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Lu X, Wu S, Ai H, Wu R, Cheng Y, Yun S, Chang M, Liu J, Meng J, Cheng F, Feng C, Cao J. Sparassis latifolia polysaccharide alleviated lipid metabolism abnormalities in kidney of lead-exposed mice by regulating oxidative stress-mediated inflammation and autophagy based on multi-omics. Int J Biol Macromol 2024; 278:134662. [PMID: 39128732 DOI: 10.1016/j.ijbiomac.2024.134662] [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: 01/31/2024] [Revised: 08/08/2024] [Accepted: 08/08/2024] [Indexed: 08/13/2024]
Abstract
Lead is a common environmental pollutant which can accumulate in the kidney and cause renal injury. However, regulatory effects and mechanisms of Sparassis latifolia polysaccharide (SLP) on lipid metabolism abnormality in kidney exposed to lead are not clarified. In this study, mice were used to construct an animal model to observe the histopathological changes in kidney, measure lead content, damage indicators, differentially expressed metabolites (DEMs) and genes (DEGs) in key signaling pathways that cause lipid metabolism abnormalities based on lipidomics and transcriptomics, which were later validated using qPCR and western blotting. Co-treatment of Pb and N-acetylcysteine (NAC) were used to verify the link between SLP and oxidative stress. Our results indicated that treatment with SLP identified 276 DEMs (including metabolism of glycerophospholipid, sphingolipid, glycerolipid and fatty acid) and 177 DEGs (including genes related to oxidative stress, inflammation, autophagy and lipid metabolism). Notably, regulatory effects of SLP on abnormal lipid metabolism in kidney were mainly associated with oxidative stress, inflammation and autophagy; SLP could regulate abnormal lipid metabolism in kidney by reducing oxidative stress and affecting its downstream-regulated autophagy and inflammatory to alleviate renal injury caused by lead exposure. This study provides a theoretical basis for SLP intervention in lead injury.
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Affiliation(s)
- Xingru Lu
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, China
| | - Shanshan Wu
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, China
| | - Honghu Ai
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, China
| | - Rui Wu
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, China
| | - Yanfen Cheng
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, China
| | - Shaojun Yun
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, China
| | - Mingchang Chang
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, China; Collaborative Innovation Center of Quality and Efficiency of Loess Plateau Edible Fungi, Taigu, Shanxi 030801, China
| | - Jingyu Liu
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, China; Shanxi Key Laboratory of Edible Fungi for Loess Plateau, Taigu, Shanxi 030801, China
| | - Junlong Meng
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, China; Shanxi Key Laboratory of Edible Fungi for Loess Plateau, Taigu, Shanxi 030801, China
| | - Feier Cheng
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, China; Shanxi Key Laboratory of Edible Fungi for Loess Plateau, Taigu, Shanxi 030801, China
| | - Cuiping Feng
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, China; Collaborative Innovation Center of Quality and Efficiency of Loess Plateau Edible Fungi, Taigu, Shanxi 030801, China.
| | - Jinling Cao
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, China; Collaborative Innovation Center of Quality and Efficiency of Loess Plateau Edible Fungi, Taigu, Shanxi 030801, China.
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Frings S, Schmidt-Schippers R, Lee WK. Epigenetic alterations in bioaccumulators of cadmium: Lessons from mammalian kidneys and plants. ENVIRONMENT INTERNATIONAL 2024; 191:109000. [PMID: 39278047 DOI: 10.1016/j.envint.2024.109000] [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: 03/30/2024] [Revised: 08/07/2024] [Accepted: 09/05/2024] [Indexed: 09/17/2024]
Abstract
Faced with unpredictable changes in global weather patterns, release and redistribution of metals through land erosion and water movements add to the increasing use of metals in industrial activities causing high levels of environmental pollution and concern to the health of all living organisms. Cadmium is released into the environment by smelting and mining, entering the food chain via contaminated soils, water, and phosphate fertilizers. Bioaccumulation of cadmium in plants represents the first major step into the human food chain and contributes to toxicity of several organs, especially the kidneys, where biomagnification of cadmium occurs over decades of exposure. Even in small amounts, cadmium brings about alterations at the molecular and cellular levels in eukaryotes through mutagenicity, molecular mimicry at metal binding sites and oxidative stress. The epigenome dictates expression of a gene's output through a number of regulatory steps involving chromatin remodeling, nucleosome unwinding, DNA accessibility, or nucleic acid modifications that ultimately impact the transcriptional and translational machinery. Several epigenetic enzymes exhibit zinc-dependence as zinc metalloenzymes and zinc finger proteins thus making them susceptible to deregulation through displacement by cadmium. In this review, we summarize the literature on cadmium-induced epigenetic mechanisms in mammalian kidneys and plants, compare similarities in the epigenetic defense between these bioaccumulators, and explore how future studies could advance our understanding of the cadmium-induced stress response and disruption to biological health.
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Affiliation(s)
- Stephanie Frings
- Center for Biotechnology, University of Bielefeld, 33615 Bielefeld, Germany; Plant Biotechnology, Faculty of Biology, Bielefeld University, 33615 Bielefeld, Germany
| | - Romy Schmidt-Schippers
- Center for Biotechnology, University of Bielefeld, 33615 Bielefeld, Germany; Plant Biotechnology, Faculty of Biology, Bielefeld University, 33615 Bielefeld, Germany
| | - Wing-Kee Lee
- Physiology and Pathophysiology of Cells and Membranes, Medical School OWL, Bielefeld University, 33615 Bielefeld, Germany.
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Thévenod F, Lee WK. Cadmium transport by mammalian ATP-binding cassette transporters. Biometals 2024; 37:697-719. [PMID: 38319451 PMCID: PMC11101381 DOI: 10.1007/s10534-024-00582-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024]
Abstract
Cellular responses to toxic metals depend on metal accessibility to intracellular targets, reaching interaction sites, and the intracellular metal concentration, which is mainly determined by uptake pathways, binding/sequestration and efflux pathways. ATP-binding cassette (ABC) transporters are ubiquitous in the human body-usually in epithelia-and are responsible for the transfer of indispensable physiological substrates (e.g. lipids and heme), protection against potentially toxic substances, maintenance of fluid composition, and excretion of metabolic waste products. Derailed regulation and gene variants of ABC transporters culminate in a wide array of pathophysiological disease states, such as oncogenic multidrug resistance or cystic fibrosis. Cadmium (Cd) has no known physiological role in mammalians and poses a health risk due to its release into the environment as a result of industrial activities, and eventually passes into the food chain. Epithelial cells, especially within the liver, lungs, gastrointestinal tract and kidneys, are particularly susceptible to the multifaceted effects of Cd because of the plethora of uptake pathways available. Pertinent to their broad substrate spectra, ABC transporters represent a major cellular efflux pathway for Cd and Cd complexes. In this review, we summarize current knowledge concerning transport of Cd and its complexes (mainly Cd bound to glutathione) by the ABC transporters ABCB1 (P-glycoprotein, MDR1), ABCB6, ABCC1 (multidrug resistance related protein 1, MRP1), ABCC7 (cystic fibrosis transmembrane regulator, CFTR), and ABCG2 (breast cancer related protein, BCRP). Potential detoxification strategies underlying ABC transporter-mediated efflux of Cd and Cd complexes are discussed.
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Affiliation(s)
- Frank Thévenod
- Institute for Physiology, Pathophysiology and Toxicology & ZBAF, Witten/Herdecke University, 58453, Witten, Germany
- Physiology and Pathophysiology of Cells and Membranes, Medical School OWL, Bielefeld University, Morgenbreede 1, 33615, Bielefeld, Germany
| | - Wing-Kee Lee
- Physiology and Pathophysiology of Cells and Membranes, Medical School OWL, Bielefeld University, Morgenbreede 1, 33615, Bielefeld, Germany.
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Decaix T, Magny R, Gouin‐Thibaut I, Delavenne X, Mismetti P, Salem J, Narjoz C, Blanchard A, Pépin M, Auzeil N, Loriot M, Laprévote O. Plasma lipidomic analysis to investigate putative biomarkers of P-glycoprotein activity in healthy volunteers. Clin Transl Sci 2023; 16:1935-1946. [PMID: 37529981 PMCID: PMC10582668 DOI: 10.1111/cts.13601] [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: 06/08/2023] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 08/03/2023] Open
Abstract
P-glycoprotein (P-gp) is an efflux transporter involved in the bioavailability of many drugs currently on the market. P-gp is responsible for several drug-drug interactions encountered in clinical practice leading to iatrogenic hospital admissions, especially in polypharmacy situations. ABCB1 genotyping only reflects an indirect estimate of P-gp activity. Therefore, it would be useful to identify endogenous biomarkers to determine the P-gp phenotype to predict in vivo activity prior to the initiation of treatment and to assess the effects of drugs on P-gp activity. The objective of this study was to assess changes in plasma lipidome composition among healthy volunteers selected on the basis of their ABCB1 genotype and who received clarithromycin, a known inhibitor of P-gp. Untargeted lipidomic analysis based on liquid chromatography-tandem mass spectrometry was performed before and after clarithromycin administration. Our results revealed changes in plasma levels of some ceramides (Cers) {Cer(d18:1/22:0), Cer(d18:1/22:1), and Cer(d18:1/20:0) by ~38% (p < 0.0001), 13% (p < 0.0001), and 13% (p < 0.0001), respectively} and phosphatidylcholines (PCs) {PC(17:0/14:1), PC(16:0/18:3), and PC(14:0/18:3) by ~24% (p < 0.001), 10% (p < 0.001), and 23.6% (p < 0.001)} associated with both ABCB1 genotype and clarithromycin intake. Through the examination of plasma lipids, our results highlight the relevance of untargeted lipidomics for studying in vivo P-gp activity and, more generally, to safely phenotyping transporters.
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Affiliation(s)
| | | | | | - Xavier Delavenne
- Clinical Pharmacology DepartmentUniversity Hospital of Saint‐EtienneSaint EtienneFrance
- INSERM, U1059Vascular Dysfunction and HemostasisSaint‐EtienneFrance
| | - Patrick Mismetti
- INSERM, U1059Vascular Dysfunction and HemostasisSaint‐EtienneFrance
- Vascular and Therapeutic Medicine DepartmentSaint‐Etienne University Hospital CenterSaint‐EtienneFrance
| | - Joe‐Elie Salem
- Pharmacology Department, APHP, Pitié‐Salpétrière HospitalGHU Sorbonne UniversityParisFrance
- CIC‐1421 and Institut de Cardiométabolisme et Nutrition (ICAN) UMR ICAN_1166INSERMParisFrance
| | - Céline Narjoz
- Department of Clinical Chemistry, APHP, GHU Paris‐CentreEuropean Georges Pompidou HospitalParisFrance
- INSERM U1138, Team 26Research Center of CordeliersParisFrance
| | - Anne Blanchard
- Sorbonne Paris CitéParis Descartes UniversityParisFrance
- Centre d'Investigation Clinique, APHP, INSERM CIC‐1418Européen Georges Pompidou HospitalParisFrance
| | - Marion Pépin
- Department of Geriatrics, APHPGHU Paris‐Saclay University, Ambroise Paré HospitalBoulogne‐BillancourtFrance
- Clinical Epidemiology, UVSQ, Inserm U1018, CESPParis‐Saclay UniversityVillejuifFrance
| | | | - Marie‐Anne Loriot
- Department of Clinical Chemistry, APHP, GHU Paris‐CentreEuropean Georges Pompidou HospitalParisFrance
- INSERM U1138, Team 26Research Center of CordeliersParisFrance
- Sorbonne Paris CitéParis Descartes UniversityParisFrance
| | - Olivier Laprévote
- CNRS, CiTCoMParis‐Cité UniversityParisFrance
- Department of Clinical Chemistry, APHP, GHU Paris‐CentreEuropean Georges Pompidou HospitalParisFrance
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Lee WK, Maaß M, Quach A, Poscic N, Prangley H, Pallott EC, Kim JL, Pierce JS, Ogretmen B, Futerman AH, Thévenod F. Dependence of ABCB1 transporter expression and function on distinct sphingolipids generated by ceramide synthases-2 and -6 in chemoresistant renal cancer. J Biol Chem 2021; 298:101492. [PMID: 34915026 PMCID: PMC8804196 DOI: 10.1016/j.jbc.2021.101492] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 12/07/2021] [Indexed: 11/18/2022] Open
Abstract
Oncogenic multidrug resistance is commonly intrinsic to renal cancer based on the physiological expression of detoxification transporters, particularly ABCB1, thus hampering chemotherapy. ABCB1 activity is directly dependent on its lipid microenvironment, localizing to cholesterol- and sphingomyelin (SM)-rich domains. As ceramides are the sole source for SMs, we hypothesized that ceramide synthase (CerS)-derived ceramides regulate ABCB1 activity. Using data from RNA-Seq databases, we found that patient kidney tumors exhibited increased CerS2 mRNA, which was inversely correlated with CerS6 mRNA in ABCB1+ clear cell carcinomas. Endogenous elevated CerS2 and lower CerS5/6 mRNA and protein resulted in disproportionately higher CerS2 to CerS5/6 activities (approximately twofold) in chemoresistant ABCB1high (A498, Caki-1) compared with chemosensitive ABCB1low (ACHN, normal human proximal convoluted tubule cell) cells. In addition, lipidomics analyses by HPLC–MS/MS showed bias toward CerS2-associated C20:0/C20:1-ceramides compared with CerS5/6-associated C14:0/C16:0-ceramides (2:1). SMs were similarly altered. We demonstrated that chemoresistance to doxorubicin in ABCB1high cells was partially reversed by inhibitors of de novo ceramide synthesis (l-cycloserine) and CerS (fumonisin B1) in cell viability assays. Downregulation of CerS2/6, but not CerS5, attenuated ABCB1 mRNA, protein, plasma membrane localization, rhodamine 123+ efflux transport activity, and doxorubicin resistance. Similar findings were observed with catalytically inactive CerS6-H212A. Furthermore, CerS6-targeting siRNA shifted ceramide and SM composition to ultra long-chain species (C22–C26). Inhibitors of endoplasmic reticulum–associated degradation (eeyarestatin I) and the proteasome (MG132, bortezomib) prevented ABCB1 loss induced by CerS2/6 downregulation. We conclude that a critical balance in ceramide/SM species is prerequisite to ABCB1 expression and functionalization, which could be targeted to reverse multidrug resistance in renal cancers.
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Affiliation(s)
- Wing-Kee Lee
- Institute for Physiology, Pathophysiology and Toxicology, ZBAF, Witten/Herdecke University, Germany; Physiology & Pathophysiology of Cells and Membranes, Medical School OWL, Bielefeld University, Germany.
| | - Michelle Maaß
- Institute for Physiology, Pathophysiology and Toxicology, ZBAF, Witten/Herdecke University, Germany
| | - Amy Quach
- Institute for Physiology, Pathophysiology and Toxicology, ZBAF, Witten/Herdecke University, Germany; Faculty of Life Sciences, University of Manchester, UK
| | - Nataliya Poscic
- Institute for Physiology, Pathophysiology and Toxicology, ZBAF, Witten/Herdecke University, Germany
| | - Holly Prangley
- Institute for Physiology, Pathophysiology and Toxicology, ZBAF, Witten/Herdecke University, Germany; Faculty of Life Sciences, University of Manchester, UK
| | - Erin-Claire Pallott
- Institute for Physiology, Pathophysiology and Toxicology, ZBAF, Witten/Herdecke University, Germany; Faculty of Life Sciences, University of Manchester, UK
| | - Jiyoon L Kim
- Department of Biomolecular Sciences, Weizmann Institute of Science, Israel
| | - Jason S Pierce
- Lipidomics Shared Resource, Medical University of South Carolina, USA
| | - Besim Ogretmen
- Lipidomics Shared Resource, Medical University of South Carolina, USA; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, USA
| | - Anthony H Futerman
- Department of Biomolecular Sciences, Weizmann Institute of Science, Israel
| | - Frank Thévenod
- Institute for Physiology, Pathophysiology and Toxicology, ZBAF, Witten/Herdecke University, Germany
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Tang Z, Motoyoshi K, Honda T, Nakamura H, Murayama T. Amyloid Beta-Peptide 25-35 (Aβ 25-35) Induces Cytotoxicity via Multiple Mechanisms: Roles of the Inhibition of Glucosylceramide Synthase by Aβ 25-35 and Its Protection by D609. Biol Pharm Bull 2021; 44:1419-1426. [PMID: 34602551 DOI: 10.1248/bpb.b21-00204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Sphingolipids (SLs), such as ceramide, glucosylceramide (GlcCer), and sphingomyelin, play important roles in the normal development/functions of the brain and peripheral tissues. Disruption of SL homeostasis in cells/organelles, specifically up-regulation of ceramide, is involved in multiple diseases including Alzheimer's disease (AD). One of the pathological features of AD is aggregates of amyloid beta (Aβ) peptides, and SLs regulate both the formation/aggregation of Aβ and Aβ-induced cellular responses. Up-regulation of ceramide levels via de novo and salvage synthesis pathways is reported in Aβ-treated cells and brains with AD; however, the effects of Aβ on ceramide decomposition pathways have not been elucidated. Thus, we investigated the effects of the 25-35-amino acid Aβ peptide (Aβ25-35), the fundamental cytotoxic domain of Aβ, on SL metabolism in cells treated with the fluorescent nitrobenzo-2-oxa-1,3-diazole-labeled C6-ceramide (NBD-ceramide). Aβ25-35 treatment reduced the formation of NBD-GlcCer mediated by GlcCer synthase (GCS) without affecting the formation of NBD-sphingomyelin or NBD-ceramide-1-phosphate, and reduced cell viability. Aβ25-35-induced responses decreased in cells treated with D609, a putative inhibitor of sphingomyelin synthases. Aβ25-35-induced cytotoxicity significantly increased in GCS-knockout cells and pharmacological inhibition of GCS alone demonstrated cytotoxicity. Our study revealed that Aβ25-35-induced cytotoxicity is at least partially mediated by the inhibition of GCS activity.
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Affiliation(s)
- Zhihui Tang
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University
| | - Kaisei Motoyoshi
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University
| | - Takuya Honda
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University
| | - Hiroyuki Nakamura
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University
| | - Toshihiko Murayama
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University
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Xu Y, Liu H, Han D, Ren L, Gong X, Jiang F, Cui Y, Liu X, Ren C, Xue J, Tian X. Metabolomic Alterations in the Digestive System of the Mantis Shrimp Oratosquilla oratoria Following Short-Term Exposure to Cadmium. Front Physiol 2021; 12:706579. [PMID: 34421644 PMCID: PMC8374601 DOI: 10.3389/fphys.2021.706579] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/12/2021] [Indexed: 02/02/2023] Open
Abstract
Mantis shrimp Oratosquilla oratoria is an economically critical aquatic species along the coast of China but strongly accumulates marine pollutant cadmium (Cd) in its digestive system. It is necessary to characterize the toxicity of Cd in the digestive system of mantis shrimp. The metabolic process is an essential target of Cd toxicity response. In this work, we used ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-TOF-MS) for untargeted metabolomics to characterize the metabolic changes in the digestive system of O. oratoria, exposed to 0.05 mg/L for 96 h. The aim of this study was to further investigate the effect of O. oratoria on Cd response to toxicity and develop biomarkers. Metabolomics analysis showed the alteration of metabolism in the digestive system of mantis shrimp under Cd stress. A total of 91 metabolites were differentially expressed and their main functions were classified into amino acids, phospholipids, and fatty acid esters. The enrichment results of differential metabolite functional pathways showed that biological processes such as amino acid metabolism, transmembrane transport, energy metabolism, and signal transduction are significantly affected. Based on the above results, the Cd-induced oxidative stress and energy metabolism disorders were characterized by the differential expression of amino acids and ADP in mantis shrimp, while the interference of transmembrane transport and signal transduction was due to the differential expression of phospholipids. Overall, this work initially discussed the toxicological response of Cd stress to O. oratoria from the metabolic level and provided new insights into the mechanism.
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Affiliation(s)
- Yingjiang Xu
- Shandong Key Laboratory of Marine Ecological Restoration, Shandong Marine Resource and Environment Research Institute, Yantai, China
| | - Huan Liu
- Shandong Key Laboratory of Marine Ecological Restoration, Shandong Marine Resource and Environment Research Institute, Yantai, China.,College of Food Sciences and Technology, Shanghai Ocean University, Shanghai, China
| | - Dianfeng Han
- Shandong Key Laboratory of Marine Ecological Restoration, Shandong Marine Resource and Environment Research Institute, Yantai, China
| | - Lihua Ren
- Shandong Key Laboratory of Marine Ecological Restoration, Shandong Marine Resource and Environment Research Institute, Yantai, China
| | - Xianghong Gong
- Shandong Key Laboratory of Marine Ecological Restoration, Shandong Marine Resource and Environment Research Institute, Yantai, China
| | - Fang Jiang
- Shandong Key Laboratory of Marine Ecological Restoration, Shandong Marine Resource and Environment Research Institute, Yantai, China
| | - Yanmei Cui
- Shandong Key Laboratory of Marine Ecological Restoration, Shandong Marine Resource and Environment Research Institute, Yantai, China
| | - Xiaojing Liu
- Shandong Key Laboratory of Marine Ecological Restoration, Shandong Marine Resource and Environment Research Institute, Yantai, China
| | - Chuanbo Ren
- Shandong Key Laboratory of Marine Ecological Restoration, Shandong Marine Resource and Environment Research Institute, Yantai, China
| | - Jinglin Xue
- Shandong Key Laboratory of Marine Ecological Restoration, Shandong Marine Resource and Environment Research Institute, Yantai, China
| | - Xiuhui Tian
- Shandong Key Laboratory of Marine Ecological Restoration, Shandong Marine Resource and Environment Research Institute, Yantai, China
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Qiao N, Yang Y, Liao J, Zhang H, Yang F, Ma F, Han Q, Yu W, Li Y, Hu L, Pan J, Hussain R, Tang Z. Metabolomics and transcriptomics indicated the molecular targets of copper to the pig kidney. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 218:112284. [PMID: 33945902 DOI: 10.1016/j.ecoenv.2021.112284] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 04/12/2021] [Accepted: 04/21/2021] [Indexed: 06/12/2023]
Abstract
Copper poses huge environmental and public health concerns due to its widespread and persistent use in the past several decades. Although it is well established that at higher levels copper causes nephrotoxicity, the exact mechanisms of its toxicity is not fully understood. Therefore, this experimental study for the first time investigates the potential molecular mechanisms including transcriptomics, metabolomics, serum biochemical, histopathological, cell apoptosis and autophagy in copper-induced renal toxicity in pigs. A total of 14 piglets were randomly assigned to two group (7 piglets per group) and treated with a standard diet (11 mg CuSO4 per kg of feed) and a high copper diet (250 mg CuSO4 per kg of feed). The results of serum biochemical tests and renal histopathology suggested that 250 mg/kg CuSO4 in the diet significantly increased serum creatinine (CREA) and induced renal tubular epithelial cell swelling. Results on transcriptomics and metabolomics showed alteration in 804 genes and 53 metabolites in kidneys of treated pigs, respectively. Combined analysis of transcriptomics and metabolomics indicated that different genes and metabolism pathways in kidneys of treated pigs were involved in glycerophospholipids metabolism and glycosphingolipid metabolism. Furthermore, copper induced mitochondrial apoptosis characterized by increased bax, bak, caspase 3, caspase 8 and caspase 9 expressions while decreased bcl-xl and bcl2/bax expression. Exposure to copper decreased the autophagic flux in terms of increased number of autophagosomes, beclin1 and LC3b/LC3a expression and p62 accumulation. These results indicated that the imbalance of glycosphingolipid metabolism, the impairment of autophagy and increase mitochondrial apoptosis play an important role in copper induced renal damage and are useful mechanisms to understand the mechanisms of copper nephrotoxicity.
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Affiliation(s)
- Na Qiao
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Yanyang Yang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Jianzhao Liao
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Hui Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Fan Yang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Feiyang Ma
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Qingyue Han
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Wenlan Yu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Ying Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Lianmei Hu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Jiaqiang Pan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Riaz Hussain
- Department of Pathology, Faculty of Veterinary and Animal Sciences, Islamia University of Bahawalpur, 63100, Pakistan
| | - Zhaoxin Tang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
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Honda T, Motoyoshi K, Kasahara J, Yamagata K, Takahashi H, Nakamura H, Murayama T. Tyrosine-phosphorylation and activation of glucosylceramide synthase by v-Src: Its role in survival of HeLa cells against ceramide. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1866:158817. [PMID: 32980536 DOI: 10.1016/j.bbalip.2020.158817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/15/2020] [Accepted: 09/18/2020] [Indexed: 10/23/2022]
Abstract
Sphingolipids represent a family of cellular lipid-molecules that regulate physiological and pathophysiological processes. Glucosylceramide (GlcCer), the simplest glycosphingolipid (GSL), is synthesized from ceramide and UDP-glucose by GlcCer synthase (GCS). Both GlcCer (and resulting GSLs) and ceramide regulate various cellular functions including cell death and multiple drug resistance. Src family tyrosine kinases are up-regulated in various human cancer cells. We examined the effect of v-Src expression on GCS activity, the formation of 4-nitrobenzo-2-oxa-1,3-diazole (NBD)-labeled GlcCer from NBD-ceramide, and the effect of tyrosine132 mutation in GCS on ceramide-induced cytotoxicity in HeLa cells. Expression of v-Src increased the formation of NBD-GlcCer in both intact cells without marked changes in other sphingolipid metabolites and cell homogenates without changing affinities of NBD-ceramide and UDP-glucose. Expression of v-Src also increased tyrosine-phosphorylated levels in GCS proteins in HeLa and HEK293T cells. In HEK293T cells transiently expressing the GCS mutant, GCS-Y132F-HA, showing replacement of the tyrosine132 residue with phenylalanine, tyrosine-phosphorylated levels in GCS proteins were significantly lower than those in control cells expressing the GCS-wild-type-HA. The formation of NBD-GlcCer in HeLa cells stably expressing GCS-Y132F-HA was significantly lower than that in the control. Ceramide-induced cytotoxicity in HeLa-GCS-Y132F-HA cells was significantly greater than in the control. In this study, we showed for the first time that expression of v-Src up-regulated GCS activity via tyrosine phosphorylation of the enzyme in a post-translational manner. Mechanisms of Src-induced resistance to ceramide-induced cytotoxicity are discussed in relation to the Src-induced up-regulation of GCS activity.
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Affiliation(s)
- Takuya Honda
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
| | - Kaisei Motoyoshi
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Junya Kasahara
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Kazuyuki Yamagata
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan; Laboratory of International Scholars in Pharmaceuticals/Systems Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Hiromasa Takahashi
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Hiroyuki Nakamura
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Toshihiko Murayama
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
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10
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Kwok ML, Chan KM. Oxidative stress and apoptotic effects of copper and cadmium in the zebrafish liver cell line ZFL. Toxicol Rep 2020; 7:822-835. [PMID: 32670800 PMCID: PMC7347715 DOI: 10.1016/j.toxrep.2020.06.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 05/08/2020] [Accepted: 06/26/2020] [Indexed: 12/11/2022] Open
Abstract
Oxidative stress and apoptosis created by Cu2+ and Cd2+ insults were studied in ZFL. Cu2+ and Cd2+ both created lipid peroxidation, causing oxidative stress in cytoplasm. Mitochondrial superoxide was induced by Cd2+ but supressed by Cu2+. Cu2+ suppressed Casp3 activity, resulting in suppressed the apoptosis. Pre-treatments of low concentration of Cu2+ protected the cell from Cd2+ insults. Copper (Cu) and cadmium (Cd) are widely used in industrial activities, resulting in Cu and Cd contamination in aquatic systems worldwide. Although Cu plays an essential role in many biological functions, an excessive amount of the metal causes cytotoxicity. In contrast, Cd is a non-essential metal that usually co-exists with Cu. Together, they cause oxidative stress in cells, leading to cell damage. These metal ions are also believed to cause cell apoptosis. In this study, we used a zebrafish liver cell line, ZFL, to study combined Cu and Cd cytotoxicity. Although Cd is more toxic than Cu, both were found to regulate the expression of oxidative stress related genes, and neither significantly altered the activity of oxidative stress related enzymes. Co-exposure tests with the antioxidant N-acetyl-l-cysteine and the Cu chelator bathocuproinedisulfonic acid disodium salt demonstrated that Cd toxicity was due to the oxidative stress caused by Cu, and that Cu at a low concentration could in fact exert an antioxidant effect against the oxidative stress in ZFL. Excessive Cu concentration triggered the expression of initiator caspases (caspase 8 and caspase 9) but suppressed that of an executioner caspase (caspase 3), halting apoptosis. Cd could only trigger the expression of initiator caspases; it could not halt apoptosis. However, a low concentration of Cu reduced the mitochondrial superoxide level, suppressing the Cd-induced apoptotic effects in ZFL.
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Key Words
- BCS, bathocuproinedisulfonic acid disodium salt
- CAT, catalase protein
- Casp3, caspase 3 protein
- Casp8, caspase 8 protein
- Casp9, caspase 9 protein
- Cd, cadmium
- Combined effects
- Cu, copper
- Cytotoxicity
- GR, glutathione reductase protein
- GST, glutathione-S-transferase protein
- LC, lethal concentration
- LC20, lethal concentration of 20 % population
- LC50, median lethal concentration
- Mitochondrial function
- NAC, N-acetyl-l-cysteine
- PBS, phosphate-buffered saline
- SOD, superoxide dismutase proteins
- VE, tocopherol (Vitamin E)
- cat, catalase gene
- ccs, copper chaperone for superoxide dismutase gene
- ef1a, elongation factor 1-alpha gene
- gr, glutathione reductase gene
- gst, glutathione-S-transferase gene
- mtDNA, mitochondrial DNA
- sod1, superoxide dismutase 1 gene
- sod2, superoxide dismutase 2 gene
- ybx1, Y box-binding protein 1 gene
- z, zebrafish
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Affiliation(s)
- Man Long Kwok
- School of Life Sciences, The Chinese University of Hong Kong, Sha Tin, N.T., Hong Kong
| | - King Ming Chan
- School of Life Sciences, The Chinese University of Hong Kong, Sha Tin, N.T., Hong Kong
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Kwok RML, Chan KM. WITHDRAWN: Oxidative Stress and Apoptotic Effects of Copper and Cadmium in the Zebrafish Liver Cell Line ZFL. Toxicol Rep 2020. [DOI: 10.1016/j.toxrep.2020.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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12
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Cell organelles as targets of mammalian cadmium toxicity. Arch Toxicol 2020; 94:1017-1049. [PMID: 32206829 DOI: 10.1007/s00204-020-02692-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 02/25/2020] [Indexed: 02/07/2023]
Abstract
Ever increasing environmental presence of cadmium as a consequence of industrial activities is considered a health hazard and is closely linked to deteriorating global health status. General animal and human cadmium exposure ranges from ingestion of foodstuffs sourced from heavily polluted hotspots and cigarette smoke to widespread contamination of air and water, including cadmium-containing microplastics found in household water. Cadmium is promiscuous in its effects and exerts numerous cellular perturbations based on direct interactions with macromolecules and its capacity to mimic or displace essential physiological ions, such as iron and zinc. Cell organelles use lipid membranes to form complex tightly-regulated, compartmentalized networks with specialized functions, which are fundamental to life. Interorganellar communication is crucial for orchestrating correct cell behavior, such as adaptive stress responses, and can be mediated by the release of signaling molecules, exchange of organelle contents, mechanical force generated through organelle shape changes or direct membrane contact sites. In this review, cadmium effects on organellar structure and function will be critically discussed with particular consideration to disruption of organelle physiology in vertebrates.
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13
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Fang Y, Xiang Y, Lu X, Dong X, Zhang J, Zhong S. Epigenetic dysregulation of Mdr1b in the blood-testis barrier contributes to dyszoospermia in mice exposed to cadmium. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 190:110142. [PMID: 31911389 DOI: 10.1016/j.ecoenv.2019.110142] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 12/24/2019] [Accepted: 12/27/2019] [Indexed: 06/10/2023]
Abstract
Cadmium (Cd) has been reported to induce reproductive toxicity. Recent study indicated that aberrant epigenetic regulation of Multidrug resistance 1b (Mdr1b) causes xenobiotic efflux failure at the blood-testis barrier (BTB). However, whether Mdr1b dysregulation is involved in Cd-mediated dyszoospermia and the underlying mechanism remain unknown. In this study, mice were intragastrically administered 0 or 2.5 mg/kg CdCl2 every other day for 2 months to investigate changes in spermatogenesis and epigenetic regulation of Mdr1b. Mouse Leydig cells TM3 were cultured to detect Mdr1b expression localization. We found that the Cd group revealed BTB disruption concomitant with obvious sperm abnormity and dynamic impairment. Hypermethylation and decreased nuclear factor Ya (Nfya) recruitment to the Mdr1b promoter were correlated with low sperm motility in response to Cd. In conclusion, these findings provide in vivo evidence that epigenetic dysregulation of Mdr1b in the BTB is a potential cause of dyszoospermia upon Cd exposure.
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Affiliation(s)
- Yu Fang
- Department of Medical Genetics, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China
| | - Ying Xiang
- Department of Medical Genetics, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China
| | - Xing Lu
- Key Laboratory of Freshwater Biodiversity Conservation and Utilization of Ministry of Agriculture, Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan, 430223, Hubei, China.
| | - Xin Dong
- Department of Medical Genetics, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China
| | - Jiexin Zhang
- Department of Medical Genetics, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China
| | - Shan Zhong
- Department of Medical Genetics, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China; Hubei Province Key Laboratory of Allergy and Immunology, Wuhan, Hubei, 430071, China.
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14
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Darwish WS, Chen Z, Li Y, Wu Y, Chiba H, Hui SP. Identification of cadmium-produced lipid hydroperoxides, transcriptomic changes in antioxidant enzymes, xenobiotic transporters, and pro-inflammatory markers in human breast cancer cells (MCF7) and protection with fat-soluble vitamins. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:1978-1990. [PMID: 31768957 DOI: 10.1007/s11356-019-06834-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 10/21/2019] [Indexed: 06/10/2023]
Abstract
Cadmium (Cd) is a toxic metal that is regarded as a metallohormone with estrogen-like properties. The present study aimed at identification of lipid hydroperoxides produced in human breast cancer (MCF7) exposed to cadmium (Cd) at environmentally relevant levels. Cd induced cytotoxicity and oxidative stress and produced a series of 26 lipid hydroperoxide species including 14 phosphatidylcholine hydroperoxides (PC-OOH), 9 triacylglycerol hydroperoxides (TG-OOH), and 3 cholesteryl ester hydroperoxides (CE-OOH). Among these hydroperoxides, PC34:2-OOH, PC34:3-OOH, TG60:14-OOH, TG48:5-OOH, TG60:15-OOH, and CE20:4-OOH were produced in a dose-dependent manner, suggesting these as possible biomarkers for Cd exposure in MCF7 cells. In addition, Cd led to significant decreases in the gene expressions of antioxidants, detoxification enzymes, and xenobiotic transporters. In a protection trial, co-exposure of MCF7 cells to fat-soluble vitamins including vitamin A, D, and E reduced Cd-induced cytotoxicity, lipid peroxidation, oxidative stress, and inflammatory responses. Fat-soluble vitamins upregulated antioxidant and detoxification enzymes, and xenobiotic transporters. Therefore, dietary supplementation of such micronutrients is recommended for people at risk for exposure to Cd.
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Affiliation(s)
- Wageh Sobhy Darwish
- Laboratory of Advanced Lipid Analysis, Faculty of Health Sciences, Hokkaido University, Kita 12, Nishi 5, Sapporo, 060-0812, Japan
- Food Control Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Zhen Chen
- Laboratory of Advanced Lipid Analysis, Faculty of Health Sciences, Hokkaido University, Kita 12, Nishi 5, Sapporo, 060-0812, Japan
| | - Yonghan Li
- Laboratory of Advanced Lipid Analysis, Faculty of Health Sciences, Hokkaido University, Kita 12, Nishi 5, Sapporo, 060-0812, Japan
| | - Yue Wu
- Laboratory of Advanced Lipid Analysis, Faculty of Health Sciences, Hokkaido University, Kita 12, Nishi 5, Sapporo, 060-0812, Japan
| | - Hitoshi Chiba
- Department of Nutrition, Sapporo University of Health Sciences, Nakanuma Nishi 4-2-1-15, Higashi Ku, Sapporo, 007-0894, Japan
| | - Shu-Ping Hui
- Laboratory of Advanced Lipid Analysis, Faculty of Health Sciences, Hokkaido University, Kita 12, Nishi 5, Sapporo, 060-0812, Japan.
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15
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Channels, transporters and receptors for cadmium and cadmium complexes in eukaryotic cells: myths and facts. Biometals 2019; 32:469-489. [DOI: 10.1007/s10534-019-00176-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 01/21/2019] [Indexed: 12/21/2022]
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16
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Stolwijk JA, Wegener J. Impedance-Based Assays Along the Life Span of Adherent Mammalian Cells In Vitro: From Initial Adhesion to Cell Death. BIOANALYTICAL REVIEWS 2019. [DOI: 10.1007/11663_2019_7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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17
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Up-regulation of P-gp via NF-κB activation confers protection against oxidative damage in the retinal pigment epithelium cells. Exp Eye Res 2018; 181:367-373. [PMID: 30496729 DOI: 10.1016/j.exer.2018.11.024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 10/30/2018] [Accepted: 11/25/2018] [Indexed: 11/20/2022]
Abstract
Dysfunction of retinal pigment epithelial (RPE) cells has been associated with the pathogenesis of age-related macular degeneration in relation to increased oxidative stress, subsequent mitochondrial dysfunction and cell death. Permeability-glycoprotein (P-gp), encoded by the multidrug resistance 1 gene (MDR1), is an active efflux pump involved in cell homeostasis and nuclear factor κB (NF-κB) shows potential involvement in P-gp regulation due to its binding to the promoter domains of MDR1 gene. This study sought to determine the role of P-gp expression regulated by NF-κB in RPE cells during oxidative stress. The human RPE D407 cells were exposed to increasing concentrations of hydrogen peroxide (H2O2) for 24 h. The small-interfering RNA (siRNA) transfection was used to down-regulate P-gp and NF-κB, and the expressions of P-gp and NF-κB p65 were determined by quantitative real-time PCR, western blot and immunofluorescence. The activity of NF-κB was detected by luciferase reporter assay. Mitochondrial membrane potential and cell death rate were detected by flow cytometry. We found that H2O2 exposure caused increasing rate of cell death and induced an elevated expression of P-gp as well as NF-κB activation and nucleus translocation in D407 cells. Inhibiting or silencing NF-κB led to a decrease in the oxidative-induced expression of P-gp. Down-regulation of P-gp by siRNA transfection further impaired the mitochondrial membrane potential and cell death rate in oxidative cells. Moreover, inhibition/knockdown of NF-κB decreased the high rate of cell death caused by H2O2. In conclusion, P-gp can provide moderate cytoprotection for the human RPE cells by ameliorating the mitochondrial dysfunction and NF-κB activation may be a potential regulator of P-gp expression response to oxidative stress.
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18
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Abstract
Cadmium is a nonessential heavy metal and an industrial and environmental pollutant. It has been known that cadmium must enter cells to cause damage. To understand the transport systems responsible for cadmium entry into cells, it is important to determine the precise mechanisms underlying cadmium toxicity. Numerous studies have sought to unravel the exact pathways by which cadmium enters various cells and the mechanisms by which it causes toxicity in the organs of human and animals. The purpose of this review is to present the progress made regarding the mechanisms of cadmium transport in various cells and the mechanisms underlying cadmium toxicity in organs.
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Affiliation(s)
- Ken-Ichi Ohba
- Kitasato University School of Allied Health Sciences
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19
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Lee WK, Kolesnick RN. Sphingolipid abnormalities in cancer multidrug resistance: Chicken or egg? Cell Signal 2017; 38:134-145. [PMID: 28687494 DOI: 10.1016/j.cellsig.2017.06.017] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 06/25/2017] [Accepted: 06/25/2017] [Indexed: 12/12/2022]
Abstract
The cancer multidrug resistance (MDR) phenotype encompasses a myriad of molecular, genetic and cellular alterations resulting from progressive oncogenic transformation and selection. Drug efflux transporters, in particular the MDR P-glycoprotein ABCB1, play an important role in MDR but cannot confer the complete phenotype alone indicating parallel alterations are prerequisite. Sphingolipids are essential constituents of lipid raft domains and directly participate in functionalization of transmembrane proteins, including providing an optimal lipid microenvironment for multidrug transporters, and are also perturbed in cancer. Here we postulate that increased sphingomyelin content, developing early in some cancers, recruits and functionalizes plasma membrane ABCB1 conferring a state of partial MDR, which is completed by glycosphingolipid disturbance and the appearance of intracellular vesicular ABCB1. In this review, the independent and interdependent roles of sphingolipid alterations and ABCB1 upregulation during the transformation process and resultant conferment of partial and complete MDR phenotypes are discussed.
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Affiliation(s)
- Wing-Kee Lee
- Laboratory of Signal Transduction, Sloan Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, United States; Institute for Physiology, Pathophysiology and Toxicology, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Witten, Germany.
| | - Richard N Kolesnick
- Laboratory of Signal Transduction, Sloan Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, United States
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20
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Xenobiotic transporters and kidney injury. Adv Drug Deliv Rev 2017; 116:73-91. [PMID: 28111348 DOI: 10.1016/j.addr.2017.01.005] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 01/02/2017] [Accepted: 01/13/2017] [Indexed: 02/07/2023]
Abstract
Renal proximal tubules are targets for toxicity due in part to the expression of transporters that mediate the secretion and reabsorption of xenobiotics. Alterations in transporter expression and/or function can enhance the accumulation of toxicants and sensitize the kidneys to injury. This can be observed when xenobiotic uptake by carrier proteins is increased or efflux of toxicants and their metabolites is reduced. Nephrotoxic chemicals include environmental contaminants (halogenated hydrocarbon solvents, the herbicide paraquat, the fungal toxin ochratoxin, and heavy metals) as well as pharmaceuticals (certain beta-lactam antibiotics, antiviral drugs, and chemotherapeutic drugs). This review explores the mechanisms by which transporters mediate the entry and exit of toxicants from renal tubule cells and influence the degree of kidney injury. Delineating how transport proteins regulate the renal accumulation of toxicants is critical for understanding the likelihood of nephrotoxicity resulting from competition for excretion or genetic polymorphisms that affect transporter function.
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21
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Yang H, Guo D, Obianom ON, Su T, Polli JE, Shu Y. Multidrug and toxin extrusion proteins mediate cellular transport of cadmium. Toxicol Appl Pharmacol 2016; 314:55-62. [PMID: 27871888 DOI: 10.1016/j.taap.2016.11.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 11/15/2016] [Accepted: 11/17/2016] [Indexed: 01/13/2023]
Abstract
Cadmium (Cd) is an environmentally prevalent toxicant posing increasing risk to human health worldwide. As compared to the extensive research in Cd tissue accumulation, little was known about the elimination of Cd, particularly its toxic form, Cd ion (Cd2+). In this study, we aimed to examine whether Cd2+ is a substrate of multidrug and toxin extrusion proteins (MATEs) that are important in renal xenobiotic elimination. HEK-293 cells overexpressing the human MATE1 (HEK-hMATE1), human MATE2-K (HEK-hMATE2-K) and mouse Mate1 (HEK-mMate1) were used to study the cellular transport and toxicity of Cd2+. The cells overexpressing MATEs showed a 2-4 fold increase of Cd2+ uptake that could be blocked by the MATE inhibitor cimetidine. A saturable transport profile was observed with the Michaelis-Menten constant (Km) of 130±15.8μM for HEK-hMATE1; 139±21.3μM for HEK-hMATE2-K; and 88.7±13.5μM for HEK-mMate1, respectively. Cd2+ could inhibit the uptake of metformin, a substrate of MATE transporters, with the half maximal inhibitory concentration (IC50) of 97.5±6.0μM, 20.2±2.6μM, and 49.9±6.9μM in HEK-hMATE1, HEK-hMATE2-K, and HEK-mMate1 cells, respectively. In addition, hMATE1 could transport preloaded Cd2+ out of the HEK-hMATE1 cells, thus resulting in a significant decrease of Cd2+-induced cytotoxicity. The present study has provided the first evidence supporting that MATEs transport Cd2+ and may function as cellular elimination machinery in Cd intoxication.
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Affiliation(s)
- Hong Yang
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD, USA
| | - Dong Guo
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD, USA
| | - Obinna N Obianom
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD, USA
| | - Tong Su
- Department of Oral Maxillofacial Surgery, the First Affiliated Hospital, Xiangya Medical School, Central South University, Hunan 410007, China
| | - James E Polli
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD, USA
| | - Yan Shu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD, USA.
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22
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Liu L, Li Y, Xiong X, Qi K, Zhang C, Fang J, Guo H. Low dose of arsenic trioxide inhibits multidrug resistant-related P-glycoprotein expression in human neuroblastoma cell line. Int J Oncol 2016; 49:2319-2330. [PMID: 27840903 DOI: 10.3892/ijo.2016.3756] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 08/22/2016] [Indexed: 11/06/2022] Open
Abstract
This study investigated arsenic trioxide (As2O3), cisplatin (DDP) and etoposide (Vp16) on the anticancer effects and P-glycoprotein (P-gp) expression in neuroblastoma (NB) SK-N-SH cells. The potential influence of As2O3, DDP and Vp16 currently included in NB routine treatment protocols on cytotoxicity in SK-N-SH cells was measured by flow cytometry and drug half-maximal inhibitory concentration (IC50) was established. Moreover, chemotherapeutic agent-mediated changes of cellular expression levels of resistant-related P-gp, was monitored using western blotting. The data showed that As2O3, DDP and Vp16 significantly inhibited the growth and survival of the SK-N-SH cells at different concentration. Notably, the levels of apoptosis were upregulated in SK-N-SH cells with an acceleration of the exposure time and the concentration of As2O3, DDP and Vp16. As2O3, DDP and Vp16 were observed with their IC50 values on SK-N-SH cells being 3 µM, 8 and 100 µg/ml, respectively. Flow cytometry analysis showed that As2O3 at low concentrations in SK-N-SH cells led to enhanced accumulation of cell populations in G2/M phase with increasing the exposure time, and increased levels of apoptosis. In contrast, we observed that SK-N-SH cell populations arrested in S phase by DDP and Vp16. In vitro examination revealed that following pretreatment of SK-N-SH cells with As2O3, the expression of P-gp was not increased. The expression of P-gp downregulation were noted following the group treated by As2O3 at 2 and 3 µM. Exposed to As2O3 at 3 µM for 72 h, SK-N-SH cells exhibited lower expression of P-gp than 2 µM As2O3 for 72 h. In contrast, the expression of P-gp was upregulated by DDP and VP16. In summary, SK-N-SH cells were responsive to chemotherapeutic agent-induced apoptosis in a dose-dependent and time-dependent manner. In particular, ours findings showed that low dose of As2O3 markedly reduced the P-gp expression and increased apoptotic cell death in human NB cell line.
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Affiliation(s)
- Ling Liu
- Department of Pediatric, Affiliated Hospital of Guangdong Medical University, Zhan Jiang, Guangdong 524000, P.R. China
| | - Yang Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Xilin Xiong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Kai Qi
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Chi Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Jianpei Fang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Haixia Guo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
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Chen M, Yin H, Bai P, Miao P, Deng X, Xu Y, Hu J, Yin J. ABC transporters affect the elimination and toxicity of CdTe quantum dots in liver and kidney cells. Toxicol Appl Pharmacol 2016; 303:11-20. [DOI: 10.1016/j.taap.2016.04.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 04/04/2016] [Accepted: 04/26/2016] [Indexed: 12/26/2022]
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A quantitative cell modeling and wound-healing analysis based on the Electric Cell-substrate Impedance Sensing (ECIS) method. Comput Biol Med 2016; 69:134-43. [PMID: 26773459 DOI: 10.1016/j.compbiomed.2015.12.022] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 12/25/2015] [Accepted: 12/26/2015] [Indexed: 01/01/2023]
Abstract
In this paper, a quantitative modeling and wound-healing analysis of fibroblast and human keratinocyte cells is presented. Our study was conducted using a continuous cellular impedance monitoring technique, dubbed Electric Cell-substrate Impedance Sensing (ECIS). In fact, we have constructed a mathematical model for quantitatively analyzing the cultured cell growth using the time series data directly derived by ECIS in a previous work. In this study, the applicability of our model into the keratinocyte cell growth modeling analysis was assessed first. In addition, an electrical "wound-healing" assay was used as a means to evaluate the healing process of keratinocyte cells at a variety of pressures. Two innovative and new-defined indicators, dubbed cell power and cell electroactivity, respectively, were developed for quantitatively characterizing the biophysical behavior of cells. We then employed the wavelet transform method to perform a multi-scale analysis so the cell power and cell electroactivity across multiple observational time scales may be captured. Numerical results indicated that our model can well fit the data measured from the keratinocyte cell culture for cell growth modeling analysis. Also, the results produced by our quantitative analysis showed that the wound healing process was the fastest at the negative pressure of 125mmHg, which consistently agreed with the qualitative analysis results reported in previous works.
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25
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Shi B, Xiang X, Ke Y, Zhou L, Ke C. Abcb1 gene expression pattern and function of copper detoxification in Fujian oyster, Crassostrea angulata. Comp Biochem Physiol B Biochem Mol Biol 2015; 190:8-15. [DOI: 10.1016/j.cbpb.2015.08.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 08/17/2015] [Accepted: 08/18/2015] [Indexed: 12/23/2022]
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Andersen V, Svenningsen K, Knudsen LA, Hansen AK, Holmskov U, Stensballe A, Vogel U. Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology. World J Gastroenterol 2015; 21:11862-11876. [PMID: 26557010 PMCID: PMC4631984 DOI: 10.3748/wjg.v21.i41.11862] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 08/07/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate ATP-binding cassette (ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer (CRC) development.
METHODS: Literature search was conducted on PubMed using combinations of the following terms: ABC transporters, ATP binding cassette transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein (P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP), Abcb1/Mdr1a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function.
RESULTS: Recently, human studies reported that changes in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes in relation to colitis was suggested by the animal studies. The finding that colitis was preceded by altered gut bacterial composition suggests that deletion of Abcb1 leads to fundamental changes of host-microbiota interaction. Also, high fat diet increases the frequency and severity of colitis in specific pathogen-free Abcb1 KO mice. The Abcb1 KO mice might thus serve as a model in which diet/environmental factors and microbes may be controlled and investigated in relation to intestinal inflammation. Potential molecular mechanisms include defective transport of inflammatory mediators and/or phospholipid translocation from one side to the other of the cell membrane lipid bilayer by ABC transporters affecting inflammatory response and/or function of tight junctions, phagocytosis and vesicle trafficking. Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters and which may additionally affect ABC transporter function through nuclear receptors and transcriptional regulation. Another critical role of ABCB1 was suggested by the finding that ABCB1 expression identifies a subpopulation of pro-inflammatory Th17 cells which were resistant to treatment with glucocorticoids. The evidence for the involvement of ABCC2 and ABCG2 in colonic pathophysiology was weak.
CONCLUSION: ABCB1, diet, and gut microbes mutually interact in colonic inflammation, a well-known risk factor for CRC. Further insight may be translated into preventive and treatment strategies.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters/genetics
- ATP-Binding Cassette Transporters/metabolism
- Animals
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/pathology
- Colorectal Neoplasms/physiopathology
- Disease Models, Animal
- Genetic Predisposition to Disease
- Humans
- Inflammatory Bowel Diseases/genetics
- Inflammatory Bowel Diseases/metabolism
- Inflammatory Bowel Diseases/pathology
- Inflammatory Bowel Diseases/physiopathology
- Mice, Transgenic
- Multidrug Resistance-Associated Protein 2
- Multidrug Resistance-Associated Proteins/genetics
- Multidrug Resistance-Associated Proteins/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Phenotype
- Polymorphism, Genetic
- Tumor Microenvironment
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Yang H, Shu Y. Cadmium transporters in the kidney and cadmium-induced nephrotoxicity. Int J Mol Sci 2015; 16:1484-94. [PMID: 25584611 PMCID: PMC4307315 DOI: 10.3390/ijms16011484] [Citation(s) in RCA: 154] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 12/30/2014] [Indexed: 12/21/2022] Open
Abstract
Among the organs in which the environmental pollutant cadmium causes toxicity, the kidney has gained the most attention in recent years. Numerous studies have sought to unravel the exact pathways by which cadmium enters the renal epithelial cells and the mechanisms by which it causes toxicity in the kidney. The purpose of this review is to present the progress made on the mechanisms of cadmium transport in the kidney and the role of transporter proteins in cadmium-induced nephrotoxicity.
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Affiliation(s)
- Hong Yang
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Baltimore, MD 21201, USA.
| | - Yan Shu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Baltimore, MD 21201, USA.
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Protopopova MV, Pavlichenko VV, Menzel R, Putschew A, Luckenbach T, Steinberg CEW. Contrasting cellular stress responses of Baikalian and Palearctic amphipods upon exposure to humic substances: environmental implications. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2014; 21:14124-14137. [PMID: 25053285 DOI: 10.1007/s11356-014-3323-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 07/09/2014] [Indexed: 06/03/2023]
Abstract
The species-rich, endemic amphipod fauna of Lake Baikal does not overlap with the common Palearctic fauna; however, the underlying mechanisms for this are poorly understood. Considering that Palearctic lakes have a higher relative input of natural organic compounds with a dominance of humic substances (HSs) than Lake Baikal, we addressed the question whether HSs are candidate factors that affect the different species compositions in these water bodies. We hypothesized that interspecies differences in stress defense might reveal that Baikalian amphipods are inferior to Palearctic amphipods in dealing with HS-mediated stress. In this study, two key mechanisms of general stress response were examined: heat-shock protein 70 (HSP70) and multixenobiotic resistance-associated transporters (ABCB1). The results of quantitative polymerase chain reaction (qPCR) showed that the basal levels (in 3-day acclimated animals) of hsp70 and abcb1 transcripts were lower in Baikalian species (Eulimnogammarus cyaneus, Eulimnogammarus verrucosus, Eulimnogammarus vittatus-the most typical littoral species) than in the Palearctic amphipod (Gammarus lacustris-the only Palearctic species distributed in the Baikalian region). In the amphipods, the stress response was induced using HSs at 10 mg L(-1) dissolved organic carbon, which was higher than in sampling sites of the studied species, but well within the range (3-10 mg L(-1)) in the surrounding water bodies populated by G. lacustris. The results of qPCR and western blotting (n = 5) showed that HS exposure led to increased hsp70/abcb1 transcripts and HSP70 protein levels in G. lacustris, whereas these transcript levels remained constant or decreased in the Baikalian species. The decreased level of stress transcripts is probably not able to confer an effective tolerance to Baikalian species against further environmental stressors in conditions with elevated HS levels. Thus, our results suggest a greater robustness of Palearctic amphipods and a higher sensitivity of Baikalian amphipods to HS challenge, which might prevent most endemic species from migrating to habitats outside Lake Baikal.
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Affiliation(s)
- Marina V Protopopova
- Siberian Institute of Plant Physiology and Biochemistry, Siberian Branch Russian Academy of Sciences, Lermontov str., 132, Irkutsk, Russia, 664033,
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Moulis JM, Bourguignon J, Catty P. Cadmium. BINDING, TRANSPORT AND STORAGE OF METAL IONS IN BIOLOGICAL CELLS 2014. [DOI: 10.1039/9781849739979-00695] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Cadmium is not an essential element for life. It is geologically marginal but anthropogenic activities have contributed significantly to its dispersion in the environment and to cadmium exposure of living species. The natural speciation of the divalent cation Cd2+ is dominated by its high propensity to bind to sulfur ligands, but Cd2+ may also occupy sites providing imidazole and carboxylate ligands. It binds to cell walls by passive adsorption (bio-sorption) and it may interact with surface receptors. Cellular uptake can occur by ion mimicry through a variety of transporters of essential divalent cations, but not always. Once inside cells, Cd2+ preferentially binds to thiol-rich molecules. It can accumulate in intracellular vesicles. It may also be transported over long distances within multicellular organisms and be trapped in locations devoid of efficient excretion systems. These locations include the renal cortex of animals and the leaves of hyper-accumulating plants. No specific regulatory mechanism monitors Cd2+ cellular concentrations. Thiol recruitment by cadmium is a major interference mechanism with many signalling pathways that rely on thiolate-disulfide equilibria and other redox-related processes. Cadmium thus compromises the antioxidant intracellular response that relies heavily on molecules with reactive thiolates. These biochemical features dominate cadmium toxicity, which is complex because of the diversity of the biological targets and the consequent pleiotropic effects. This chapter compares the cadmium-handling systems known throughout phylogeny and highlights the basic principles underlying the impact of cadmium in biology.
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Affiliation(s)
- Jean-Marc Moulis
- CEA, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Chimie et Biologie des Métaux 17 rue des Martyrs F-38054 Grenoble France
- CNRS UMR5249 F-38054 Grenoble France
- Université Joseph Fourier-Grenoble I UMR5249 F-38041 Grenoble France
| | - Jacques Bourguignon
- CEA, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Physiologie Cellulaire et Végétale F-38054 Grenoble France
- CNRS UMR5168 F-38054 Grenoble France
- Université Joseph Fourier-Grenoble I UMR5168 F-38041 Grenoble France
- INRA USC1359 F-38054 Grenoble France
| | - Patrice Catty
- CEA, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Chimie et Biologie des Métaux 17 rue des Martyrs F-38054 Grenoble France
- CNRS UMR5249 F-38054 Grenoble France
- Université Joseph Fourier-Grenoble I UMR5249 F-38041 Grenoble France
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30
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Differential transcytosis and toxicity of the hNGAL receptor ligands cadmium-metallothionein and cadmium-phytochelatin in colon-like Caco-2 cells: Implications for in vivo cadmium toxicity. Toxicol Lett 2014; 226:228-35. [DOI: 10.1016/j.toxlet.2014.01.049] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 01/30/2014] [Accepted: 01/31/2014] [Indexed: 12/30/2022]
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31
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Dahdouh F, Raane M, Thévenod F, Lee WK. Nickel-induced cell death and survival pathways in cultured renal proximal tubule cells: roles of reactive oxygen species, ceramide and ABCB1. Arch Toxicol 2014; 88:881-92. [DOI: 10.1007/s00204-014-1194-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 01/09/2014] [Indexed: 12/17/2022]
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32
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De Simone U, Manzo L, Profumo A, Coccini T. In vitro toxicity evaluation of engineered cadmium-coated silica nanoparticles on human pulmonary cells. J Toxicol 2013; 2013:931785. [PMID: 24194755 PMCID: PMC3806223 DOI: 10.1155/2013/931785] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 08/26/2013] [Indexed: 01/16/2023] Open
Abstract
Cytotoxicity of cadmium-containing silica nanoparticles Cd-SiO2NPs (0.05-100 µg/mL) versus SiO2NPs and CdCl2 was evaluated by an in vitro test battery in A549 by assessing (i) mitochondrial function, (ii) membrane integrity/cell morphology, (iii) cell growth/proliferation, (iv) apoptotic pathway, (v) oxidative stress, after short- (24-48 h) and long-term (10 days) exposure. Both Cd-SiO2NPs and CdCl2 produced dose-dependent cytotoxic effects: (i) MTT-assay: similar cytotoxicity pattern was observed at both 24 and 48 h, with a more Cd-SiO2NPs pronounced effect than CdCl2. Cd-SiO2NPs induced mortality (about 50%) at 1 μ g/mL, CdCl2 at 25 μ g/mL; (ii) calcein-AM/PI staining: decrease in cell viability, noticeable at 25 μ g/mL, enhanced markedly at 50 and 100 μ g/mL, after 24 h. Cd-SiO2NPs induced higher mortality than CdCl2 (25% versus 4%, resp., at 25 μ g/mL) with further exacerbation after 48h; (iii) clonogenic assay: exposure for longer period (10 days) compromised the A549 proliferative capacity at very low dose (0.05 μ g/mL); (iv) a progressive activation of caspase-3 immunolabelling was detected already at 1 μ g/mL; (v) GSH intracellular level was modified by all compounds. In summary, in vitro data demonstrated that both Cd-SiO2NPs and CdCl2 affected all investigated endpoints, more markedly after Cd-SiO2NPs, while SiO2NPs influenced GSH only.
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Affiliation(s)
- Uliana De Simone
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy
| | - Luigi Manzo
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy
- Laboratory of Clinical Toxicology, IRCCS Maugeri Foundation, Medical Institute of Pavia, 27100 Pavia, Italy
| | | | - Teresa Coccini
- Laboratory of Clinical Toxicology, IRCCS Maugeri Foundation, Medical Institute of Pavia, 27100 Pavia, Italy
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Cadmium and cellular signaling cascades: interactions between cell death and survival pathways. Arch Toxicol 2013; 87:1743-86. [PMID: 23982889 DOI: 10.1007/s00204-013-1110-9] [Citation(s) in RCA: 183] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2013] [Accepted: 07/29/2013] [Indexed: 12/20/2022]
Abstract
Cellular stress elicited by the toxic metal Cd(2+) does not coerce the cell into committing to die from the onset. Rather, detoxification and adaptive processes are triggered concurrently, allowing survival until normal function is restored. With high Cd(2+), death pathways predominate. However, if sublethal stress levels affect cells for prolonged periods, as in chronic low Cd(2+) exposure, adaptive and survival mechanisms may deregulate, such that tumorigenesis ensues. Hence, death and malignancy are the two ends of a continuum of cellular responses to Cd(2+), determined by magnitude and duration of Cd(2+) stress. Signaling cascades are the key factors affecting cellular reactions to Cd(2+). This review critically surveys recent literature to outline major features of death and survival signaling pathways as well as their activation, interactions and cross talk in cells exposed to Cd(2+). Under physiological conditions, receptor activation generates 2nd messengers, which are short-lived and act specifically on effectors through their spatial and temporal dynamics to transiently alter effector activity. Cd(2+) recruits physiological 2nd messenger systems, in particular Ca(2+) and reactive oxygen species (ROS), which control key Ca(2+)- and redox-sensitive molecular switches dictating cell function and fate. Severe ROS/Ca(2+) signals activate cell death effectors (ceramides, ASK1-JNK/p38, calpains, caspases) and/or cause irreversible damage to vital organelles, such as mitochondria and endoplasmic reticulum (ER), whereas low localized ROS/Ca(2+) levels act as 2nd messengers promoting cellular adaptation and survival through signal transduction (ERK1/2, PI3K/Akt-PKB) and transcriptional regulators (Ref1-Nrf2, NF-κB, Wnt, AP-1, bestrophin-3). Other cellular proteins and processes targeted by ROS/Ca(2+) (metallothioneins, Bcl-2 proteins, ubiquitin-proteasome system, ER stress-associated unfolded protein response, autophagy, cell cycle) can evoke death or survival. Hence, temporary or permanent disruptions of ROS/Ca(2+) induced by Cd(2+) play a crucial role in eliciting, modulating and linking downstream cell death and adaptive and survival signaling cascades.
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34
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Lee WK, Chakraborty PK, Thévenod F. Pituitary homeobox 2 (PITX2) protects renal cancer cell lines against doxorubicin toxicity by transcriptional activation of the multidrug transporter ABCB1. Int J Cancer 2013; 133:556-67. [PMID: 23354914 DOI: 10.1002/ijc.28060] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Revised: 12/16/2012] [Accepted: 01/08/2013] [Indexed: 12/21/2022]
Abstract
The multidrug resistance (MDR) P-glycoprotein ABCB1 plays a major role in MDR of malignant cells and is regulated by various transcription factors, including Wnt/β-catenin/TCF4. The transcription factor PITX2 (Pituitary homeobox-2) is essential for embryonic development. PITX2 operates by recruiting and interacting with β-catenin to increase the expression of growth-regulating genes, such as cyclin D1/2 and c-Myc. The importance of PITX2 in malignancy is not yet known. Here we demonstrate that in the renal cancer cell lines ACHN and A498, the level of ABCB1 expression and function correlate with nuclear PITX2 localization and PITX2-luciferase reporter gene activity (A498 > ACHN). In A498 cells, doxorubicin toxicity is augmented by the ABCB1 inhibitor, PSC833. PITX2 overexpression increases ABCB1 expression and cell survival in ACHN cells. Silencing of PITX2 by siRNA downregulates ABCB1 and induces a greater chemotherapeutic response to doxorubicin in A498 cells, as determined by MTT cell viability and clonogenic survival assays. Two PITX2 binding sequences were identified in the ABCB1 promoter sequence. PITX2 binding was confirmed by chromatin immunoprecipitation. β-Catenin is not required for PITX2 upregulation of ABCB1 because ABCB1 mRNA increased and doxorubicin toxicity decreased upon PITX2 overexpression in β-catenin(-/-) cells. The data show for the first time that ABCB1 is a target gene of PITX2 transcriptional activity, promoting MDR and cell survival of cancer cells.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors
- ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Antibiotics, Antineoplastic/pharmacology
- Carcinoma, Renal Cell/drug therapy
- Cell Line, Tumor
- Cell Survival
- Chromatin Immunoprecipitation
- Cyclosporins/pharmacology
- Doxorubicin/pharmacology
- Gene Expression Regulation, Neoplastic
- Homeodomain Proteins/metabolism
- Humans
- Kidney Neoplasms/drug therapy
- Promoter Regions, Genetic
- RNA Interference
- RNA, Messenger/biosynthesis
- RNA, Small Interfering
- Signal Transduction/genetics
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Transcriptional Activation
- beta Catenin/genetics
- Homeobox Protein PITX2
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Affiliation(s)
- Wing-Kee Lee
- Institute of Physiology and Pathophysiology, ZBAF, Witten/Herdecke University, Witten, North-Rhine Westphalia, Germany
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Thévenod F, Ciarimboli G, Leistner M, Wolff NA, Lee WK, Schatz I, Keller T, Al-Monajjed R, Gorboulev V, Koepsell H. Substrate- and cell contact-dependent inhibitor affinity of human organic cation transporter 2: studies with two classical organic cation substrates and the novel substrate cd2+. Mol Pharm 2013; 10:3045-56. [PMID: 23763587 DOI: 10.1021/mp400113d] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Polyspecific organic cation transporter Oct2 from rat (gene Slc22A2) has been previously shown to transport Cs(+). Here we report that human OCT2 (hOCT2) is able to transport Cd(2+) showing substrate saturation with a Michaelis-Menten constant (Km) of 54 ± 5.8 μM. Uptake of Cd(2+) by hOCT2 was inhibited by typical hOCT2 ligands (unlabeled substrates and inhibitors), and the rate of uptake was decreased by a point mutation in a substrate binding domain of hOCT2. Incubation of hOCT2 overexpressing human embryonic kidney 293 cells (HEK-hOCT2-C) or rat renal proximal tubule cells expressing rOct2 (NRK-52E-C) with Cd(2+) resulted in an increased level of apoptosis that was reduced by OCT2 inhibitory ligand cimetidine(+). HEK-hOCT2-C exhibited different functional properties when they were confluent or had been dissociated by removal of Ca(2+) and Mg(2+). Only confluent HEK-hOCT2-C transported Cd(2+), and confluent and dissociated cells exhibited different potencies for inhibition of uptake of 1-methyl-4-phenylpyridinium(+) (MPP(+)) by Cd(2+), MPP(+), tetraethylammonium(+), cimetidine(+), and corticosterone. In confluent HEK-hOCT2-C, largely different inhibitor potencies were obtained upon comparison of inhibition of Cd(2+) uptake, 4-[4-(dimethylamino)styryl]-N-methylpyridinium(+) (ASP(+)) uptake, and MPP(+) uptake using substrate concentrations far below the respective Km values. Employing a point mutation in the previously identified substrate binding site of rat Oct1 produced evidence that short distance allosteric effects between binding sites for substrates and inhibitors are involved in substrate-dependent inhibitor potency. Substrate-dependent inhibitor affinity is probably a common property of OCTs. To predict interactions between drugs that are transported by OCTs and inhibitory drugs, it is necessary to employ the specific transported drug rather than a model substrate for in vitro measurements.
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Affiliation(s)
- Frank Thévenod
- Institute of Physiology and Pathophysiology, ZBAF, University of Witten/Herdecke , Witten, Germany.
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Abstract
Cadmium is known for its toxicity in animals and man as it is not used in these species. Its only role in biology is as a zinc replacement at the catalytic site of a particular class of carbonic anhydrases in some marine diatoms. The toxicity of cadmium continues to be a significant public health concern as cadmium enters the food chain and it is taken up by tobacco smokers. The biochemical basis for its toxicity has been the objective of research for over 50 years. Cadmium damages the kidneys, the lungs upon inhalation, and interferes with bone metabolism. Evidence is accumulating that it affects the cardiovascular system. Cadmium is classified as a human carcinogen. It generates oxidative stress. This chapter discusses the chemistry and biochemistry of cadmium(II) ions, the only important state of cadmium in biology. This background is needed to interpret the countless effects of cadmium in laboratory experiments with cultured cells or with animals with regard to their significance for human health. Evaluation of the risks of cadmium exposure and the risk factors that affect cadmium's biological effects in tissues is an on-going process. It appears that the more we learn about the biochemistry of cadmium and the more sensitive assays we develop for determining exposure, the lower we need to set the upper limits for exposure to protect those at risk. But proper control of cadmium's presence and interactions with living species and the environment still needs to be based on improved knowledge about the mechanisms of cadmium toxicity; the gaps in our knowledge in this area are discussed herein.
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38
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Current world literature. Curr Opin Nephrol Hypertens 2012; 21:557-66. [PMID: 22874470 DOI: 10.1097/mnh.0b013e3283574c3b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Stordal B, Hamon M, McEneaney V, Roche S, Gillet JP, O'Leary JJ, Gottesman M, Clynes M. Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein. PLoS One 2012. [PMID: 22792399 DOI: 10.1371/journal.pone.0040717] [] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.
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Affiliation(s)
- Britta Stordal
- National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
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40
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Stordal B, Hamon M, McEneaney V, Roche S, Gillet JP, O'Leary JJ, Gottesman M, Clynes M. Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein. PLoS One 2012. [PMID: 22792399 DOI: 10.1371/journal.pone.0040717]+[] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.
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Affiliation(s)
- Britta Stordal
- National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
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Stordal B, Hamon M, McEneaney V, Roche S, Gillet JP, O'Leary JJ, Gottesman M, Clynes M. Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein. PLoS One 2012; 7:e40717. [PMID: 22792399 PMCID: PMC3394717 DOI: 10.1371/journal.pone.0040717] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Accepted: 06/12/2012] [Indexed: 02/07/2023] Open
Abstract
The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.
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Affiliation(s)
- Britta Stordal
- National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
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Bochud M, Burnier M, Guessous I. Top Three Pharmacogenomics and Personalized Medicine Applications at the Nexus of Renal Pathophysiology and Cardiovascular Medicine. CURRENT PHARMACOGENOMICS AND PERSONALIZED MEDICINE 2011; 9:299-322. [PMID: 23049672 PMCID: PMC3460365 DOI: 10.2174/187569211798377135] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Revised: 10/08/2011] [Accepted: 10/13/2011] [Indexed: 12/18/2022]
Abstract
Pharmacogenomics is a field with origins in the study of monogenic variations in drug metabolism in the 1950s. Perhaps because of these historical underpinnings, there has been an intensive investigation of 'hepatic pharmacogenes' such as CYP450s and liver drug metabolism using pharmacogenomics approaches over the past five decades. Surprisingly, kidney pathophysiology, attendant diseases and treatment outcomes have been vastly under-studied and under-theorized despite their central importance in maintenance of health, susceptibility to disease and rational personalized therapeutics. Indeed, chronic kidney disease (CKD) represents an increasing public health burden worldwide, both in developed and developing countries. Patients with CKD suffer from high cardiovascular morbidity and mortality, which is mainly attributable to cardiovascular events before reaching end-stage renal disease. In this paper, we focus our analyses on renal function before end-stage renal disease, as seen through the lens of pharmacogenomics and human genomic variation. We herein synthesize the recent evidence linking selected Very Important Pharmacogenes (VIP) to renal function, blood pressure and salt-sensitivity in humans, and ways in which these insights might inform rational personalized therapeutics. Notably, we highlight and present the rationale for three applications that we consider as important and actionable therapeutic and preventive focus areas in renal pharmacogenomics: 1) ACE inhibitors, as a confirmed application, 2) VDR agonists, as a promising application, and 3) moderate dietary salt intake, as a suggested novel application. Additionally, we emphasize the putative contributions of gene-environment interactions, discuss the implications of these findings to treat and prevent hypertension and CKD. Finally, we conclude with a strategic agenda and vision required to accelerate advances in this under-studied field of renal pharmacogenomics with vast significance for global public health.
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Affiliation(s)
- Murielle Bochud
- Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
| | - Michel Burnier
- Service of Nephrology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
| | - Idris Guessous
- Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
- Unit of Population Epidemiology, Division of Primary Care medicine, Department of Community Medicine and Primary Care and Emergency Medicine, Geneva University Hospital, Geneva, Switzerland
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Adibhatla RM, Hatcher JF, Gusain A. Tricyclodecan-9-yl-xanthogenate (D609) mechanism of actions: a mini-review of literature. Neurochem Res 2011; 37:671-9. [PMID: 22101393 DOI: 10.1007/s11064-011-0659-z] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Revised: 10/14/2011] [Accepted: 11/10/2011] [Indexed: 12/21/2022]
Abstract
Tricyclodecan-9-yl-xanthogenate (D609) is known for its antiviral and antitumor properties. D609 actions are widely attributed to inhibiting phosphatidylcholine (PC)-specific phospholipase C (PC-PLC). D609 also inhibits sphingomyelin synthase (SMS). PC-PLC and/or SMS inhibition will affect lipid second messengers 1,2-diacylglycerol (DAG) and/or ceramide. Evidence indicates either PC-PLC and/or SMS inhibition affected the cell cycle and arrested proliferation, and stimulated differentiation in various in vitro and in vivo studies. Xanthogenate compounds are also potent antioxidants and D609 reduced Aß-induced toxicity, attributed to its antioxidant properties. Zn²⁺ is necessary for PC-PLC enzymatic activity; inhibition by D609 might be attributed to its Zn²⁺ chelation. D609 has also been proposed to inhibit acidic sphingomyelinase or down-regulate hypoxia inducible factor-1α; however these are down-stream events related to PC-PLC inhibition. Characterization of the mammalian PC-PLC is limited to inhibition of enzymatic activity (frequently measured using Amplex red assay with bacterial PC-PLC as a standard). The mammalian PC-PLC has not been cloned; sequenced and structural information is unavailable. D609 showed promise in cancer studies, reduced atherosclerotic plaques (inhibition of PC-PLC) and cerebral infarction after stroke (PC-PLC or SMS). D609 actions as an antagonist to pro-inflammatory cytokines have been attributed to PC-PLC. The purpose of this review is to comprehensively evaluate the literature and summarize the findings and relevance to cell cycle and CNS pathologies.
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Affiliation(s)
- Rao Muralikrishna Adibhatla
- Department of Neurological Surgery, Clinical Science Center, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Madison, WI 53792-3232, USA.
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Langelueddecke C, Roussa E, Fenton RA, Wolff NA, Lee WK, Thévenod F. Lipocalin-2 (24p3/neutrophil gelatinase-associated lipocalin (NGAL)) receptor is expressed in distal nephron and mediates protein endocytosis. J Biol Chem 2011; 287:159-169. [PMID: 22084236 DOI: 10.1074/jbc.m111.308296] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
In the kidney, bulk reabsorption of filtered proteins occurs in the proximal tubule via receptor-mediated endocytosis (RME) through the multiligand receptor complex megalin-cubilin. Other mechanisms and nephron sites for RME of proteins are unclear. Recently, the secreted protein 24p3 (lipocalin-2, neutrophil gelatinase-associated lipocalin (NGAL)), which is expressed in the distal nephron, has been identified as a sensitive biomarker of kidney damage. A high-affinity receptor for 24p3 (24p3R) that is involved in endocytotic iron delivery has also been cloned. We investigated the localization of 24p3R in rodent kidney and its role in RME of protein-metal complexes and albumin. Immunostaining of kidney tissue showed expression of 24p3R in apical membranes of distal tubules and collecting ducts, but not of proximal tubule. The differential expression of 24p3R in these nephron segments was confirmed in the respective cell lines. CHO cells transiently transfected with 24p3R or distal tubule cells internalized submicromolar concentrations of fluorescence-coupled proteins transferrin, albumin, or metallothionein (MT) as well as the toxic cadmium-MT (Cd2+(7)-MT) complex, which caused cell death. Uptake of MT or transferrin and Cd2+(7)-MT toxicity were prevented by picomolar concentrations of 24p3. An EC50 of 123±50 nM was determined for binding of MT to 24p3R by microscale thermophoresis. Hence, 24p3R binds proteins filtered by the kidney with high affinity and may contribute to RME of proteins, including 24p3, and to Cd2+(7)-MT toxicity in distal nephron segments.
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Affiliation(s)
- Christian Langelueddecke
- Institute of Physiology and Pathophysiology, Centre for Biomedical Training and Research (ZBAF), University of Witten/Herdecke, 58453 Witten, Germany
| | - Eleni Roussa
- Institute of Anatomy and Cell Biology II, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany
| | - Robert A Fenton
- Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark
| | - Natascha A Wolff
- Institute of Physiology and Pathophysiology, Centre for Biomedical Training and Research (ZBAF), University of Witten/Herdecke, 58453 Witten, Germany
| | - Wing-Kee Lee
- Institute of Physiology and Pathophysiology, Centre for Biomedical Training and Research (ZBAF), University of Witten/Herdecke, 58453 Witten, Germany
| | - Frank Thévenod
- Institute of Physiology and Pathophysiology, Centre for Biomedical Training and Research (ZBAF), University of Witten/Herdecke, 58453 Witten, Germany.
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