); (J.H.); (Y.L.); (J.Y.)
| | - Xiong Cai
- Institute of Innovation and Applied Research in Chinese Medicine, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha 410208, China; (Y.H.); (H.H.); (G.L.); (Y.Z.); (J.H.); (Y.L.); (J.Y.)
| | - Liang Liu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China
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Chen Q, Zhang YL, Shi YQ, Zheng L. Mesalazine alleviated the symptoms of spontaneous colitis in interleukin-10 knockout mice by regulating the STAT3/NF-κB signaling pathway. World J Gastroenterol 2025; 31:96459. [PMID: 39991681 PMCID: PMC11755248 DOI: 10.3748/wjg.v31.i7.96459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 12/01/2024] [Accepted: 12/27/2024] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND Excessive endoplasmic reticulum (ER) stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier, activate the signal transducer and activator of transcription 3 (STAT3)/nuclear factor kappa B (NF-κB) signaling pathway, and exacerbate the inflammatory response, thus participating in the pathogenesis of ulcerative colitis (UC). Mesalazine is a commonly used drug in the clinical treatment of UC. However, further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells, down-regulates the STAT3/NF-κB pathway to play a role in the treatment of UC. AIM To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10 (IL-10)-/- mice. METHODS The 24-week-old IL-10-/- mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group. Littermates of wild-type mice of the same age group served as the control. There were eight mice in each group, four males and four females. The severity of symptoms of spontaneous colitis in IL-10-/- mice was assessed using disease activity index scores. On day 15, the mice were sacrificed. The colon length was measured, and the histopathological changes and ultrastructure of colonic epithelial cells were detected. The protein expressions of STAT3, p-STAT3, NF-κB, IκB, p-IκB, and glucose-regulated protein 78 were identified using Western blotting. The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction. The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence. RESULTS Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues, and alleviated the ER stress in epithelial cells of colitis mice. Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated, suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target. Mesalazine could down-regulate the protein expressions of p-STAT3, NF-κB and p-IκB, and down-regulate the mRNA expression of STAT3 and NF-κB. CONCLUSION Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.
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Affiliation(s)
- Qian Chen
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Ya-Li Zhang
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yong-Quan Shi
- Department of Gastroenterology, Xijing Hospital affiliated to Air Force Medical University, Xi’an 710032, Shaanxi Province, China
| | - Lie Zheng
- Department of Gastroenterology, Traditional Chinese Medicine Hospital of Shaanxi Province, Xi’an 710003, Shaanxi Province, China
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Kuklina EM. Mechanisms of Glucocorticoid Resistance in Nonclassical T Helper Populations Th17.1/Ex-Th17. BIOCHEMISTRY. BIOKHIMIIA 2025; 90:188-199. [PMID: 40254398 DOI: 10.1134/s0006297924604222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/15/2025] [Accepted: 01/20/2025] [Indexed: 04/22/2025]
Abstract
The nonclassical population of Th1-polarized Th17 lymphocytes (Th17.1/ex-Th17) is currently in the focus of researchers' attention. These cells possess a unique proinflammatory potential and ability to penetrate blood-tissue barriers and play a key role in the pathogenesis of many inflammatory diseases, primarily autoimmune ones. Th1-polarized Th17 lymphocytes prevail in the autoimmune lesion foci and are considered to be a promising therapeutic target in these pathologies. At the same time, recent studies have shown another distinctive feature of Th1-polarized Th17 - their selective resistance to glucocorticoids. Since glucocorticoids are the first-line drugs for the treatment of the autoimmune disease exacerbation, understanding the causes of this phenomenon is crucial for predicting patients' response to therapy and improving the treatment effectiveness. This review analyzes the mechanisms of drug resistance of Th1-polarized Th17 cells, compares these mechanisms with those typical of nonpathogenic classical Th17 cells, and discusses the role of glucocorticoid resistance in the body's response to glucocorticoid therapy.
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Affiliation(s)
- Elena M Kuklina
- Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, Ural Branch of the Russian Academy of Sciences, Perm, 614081, Russia.
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Malinowski D, Piotrowska K, Droździk M, Pawlik A. Solute Carrier Transporters in Synovial Membrane and Hoffa's Pad of Patients with Rheumatoid Arthritis. Arch Immunol Ther Exp (Warsz) 2024; 72:aite-2024-0014. [PMID: 38932672 DOI: 10.2478/aite-2024-0014] [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: 03/05/2024] [Accepted: 05/13/2024] [Indexed: 06/28/2024]
Abstract
Rheumatoid arthritis (RA) is a complex autoimmune disease that leads to joint destruction. A number of immune cells that affect joint tissues are involved in the pathogenesis of this disease. This leads to the synthesis of many pro-inflammatory mediators. The transport of drugs, as well as many cytokines involved in the development of inflammation in RA patients, is mediated by membrane transporters. Membrane transporters are proteins that mediate the transfer of substrates across biological membranes. But to date there are no studies examining the expression of solute carrier (SLC) transporters in joint tissues. The aim of the study was to evaluate the expression of individual SLC family transporters in the synovial membranes (SMs) and infrapatellar fat pad (Hoffa's pad) of RA patients. The study included 20 patients with rheumatoid arthritis and 20 with osteoarthritis as the control group who were undergoing joint replacement surgery as a normal part of clinical care. In the SM and Hoffa's pad of RA patients the following 17 membrane transporters were defined at relevant expression levels for SLC transporter superfamily: SLC15A2, SLC16A3, SLC19A1, SLC2A9, SLC22A1, SLC22A3, SLC22A4, SLC22A5, SLC22A18, SLC33A1, SLC47A1, SLC51A, SLC7A5, SLC7A6, SLC01C1, SLC02B1, SLC04A1. The confirmed expression of these transporters in the SMs as well as Hoffa's pad of patients with RA and OA, and the differences in their expression between these groups, suggests the involvement of SLC transporters in both the maintenance of homeostasis under physiological conditions in the tissues of the joints, as well as in the inflammatory process in RA.
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Affiliation(s)
- Damian Malinowski
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, Szczecin, Poland
| | | | - Marek Droździk
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin, Poland
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland
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Pavlova EN, Lepekha LN, Rybalkina EY, Tarasov RV, Sychevskaya KA, Voronezhskaya EE, Masyutin AG, Ergeshov AE, Erokhina MV. High and Low Levels of ABCB1 Expression Are Associated with Two Distinct Gene Signatures in Lung Tissue of Pulmonary TB Patients with High Inflammation Activity. Int J Mol Sci 2023; 24:14839. [PMID: 37834286 PMCID: PMC10573207 DOI: 10.3390/ijms241914839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/23/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
P-glycoprotein (encoded by the ABCB1 gene) has a dual role in regulating inflammation and reducing chemotherapy efficacy in various diseases, but there are few studies focused on pulmonary TB patients. In this study, our objective was to identify a list of genes that correlate with high and low levels of ABCB1 gene expression in the lungs of pulmonary TB patients with different activity of chronic granulomatous inflammation. We compared gene expression in two groups of samples (with moderate and high activity of tuberculomas) to identify their characteristic gene signatures. Gene expression levels were determined using quantitative PCR in samples of perifocal area of granulomas, which were obtained from 65 patients after surgical intervention. Subsequently, two distinct gene signatures associated with high inflammation activity were identified. The first signature demonstrated increased expression of HIF1a, TGM2, IL6, SOCS3, and STAT3, which correlated with high ABCB1 expression. The second signature was characterized by high expression of TNFa and CD163 and low expression of ABCB1. These results provide insight into various inflammatory mechanisms and association with P-gp gene expression in lung tissue of pulmonary TB patients and will be useful in the development of a host-directed therapy approach to improving the effectiveness of anti-TB treatment.
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Affiliation(s)
- Ekaterina N. Pavlova
- Central Tuberculosis Research Institute, 107564 Moscow, Russia; (E.N.P.); (A.G.M.)
- Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Larisa N. Lepekha
- Central Tuberculosis Research Institute, 107564 Moscow, Russia; (E.N.P.); (A.G.M.)
| | - Ekaterina Yu. Rybalkina
- Central Tuberculosis Research Institute, 107564 Moscow, Russia; (E.N.P.); (A.G.M.)
- FSBI N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | - Ruslan V. Tarasov
- Central Tuberculosis Research Institute, 107564 Moscow, Russia; (E.N.P.); (A.G.M.)
| | - Ksenia A. Sychevskaya
- Central Tuberculosis Research Institute, 107564 Moscow, Russia; (E.N.P.); (A.G.M.)
- FSBI N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
| | - Elena E. Voronezhskaya
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, 119334 Moscow, Russia
| | - Alexander G. Masyutin
- Central Tuberculosis Research Institute, 107564 Moscow, Russia; (E.N.P.); (A.G.M.)
- Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Atadzhan E. Ergeshov
- Director of the Institute, Central Tuberculosis Research Institute, 2 Yauzskaya Alleya, 107564 Moscow, Russia;
| | - Maria V. Erokhina
- Central Tuberculosis Research Institute, 107564 Moscow, Russia; (E.N.P.); (A.G.M.)
- Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
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Ochiai M, Fierstein S, XsSali F, DeVito N, Purkey LR, May R, Correa-Medina A, Kelley M, Page TD, DeCicco-Skinner K. Unlocking Drug Resistance in Multiple Myeloma: Adipocytes as Modulators of Treatment Response. Cancers (Basel) 2023; 15:4347. [PMID: 37686623 PMCID: PMC10486466 DOI: 10.3390/cancers15174347] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/13/2023] [Accepted: 08/24/2023] [Indexed: 09/10/2023] Open
Abstract
Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of malignant plasma cells. Despite the development of a diverse array of targeted drug therapies over the last decade, patients often relapse and develop refractory disease due to multidrug resistance. Obesity is a growing public health threat and a risk factor for multiple myeloma, although the mechanisms by which obesity contributes to MM growth and progression have not been fully elucidated. In the present study, we evaluated whether crosstalk between adipocytes and MM cells promoted drug resistance and whether this was amplified by obesity. Human adipose-derived stem cells (ASCs) from nineteen normal (BMI = 20-25 kg/m2), overweight (25-30 kg/m2), or obese (30-35 kg/m2) patients undergoing elective liposuction were utilized. Cells were differentiated into adipocytes, co-cultured with RPMI 8226 or U266B1 multiple myeloma cell lines, and treated with standard MM therapies, including bortezomib or a triple combination of bortezomib, dexamethasone, and lenalidomide. We found that adipocytes from overweight and obese individuals increased cell adhesion-mediated drug resistance (CAM-DR) survival signals in MM cells, and P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) drug transporter expression. Further, co-culture enhanced in vitro angiogenesis, MMP-2 activity, and protected MM cells from drug-induced decreases in viability. In summary, we provide an underlying mechanism by which obesity can impair the drug response to MM and allow for recurrence and/or disease progression.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Kathleen DeCicco-Skinner
- Department of Biology, American University, 4400 Massachusetts Ave, NW, Washington, DC 20016, USA
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Andrade CBV, Lopes LVA, Ortiga-Carvalho TM, Matthews SG, Bloise E. Infection and disruption of placental multidrug resistance (MDR) transporters: Implications for fetal drug exposure. Toxicol Appl Pharmacol 2023; 459:116344. [PMID: 36526072 DOI: 10.1016/j.taap.2022.116344] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 12/07/2022] [Accepted: 12/11/2022] [Indexed: 12/15/2022]
Abstract
P-glycoprotein (P-gp, encoded by the ABCB1 gene) and breast cancer resistance protein (BCRP/ABCG2) are efflux multidrug resistance (MDR) transporters localized at the syncytiotrophoblast barrier of the placenta and protect the conceptus from drug and toxin exposure throughout pregnancy. Infection is an important modulator of MDR expression and function. This review comprehensively examines the effect of infection on the MDR transporters, P-gp and BCRP in the placenta. Infection PAMPs such as bacterial lipopolysaccharide (LPS) and viral polyinosinic-polycytidylic acid (poly I:C) and single-stranded (ss)RNA, as well as infection with Zika virus (ZIKV), Plasmodium berghei ANKA (modeling malaria in pregnancy - MiP) and polymicrobial infection of intrauterine tissues (chorioamnionitis) all modulate placental P-gp and BCRP at the levels of mRNA, protein and or function; with specific responses varying according to gestational age, trophoblast type and species (human vs. mice). Furthermore, we describe the expression and localization profile of Toll-like receptor (TLR) proteins of the innate immune system at the maternal-fetal interface, aiming to better understand how infective agents modulate placental MDR. We also highlight important gaps in the field and propose future research directions. We conclude that alterations in placental MDR expression and function induced by infective agents may not only alter the intrauterine biodistribution of important MDR substrates such as drugs, toxins, hormones, cytokines, chemokines and waste metabolites, but also impact normal placentation and adversely affect pregnancy outcome and maternal/neonatal health.
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Affiliation(s)
- C B V Andrade
- Instituto de Biofisica Carlos Chagas Filho, Laboratorio de Endocrinologia Translacional, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Departamento de Histologia e Embriologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - L V A Lopes
- Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - T M Ortiga-Carvalho
- Instituto de Biofisica Carlos Chagas Filho, Laboratorio de Endocrinologia Translacional, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - S G Matthews
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada; Department of Obstetrics & Gynecology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada; Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Sinai Health System, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - E Bloise
- Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
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Nicolas M, Lasalo M, Chow S, Antheaume C, Huet K, Hnawia E, Guillemin GJ, Nour M, Matsui M. Anti-inflammatory activities of Coleus forsteri (formerly Plectranthus forsteri) extracts on human macrophages and chemical characterization. Front Pharmacol 2023; 13:1081310. [PMID: 36699063 PMCID: PMC9868419 DOI: 10.3389/fphar.2022.1081310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/22/2022] [Indexed: 01/11/2023] Open
Abstract
Introduction: Formerly named Plectranthus forsteri, Coleus forsteri (Benth.) A.J.Paton, 2019 is a Lamiaceae traditionally used to treat flu-like symptoms and shock-related ecchymosis, especially in the Pacific region. Few studies investigated chemical composition and anti-inflammatory potential of this plant. Method: Herein, we investigated anti-inflammatory potential of C. forsteri ethanolic (ePE) and cyclohexane (cPE) plant extract on LPS-induced human macrophages models and quantified cytokines and quinolinic acid (QUIN) as inflammatory markers. Results: Our results show that extract of ePE and cPE significantly inhibit inflammatory cytokine IL-6 and TNF-α induced by LPS on PMA-derived THP-1 macrophages. QUIN production is also diminished under ePE and cPE treatment in activated human monocyte-derived macrophages (MDMs). Seven abietane diterpenes were characterized from C. forsteri cPE including coleon U (1), coleon U-quinone (2), 8α,9α-epoxycoleon U-quinone (3), horminone or 7α-hydroxyroyleanone (4), 6β,7α-dihydroxyroyleanone (5), 7α-acetoxy-6β-hydroxyroyleanone (6) and 7α-formyloxy-6β-hydroxyroyleanone (7). Discussion: We discussed potential contributions of these molecules from C. forsteri extracts for their anti-inflammatory activities.
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Affiliation(s)
- Mael Nicolas
- Département de Chimie, Université Côte d’Azur, Nice, France
| | - Malia Lasalo
- Group Bioactivities of Natural compounds and derivatives (BIONA), Formerly Group Immunity and Inflammation (GIMIN), Institut Pasteur of New Caledonia, Member of the Pasteur Network, Noumea, New Caledonia
| | - Sharron Chow
- Neuroinflammation Group, Macquarie Medical School, Macquarie University, Sydney, NSW, Australia
| | - Cyril Antheaume
- Institut de Science et d’Ingénierie Supramoléculaires, Université de Strasbourg, Strasbourg, France
| | - Karl Huet
- Group Bioactivities of Natural compounds and derivatives (BIONA), Formerly Group Immunity and Inflammation (GIMIN), Institut Pasteur of New Caledonia, Member of the Pasteur Network, Noumea, New Caledonia
| | - Edouard Hnawia
- PHARMADEV, UMR152, Institut de Recherche pour le Développement (IRD), Noumea Center, Noumea, New Caledonia
| | - Gilles J. Guillemin
- Neuroinflammation Group, Macquarie Medical School, Macquarie University, Sydney, NSW, Australia
| | - Mohammed Nour
- Institut des Sciences Exactes et Appliqués (ISEA), EA7484, Université de Nouvelle-Calédonie, Noumea, New Caledonia
| | - Mariko Matsui
- Group Bioactivities of Natural compounds and derivatives (BIONA), Formerly Group Immunity and Inflammation (GIMIN), Institut Pasteur of New Caledonia, Member of the Pasteur Network, Noumea, New Caledonia
- Institut des Sciences Exactes et Appliqués (ISEA), EA7484, Université de Nouvelle-Calédonie, Noumea, New Caledonia
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Chai AB, Callaghan R, Gelissen IC. Regulation of P-Glycoprotein in the Brain. Int J Mol Sci 2022; 23:ijms232314667. [PMID: 36498995 PMCID: PMC9740459 DOI: 10.3390/ijms232314667] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/18/2022] [Accepted: 11/22/2022] [Indexed: 11/27/2022] Open
Abstract
Maintenance of the tightly regulated homeostatic environment of the brain is facilitated by the blood-brain barrier (BBB). P-glycoprotein (P-gp), an ATP-binding cassette transporter, is expressed on the luminal surface of the endothelial cells in the BBB, and actively exports a wide variety of substrates to limit exposure of the vulnerable brain environment to waste buildup and neurotoxic compounds. Downregulation of P-gp expression and activity at the BBB have been reported with ageing and in neurodegenerative diseases. Upregulation of P-gp at the BBB contributes to poor therapeutic outcomes due to altered pharmacokinetics of CNS-acting drugs. The regulation of P-gp is highly complex, but unravelling the mechanisms involved may help the development of novel and nuanced strategies to modulate P-gp expression for therapeutic benefit. This review summarises the current understanding of P-gp regulation in the brain, encompassing the transcriptional, post-transcriptional and post-translational mechanisms that have been identified to affect P-gp expression and transport activity.
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Affiliation(s)
- Amanda B. Chai
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Richard Callaghan
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
| | - Ingrid C. Gelissen
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
- Correspondence: ; Tel.: +61-2-8627-0357
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Electrolyzed Hydrogen Water Alleviates Abdominal Pain through Suppression of Colonic Tissue Inflammation in a Rat Model of Inflammatory Bowel Disease. Nutrients 2022; 14:nu14214451. [PMID: 36364715 PMCID: PMC9655279 DOI: 10.3390/nu14214451] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/14/2022] [Accepted: 10/20/2022] [Indexed: 01/24/2023] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the digestive tract and is typically accompanied by characteristic symptoms, such as abdominal pain, diarrhea, and bloody stool, severely deteriorating the quality of the patient's life. Electrolyzed hydrogen water (EHW) has been shown to alleviate inflammation in several diseases, such as renal disease and polymyositis/dermatomyositis. To investigate whether and how daily EHW consumption alleviates abdominal pain, the most common symptom of IBD, we examined the antioxidative and anti-inflammatory effects of EHW in an IBD rat model, wherein colonic inflammation was induced by colorectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). We found that EHW significantly alleviated TNBS-induced abdominal pain and tissue inflammation. Moreover, the production of proinflammatory cytokines in inflamed colon tissue was also decreased significantly. Meanwhile, the overproduction of reactive oxygen species (ROS), which is intricately involved in intestinal inflammation, was significantly suppressed by EHW. Additionally, expression of S100A9, an inflammatory biomarker of IBD, was significantly suppressed by EHW. These results suggest that the EHW prevented the overproduction of ROS due to its powerful free-radical scavenging ability and blocked the crosstalk between oxidative stress and inflammation, thereby suppressing colonic inflammation and alleviating abdominal pain.
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Todosenko N, Yurova K, Khaziakhmatova O, Malashchenko V, Khlusov I, Litvinova L. Heparin and Heparin-Based Drug Delivery Systems: Pleiotropic Molecular Effects at Multiple Drug Resistance of Osteosarcoma and Immune Cells. Pharmaceutics 2022; 14:pharmaceutics14102181. [PMID: 36297616 PMCID: PMC9612132 DOI: 10.3390/pharmaceutics14102181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/29/2022] [Accepted: 10/10/2022] [Indexed: 11/23/2022] Open
Abstract
One of the main problems of modern health care is the growing number of oncological diseases both in the elderly and young population. Inadequately effective chemotherapy, which remains the main method of cancer control, is largely associated with the emergence of multidrug resistance in tumor cells. The search for new solutions to overcome the resistance of malignant cells to pharmacological agents is being actively pursued. Another serious problem is immunosuppression caused both by the tumor cells themselves and by antitumor drugs. Of great interest in this context is heparin, a biomolecule belonging to the class of glycosaminoglycans and possessing a broad spectrum of biological activity, including immunomodulatory and antitumor properties. In the context of the rapid development of the new field of “osteoimmunology,” which focuses on the collaboration of bone and immune cells, heparin and delivery systems based on it may be of intriguing importance for the oncotherapy of malignant bone tumors. Osteosarcoma is a rare but highly aggressive, chemoresistant malignant tumor that affects young adults and is characterized by constant recurrence and metastasis. This review describes the direct and immune-mediated regulatory effects of heparin and drug delivery systems based on it on the molecular mechanisms of (multiple) drug resistance in (onco) pathological conditions of bone tissue, especially osteosarcoma.
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Affiliation(s)
- Natalia Todosenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Kristina Yurova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Olga Khaziakhmatova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Vladimir Malashchenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Igor Khlusov
- Department of Morphology and General Pathology, Siberian State Medical University, 634050 Tomsk, Russia
| | - Larisa Litvinova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
- Correspondence:
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Steroid Resistance Associated with High MIF and P-gp Serum Levels in SLE Patients. Molecules 2022; 27:molecules27196741. [PMID: 36235275 PMCID: PMC9573564 DOI: 10.3390/molecules27196741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/07/2022] [Accepted: 10/08/2022] [Indexed: 11/16/2022] Open
Abstract
Approximately 30% of patients with systemic lupus erythematosus (SLE) present steroid resistance (SR). Macrophage migration inhibition factor (MIF) and P-glycoprotein (P-gp) could be related to SR. This work aims to evaluate the relationship between MIF and P-pg serum levels in SR in SLE. Methods: Case−control study including 188 SLE patients who were divided into two groups (90 in the steroid-resistant group and 98 in the steroid-sensitive (SS) group) and 35 healthy controls. MIF and P-gp serum levels were determined by ELISA. Multivariable logistic regression and chi-squared automatic interaction detection (CHAID) were used to explore risk factors for SR. Results: The steroid-resistant group presented higher MIF and P-gp serum levels in comparison with the SS (p < 0.001) and reference (p < 0.001) groups. MIF correlated positively with P-gp (rho = 0.41, p < 0.001). MIF (≥15.75 ng/mL) and P-gp (≥15.22 ng/mL) were a risk factor for SR (OR = 2.29, OR = 5.27). CHAID identified high P-gp as the main risk factor for SR and high MIF as the second risk factor in those patients with low P-gp. Conclusions: An association between MIF and P-gp serum levels was observed in SR. CHAID identified P-gp ≥ 15.22 ng/mL as the main risk factor for SR. More studies are needed to validate these results.
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Udomkarnjananun S, Francke MI, Dieterich M, van de Velde D, Verhoeven JGHP, Boer K, Clahsen-Van Groningen MC, De Winter BCM, Baan CC, Hesselink DA. Association Between the Intracellular Tacrolimus Concentration in CD3 + T Lymphocytes and CD14 + Monocytes and Acute Kidney Transplant Rejection. Ther Drug Monit 2022; 44:625-632. [PMID: 35358111 DOI: 10.1097/ftd.0000000000000982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/16/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Intracellular tacrolimus concentration in peripheral blood mononuclear cells (PBMCs) (TAC [PBMC] ) has been proposed to better represent its active concentration than its whole blood concentration. As tacrolimus acts on T lymphocytes and other white blood cells, including monocytes, we investigated the association of tacrolimus concentration in CD3 + T lymphocytes (TAC [CD3] ) and CD14 + monocytes (TAC [CD14] ) with acute rejection after kidney transplantation. METHODS From a total of 61 samples in this case-control study, 28 samples were obtained during biopsy-proven acute rejection (rejection group), and 33 samples were obtained in the absence of rejection (control group). PBMCs were collected from both cryopreserved (retrospectively) and freshly obtained (prospectively) samples. CD3 + T lymphocytes and CD14 + monocytes were isolated from PBMCs, and their intracellular tacrolimus concentrations were measured. RESULTS The correlation between tacrolimus whole-blood and intracellular concentrations was poor. TAC [CD3] was significantly lower than TAC [CD14] (median 12.8 versus 81.6 pg/million cells; P < 0.001). No difference in TAC [PBMC] (48.5 versus 44.4 pg/million cells; P = 0.82), TAC [CD3] (13.4 versus 12.5 pg/million cells; P = 0.28), and TAC [CD14] (90.0 versus 72.8 pg/million cells; P = 0.27) was found between the rejection and control groups. However, freshly isolated PBMCs showed significantly higher TAC [PBMC] than PBMCs from cryopreserved samples. Subgroup analysis of intracellular tacrolimus concentrations from freshly isolated cells did not show a difference between rejectors and nonrejectors. CONCLUSIONS Differences in TAC [CD3] and TAC [CD14] between patients with and without rejection could not be demonstrated. However, further optimization of the cell isolation process is required because a difference in TAC [PBMC] between fresh and cryopreserved cells was observed. These results need to be confirmed in a study with a larger number of patients.
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Affiliation(s)
- Suwasin Udomkarnjananun
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Erasmus MC Transplant Institute, Rotterdam, the Netherlands
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Marith I Francke
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Erasmus MC Transplant Institute, Rotterdam, the Netherlands
| | - Marjolein Dieterich
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Daan van de Velde
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; and
| | - Jeroen G H P Verhoeven
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Erasmus MC Transplant Institute, Rotterdam, the Netherlands
| | - Karin Boer
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Erasmus MC Transplant Institute, Rotterdam, the Netherlands
| | - Marian C Clahsen-Van Groningen
- Erasmus MC Transplant Institute, Rotterdam, the Netherlands
- Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Brenda C M De Winter
- Erasmus MC Transplant Institute, Rotterdam, the Netherlands
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; and
| | - Carla C Baan
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Erasmus MC Transplant Institute, Rotterdam, the Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Erasmus MC Transplant Institute, Rotterdam, the Netherlands
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14
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Efflux Capacity and Aldehyde Dehydrogenase Both Contribute to CD8+ T-cell Resistance to Posttransplant Cyclophosphamide. Blood Adv 2022; 6:4994-5008. [PMID: 35819449 PMCID: PMC9631635 DOI: 10.1182/bloodadvances.2022006961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 07/04/2022] [Indexed: 11/21/2022] Open
Abstract
CD8+ T cells increase drug effluxing and aldehyde dehydrogenase expression in allogeneic reactions, enhancing resistance to cyclophosphamide. Common γ-chain cytokines and the proliferative state of the cell modulate these resistance pathways. Mechanisms of T-cell survival after cytotoxic chemotherapy, including posttransplantation cyclophosphamide (PTCy), are not well understood. Here, we explored the impact of PTCy on human CD8+ T-cell survival and reconstitution, including what cellular pathways drive PTCy resistance. In major histocompatibility complex (MHC)-mismatched mixed lymphocyte culture (MLC), treatment with mafosfamide, an in vitro active cyclophosphamide analog, preserved a relatively normal distribution of naïve and memory CD8+ T cells, whereas the percentages of mucosal-associated invariant T (MAIT) cells and phenotypically stem cell memory (Tscm) T-cell subsets were increased. Activated (CD25+) and proliferating CD8+ T cells were derived from both naïve and memory subsets and were reduced but still present after mafosfamide. By contrast, cyclosporine-A (CsA) or rapamycin treatment preferentially maintained nonproliferating CD25− naïve cells. Drug efflux capacity and aldehyde dehydrogenase-1A1 expression were increased in CD8+ T cells in allogeneic reactions in vitro and in patients, were modulated by common γ-chain cytokines and the proliferative state of the cell, and contributed to CD8+ T-cell survival after mafosfamide. The CD8+ T-cell composition early after hematopoietic cell transplantation (HCT) in PTCy-treated patients was dominated by CD25+ and phenotypically memory, including Tscm and MAIT, cells, consistent with MLC. Yet, MHC-mismatched murine HCT studies revealed that peripherally expanded, phenotypically memory T cells 1 to 3 months after transplant originated largely from naïve-derived rather than memory-derived T cells surviving PTCy, suggesting that initial resistance and subsequent immune reconstitution are distinct. These studies provide insight into the complex immune mechanisms active in CD8+ T-cell survival, differentiation, and reconstitution after cyclophosphamide, with relevance for post-HCT immune recovery, chemotherapy use in autologous settings, and adoptive cellular therapies.
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15
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Morsy MA, El-Sheikh AAK, Abdel-Hafez SMN, Kandeel M, Abdel-Gaber SA. Paeonol Protects Against Methotrexate-Induced Nephrotoxicity via Upregulation of P-gp Expression and Inhibition of TLR4/NF-κB Pathway. Front Pharmacol 2022; 13:774387. [PMID: 35185559 PMCID: PMC8854802 DOI: 10.3389/fphar.2022.774387] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 01/13/2022] [Indexed: 01/15/2023] Open
Abstract
Methotrexate (MTX) is a well-known anticancer drug that causes nephrotoxicity as a side effect. To investigate the mechanisms by which paeonol, a natural phenolic compound, can protect against MTX-induced nephrotoxicity, paeonol (100 mg/kg/day orally) was given to rats for 10 days, with or without MTX (20 mg/kg once i.p. at day 5). Compared to control, MTX caused nephrotoxic effects manifested by increased serum urea and creatinine and distortion in renal histological architecture, with a significant increase in the mean glomerular diameter and upregulation of kidney injury molecule-1. MTX caused oxidative stress manifested by decreasing reduced glutathione and superoxide dismutase while increasing malondialdehyde and nitric oxide. MTX also induced renal inflammation by upregulating TLR4, NF-κB, and IL-1β and caused apoptosis by induction of caspase 3. Administering paeonol with MTX improved kidney functional and structural parameters, as well as all oxidative, inflammatory, and apoptotic markers tested. Interestingly, both MTX and paeonol increased the expression of the renal efflux transporter P-glycoprotein (P-gp) that helps in MTX elimination, and their drug combination further upregulated renal P-gp. In silico, paeonol was neither a substrate nor an inhibitor of P-gp, suggesting that its effect on P-gp is not on functional but on the expression level. In vitro, paeonol and MTX were administered to colon cancer cells and their combination caused a progressive cellular cytotoxic effect, which was dose-dependent with the increase of paeonol concentration. In conclusion, paeonol protects against MTX-induced nephrotoxicity through antioxidant, anti-inflammatory, and antiapoptotic mechanisms and might potentiate MTX chemotherapeutic efficacy.
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Affiliation(s)
- Mohamed A. Morsy
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
- Department of Pharmacology, Faculty of Medicine, Minia University, Minia, Egypt
- *Correspondence: Mohamed A. Morsy,
| | - Azza A. K. El-Sheikh
- Department of Pharmacology, Faculty of Medicine, Minia University, Minia, Egypt
- Department of Basic Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | | | - Mahmoud Kandeel
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
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Affiliation(s)
- Elise P Gomez-Sanchez
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, and G.V. (Sonny) Montgomery VA Medical Center, Jackson, MS
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How Macrophages Become Transcriptionally Dysregulated: A Hidden Impact of Antitumor Therapy. Int J Mol Sci 2021; 22:ijms22052662. [PMID: 33800829 PMCID: PMC7961970 DOI: 10.3390/ijms22052662] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor-associated macrophages (TAMs) are the essential components of the tumor microenvironment. TAMs originate from blood monocytes and undergo pro- or anti-inflammatory polarization during their life span within the tumor. The balance between macrophage functional populations and the efficacy of their antitumor activities rely on the transcription factors such as STAT1, NF-κB, IRF, and others. These molecular tools are of primary importance, as they contribute to the tumor adaptations and resistance to radio- and chemotherapy and can become important biomarkers for theranostics. Herein, we describe the major transcriptional mechanisms specific for TAM, as well as how radio- and chemotherapy can impact gene transcription and functionality of macrophages, and what are the consequences of the TAM-tumor cooperation.
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18
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Gao J, Wang C, Wei W. The effects of drug transporters on the efficacy of methotrexate in the treatment of rheumatoid arthritis. Life Sci 2021; 268:118907. [PMID: 33428880 DOI: 10.1016/j.lfs.2020.118907] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 12/08/2020] [Accepted: 12/10/2020] [Indexed: 12/12/2022]
Abstract
The ATP-binding cassette (ABC) and solute carrier (SLC) transporter families consist of common drug transporters that mediate the efflux and uptake of drugs, respectively, and play an important role in the absorption, distribution, metabolism and excretion of drugs in vivo. Rheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis, and there are many RA patients worldwide. Methotrexate (MTX), the first-choice treatment for RA, can reduce the level of inflammation, prevent joint erosion and functional damage, and greatly reduce pain in RA patients. However, many patients show resistance to MTX, greatly affecting the efficacy of MTX. Many factors, such as irrational drug use and heredity, are associated with drug resistance. Considering the effect of drug transporters on drugs, many studies have compared the expression of drug transporters in drug-resistant and drug-sensitive patients, and abnormal transporter expression and transport activity have been found in patients with MTX resistance. Thus, drug transporters are involved in drug resistance. This article reviews the effects of transporters on the efficacy of MTX in the treatment of RA.
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Affiliation(s)
- Jinzhang Gao
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, China
| | - Chun Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, China.
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Kawase A, Chuma T, Irie K, Kazaoka A, Kakuno A, Matsuda N, Shimada H, Iwaki M. Increased penetration of diphenhydramine in brain via proton-coupled organic cation antiporter in rats with lipopolysaccharide-induced inflammation. Brain Behav Immun Health 2020; 10:100188. [PMID: 34589723 PMCID: PMC8474606 DOI: 10.1016/j.bbih.2020.100188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/30/2020] [Accepted: 12/03/2020] [Indexed: 01/18/2023] Open
Abstract
Uptake transporters in brain microvascular endothelial cells (BMECs) are involved in the penetration of basic (cationic) drugs such as diphenhydramine (DPHM) into the brain. Lipopolysaccharide (LPS)-induced inflammation alters the expression levels and activities of uptake transporters, which change the penetration of DPHM into the brain. A brain microdialysis study showed that the unbound brain-to-plasma partition coefficient (Kp,uu,brain) for DPHM in LPS rats was approximately two times higher than that in control rats. The transcellular transport of DPHM to BMECs was increased when BMECs were cultured with serum from LPS rats. Compared with control rats or BMECs, the brain uptake of DPHM in LPS rats was increased and the intracellular accumulation of DPHM was increased under a high intracellular pH in BMECs from LPS rats, respectively. Treatment of BMECs with transporter inhibitors or inflammatory cytokines had little impact on the intracellular accumulation of DPHM in BMECs. This study suggests that LPS-induced inflammation promotes unidentified proton-coupled organic cation (H+/OC) antiporters that improve the penetration of DPHM into rat brain via the blood-brain barrier.
The unbound brain-to-plasma partition coefficient for diphenhydramine (DPHM) was increased in lipopolysaccharide-induced inflammation in rats. The uptake of DPHM to brain microvascular endothelial cells (BMECs) was promoted by treatments of serum from rats with inflammation. Treatment of BMECs with transporter inhibitors or inflammatory cytokines had little impact on the intracellular accumulation of DPHM in BMECs. LPS-induced inflammation promotes unidentified proton-coupled organic cation antiporters that improve the brain penetration of DPHM.
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Affiliation(s)
- Atsushi Kawase
- Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan
- Corresponding author. 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502, Japan.
| | - Taihei Chuma
- Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan
| | - Kota Irie
- Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan
| | - Akira Kazaoka
- Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan
| | - Asuka Kakuno
- Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan
| | - Naoya Matsuda
- Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan
| | - Hiroaki Shimada
- Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan
| | - Masahiro Iwaki
- Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan
- Pharmaceutical Research and Technology Institute, Kindai University, Osaka, Japan
- Antiaging Center, Kindai University, Osaka, Japan
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20
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Koetzier SC, van Langelaar J, Blok KM, van den Bosch TPP, Wierenga-Wolf AF, Melief MJ, Pol K, Siepman TA, Verjans GMGM, Smolders J, Lubberts E, de Vries HE, van Luijn MM. Brain-homing CD4 + T cells display glucocorticoid-resistant features in MS. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2020; 7:7/6/e894. [PMID: 33037101 PMCID: PMC7577536 DOI: 10.1212/nxi.0000000000000894] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 08/20/2020] [Indexed: 12/20/2022]
Abstract
Objective To study whether glucocorticoid (GC) resistance delineates disease-relevant T helper (Th) subsets that home to the CNS of patients with early MS. Methods The expression of key determinants of GC sensitivity, multidrug resistance protein 1 (MDR1/ABCB1) and glucocorticoid receptor (GR/NR3C1), was investigated in proinflammatory Th subsets and compared between natalizumab-treated patients with MS and healthy individuals. Blood, CSF, and brain compartments from patients with MS were assessed for the recruitment of GC-resistant Th subsets using fluorescence-activated cell sorting (FACS), quantitative polymerase chain reaction (qPCR), immunohistochemistry, and immunofluorescence. Results An MS-associated Th subset termed Th17.1 showed a distinct GC-resistant phenotype as reflected by high MDR1 and low GR expression. This expression ratio was further elevated in Th17.1 cells that accumulated in the blood of patients with MS treated with natalizumab, a drug that prevents their entry into the CNS. Proinflammatory markers C-C chemokine receptor 6, IL-23R, IFN-γ, and GM-CSF were increased in MDR1-expressing Th17.1 cells. This subset predominated the CSF of patients with early MS, which was not seen in the paired blood or in the CSF from patients with other inflammatory and noninflammatory neurologic disorders. The potential of MDR1-expressing Th17.1 cells to infiltrate brain tissue was confirmed by their presence in MS white matter lesions. Conclusion This study reveals that GC resistance coincides with preferential CNS recruitment of pathogenic Th17.1 cells, which may hamper the long-term efficacy of GCs in early MS.
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Affiliation(s)
- Steven C Koetzier
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands
| | - Jamie van Langelaar
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands
| | - Katelijn M Blok
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands
| | - Thierry P P van den Bosch
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands
| | - Annet F Wierenga-Wolf
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands
| | - Marie-José Melief
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands
| | - Kim Pol
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands
| | - Theodora A Siepman
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands
| | - Georges M G M Verjans
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands
| | - Joost Smolders
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands
| | - Erik Lubberts
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands
| | - Helga E de Vries
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands
| | - Marvin M van Luijn
- From the Departments of Immunology (S.C.K., J.v.L., A.F.W.-W., M.-J.M., K.P., J.S., M.M.v.L.); Neurology (K.M.B, T.A.S., J.S.); Pathology (T.P.P.v.d.B.); Viroscience (G.M.G.M.V.); Rheumatology (E.L.); and MS Center ErasMS at Erasmus MC (S.C.K, J.v.L., K.M.B., A.F.W.-W, M.-J.M., K.P., T.A.S., J.S., M.M.v.L.), University Medical Center, Rotterdam, The Netherlands; Research Center for Emerging Infections and Zoonosis (G.M.G.M.V.), University of Veterinary Medicine, Hannover, Germany; Department of Neuroimmunology (J.S.), Netherlands Institute for Neuroscience, Amsterdam; Department of Molecular Cell Biology and Immunology (H.E.d.V.), Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, the Netherlands.
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21
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Kikuchi H, Maishi N, Annan DA, Alam MT, Dawood RIH, Sato M, Morimoto M, Takeda R, Ishizuka K, Matsumoto R, Akino T, Tsuchiya K, Abe T, Osawa T, Miyajima N, Maruyama S, Harabayashi T, Azuma M, Yamashiro K, Ameda K, Kashiwagi A, Matsuno Y, Hida Y, Shinohara N, Hida K. Chemotherapy-Induced IL8 Upregulates MDR1/ABCB1 in Tumor Blood Vessels and Results in Unfavorable Outcome. Cancer Res 2020; 80:2996-3008. [PMID: 32536602 DOI: 10.1158/0008-5472.can-19-3791] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 04/10/2020] [Accepted: 05/29/2020] [Indexed: 11/16/2022]
Abstract
Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TECs resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified. Here, we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues (n = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. In vivo, the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone. Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance. SIGNIFICANCE: These findings show that inhibition of ABCB1 in tumor endothelial cells may improve clinical outcome, where ABCB1 expression contributes to drug resistance and metastasis following first-line chemotherapy.
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Affiliation(s)
- Hiroshi Kikuchi
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.,Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Nako Maishi
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.,Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan
| | - Dorcas A Annan
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.,Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan
| | - Mohammad Towfik Alam
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan.,Department of Dental Radiology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan
| | - Randa Ibrahim Hassan Dawood
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Masumi Sato
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Masahiro Morimoto
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.,Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan
| | - Ryo Takeda
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Keita Ishizuka
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Ryuji Matsumoto
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.,Department of Urology, Teine Keijinkai Hospital, Sapporo, Hokkaido, Japan
| | - Tomoshige Akino
- Department of Urology, Sapporo City General Hospital, Sapporo, Hokkaido, Japan.,Department of Urology, Tonan Hospital, Sapporo, Hokkaido, Japan
| | - Kunihiko Tsuchiya
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.,Department of Urology, KKR Sapporo Medical Center, Sapporo, Hokkaido, Japan
| | - Takashige Abe
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Takahiro Osawa
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Naoto Miyajima
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.,Department of Urology, Teine Keijinkai Hospital, Sapporo, Hokkaido, Japan
| | - Satoru Maruyama
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.,Department of Urology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan
| | - Toru Harabayashi
- Department of Urology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan
| | - Manabu Azuma
- Department of Pathology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan
| | | | - Kaname Ameda
- Hokkaido Hinyokika Kinen Hospital, Sapporo, Hokkaido, Japan
| | - Akira Kashiwagi
- Department of Urology, Teine Keijinkai Hospital, Sapporo, Hokkaido, Japan
| | - Yoshihiro Matsuno
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Yasuhiro Hida
- Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Nobuo Shinohara
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Kyoko Hida
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan. .,Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan
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22
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Yuan J, Cheng W, Zhang G, Ma Q, Li X, Zhang B, Hu T, Song G. Protective effects of iridoid glycosides on acute colitis via inhibition of the inflammatory response mediated by the STAT3/NF-кB pathway. Int Immunopharmacol 2020; 81:106240. [PMID: 32044657 DOI: 10.1016/j.intimp.2020.106240] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 12/24/2019] [Accepted: 01/20/2020] [Indexed: 02/08/2023]
Abstract
Morroniside and loganin are iridoid glycosides extracted from Cornus officinalis, a plant species widely used in traditional Chinese medicine. However, the anti-inflammatory effects of morroniside and loganin in colitis are barely understood. The aim of the present study was to explore the effects of morroniside and loganin on the dextran sodium sulfate (DSS)-induced murine model of colitis and an LPS-induced colorectal cancer (CRC) cell inflammation model, and to clarify the underlying mechanisms. We found that morroniside and loganin were able to ameliorate clinical features, including disease activity index (DAI), histological inflammation score and periodic acid-Schiff staining (PAS). In the mouse model, morroniside and loganin treatment increased expression of tight junction proteins (TJs) and decreased pro-inflammatory cytokine production. Moreover, our findings showed that the expression of p-STAT3 and p-p65 were suppressed compared to the disease group. In in vitro experiments, treatment with morroniside and loganin had no obvious effects on proliferative activity in HCT116 cells and HIEC-6 cells. Expression of pro-inflammatory cytokines was inhibited by morroniside and loganin treatment in comparison with the LPS-treated group. Taken together, morroniside and loganin have beneficial effects on colitis in vivo and are anti-inflammatory in vitro. Possible mechanisms of the anti-inflammatory response may include blockade of the STAT3/NF-κB pathway.
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Affiliation(s)
- Jiahui Yuan
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Weipeng Cheng
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Gongye Zhang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Qiujuan Ma
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Xiaomei Li
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Bing Zhang
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Tianhui Hu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Gang Song
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China.
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23
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Tang H, Wu YJ, Xiao F, Wang B, Asenso J, Wang Y, Sun W, Wang C, Wei W. Regulation of CP-25 on P-glycoprotein in synoviocytes of rats with adjuvant arthritis. Biomed Pharmacother 2019; 119:109432. [PMID: 31521892 DOI: 10.1016/j.biopha.2019.109432] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/02/2019] [Accepted: 09/02/2019] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Methotrexate (MTX) is a commonly used drug for the treatment of rheumatoid arthritis (RA) and it has been studied in RA resistance recently. P-glycoprotein (P-gp) is one of the important transporters that mediate MTX resistance. This study investigated the effect of Paeoniflorin-6'-O-benzene sulfonate (code: CP-25) in the resistance of P-gp-mediated MTX to RA. METHODS Adjuvant arthritis (AA) was induced in rats via complete Freund's adjuvant. The experimental groups were divided into normal group; AA model group; monotherapy groups, including CP-25, MTX and dexamethasone; and CP-25 combined with MTX group. The expression of P-gp in synovial tissue was measured by western blot and histochemistry. Besides, P-gp high expression of human hepatoma cell line Bel7402/5-FU and Bel7402 were chose to study in MTX resistance and the function of P-gp was detected by Flow cytometry. RESULTS CP-25 had a good therapeutic effect on AA rats, significantly improved manifestations and reduced the expression of P-gp in synovial tissue, spleen medulla and small intestinal epithelial cells in the apical tissues of AA rats. In addition, CP-25 significantly inhibited the up-regulation of P-gp induced by TNF-α stimulation in synoviocytes. Furthermore, according to the accumulation and efflux of rhodamine 123 in Bel7402/5-FU resistant cells and Bel7402 sensitive cells, CP-25 could reverse the resistance of MTX in Bel7402/5-FU cells compared with Bel7402 cells, which was reflected by the reduced IC50 values of MTX. Further study indicated that CP-25 could decrease P-gp expression and inhibit P-gp function in Bel7402/5-FU cells. CONCLUSION CP-25 regulates the expression of P-gp and inhibits the function of P-gp, thereby improving the resistance of MTX.
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Affiliation(s)
- Hao Tang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Yi-Jin Wu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Feng Xiao
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Bin Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - James Asenso
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Yong Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Wei Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Chun Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China.
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24
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Wang J, Mao N, Liu Y, Xie X, Tian J, Li F, Chen J. Inhibition of miR-16 enhances the sensitivity of fibroblast-like synovial cells to methotrexate by restraining MDR1/P-gp expression via NF-κB pathway. RSC Adv 2019; 9:26619-26627. [PMID: 35528582 PMCID: PMC9070447 DOI: 10.1039/c9ra04991f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 08/16/2019] [Indexed: 01/19/2023] Open
Abstract
MicroRNAs (miRNAs) are demonstrated to contribute to the regulation of drug resistance in a number of diseases. Nevertheless, little is known about the role and the underlying mechanism of miR-16 in rheumatoid arthritis (RA) methotrexate resistance. In this study, we firstly examined the miR-16 expression in the serum and synovial fluid from RA patients who were unresponsive to methotrexate monotherapy (UR-MTX patients) and responsive RA patients (R-MTX patients). Secondly, the miR-16 expression was measured in both fibroblast-like synovial cells (FLS) and methotrexate resistance RA-FLS cells (FLS-MTX). FLS cells used in this study were isolated from synovial tissue specimens obtained from patients with RA who underwent total joint replacement. FLS-MTX cells were conducted by gradually increasing the concentration of methotrexate in the medium. The construction of FLS-MTX cells was confirmed by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay. Thirdly, in order to further investigate the role of miR-16 in FLS-MTX cells, we introduced miR-16 inhibitor into FLS-MTX cells to knockdown the expression of miR-16, used fluorescence quantitative PCR to detect the inhibition efficiency. The effects of miR-16 inhibition on cell viability, cell cycle arrest and apoptosis in FLS-MTX cells were monitored with MTT and flow cytometry analysis, respectively. And the regulation of miR-16 on P-glycoprotein (P-gp) was performed using qRT-PCR, western blotting, and immunofluorescence staining. Fourthly, ammonium pyrrolidinedithiocarbamate (PDTC), a NF-κB pathway inhibitor, was applied to verify the mechanism by which miR-16 involved in to regulate the P-gp expression, and thus contributing to the methotrexate resistance in FLS-MTX cells. MiR-16 was upregulated in the in serum and synovial fluid from UR-MTX patients as well as in FLS-MTX cells. Inhibition of miR-16 re-sensitized the FLS-MTX cells to methotrexate by suppressing the cell viability, cell promoting cycle arrest at G0/G1 phase and enhancing apoptosis. Knockdown of miR-16 significantly reduced MDR1 mRNA expression and P-gp protein expression in FLS-MTX cells. Furthermore, inhibition of NF-κB pathway by PDTC reinforced the effect of miR-16 knockdown on P-gp expression, cell viability, cell cycle arrest and apoptosis. In conclusion, our study illustrated that inhibition of miR-16 in FLS-MTX cells alleviated methotrexate resistance by inhibiting MDR1/P-gp expression through inactivation of the NF-κB pathway. MicroRNAs (miRNAs) are demonstrated to contribute to the regulation of drug resistance in a number of diseases.![]()
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Affiliation(s)
- Jing Wang
- Department of Rheumatology and Immunology, The First People's Hospital of Yunnan Province Kunming 650034 Yunnan Province China.,Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University No. 139 Middle Renmin Road Changsha 410011 Hunan Province China +86-731-85533525 +86-731-85295888
| | - Ni Mao
- Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University No. 139 Middle Renmin Road Changsha 410011 Hunan Province China +86-731-85533525 +86-731-85295888
| | - Yiming Liu
- Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University No. 139 Middle Renmin Road Changsha 410011 Hunan Province China +86-731-85533525 +86-731-85295888
| | - Xi Xie
- Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University No. 139 Middle Renmin Road Changsha 410011 Hunan Province China +86-731-85533525 +86-731-85295888
| | - Jing Tian
- Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University No. 139 Middle Renmin Road Changsha 410011 Hunan Province China +86-731-85533525 +86-731-85295888
| | - Fen Li
- Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University No. 139 Middle Renmin Road Changsha 410011 Hunan Province China +86-731-85533525 +86-731-85295888
| | - Jinwei Chen
- Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University No. 139 Middle Renmin Road Changsha 410011 Hunan Province China +86-731-85533525 +86-731-85295888
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25
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Conserved transcriptomic profile between mouse and human colitis allows unsupervised patient stratification. Nat Commun 2019; 10:2892. [PMID: 31253778 PMCID: PMC6598981 DOI: 10.1038/s41467-019-10769-x] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 05/31/2019] [Indexed: 02/07/2023] Open
Abstract
Clinical manifestations and response to therapies in ulcerative colitis (UC) are heterogeneous, yet patient classification criteria for tailored therapies are currently lacking. Here, we present an unsupervised molecular classification of UC patients, concordant with response to therapy in independent retrospective cohorts. We show that classical clustering of UC patient tissue transcriptomic data sets does not identify clinically relevant profiles, likely due to associated covariates. To overcome this, we compare cross-sectional human data sets with a newly generated longitudinal transcriptome profile of murine DSS-induced colitis. We show that the majority of colitis risk-associated gene expression peaks during the inflammatory rather than the recovery phase. Moreover, we achieve UC patient clustering into two distinct transcriptomic profiles, differing in neutrophil-related gene activation. Notably, 87% of patients in UC1 cluster are unresponsive to two most widely used biological therapies. These results demonstrate that cross-species comparison enables stratification of patients undistinguishable by other molecular approaches.
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Modulation of reactive oxygen levels and gene expression in sensitive and resistant tumoral cells by C-phyocyanin. Mol Biol Rep 2018; 46:1349-1356. [DOI: 10.1007/s11033-018-4569-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 12/10/2018] [Indexed: 12/29/2022]
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Bossennec M, Di Roio A, Caux C, Ménétrier-Caux C. MDR1 in immunity: friend or foe? Oncoimmunology 2018; 7:e1499388. [PMID: 30524890 PMCID: PMC6279327 DOI: 10.1080/2162402x.2018.1499388] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 07/08/2018] [Indexed: 02/09/2023] Open
Abstract
MDR1 is an ATP-dependent transmembrane transporter primarily studied for its role in the detoxification of tissues and for its implication in resistance of tumor cells to chemotherapy treatment. Several studies also report on its expression on immune cells where it plays a protective role from xenobiotics and toxins. This review provides an overview of what is known on MDR1 expression in immune cells in human, and its implications in different pathologies and their treatment options.
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Affiliation(s)
- Marion Bossennec
- Centre Léon Bérard, Cancer Research Center of Lyon (CRCL), Univ Lyon, Université Claude Bernard Lyon 1, Lyon France.,Immunology Virology Inflammation (IVI) department, Team "Therapeutic targeting of the tumor cells and their immune stroma", Lyon, France
| | - Anthony Di Roio
- Centre Léon Bérard, Cancer Research Center of Lyon (CRCL), Univ Lyon, Université Claude Bernard Lyon 1, Lyon France.,Immunology Virology Inflammation (IVI) department, Team "Therapeutic targeting of the tumor cells and their immune stroma", Lyon, France
| | - Christophe Caux
- Centre Léon Bérard, Cancer Research Center of Lyon (CRCL), Univ Lyon, Université Claude Bernard Lyon 1, Lyon France.,Immunology Virology Inflammation (IVI) department, Team "Therapeutic targeting of the tumor cells and their immune stroma", Lyon, France
| | - Christine Ménétrier-Caux
- Centre Léon Bérard, Cancer Research Center of Lyon (CRCL), Univ Lyon, Université Claude Bernard Lyon 1, Lyon France.,Immunology Virology Inflammation (IVI) department, Team "Therapeutic targeting of the tumor cells and their immune stroma", Lyon, France
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28
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Wu YJ, Wang C, Wei W. The effects of DMARDs on the expression and function of P-gp, MRPs, BCRP in the treatment of autoimmune diseases. Biomed Pharmacother 2018; 105:870-878. [DOI: 10.1016/j.biopha.2018.06.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 05/24/2018] [Accepted: 06/04/2018] [Indexed: 12/17/2022] Open
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Zhang ZL, Jiang QC, Wang SR. Schisandrin A reverses doxorubicin-resistant human breast cancer cell line by the inhibition of P65 and Stat3 phosphorylation. Breast Cancer 2017; 25:233-242. [PMID: 29181822 DOI: 10.1007/s12282-017-0821-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 11/15/2017] [Indexed: 01/07/2023]
Abstract
BACKGROUND Multidrug resistance (MDR) in breast cancer therapy occurs frequently. Thus, anti-MDR agents from natural products or synthetic compounds were tested extensively. We have also explored the reverse effect and mechanism of Schisandrin A (Sch A), a natural product, on MCF-7 breast cancer doxorubicin (DOX)-resistant subline MCF-7/DOX. METHODS MTT assay was performed to measure the viability of MCF-7 cells to assess the reverse effect of Sch A. Western blot analysis was used to study the protein levels. Laser scanning confocal microscopy was performed to detect the intercellular DOX and Rhodamine 123 accumulation. The qRT-PCR was used to analysis the target gene expression. Dual-luciferase reporter assay was performed to test the transcriptional activity of P-glycoprotein (P-gp). RESULTS Sch A, at the concentration of 20 µM, showed selective reverse effect (better than the positive control, verapamil at 5 µM) on MCF-7/DOX cell line but not on BEL-7402/DOX, Hep G2/DOX, and K-562/DOX cells. In addition, Sch A enhanced DOX-induced cleavage of Caspase-9 and PARP levels by increasing intracellular DOX accumulation and inhibiting P-gp function. Furthermore, Sch A selectively suppressed P-gp at gene and protein levels in MCF-7/DOX cells which express high level of MDR1 but not MRP1, MRP3, or BCRP. Besides, Sch A showed inhibitory effect on P-gp transcriptional activity. Sch A significantly reduced p-IκB-α (Ser32) and p-Stat3 (Tyr705) levels which mediate P-gp expression. In addition, Stat3 knockdown enhanced the reverse effect of siP65. The combined effect of siStat3 and siP65 was better than Sch A single treatment in MCF-7/DOX cells. CONCLUSION Sch A specifically reverses P-gp-mediated DOX resistance in MCF-7/DOX cells by blocking P-gp, NF-κB, and Stat3 signaling. Inhibition of P65 and Stat3 shows potent anti-MDR effect on MCF-7/DOX cells.
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Affiliation(s)
- Zong-Lin Zhang
- Department of Pharmacy, Linyi People's Hospital, Linyi, Shandong, China
| | - Qing-Cheng Jiang
- Department of Pharmacy, First People's Hospital of Tancheng County, Tancheng, Shandong, China
| | - Su-Rong Wang
- Department of Gynecology and Obstetrics, Linyi People's Hospital, 27# Jie fang lu dong duan, Linyi, Shandong, China.
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Yao J, Lu Y, Zhi M, Hu P, Wu W, Gao X. Dietary n‑3 polyunsaturated fatty acids ameliorate Crohn's disease in rats by modulating the expression of PPAR‑γ/NFAT. Mol Med Rep 2017; 16:8315-8322. [PMID: 28990050 DOI: 10.3892/mmr.2017.7673] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Accepted: 08/07/2017] [Indexed: 11/06/2022] Open
Abstract
Dietary n‑3 polyunsaturated fatty acid (PUFA) exerts anti‑inflammatory and immunoregulatory effects via downregulation of the innate and adaptive immune responses. However, the effect of dietary n‑3 PUFA on experimental Crohn's Disease (CD) in rats and the underlying mechanisms are unclear. The present study aimed to investigate the effects of n‑3 PUFA on CD induced by 2,4,6‑trinitrobenzene sulfonic acid (TNBS) in rats, and to determine the underlying mechanisms, including the peroxisome proliferator‑activated receptor (PPAR)‑γ and nuclear factor of activated T‑cells (NFAT) pathway. Sprague‑Dawley rats (n=90) were randomly assigned to the following groups: Control (intragastric distilled water); PUFA control (intragastric n‑3 PUFA, 20 mg/kg/day); trans‑fatty acid (TFA) control (intragastric TFA, 13 mg/kg/day); model (intragastric distilled water + TNBS); PUFA model (intragastric n‑3 PUFA, 20 mg/kg/day + TNBS); and TFA model (intragastric TFA, 13 mg/kg/day + TNBS). The disease activity index (DAI), colon macroscopic damage index (CMDI) and tissue damage index (TDI) were evaluated. The expression of PPAR‑γ, NFAT, interleukin (IL)‑4 and IL‑2 mRNA in colonic tissues was determined by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), and the serum levels of IL‑6, IL‑12, tumor necrosis factor‑α and interferon‑γ were measured by ELISA. The results demonstrated that dietary n‑3 PUFA markedly attenuated colonic inflammation compared with the model group, as indicated by reduced DAI, CMDI and TDI scores, amelioration in pathological evaluation and improvements in localized mucosal inflammation, as indicated by the levels of cytokines associated with local mucosal immunity. Treatment with n‑3 PUFA increased the gene expression of PPAR‑γ in TNBS‑treated rats, and reduced the expression of NFAT, which ultimately reduced the release of IL‑4 and IL‑2 detected by RT‑qPCR. A TFA‑enriched diet was observed to increase DAI and TDI scores, aggravate pathological inflammation with epithelioid granulomas and enhance the release of proinflammatory cytokines, compared with the model group. In conclusion, the present study demonstrated that dietary n‑3 PUFA may attenuate experimental CD induced by TNBS in rats by regulating the expression and activity of the PPAR‑γ/NFAT signaling pathway. These results provide a promising potential therapeutic method for the treatment of CD.
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Affiliation(s)
- Jiayin Yao
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Yi Lu
- Department of Anesthesiology, Guangzhou Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong 510130, P.R. China
| | - Min Zhi
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Pinjin Hu
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Wei Wu
- Department of Cardiology, Sun Yat‑Sen Memorial Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510235, P.R. China
| | - Xiang Gao
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510655, P.R. China
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Ge F, Zhu S, Liu L, Yan J, Ji Y, Sun Z. Anti-inflammatory effects of Fagopyrum cymosum administered as a potential drug for ulcerative colitis. Exp Ther Med 2017; 14:4745-4754. [PMID: 29201175 PMCID: PMC5704331 DOI: 10.3892/etm.2017.5153] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 06/29/2017] [Indexed: 12/21/2022] Open
Abstract
Fagopyrum cymosum (Trev.) Meisn (Fag), which belongs to the Polygonaceae family, has been widely used to treat inflammatory diseases. Previous studies have revealed that Fag components exhibit anti-inflammatory activities; however, their potential use in treating inflammatory bowel disease (IBD) has not been explored. In the present study, mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis were used as a model of IBD. Fag extract was orally administered for 3 days following the induction of colitis and the conventional drug, salicylazosulfapyridine (SASP), was used as a control. The results revealed that Fag significantly ameliorated TNBS-induced body weight loss and colonic shortening in mice (P<0.05). Furthermore, Fag suppressed levels of proinflammatory cytokines and reduced macrophage infiltration into colonic tissues (P<0.05). To further verify the anti-inflammatory effects of Fag at the molecular level, a murine macrophage cell line, Raw264.7, was used. Nuclear translocation of nuclear factor (NF)-κB p65 and the phosphorylation of inhibitor of NF-κB (IκB) were assessed using western blotting. The results demonstrated that Fag inhibited the production of proinflammatory cytokines via inhibiting NF-κB p65 nuclear translocation and IκB phosphorylation (P<0.05). Furthermore, the clinical study results revealed that Fag had significantly fewer side effects (P<0.05) and served as a better anti-inflammatory drug for ulcerative colitis compared with SASP.
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Affiliation(s)
- Fei Ge
- Department of Gastroenterology, Haian Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Haian, Jiangsu 226600, P.R. China.,First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Shilin Zhu
- Department of Gastroenterology, Haian Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Haian, Jiangsu 226600, P.R. China
| | - Lina Liu
- Department of Liver Disease, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Jing Yan
- First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Yu Ji
- Department of Gastroenterology, Haian Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Haian, Jiangsu 226600, P.R. China
| | - Zhiguang Sun
- First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
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32
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Fernandes E Silva E, Figueira FDS, Lettnin AP, Carrett-Dias M, Filgueira DDMVB, Kalil S, Trindade GS, Votto APDS. C-Phycocyanin: Cellular targets, mechanisms of action and multi drug resistance in cancer. Pharmacol Rep 2017; 70:75-80. [PMID: 29331790 DOI: 10.1016/j.pharep.2017.07.018] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 06/30/2017] [Accepted: 07/25/2017] [Indexed: 02/07/2023]
Abstract
C-Phycocyanin (C-PC) has been shown to be promising in cancer treatment; however, although several articles detailing this have been published, its main mechanisms of action and its cellular targets have not yet been defined, nor has a detailed exploration been conducted of its role in the resistance of cancer cells to chemotherapy, rendering clinical use impossible. From our extensive examination of the literature, we have determined as our main hypothesis that C-PC has no one specific target, but rather acts on the membrane, cytoplasm, and nucleus with diverse mechanisms of action. We highlight the cell targets with which C-PC interacts (the MDR1 gene, cytoskeleton proteins, and COX-2 enzyme) that make it capable of killing cells resistant to chemotherapy. We also propose future analyses of the interaction between C-PC and drug extrusion proteins, such as ABCB1 and ABCC1, using in silico and in vitro studies.
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Affiliation(s)
- Estela Fernandes E Silva
- Programa de Pós-graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande (FURG), Rio Grande, RS, Brazil.
| | | | - Aline Portantiolo Lettnin
- Programa de Pós-graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande (FURG), Rio Grande, RS, Brazil.
| | - Michele Carrett-Dias
- Programa de Pós-graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande (FURG), Rio Grande, RS, Brazil.
| | - Daza de Moraes Vaz Batista Filgueira
- Programa de Pós-graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande (FURG), Rio Grande, RS, Brazil.
| | - Susana Kalil
- Escola de Química e Alimentos, FURG, Rio Grande, RS, Brazil.
| | - Gilma Santos Trindade
- Programa de Pós-graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande (FURG), Rio Grande, RS, Brazil.
| | - Ana Paula de Souza Votto
- Programa de Pós-graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande (FURG), Rio Grande, RS, Brazil.
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33
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Ge C, Cao B, Feng D, Zhou F, Zhang J, Yang N, Feng S, Wang G, Aa J. The down-regulation of SLC7A11 enhances ROS induced P-gp over-expression and drug resistance in MCF-7 breast cancer cells. Sci Rep 2017; 7:3791. [PMID: 28630426 PMCID: PMC5476638 DOI: 10.1038/s41598-017-03881-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 05/08/2017] [Indexed: 12/20/2022] Open
Abstract
Adriamycin (ADR) induces the over-expression of P-glycoprotein (P-gp) and multiple drug resistance in breast cancer cells. However, the biochemical process and underlying mechanisms are not clear. Our previous study revealed that ADR increased reactive oxygen species (ROS) generation and decreased glutathione (GSH) biosynthesis, while N-acetylcysteine, the ROS scavenger, reversed the over-expression of P-gp. The present study showed that ADR inhibited the influx of cystine (the source material of GSH) and the activity of the SLC7A11 transporter (in charge of cystine uptake) in MCF-7 cells. For the first time, we showed that the down-regulation/silence of SLC7A11, or cystine deprivation, or enhanced ROS exposure significantly increased P-gp expression in MCF-7 cells. The down-regulation of SLC7A11 markedly enhanced ROS induced P-gp over-expression and drug resistance in MCF-7 cells; a combination of either an inhibited/silenced SLC7A11 or cystine deprivation and increased ROS dramatically promoted P-gp expression, which could be reversed by N-acetylcysteine. In contrast, the over-expression of SLC7A11, or supplementation with sufficiently cystine, or treatment with N-acetylcysteine significantly decreased P-gp expression and activity. It was suggested that ROS and SLC7A11/cystine were the two relevant factors responsible for the expression and function of P-gp, and that SLC7A11 might be a potential target modulating ADR resistance.
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Affiliation(s)
- Chun Ge
- Laboratory of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Bei Cao
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210009, China
| | - Dong Feng
- Laboratory of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Fang Zhou
- Laboratory of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Jingwei Zhang
- Laboratory of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Na Yang
- Laboratory of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Siqi Feng
- Laboratory of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Guangji Wang
- Laboratory of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China.
| | - Jiye Aa
- Laboratory of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China.
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34
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Duan C, Guo JM, Dai Y, Xia YF. The absorption enhancement of norisoboldine in the duodenum of adjuvant-induced arthritis rats involves the impairment of P-glycoprotein. Biopharm Drug Dispos 2017; 38:75-83. [PMID: 27925244 DOI: 10.1002/bdd.2053] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 11/25/2016] [Accepted: 11/30/2016] [Indexed: 01/15/2023]
Abstract
Lindera aggregata (Sims) Kosterm root has been used in traditional Chinese medicine for the treatment of rheumatism palsy, dyspepsia and frequent urination for a long time. Norisoboldine, the main active constituent of this herb drug, possesses outstanding anti-arthritis activity. However, the in vivo disposition of norisoboldine is known to a limited extent, especially under the pathological condition of rheumatoid arthritis (RA). The aim of this study is to investigate whether and how the absorption of norisoboldine is altered in adjuvant-induced arthritis (AIA) rats. Comparative studies of the intestinal absorption of norisoboldine in normal and AIA rats at different pathological stages of the arthritis were performed using in situ single-pass intestinal perfusion, and the effects of an inhibitor of efflux proteins were also investigated. Norisoboldine was shown to be a substrate of P-glycoprotein (P-gp), as P-gp inhibitor verapamil markedly increased the permeability coefficient (Peff ) of norisoboldine by 88% in the intestine of normal rats. Compared with normal rats, AIA rats displayed increased Peff values of norisoboldine by 84% and 86% on day 5 and day 10 after the appearance of the secondary response of arthritis, respectively. Verapamil could eliminate the difference of intestinal absorption of norisoboldine between normal and AIA rats. Further studies showed that impaired expression and activity of P-gp in AIA rats play a decisive role in the absorption enhancement of norisoboldine. Notably, the impairment of P-gp function positively correlated with the severity of arthritis. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Cong Duan
- Department of Chinese Materia Medica Analysis, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Jiao-Mei Guo
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Yue Dai
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Yu-Feng Xia
- Department of Chinese Materia Medica Analysis, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
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35
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Wang Q, Jiang C, Zheng X, Zhu X, Yan S, Wang H, Fu R, Fan H, Chen Y. Insight into the pharmacokinetic behavior of tanshinone IIA in the treatment of Crohn's disease: comparative data for tanshinone IIA and its two glucuronidated metabolites in normal and recurrent colitis models after oral administration. Xenobiotica 2016; 47:66-76. [PMID: 27045386 DOI: 10.3109/00498254.2016.1160158] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
1. Previous reports implied that tanshinone IIA (TSA) may offer potential benefits for Crohn's disease (CD). However, the detailed pharmacokinetic behavior of TSA in the treatment of colitis remain unclear. Herein, a recurrent trinitrobenzene sulfonic acid (TNBS)-colitis mouse model was used to investigate whether TSA possesses favorable pharmacokinetic and colonic distribution profiles to serve as a candidate drug. 2. Although the systemic TSA exposures were low (AUC0-t approximately 330 ng*h/ml) in both the normal and colitis models after oral administration TSA 20 mg/kg, high levels of TSA were found in the gastrointestinal tract (GI). Such a GI exposure of TSA in colitis mice is adequate to exert anti-inflammatory effects as observed in various in vitro studies. 3. Interestingly, colonic TSA exposure in the colitis mouse model was much lower than that in the normal mice, which may be explained by a significant upregulation of colonic UDP-glucuronosyltransferase (Ugt)1a9 expression and a higher plasma concentration of TSA glucuronides in the model mice at 0.5, 1 and 2 h after TSA administration. 4. Together, these results reveal high accumulation at the site of inflammation and minimal systemic concentration of TSA, which are favorable pharmacokinetic behaviors to meet the requirements for CD treatment.
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Affiliation(s)
| | - Chao Jiang
- b Department of Digestive Tumor Surgery , and
| | - Xiao Zheng
- c Department of Pharmacy , Affiliated Hospital of Nanjing University of Chinese Medicine , Nanjing , China
| | | | | | | | - Rui Fu
- a Department of Pharmacology
| | - Hongwei Fan
- d Department of Clinical Pharmacology Laboratory , Nanjing First Hospital of Nanjing Medical University , Nanjing , China , and
| | - Yugen Chen
- e Department of Colorectal Surgery , Affiliated Hospital of Nanjing University of Chinese Medicine , Nanjing , China
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36
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Liu J, Xiao HT, Wang HS, Mu HX, Zhao L, Du J, Yang D, Wang D, Bian ZX, Lin SH. Halofuginone reduces the inflammatory responses of DSS-induced colitis through metabolic reprogramming. MOLECULAR BIOSYSTEMS 2016; 12:2296-2303. [DOI: 10.1039/c6mb00154h] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Halofuginone inhibits both HIF-1alpha and incomplete FAO to reduce the inflammatory response in DSS-induced colitis.
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Affiliation(s)
- Jing Liu
- School of Pharmaceutical Sciences
- Sun Yat-Sen University
- Guangzhou 510006
- China
- School of Chinese Medicine
| | - Hai-Tao Xiao
- School of Chinese Medicine
- Hong Kong Baptist University
- China
- School of Pharmacy
- Guizhou Medicial University
| | - Hong-Sheng Wang
- School of Pharmaceutical Sciences
- Sun Yat-Sen University
- Guangzhou 510006
- China
| | - Huai-Xue Mu
- School of Chinese Medicine
- Hong Kong Baptist University
- China
| | - Ling Zhao
- School of Chinese Medicine
- Hong Kong Baptist University
- China
| | - Jun Du
- School of Pharmaceutical Sciences
- Sun Yat-Sen University
- Guangzhou 510006
- China
| | - Depo Yang
- School of Pharmaceutical Sciences
- Sun Yat-Sen University
- Guangzhou 510006
- China
| | - Dongmei Wang
- School of Pharmaceutical Sciences
- Sun Yat-Sen University
- Guangzhou 510006
- China
| | | | - Shu-Hai Lin
- School of Chinese Medicine
- Hong Kong Baptist University
- China
- Department of Biochemistry and Molecular Cell Biology
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation
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