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House RRJ, Soper-Hopper MT, Vincent MP, Ellis AE, Capan CD, Madaj ZB, Wolfrum E, Isaguirre CN, Castello CD, Johnson AB, Escobar Galvis ML, Williams KS, Lee H, Sheldon RD. A diverse proteome is present and enzymatically active in metabolite extracts. Nat Commun 2024; 15:5796. [PMID: 38987243 PMCID: PMC11237058 DOI: 10.1038/s41467-024-50128-z] [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: 01/26/2024] [Accepted: 07/02/2024] [Indexed: 07/12/2024] Open
Abstract
Metabolite extraction is the critical first-step in metabolomics experiments, where it is generally regarded to inactivate and remove proteins. Here, arising from efforts to improve extraction conditions for polar metabolomics, we discover a proteomic landscape of over 1000 proteins within metabolite extracts. This is a ubiquitous feature across several common extraction and sample types. By combining post-resuspension stable isotope addition and enzyme inhibitors, we demonstrate in-extract metabolite interconversions due to residual transaminase activity. We extend these findings with untargeted metabolomics where we observe extensive protein-mediated metabolite changes, including in-extract formation of glutamate dipeptide and depletion of total glutathione. Finally, we present a simple extraction workflow that integrates 3 kDa filtration for protein removal as a superior method for polar metabolomics. In this work, we uncover a previously unrecognized, protein-mediated source of observer effects in metabolomics experiments with broad-reaching implications across all research fields using metabolomics and molecular metabolism.
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Affiliation(s)
- Rachel Rae J House
- Department of Cell Biology, Van Andel Institute, Grand Rapids, MI, USA
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
- Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA
| | | | | | - Abigail E Ellis
- Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Colt D Capan
- Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Zachary B Madaj
- Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Emily Wolfrum
- Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USA
| | | | | | - Amy B Johnson
- Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Martha L Escobar Galvis
- Office of the Cores, Core Technologies and Services, Van Andel Institute, Grand Rapids, MI, USA
| | - Kelsey S Williams
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
| | - Hyoungjoo Lee
- Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Ryan D Sheldon
- Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA.
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2
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Bellanti F, Mangieri D, Vendemiale G. Redox Biology and Liver Fibrosis. Int J Mol Sci 2023; 25:410. [PMID: 38203581 PMCID: PMC10778611 DOI: 10.3390/ijms25010410] [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: 11/24/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Hepatic fibrosis is a complex process that develops in chronic liver diseases. Even though the initiation and progression of fibrosis rely on the underlying etiology, mutual mechanisms can be recognized and targeted for therapeutic purposes. Irrespective of the primary cause of liver disease, persistent damage to parenchymal cells triggers the overproduction of reactive species, with the consequent disruption of redox balance. Reactive species are important mediators for the homeostasis of both hepatocytes and non-parenchymal liver cells. Indeed, other than acting as cytotoxic agents, reactive species are able to modulate specific signaling pathways that may be relevant to hepatic fibrogenesis. After a brief introduction to redox biology and the mechanisms of fibrogenesis, this review aims to summarize the current evidence of the involvement of redox-dependent pathways in liver fibrosis and focuses on possible therapeutic targets.
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Affiliation(s)
- Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
| | - Domenica Mangieri
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy;
| | - Gianluigi Vendemiale
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
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Georgiou-Siafis SK, Tsiftsoglou AS. The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates. Antioxidants (Basel) 2023; 12:1953. [PMID: 38001806 PMCID: PMC10669396 DOI: 10.3390/antiox12111953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/18/2023] [Accepted: 10/23/2023] [Indexed: 11/26/2023] Open
Abstract
Glutathione (GSH) is a ubiquitous tripeptide that is biosynthesized in situ at high concentrations (1-5 mM) and involved in the regulation of cellular homeostasis via multiple mechanisms. The main known action of GSH is its antioxidant capacity, which aids in maintaining the redox cycle of cells. To this end, GSH peroxidases contribute to the scavenging of various forms of ROS and RNS. A generally underestimated mechanism of action of GSH is its direct nucleophilic interaction with electrophilic compounds yielding thioether GSH S-conjugates. Many compounds, including xenobiotics (such as NAPQI, simvastatin, cisplatin, and barbital) and intrinsic compounds (such as menadione, leukotrienes, prostaglandins, and dopamine), form covalent adducts with GSH leading mainly to their detoxification. In the present article, we wish to present the key role and significance of GSH in cellular redox biology. This includes an update on the formation of GSH-S conjugates or GSH adducts with emphasis given to the mechanism of reaction, the dependence on GST (GSH S-transferase), where this conjugation occurs in tissues, and its significance. The uncovering of the GSH adducts' formation enhances our knowledge of the human metabolome. GSH-hematin adducts were recently shown to have been formed spontaneously in multiples isomers at hemolysates, leading to structural destabilization of the endogenous toxin, hematin (free heme), which is derived from the released hemoglobin. Moreover, hemin (the form of oxidized heme) has been found to act through the Kelch-like ECH associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway as an epigenetic modulator of GSH metabolism. Last but not least, the implications of the genetic defects in GSH metabolism, recorded in hemolytic syndromes, cancer and other pathologies, are presented and discussed under the framework of conceptualizing that GSH S-conjugates could be regarded as signatures of the cellular metabolism in the diseased state.
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Affiliation(s)
| | - Asterios S. Tsiftsoglou
- Laboratory of Pharmacology, Department of Pharmaceutical Sciences, School of Health Sciences, Aristotle University of Thessaloniki (AUTh), 54124 Thessaloniki, Greece;
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Jin ES, Malloy CR, Sharma G, Finn E, Fuller KNZ, Reyes YG, Lovell MA, Derderian SC, Schoen JA, Inge TH, Cree MG. Glycerol as a precursor for hepatic de novo glutathione synthesis in human liver. Redox Biol 2023; 63:102749. [PMID: 37224695 PMCID: PMC10225920 DOI: 10.1016/j.redox.2023.102749] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/10/2023] [Accepted: 05/14/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Glycerol is a substrate for gluconeogenesis and fatty acid esterification in the liver, processes which are upregulated in obesity and may contribute to excess fat accumulation. Glycine and glutamate, in addition to cysteine, are components of glutathione, the major antioxidant in the liver. In principle, glycerol could be incorporated into glutathione via the TCA cycle or 3-phosphoglycerate, but it is unknown whether glycerol contributes to hepatic de novo glutathione biosynthesis. METHODS Glycerol metabolism to hepatic metabolic products including glutathione was examined in the liver from adolescents undergoing bariatric surgery. Participants received oral [U-13C3]glycerol (50 mg/kg) prior to surgery and liver tissue (0.2-0.7g) was obtained during surgery. Glutathione, amino acids, and other water-soluble metabolites were extracted from the liver tissue and isotopomers were quantified with nuclear magnetic resonance spectroscopy. RESULTS Data were collected from 8 participants (2 male, 6 female; age 17.1 years [range 14-19]; BMI 47.4 kg/m2 [range 41.3-63.3]). The concentrations of free glutamate, cysteine, and glycine were similar among participants, and so were the fractions of 13C-labeled glutamate and glycine derived from [U-13C3]glycerol. The signals from all component amino acids of glutathione - glutamate, cysteine and glycine - were strong and analyzed to obtain the relative concentrations of the antioxidant in the liver. The signals from glutathione containing [13C2]glycine or [13C2]glutamate derived from the [U-13C3]glycerol drink were readily detected, and 13C-labelling patterns in the moieties were consistent with the patterns in corresponding free amino acids from the de novo glutathione synthesis pathway. The newly synthesized glutathione with [U-13C3]glycerol trended to be lower in obese adolescents with liver pathology. CONCLUSIONS This is the first report of glycerol incorporation into glutathione through glycine or glutamate metabolism in human liver. This could represent a compensatory mechanism to increase glutathione in the setting of excess glycerol delivery to the liver.
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Affiliation(s)
- Eunsook S Jin
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Craig R Malloy
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; VA North Texas Health Care System, Dallas, TX, 75216, USA
| | - Gaurav Sharma
- Department of Cardiovascular & Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; VA North Texas Health Care System, Dallas, TX, 75216, USA
| | - Erin Finn
- Department of Pediatrics, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO, 80045, USA; Children's Hospital of Colorado, Aurora, CO, 80045, USA
| | - Kelly N Z Fuller
- Department of Pediatrics, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO, 80045, USA; Children's Hospital of Colorado, Aurora, CO, 80045, USA
| | - Yesenia Garcia Reyes
- Department of Pediatrics, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO, 80045, USA; Children's Hospital of Colorado, Aurora, CO, 80045, USA
| | - Mark A Lovell
- Children's Hospital of Colorado, Aurora, CO, 80045, USA; Department of Pathology, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Sarkis C Derderian
- Children's Hospital of Colorado, Aurora, CO, 80045, USA; Department of Surgery, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Jonathan A Schoen
- Children's Hospital of Colorado, Aurora, CO, 80045, USA; Department of Surgery, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Thomas H Inge
- Children's Hospital of Colorado, Aurora, CO, 80045, USA; Department of Surgery, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO, 80045, USA; Ann and Robert Lurie Children's Hospital of Chicago, USA
| | - Melanie G Cree
- Department of Pediatrics, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO, 80045, USA; Children's Hospital of Colorado, Aurora, CO, 80045, USA.
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Lamanilao GG, Dogan M, Patel PS, Azim S, Patel DS, Bhattacharya SK, Eason JD, Kuscu C, Kuscu C, Bajwa A. Key hepatoprotective roles of mitochondria in liver regeneration. Am J Physiol Gastrointest Liver Physiol 2023; 324:G207-G218. [PMID: 36648139 PMCID: PMC9988520 DOI: 10.1152/ajpgi.00220.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 12/28/2022] [Accepted: 01/11/2023] [Indexed: 01/18/2023]
Abstract
Treatment of advanced liver disease using surgical modalities is possible due to the liver's innate ability to regenerate following resection. Several key cellular events in the regenerative process converge at the mitochondria, implicating their crucial roles in liver regeneration. Mitochondria enable the regenerating liver to meet massive metabolic demands by coordinating energy production to drive cellular proliferative processes and vital homeostatic functions. Mitochondria are also involved in terminating the regenerative process by mediating apoptosis. Studies have shown that attenuation of mitochondrial activity results in delayed liver regeneration, and liver failure following resection is associated with mitochondrial dysfunction. Emerging mitochondria therapy (i.e., mitotherapy) strategies involve isolating healthy donor mitochondria for transplantation into diseased organs to promote regeneration. This review highlights mitochondria's inherent role in liver regeneration.
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Affiliation(s)
- Gene G Lamanilao
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Murat Dogan
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Prisha S Patel
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Shafquat Azim
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Disha S Patel
- Department of Legal Studies, Belmont University, Nashville, Tennessee, United States
| | - Syamal K Bhattacharya
- Division of Cardiovascular Diseases, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - James D Eason
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Canan Kuscu
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Cem Kuscu
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Amandeep Bajwa
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
- Department of Genetics, Genomics, and Informatics, The University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee, United States
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
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Tan W, Zhang Q, Hong P, Xu B. A Self-Assembling Probe for Imaging the States of Golgi Apparatus in Live Single Cells. Bioconjug Chem 2022; 33:1983-1988. [PMID: 35312281 PMCID: PMC9489815 DOI: 10.1021/acs.bioconjchem.2c00084] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Despite the enormous progress in genomics and proteomics, it is still challenging to assess the states of organelles in living cells with high spatiotemporal resolution. Based on our recent finding of enzyme-instructed self-assembly of a thiophosphopeptide that targets the Golgi Apparatus (GA) instantly, we use the thiophosphopeptide, which is enzymatically responsive and redox active, as an integrative probe for revealing the state of the GA of live cells at the single cell level. By imaging the probe in the GA of live cells over time, our results show that the accumulation of the probe at the GA depends on cell types. By comparison to a conventional Golgi probe, this self-assembling probe accumulates at the GA much faster and are sensitive to the expression of alkaline phosphatases. In addition, subtle changes of the fluorophore results in slightly different GA responses. This work illustrates a novel class of active molecular probes that combine enzyme-instructed self-assembly and redox reaction for high-resolution imaging of the states of subcellular organelles over a large area and extended times.
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Affiliation(s)
- Weiyi Tan
- Department of Chemistry, Brandeis University, 415 South St., Waltham, MA 02454, USA
| | - Qiuxin Zhang
- Department of Chemistry, Brandeis University, 415 South St., Waltham, MA 02454, USA
| | - Pengyu Hong
- Department of Computer Science, Brandeis University, 415 South St., Waltham, MA 02453, USA
| | - Bing Xu
- Department of Chemistry, Brandeis University, 415 South St., Waltham, MA 02454, USA
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7
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Wang Y, Charkoftaki G, Davidson E, Orlicky DJ, Tanguay RL, Thompson DC, Vasiliou V, Chen Y. Oxidative stress, glutathione, and CYP2E1 in 1,4-dioxane liver cytotoxicity and genotoxicity: insights from animal models. CURRENT OPINION IN ENVIRONMENTAL SCIENCE & HEALTH 2022; 29:100389. [PMID: 37483863 PMCID: PMC10361651 DOI: 10.1016/j.coesh.2022.100389] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
1,4-Dioxane (DX) is an emerging drinking water contaminant worldwide, which poses a threat to public health due to its demonstrated liver carcinogenicity and potential for human exposure. The lack of drinking water standards for DX is attributed to undetermined mechanisms of DX carcinogenicity. This mini-review provides a brief discussion of a series of mechanistic studies, wherein unique mouse models were exposed to DX in drinking water to elucidate redox changes associated with DX cytotoxicity and genotoxicity. The overall conclusions from these studies support a direct genotoxic effect by high dose DX and imply that oxidative stress involving CYP2E1 activation may play a causal role in DX liver genotoxicity and potentially carcinogenicity. The mechanistic data derived from these studies can serve as important references to refine the assessment of carcinogenic pathways that may be triggered at environmentally relevant low doses of DX in future animal and human studies.
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Affiliation(s)
- Yewei Wang
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06510, USA
| | - Georgia Charkoftaki
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06510, USA
| | - Emily Davidson
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06510, USA
- Department of Cellular & Molecular Physiology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - David J. Orlicky
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Center, University of Colorado, Aurora, CO 80045, USA
| | - Robyn L. Tanguay
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
| | - David C. Thompson
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06510, USA
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06510, USA
| | - Ying Chen
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06510, USA
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Tan W, Zhang Q, Quiñones-Frías MC, Hsu AY, Zhang Y, Rodal A, Hong P, Luo HR, Xu B. Enzyme-Responsive Peptide Thioesters for Targeting Golgi Apparatus. J Am Chem Soc 2022; 144:6709-6713. [PMID: 35404599 PMCID: PMC9069992 DOI: 10.1021/jacs.2c02238] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The Golgi apparatus (GA) is the hub of intracellular trafficking, but selectively targeting GA remains a challenge. We show an unconventional types of peptide thioesters, consisting of an aminoethyl thioester and acting as substrates of thioesterases, for instantly targeting the GA of cells. The peptide thioesters, above or below their critical micelle concentrations, enter cells mainly via caveolin-mediated endocytosis or macropinocytosis, respectively. After being hydrolyzed by GA-associated thioesterases, the resulting thiopeptides form dimers and accumulate in the GA. After saturating the GA, the thiopeptides are enriched in the endoplasmic reticulum (ER). Their buildup in ER and GA disrupts protein trafficking, thus leading to cell death via multiple pathways. The peptide thioesters target the GA of a wide variety of cells, including human, murine, and Drosophila cells. Changing d-diphenylalanine to l-diphenylalanine in the peptide maintains the GA-targeting ability. In addition, targeting GA redirects protein (e.g., NRAS) distribution. This work illustrates a thioesterase-responsive and redox-active molecular platform for targeting the GA and controlling cell fates.
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Affiliation(s)
- Weiyi Tan
- Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02453, USA
| | - Qiuxin Zhang
- Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02453, USA
| | | | - Alan Y. Hsu
- Department of Pathology, Harvard Medical School and Department of Laboratory Medicine, Children’s Hospital Boston and Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA
| | - Yichi Zhang
- Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02453, USA
| | - Avital Rodal
- Department of Biology, Brandeis University, Waltham, MA 02453, USA
| | - Pengyu Hong
- Department of Computer Science, Brandeis University, Waltham, MA 02453, USA
| | - Hongbo R. Luo
- Department of Pathology, Harvard Medical School and Department of Laboratory Medicine, Children’s Hospital Boston and Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA
| | - Bing Xu
- Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02453, USA
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Wu S, Wang M, Zhang M, He JQ. Metabolomics and microbiomes for discovering biomarkers of antituberculosis drugs-induced hepatotoxicity. Arch Biochem Biophys 2022; 716:109118. [PMID: 34999018 DOI: 10.1016/j.abb.2022.109118] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 12/13/2021] [Accepted: 01/04/2022] [Indexed: 02/08/2023]
Abstract
Anti-tuberculosis (TB) drug-induced hepatotoxicity (ATDH) was related to metabolic and microbial dysregulation, but only limited data was available about the metabolomes and microbiomes in ATDH. We aimed at detecting the metabolic and microbial signatures of ATDH. Urine samples were obtained from ATDH (n = 33) and non-ATDH control (n = 41) and analyzed by untargeted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). Metabolites were analyzed by orthogonal projections to latent structures-discriminate analysis (OPLS-DA) and pathway analysis. Eight ATDH and eight non-ATDH control were evaluated by sequencing of 16S rRNA genes, and the Clusters of Orthologous Groups of proteins (COG) database were used for function prediction. Linear discriminant analysis (LDA) effect size (LEfSe) was applied to detect the differential microbiotas between the two groups. The differential microbiotas were further validated by correlation analysis with differential metabolites. OPLS-DA analysis suggested 11 metabolites that differed ATDH from non-ATDH control. Pathway analysis demonstrated that metabolism of arginine and proline, metabolism of d-arginine and d-ornithine, glutathione glycine metabolism, galactose metabolism, niacin and nicotinamide metabolism, and glycine, serine and threonine metabolism were related to ATDH. LEfSe suggested significant differences in microbiotas between the two groups. The o_ Bacteroidales, f_Prevotellaceae, and g_Prevotella were significantly increased in ATDH. In contrast, the f_Chitinophagaceae, c_Gammaproteobacteria, and p_Proteobacteria were significantly increased in non-ATDH group. The biological functions of the sequenced microbiota in this study were related to amino acid transport and metabolism and defense mechanisms. Finally, we detected strong association between urine metabolites and specific urine bacteria (|r| > 0.8). d-glucoheptose showed a strong relationship to Symbiobacterium. Creatine (r = -0.901; P < 0.001) and diglycerol were strongly associated with Alishewanella. Metabolomics and microbiomes indicate ATDH characterized by metabolic and microbial profiles may differ from non-ATDH control.
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Affiliation(s)
- Shouquan Wu
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Minggui Wang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Miaomiao Zhang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jian-Qing He
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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10
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Barfuss DW, Buchanan JT, Joshee L, Pittman EH, D'Souza N, Matta KE, Brownlee RT, Bridges CC. Hepatic Processing of Mercuric Ions Facilitates Delivery to Renal Proximal Tubules. Toxicol Lett 2022; 359:1-9. [DOI: 10.1016/j.toxlet.2022.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/16/2021] [Accepted: 01/18/2022] [Indexed: 11/25/2022]
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Determination of metabolic phenotype and potential biomarkers in the liver of heroin addicted mice with hepatotoxicity. Life Sci 2021; 287:120103. [PMID: 34743944 DOI: 10.1016/j.lfs.2021.120103] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/22/2021] [Accepted: 10/25/2021] [Indexed: 01/04/2023]
Abstract
BACKGROUND Heroin is a semi-synthetic opioid that is commonly abused drugs in the world. It can cause hepatic injury and lead to multiple organs dysfunction to its addicts. Only a few reports exist on the metabolic changes and mechanisms in the liver of heroin-addicted mice with hepatic injury. METHODS Twelve adult male Kunming mice (30-40 g) were divided into two groups randomly. The mice in the heroin-addicted group were injected subcutaneously in the first ten days with an increased dosage of heroin from 10 mg/kg to 55 mg/kg. The dosage was then stabilized at 55 mg/kg for three days. The control group was injected with the same amount of saline in the same manner. The hepatic injury was confirmed through the combination of histopathological observation and aminotransferase (AST) and alanine aminotransferase (ALT) determination. The withdrawal symptoms were recorded and used for assessment of heroin addiction. Eventually, liver metabolic biomarkers of heroin-addicted mice with hepatotoxicity were measured using UHPLC-MS/MS. RESULTS Biochemical analysis and histopathological observation showed that heroin-addicted mice had a liver injury. The liver metabolites of heroin-addicted mice changed significantly. Metabonomics analysis revealed 41 metabolites in the liver of addicted heroin mice as biomarkers involving 34 metabolic pathways. Among them, glutathione metabolism, taurine and hypotaurine metabolism, vitamin B2 metabolism, riboflavin metabolism, and single-carbon metabolism pathways were markedly dispruted. CONCLUSIONS Heroin damages the liver and disrupts the liver's metabolic pathways. Glutathione, taurine, riboflavin, 4-pyridoxate, folic acid, and methionine are important metabolic biomarkers, which may be key targets of heroin-induced liver damage. Thus, this study provides an in-depth understanding of the mechanisms of heroin-induced hepatotoxicity and potential biomarkers of liver damage.
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12
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Abstract
Significance: During aging, excessive production of reactive species in the liver leads to redox imbalance with consequent oxidative damage and impaired organ homeostasis. Nevertheless, slight amounts of reactive species may modulate several transcription factors, acting as second messengers and regulating specific signaling pathways. These redox-dependent alterations may impact the age-associated decline in liver regeneration. Recent Advances: In the last few decades, relevant findings related to redox alterations in the aging liver were investigated. Consistently, recent research broadened understanding of redox modifications and signaling related to liver regeneration. Other than reporting the effect of oxidative stress, epigenetic and post-translational modifications, as well as modulation of specific redox-sensitive cellular signaling, were described. Among them, the present review focuses on Wnt/β-catenin, the nuclear factor (erythroid-derived 2)-like 2 (NRF2), members of the Forkhead box O (FoxO) family, and the p53 tumor suppressor. Critical Issues: Even though alteration in redox homeostasis occurs both in aging and in impaired liver regeneration, the associative mechanisms are not clearly defined. Of note, antioxidants are not effective in slowing hepatic senescence, and do not clearly improve liver repopulation after hepatectomy or transplant in humans. Future Directions: Further investigations are needed to define mutual redox-dependent molecular pathways involved both in aging and in the decline of liver regeneration. Preclinical studies aimed at the characterization of these pathways would define possible therapeutic targets for human trials. Antioxid. Redox Signal. 35, 832-847.
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Affiliation(s)
- Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Vendemiale
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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13
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Case Study 11: Considerations for Enzyme Mapping Experiments-Interaction Between the Aldehyde Oxidase Inhibitor Hydralazine and Glutathione. Methods Mol Biol 2021. [PMID: 34272718 DOI: 10.1007/978-1-0716-1554-6_30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
Often it may be convenient and efficient to address multiple research questions with a single experiment. In many instances, however, the best approach is to design the experiment to address one question at a time. The design of enzyme mapping experiments is discussed in this chapter, focusing on considerations pertinent to the study of aldehyde oxidase (AO) vs. cytochrome P450 metabolism. Specifically, a case is presented in which reduced glutathione (GSH) was included in an experiment with human liver S9 fraction to trap reactive metabolites generated from cytochrome P450-mediated metabolism of lapatinib and its O-dealkylated metabolite, M1 (question 1). The AO inhibitor hydralazine was included in this experiment to investigate the involvement of AO-mediated metabolism of M1 (question 2). The presence of GSH was found to interfere with the inhibitory activity of hydralazine. Consideration of the time-dependent nature of hydralazine inhibitory activity toward AO when designing this experiment could have predicted the potential for GSH to interfere with hydralazine. This case underscores the importance of clearly identifying the research question, tailoring the experimental protocol to answer that question, and then meticulously considering how the experimental conditions could influence the results, particularly if attempting to address multiple questions with a single experiment.
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Tan W, Zhang Q, Wang J, Yi M, He H, Xu B. Enzymatic Assemblies of Thiophosphopeptides Instantly Target Golgi Apparatus and Selectively Kill Cancer Cells*. Angew Chem Int Ed Engl 2021; 60:12796-12801. [PMID: 33783926 PMCID: PMC8159897 DOI: 10.1002/anie.202102601] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/19/2021] [Indexed: 01/01/2023]
Abstract
Changing an oxygen atom of the phosphoester bond in phosphopeptides by a sulfur atom enables instantly targeting Golgi apparatus (GA) and selectively killing cancer cells by enzymatic self-assembly. Specifically, conjugating cysteamine S-phosphate to the C-terminal of a self-assembling peptide generates a thiophosphopeptide. Being a substrate of alkaline phosphatase (ALP), the thiophosphopeptide undergoes rapid ALP-catalyzed dephosphorylation to form a thiopeptide that self-assembles. The thiophosphopeptide enters cells via caveolin-mediated endocytosis and macropinocytosis and instantly accumulates in GA because of dephosphorylation and formation of disulfide bonds in Golgi by themselves and with Golgi proteins. Moreover, the thiophosphopeptide potently and selectively inhibits cancer cells (HeLa) with the IC50 (about 3 μM), which is an order of magnitude more potent than that of the parent phosphopeptide.
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Affiliation(s)
- Weiyi Tan
- Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA, 02453, USA
| | - Qiuxin Zhang
- Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA, 02453, USA
| | - Jiaqing Wang
- Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA, 02453, USA
| | - Meihui Yi
- Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA, 02453, USA
| | - Hongjian He
- Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA, 02453, USA
| | - Bing Xu
- Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA, 02453, USA
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15
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Tan W, Zhang Q, Wang J, Yi M, He H, Xu B. Enzymatic Assemblies of Thiophosphopeptides Instantly Target Golgi Apparatus and Selectively Kill Cancer Cells**. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202102601] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Weiyi Tan
- Department of Chemistry Brandeis University 415 South Street Waltham MA 02453 USA
| | - Qiuxin Zhang
- Department of Chemistry Brandeis University 415 South Street Waltham MA 02453 USA
| | - Jiaqing Wang
- Department of Chemistry Brandeis University 415 South Street Waltham MA 02453 USA
| | - Meihui Yi
- Department of Chemistry Brandeis University 415 South Street Waltham MA 02453 USA
| | - Hongjian He
- Department of Chemistry Brandeis University 415 South Street Waltham MA 02453 USA
| | - Bing Xu
- Department of Chemistry Brandeis University 415 South Street Waltham MA 02453 USA
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Szabo L, Molnar R, Tomesz A, Deutsch A, Darago R, Nowrasteh G, Varjas T, Nemeth B, Budan F, Kiss I. The effects of flavonoids, green tea polyphenols and coffee on DMBA induced LINE-1 DNA hypomethylation. PLoS One 2021; 16:e0250157. [PMID: 33878138 PMCID: PMC8057585 DOI: 10.1371/journal.pone.0250157] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/31/2021] [Indexed: 12/22/2022] Open
Abstract
The intake of carcinogenic and chemopreventive compounds are important nutritional factors related to the development of malignant tumorous diseases. Repetitive long interspersed element-1 (LINE-1) DNA methylation pattern plays a key role in both carcinogenesis and chemoprevention. In our present in vivo animal model, we examined LINE-1 DNA methylation pattern as potential biomarker in the liver, spleen and kidney of mice consuming green tea (Camellia sinensis) extract (catechins 80%), a chinese bayberry (Morella rubra) extract (myricetin 80%), a flavonoid extract (with added resveratrol) and coffee (Coffee arabica) extract. In the organs examined, carcinogen 7,12-dimethylbenz(a)anthracene (DMBA)-induced hypomethylation was prevented by all test materials except chinese bayberry extract in the kidneys. Moreover, the flavonoid extract caused significant hypermethylation in the liver compared to untreated controls and to other test materials. The tested chemopreventive substances have antioxidant, anti-inflammatory properties and regulate molecular biological signaling pathways. They increase glutathione levels, induce antioxidant enzymes, which decrease free radical damage caused by DMBA, and ultimately, they are able to increase the activity of DNA methyltransferase enzymes. Furthermore, flavonoids in the liver may inhibit the procarcinogen to carcinogen activation of DMBA through the inhibition of CYP1A1 enzyme. At the same time, paradoxically, myricetin can act as a prooxidant as a result of free radical damage, which can explain that it did not prevent hypomethylation in the kidneys. Our results demonstrated that LINE-1 DNA methylation pattern is a useful potential biomarker for detecting and monitoring carcinogenic and chemopreventive effects of dietary compounds.
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Affiliation(s)
- Laszlo Szabo
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Richard Molnar
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Andras Tomesz
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Arpad Deutsch
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Richard Darago
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | | | - Timea Varjas
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Balazs Nemeth
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Ferenc Budan
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
- Institute of Physiology, Medical School, University of Pécs, Pécs, Hungary
- Institute of Environmental Engineering, Faculty of Engineering, University of Pannonia, Veszprém, Hungary
- Szentagothai Research Centre, University of Pécs, Pécs, Hungary
| | - Istvan Kiss
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
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17
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Atli G. How metals directly affect the antioxidant status in the liver and kidney of Oreochromis niloticus? An in vitro study. J Trace Elem Med Biol 2020; 62:126567. [PMID: 32505902 DOI: 10.1016/j.jtemb.2020.126567] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 05/19/2020] [Accepted: 05/22/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Metals can disturb the integrity of physiological and biochemical mechanisms in fish. Thus components of defense as an antioxidant system are significant biomarkers due to their vital role in coping with metal stress. The aim of the current study is to investigate the direct effects of Cd, Cu, and Zn sublethal exposures (in vitro) on the antioxidant system parameters in the liver and kidney of Nile tilapia. METHODS The antioxidant enzyme activities and GSH levels were analyzed after in vitro sublethal metal (200 and 400 μg/L Cd, Cu, and Zn) treatments of Oreochromis niloticus liver and kidney supernatants. RESULTS Metals even at lower levels caused significant changes in the levels of antioxidant system parameters due to concentration, metal, and tissue type. GSH metabolism parameters were more responsive to the metal effect. TBARS levels and GPX activity were mostly increased while CAT, SOD, rGSH, and GSH/GSSG levels decreased. The kidney was more affected than the liver in vitro conditions. Cu was more effective in the liver whereas it was Zn for the kidney. Cd caused negative correlations among the antioxidant enzymes. Significant correlations were found between enzymes and GSH levels upon Zn and Cu exposures. CONCLUSIONS Direct metal effects may trigger different response trends due to their nature and tissue differences. The current data provide a knowledge about which antioxidant biomarkers can define better the oxidative stress caused by direct metal effect for further studies including in vivo experiments.
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Affiliation(s)
- Gülüzar Atli
- Biotechnology Center, Cukurova University, Adana, Turkey; Vocational School of Imamoğlu, Cukurova University, Adana, Turkey.
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Krupenko NI, Sharma J, Pediaditakis P, Helke KL, Hall MS, Du X, Sumner S, Krupenko SA. Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder. Hum Genomics 2020; 14:41. [PMID: 33168096 PMCID: PMC7654619 DOI: 10.1186/s40246-020-00291-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 10/14/2020] [Indexed: 12/29/2022] Open
Abstract
Background Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 simultaneously producing NADPH. We have recently reported that the lack of the enzyme due to compound heterozygous mutations was associated with neuro-ichthyotic syndrome in a male patient. Here, we address the role of ALDH1L2 in cellular metabolism and highlight the mechanism by which the enzyme regulates lipid oxidation. Methods We generated Aldh1l2 knockout (KO) mouse model, characterized its phenotype, tissue histology, and levels of reduced folate pools and applied untargeted metabolomics to determine metabolic changes in the liver, pancreas, and plasma caused by the enzyme loss. We have also used NanoString Mouse Inflammation V2 Code Set to analyze inflammatory gene expression and evaluate the role of ALDH1L2 in the regulation of inflammatory pathways. Results Both male and female Aldh1l2 KO mice were viable and did not show an apparent phenotype. However, H&E and Oil Red O staining revealed the accumulation of lipid vesicles localized between the central veins and portal triads in the liver of Aldh1l2-/- male mice indicating abnormal lipid metabolism. The metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Specifically, drastically increased plasma acylcarnitine and acylglycine conjugates were indicative of impaired β-oxidation in the liver. Our metabolomics data further showed that mechanistically, the regulation of lipid metabolism by ALDH1L2 is linked to coenzyme A biosynthesis through the following steps. ALDH1L2 enables sufficient NADPH production in mitochondria to maintain high levels of glutathione, which in turn is required to support high levels of cysteine, the coenzyme A precursor. As the final outcome, the deregulation of lipid metabolism due to ALDH1L2 loss led to decreased ATP levels in mitochondria. Conclusions The ALDH1L2 function is important for CoA-dependent pathways including β-oxidation, TCA cycle, and bile acid biosynthesis. The role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous diseases. On a broader scale, our study links folate metabolism to the regulation of lipid homeostasis and the energy balance in the cell. Supplementary Information The online version contains supplementary material available at 10.1186/s40246-020-00291-3.
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Affiliation(s)
- Natalia I Krupenko
- Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA.,Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA
| | - Jaspreet Sharma
- Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA
| | - Peter Pediaditakis
- Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA
| | - Kristi L Helke
- Department of Comparative Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Madeline S Hall
- Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA
| | - Xiuxia Du
- Department of Bioinformatics & Genomics, UNC Charlotte, Charlotte, NC, USA
| | - Susan Sumner
- Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA.,Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA
| | - Sergey A Krupenko
- Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA. .,Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
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19
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Castro FLS, Tompkins YH, Pazdro R, Kim WK. The effects of total sulfur amino acids on the intestinal health status of broilers challenged with Eimeria spp. Poult Sci 2020; 99:5027-5036. [PMID: 32988539 PMCID: PMC7598302 DOI: 10.1016/j.psj.2020.06.055] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/14/2020] [Accepted: 06/17/2020] [Indexed: 11/18/2022] Open
Abstract
This study evaluated the effects of total sulfur amino acid (TSAA) levels on the performance and intestinal health of broilers challenged with Eimeria spp. A total of 432 one-day-old off-sex Cobb 500 male chicks were randomly assigned to a 3 × 2 factorial arrangement (6 replicates/12 birds), with diets and Eimeria challenge as the main factors. The diets were as follows: 70% (no methionine [Met] supplementation), 85, and 100% TSAA, supplemented with L-Met. At day 14, the challenged birds (n = 216) were orally gavaged with a pool of Eimeria acervulina, Eimeria maxima, and Eimeria tenella sporulated oocysts, and the unchallenged birds (n = 216) received water. At 6 and 12 D post inoculation (dpi), performance and intestinal health were evaluated. The challenge, regardless of diets, significantly impaired the performance, intestinal villi height, villus-to-crypt ratio, and ileal digestibility of dry matter, energy, and crude protein (CP) and modulated the tight junction protein (TJP) expression throughout the experiment. Moreover, the superoxide dismutase activity was increased, whereas the reduced glutathione (GSH)-to-oxidized glutathione (GSSG) ratio was decreased by the challenge at 6 dpi. Regardless of the challenge, the 70% TSAA diet reduced the body weight and feed intake in all phases, whereas the ileal digestibility of CP was higher in birds fed with the 70% TSAA diet than in those fed with the 100% TSAA diet at 6 dpi. No major differences were observed among the diets with regard to the intestinal histomorphology and TJP expression, and birds fed with the 100% TSAA diet had the highest GSH concentration at 12 dpi. Few interactions were observed, and the Met supplementation counteracted the negative effects of the Eimeria challenge on GSH concentration when 85 and 100% of TSAA levels were reached. Overall, the Eimeria challenge had a negative impact on growth and intestinal health. Moreover, the supplementation of L-Met until either 85 or 100% of TSAA levels were reached was enough to assure good performance and intestinal health in birds challenged or not challenged with Eimeria spp.
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Affiliation(s)
- F L S Castro
- Department of Poultry Science, University of Georgia, Athens, GA 30602, USA
| | - Y H Tompkins
- Department of Poultry Science, University of Georgia, Athens, GA 30602, USA
| | - R Pazdro
- Department of Foods and Nutrition, University of Georgia (UGA), Athens, GA, USA
| | - W K Kim
- Department of Poultry Science, University of Georgia, Athens, GA 30602, USA.
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20
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Phenolic profile of bayberry followed by simulated gastrointestinal digestion and gut microbiota fermentation and its antioxidant potential in HepG2 cells. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.103987] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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21
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Daga M, de Graaf IAM, Argenziano M, Barranco ASM, Loeck M, Al-Adwi Y, Cucci MA, Caldera F, Trotta F, Barrera G, Casini A, Cavalli R, Pizzimenti S. Glutathione-responsive cyclodextrin-nanosponges as drug delivery systems for doxorubicin: Evaluation of toxicity and transport mechanisms in the liver. Toxicol In Vitro 2020; 65:104800. [PMID: 32084521 DOI: 10.1016/j.tiv.2020.104800] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 01/27/2020] [Accepted: 02/15/2020] [Indexed: 12/12/2022]
Abstract
The potential mammalian hepatotoxicity of a new class of GSH-responsive cyclodextrin-based nanosponges loaded with the anticancer drug doxorubicin (Dox-GSH-NS) was investigated. Previous studies showed that these nanosponges can release medicaments preferentially in cells having high GSH content, a common feature of chemoresistant cells, and showed enhanced anti-tumoral activity compared to free Dox in vitro and in vivo in cells with high GSH content. Following these promising results, we investigated here the Dox-GSH-NS hepatotoxicity in human HepG2 cells (in vitro) and in the organotypic cultures of rat precision-cut liver slices (PCLS, ex vivo), while their accumulation in rat liver was assessed in vivo. Moreover, the transport in Dox uptake, as well as its efflux, was studied in vitro. Overall, benefiting of the integration of different investigational models, a good safety profile of Dox-GSH-NSs was evidenced, and their hepatotoxicity resulted to be comparable with respect to free Dox both in vitro and ex vivo. Furthermore, in vivo studies showed that the hepatic accumulation of the Dox loaded in the NS is comparable with respect to the free drug. In addition, Dox-GSH-NSs are taken up by active mechanisms, and can escape the efflux drug pump, thus, contributing to overcoming drug resistance.
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Affiliation(s)
- Martina Daga
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Inge A M de Graaf
- Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Monica Argenziano
- Department of Drug Science and Technology, University of Turin, Turin, Italy
| | | | - Maximillian Loeck
- Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Yehya Al-Adwi
- Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Marie Angele Cucci
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | | | | | - Giuseppina Barrera
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Angela Casini
- Department of Chemistry, Technical University of Munich (TUM), Garching b. München, Germany.
| | - Roberta Cavalli
- Department of Drug Science and Technology, University of Turin, Turin, Italy.
| | - Stefania Pizzimenti
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
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22
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Wang Z, Gao S, Xie J, Li R. Identification of multiple dysregulated metabolic pathways by GC-MS-based profiling of liver tissue in mice with OVA-induced asthma exposed to PM 2.5. CHEMOSPHERE 2019; 234:277-286. [PMID: 31220661 DOI: 10.1016/j.chemosphere.2019.06.063] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 06/04/2019] [Accepted: 06/09/2019] [Indexed: 06/09/2023]
Abstract
Particulate matter (PM) exposure increases the risk of asthma. However, the effect of PM2.5 exposure on liver metabolism in mice with asthma symptoms remains unclear. We established an ovalbumin (OVA)-induced asthma model in mice and divided the animals into four groups: control group (C), PM2.5 exposure group (P), OVA-induced asthma group (O) and OVA-induced asthma PM2.5 exposure group (OP). Gas chromatography-mass spectrometry (GC-MS) was used to identify the metabolite markers and related perturbed metabolic pathways in mouse liver tissue after PM2.5 exposure. Multivariate analysis showed 9 and 12 potential metabolite markers in the P and OP groups, respectively, after PM2.5 exposure that were significantly correlated with lipid peroxidation indices. PM2.5 exposure perturbed 5 and 7 metabolic pathways in the P and OP groups, respectively. These metabolic pathways mainly involve the lipid metabolism, amino acid metabolism, carbohydrate metabolism, and nucleotide metabolism. These results highlight the potential to study PM2.5-triggered alterations via liver tissue in normal and OVA-induced asthmatic mice to gain a more realistic appraisal of the resulting early toxicity events. Additionally, these results revealed potential metabolite markers of early antioxidant defense events triggered by PM2.5 and indicated that metabolite markers are more sensitive than antioxidant indicators.
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Affiliation(s)
- Zhentao Wang
- College of Environment and Resource, Shanxi University, Taiyuan, 030006, PR China
| | - Shaolong Gao
- State Environmental Protection Key Laboratory on Efficient Resource-utilization Techniques of Coal Waste, Institute of Resources and Environment Engineering, Shanxi University, Taiyuan, 030006, PR China
| | - Jingfang Xie
- College of Environment and Resource, Shanxi University, Taiyuan, 030006, PR China.
| | - Ruijin Li
- Institute of Environmental Science, Shanxi University, Taiyuan, 030006, PR China
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da Silva Caetano CC, Camini FC, Almeida LT, Ferraz AC, da Silva TF, Lima RLS, de Freitas Carvalho MM, de Freitas Castro T, Carneiro CM, de Mello Silva B, de Queiroz Silva S, de Magalhães JC, de Brito Magalhães CL. Mayaro Virus Induction of Oxidative Stress is Associated With Liver Pathology in a Non-Lethal Mouse Model. Sci Rep 2019; 9:15289. [PMID: 31653913 PMCID: PMC6814867 DOI: 10.1038/s41598-019-51713-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 10/01/2019] [Indexed: 02/01/2023] Open
Abstract
Mayaro virus (MAYV) causes Mayaro fever in humans, a self-limiting acute disease, with persistent arthralgia and arthritis. Although MAYV has a remerging potential, its pathogenic mechanisms remain unclear. Here, we characterized a model of MAYV infection in 3-4-week BALB/c mice. We investigated whether the liver acts as a site of viral replication and if the infection could cause histopathological alterations and an imbalance in redox homeostasis, culminating with oxidative stress. MAYV-infected mice revealed lower weight gain; however, the disease was self-resolving. High virus titre, neutralizing antibodies, and increased levels of aspartate and alanine aminotransferases were detected in the serum. Infectious viral particles were recovered in the liver of infected animals and the histological examination of liver tissues revealed significant increase in the inflammatory infiltrate. MAYV induced significant oxidative stress in the liver of infected animals, as well as a deregulation of enzymatic antioxidant components. Collectively, this is the first study to report that oxidative stress occurs in MAYV infection in vivo, and that it may be crucial in virus pathogenesis. Future studies are warranted to address the alternative therapeutic strategies for Mayaro fever, such as those based on antioxidant compounds.
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Affiliation(s)
- Camila Carla da Silva Caetano
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Fernanda Caetano Camini
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Letícia Trindade Almeida
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Ariane Coelho Ferraz
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Tales Fernando da Silva
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | | | - Mayara Medeiros de Freitas Carvalho
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Thalles de Freitas Castro
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Cláudia Martins Carneiro
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
- Clinical Analysis Departament, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
- Postgraduate Program of Biotechnology, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Breno de Mello Silva
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
- Biological Science Departament, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
- Postgraduate Program of Biotechnology, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Silvana de Queiroz Silva
- Biological Science Departament, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
- Postgraduate Program of Biotechnology, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - José Carlos de Magalhães
- Department of Chemistry, Biotechnology and Bioprocess Engineering, Universidade Federal de São João del-Rei, Ouro Branco, Minas Gerais, Brazil
| | - Cintia Lopes de Brito Magalhães
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
- Biological Science Departament, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
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Batoryna M, Semla-Kurzawa M, Zyśk B, Bojarski B, Formicki G. Acrylamide-induced alterations in lungs of mice in relation to oxidative stress indicators. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART. B, PESTICIDES, FOOD CONTAMINANTS, AND AGRICULTURAL WASTES 2019; 54:745-751. [PMID: 31264935 DOI: 10.1080/03601234.2019.1634418] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
The aim of the experiment was to study the influence of acrylamide (ACR) on major antioxidants in the lungs of Swiss mice. The experiment was conducted on male mice that were 8 weeks old. The mice were exposed to ACR at a single dose of 26 µg per animal, which was administered orally. Mice were anesthetized 3, 24, and 48 h after the ACR gavage. Next, histopathological and biochemical analyses of GSH concentration and the activities of SOD, GPx, and CAT were performed in the lungs. Animals exposed to ACR showed demonstrated symptoms of inflammation in lungs, hypertrophy of bronchiolar epithelium, and hyperplasia of alveolar epithelium. GSH concentration was significantly decreased 3 h after ACR gavage, which was followed by a significant increase 48 h after ACR gavage. Similarly, SOD and GPx demonstrated decreased activities 3 h after exposure to ACR, followed by increased activities 48 h after exposure to ACR. CAT activity was significantly increased 24 and 48 h after exposure to ACR. We conclude that oral exposure of mice to ACR results in alterations of lung microstructure, accompanied by the symptoms of redox imbalance.
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Affiliation(s)
- Marta Batoryna
- Department of Animal Physiology and Toxicology, Institute of Biology, Faculty of Geography and Biology, Pedagogical University of Cracow , Krakow , Poland
| | - Magdalena Semla-Kurzawa
- Department of Animal Physiology and Toxicology, Institute of Biology, Faculty of Geography and Biology, Pedagogical University of Cracow , Krakow , Poland
| | - Bartłomiej Zyśk
- Department of Vertebrate Zoology and Human Biology, Institute of Biology, Faculty of Geography and Biology, Pedagogical University of Cracow , Krakow , Poland
| | - Bartosz Bojarski
- Department of Veterinary Science, Animal Reproduction and Welfare, Institute of Veterinary Sciences, Faculty of Animal Sciences, University of Agriculture in Krakow , Krakow , Poland
| | - Grzegorz Formicki
- Department of Animal Physiology and Toxicology, Institute of Biology, Faculty of Geography and Biology, Pedagogical University of Cracow , Krakow , Poland
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DNA polymerase-γ hypothesis in nucleoside reverse transcriptase-induced mitochondrial toxicity revisited: A potentially protective role for citrus fruit-derived naringenin? Eur J Pharmacol 2019; 852:159-166. [PMID: 30876974 DOI: 10.1016/j.ejphar.2019.03.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 03/11/2019] [Accepted: 03/11/2019] [Indexed: 12/23/2022]
Abstract
Nucleoside reverse transcriptase inhibitors (NRTIs) form the backbone in combination antiretroviral therapy (cARVs). They halt chain elongation of the viral cDNA by acting as false substrates in counterfeit incorporation mechanism to viral RNA-dependent DNA polymerase. In the process genomic DNA polymerase as well as mitochondrial DNA (mtDNA) polymerase-γ (which has a much higher affinity for these drugs at therapeutic doses) are also impaired. This leads to mitochondrial toxicity that manifests clinically as mitochondrial myopathy, peripheral neuropathy, hyperlactatemia or lactic acidosis and lipoatrophy. This has led to the revision of clinical guidelines by World Health Organization to remove stavudine from first-line listing in the treatment of HIV infections. Recent reports have implicated oxidative stress besides mtDNA polymerase-γ hypothesis in NRTI-induced metabolic complications. Reduced plasma antioxidant concentrations have been reported in HIV positive patients on cARVs but clinical intervention with antioxidant supplements have not been successful either due to low efficacy or poor experimental designs. Citrus fruit-derived naringenin has previously been demonstrated to possess antioxidant and free radical scavenging properties which could prevent mitochondrial toxicity associated with these drugs. This review revisits the controversy surrounding mtDNA polymerase-γ hypothesis and evaluates the potential benefits of naringenin as a potent anti-oxidant and free radical scavenger which as a nutritional supplement or therapeutic adjunct could mitigate the development of mitochondrial toxicity associated with these drugs.
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Lai CY, Cheng SB, Lee TY, Liu HT, Huang SC, Huang YC. Possible Synergistic Effects of Glutathione and C-Reactive Protein in the Progression of Liver Cirrhosis. Nutrients 2018; 10:E678. [PMID: 29861471 PMCID: PMC6024608 DOI: 10.3390/nu10060678] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 04/28/2018] [Accepted: 05/24/2018] [Indexed: 02/07/2023] Open
Abstract
Liver cirrhosis is often associated with increased inflammatory responses and changes of glutathione (GSH) status. The possible interactions between these two factors in mediating damages of liver function remain unclear. Here, we measured the inflammatory responses and GSH status in liver cirrhotic patients and compared them with healthy subjects. In addition, we assessed the relationship of the GSH status and levels of inflammatory markers with the severity of the disease. This was a cross-sectional study. In total, we recruited 63 liver cirrhotic patients with Child⁻Turcotte⁻Pugh class A scores, and 12 patients with class B⁻C scores, together with 110 healthy subjects. Patients with class B⁻C scores showed the highest level of high-sensitivity C-reactive protein (hs-CRP) when compared with class A patients or healthy subjects. Patients in class A group had significantly higher GSH levels when compared with class B⁻C group or healthy subjects. After adjusting for potential confounders and each other, serum hs-CRP levels showed positive association with the Child⁻Turcotte⁻Pugh scores, while GSH levels showed negative association with Child⁻Turcotte⁻Pugh scores. Interactions were found between levels of plasma GSH and serum hs-CRP (β = 0.004, p = 0.016). CRP and GSH levels, which had showed interactions, were associated with the severity of liver cirrhosis.
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Affiliation(s)
- Chia-Yu Lai
- Division of General Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
- Graduate Program in Nutrition, Chung Shan Medical University, Taichung 40201, Taiwan.
| | - Shao-Bin Cheng
- Division of General Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
| | - Teng-Yu Lee
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
- Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
| | - Hsiao-Tien Liu
- Division of General Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
| | - Shih-Chien Huang
- Department of Nutrition, Chung Shan Medical University, Taichung 40201, Taiwan.
- Department of Nutrition, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
| | - Yi-Chia Huang
- Department of Nutrition, Chung Shan Medical University, Taichung 40201, Taiwan.
- Department of Nutrition, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
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Hernández-Aquino E, Muriel P. Beneficial effects of naringenin in liver diseases: Molecular mechanisms. World J Gastroenterol 2018; 24:1679-1707. [PMID: 29713125 PMCID: PMC5922990 DOI: 10.3748/wjg.v24.i16.1679] [Citation(s) in RCA: 224] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/04/2018] [Accepted: 04/15/2018] [Indexed: 02/06/2023] Open
Abstract
Liver diseases are caused by different etiological agents, mainly alcohol consumption, viruses, drug intoxication or malnutrition. Frequently, liver diseases are initiated by oxidative stress and inflammation that lead to the excessive production of extracellular matrix (ECM), followed by a progression to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). It has been reported that some natural products display hepatoprotective properties. Naringenin is a flavonoid with antioxidant, antifibrogenic, anti-inflammatory and anticancer properties that is capable of preventing liver damage caused by different agents. The main protective effects of naringenin in liver diseases are the inhibition of oxidative stress, transforming growth factor (TGF-β) pathway and the prevention of the transdifferentiation of hepatic stellate cells (HSC), leading to decreased collagen synthesis. Other effects include the inhibition of the mitogen activated protein kinase (MAPK), toll-like receptor (TLR) and TGF-β non-canonical pathways, the inhibition of which further results in a strong reduction in ECM synthesis and deposition. In addition, naringenin has shown beneficial effects on nonalcoholic fatty liver disease (NAFLD) through the regulation of lipid metabolism, modulating the synthesis and oxidation of lipids and cholesterol. Moreover, naringenin protects from HCC, since it inhibits growth factors such as TGF-β and vascular endothelial growth factor (VEGF), inducing apoptosis and regulating MAPK pathways. Naringenin is safe and acts by targeting multiple proteins. However, it possesses low bioavailability and high intestinal metabolism. In this regard, formulations, such as nanoparticles or liposomes, have been developed to improve naringenin bioavailability. We conclude that naringenin should be considered in the future as an important candidate in the treatment of different liver diseases.
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Affiliation(s)
- Erika Hernández-Aquino
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 07000, Mexico
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 07000, Mexico
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Wang F, Zhou RJ, Zhao X, Ye H, Xie ML. Apigenin inhibits ethanol-induced oxidative stress and LPS-induced inflammatory cytokine production in cultured rat hepatocytes. J Appl Biomed 2018. [DOI: 10.1016/j.jab.2017.11.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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Noh S, Sung J, Lee H, Jeong HS, Kim IH, Lee J. Protective Effects of Methanol Extract of Perilla Seed Meal against Oxidative Stress in HepG2 Cells. FOOD SCIENCE AND TECHNOLOGY RESEARCH 2018. [DOI: 10.3136/fstr.24.583] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Seungwoo Noh
- Division of Food and Animal Sciences, Chungbuk National University
| | - Jeehye Sung
- Department of Food Science and Human Nutrition, Citrus Research and Education Center, University of Florida
| | - Hana Lee
- Division of Food and Animal Sciences, Chungbuk National University
| | - Heon Sang Jeong
- Division of Food and Animal Sciences, Chungbuk National University
| | - In-Hwan Kim
- Department of Public Health Sciences, Graduate School, Korea University
| | - Junsoo Lee
- Division of Food and Animal Sciences, Chungbuk National University
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Batoryna M, Lis MW, Formicki G. Antioxidant defence in the brain of 1-d-old chickens exposed in ovo to acrylamide. Br Poult Sci 2017; 59:198-204. [PMID: 29228782 DOI: 10.1080/00071668.2017.1415427] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
1. Acrylamide (ACR) is a potent neurotoxicant, although information on its toxic influence on the developing neural system is still limited. The effects of in-ovo-injected ACR on the antioxidant system activity in the brain of newly hatched chickens was examined. This model eliminated the mother's contribution to embryonic development. It was also recognised as an adequate model for animal embryonic development. 2. ACR was injected on d 4 of embryogenesis - in doses of 1.25 and 2.50 mg/egg (n = 40 eggs/group/120 eggs). The doses corresponded well with ACR doses used in other animal studies and their concentrations in certain animal feeds. 3. Mortality and incidences of malformations were not found to increase significantly. Significant depletion of glutathione was detected in the cerebellum, cerebrum and medulla oblongata of specimens exposed to the highest doses of ACR. Enzymatic activity was affected by the highest ACR doses. Glutathione peroxidase (GPx) activity increased significantly in the cerebrum, medulla oblongata and the hypothalamus. Superoxide dismutase (SOD) activity increased significantly in hypothalamus and decreased in cerebellum and cerebrum. A significant depletion of catalase (CAT) activity was detected in cerebellum. In the hypothalamus, the increased SOD/GPx and SOD/CAT ratios suggest the risk of H2O2. 4. It was concluded that ACR significantly influences the antioxidative defence in the chicken brain at doses of 1.25 and 2.50 mg/egg.
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Affiliation(s)
- M Batoryna
- a Department of Animal Physiology and Toxicology, Institute of Biology, Faculty of Geography and Biology , Pedagogical University of Cracow , Kraków , Poland
| | - M W Lis
- b Department of Veterinary, Animal Reproduction and Welfare, Institute of Veterinary Science , Agricultural University in Krakow , Kraków , Poland
| | - G Formicki
- a Department of Animal Physiology and Toxicology, Institute of Biology, Faculty of Geography and Biology , Pedagogical University of Cracow , Kraków , Poland
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Xu J, Zhang W, Lu Z, Zhang F, Ding W. Airborne PM 2.5-Induced Hepatic Insulin Resistance by Nrf2/JNK-Mediated Signaling Pathway. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2017; 14:ijerph14070787. [PMID: 28708100 PMCID: PMC5551225 DOI: 10.3390/ijerph14070787] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 07/07/2017] [Accepted: 07/10/2017] [Indexed: 12/20/2022]
Abstract
Animal and epidemiological studies have suggested that exposure to airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM2.5) is associated with the risk of developing type 2 diabetes. However, the mechanism underlying this risk is poorly understood. In the present study, we investigated the effects of PM2.5 exposure on glucose homeostasis and related signaling pathways in mice. Wild-type and nuclear factor erythroid 2-related factor 2 (Nrf2) knockout (Nrf2−/−) C57BL/6 male mice were exposed to either ambient concentrated PM2.5 or filtered air (FA) for 12 weeks through a whole-body PM exposure system. At the end of the exposure, we assessed liver damage, and performed metabolic studies, gene expressions, as well as molecular signal transductions to determine the signaling pathways involving oxidative responses, insulin signaling, and glucose metabolism. Our results indicated that PM2.5 exposure for 12 weeks caused significant liver damage as evidenced by elevated levels of aminotransferase (AST) and alanine aminotransferase (ALT). Furthermore, PM2.5 exposure induced impaired glucose tolerance and inhibited glycogen synthesis, leading to hepatic insulin resistance indicated by higher glucose levels, higher area under the curve (AUC), and homeostasis model assessment of insulin resistance (HOMA-IR) values. We further found that PM2.5 exposure significantly increased the expressions of Nrf2 and Nrf2-regulated antioxidant genes. Moreover, PM2.5 exposure activated the c-Jun N-terminal kinase (JNK) signaling pathway and increased insulin receptor substrate-1 (IRS-1) phosphorylation at Ser307, but reduced protein kinase B phosphorylation at Ser473. Taken together, our study demonstrated PM2.5 exposure triggered Nrf2-mediated oxidative responses and activated the JNK-mediated inhibitory signaling pathway, resulting in hepatic insulin resistance.
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Affiliation(s)
- Jinxia Xu
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
- Sino-Danish College, University of Chinese Academy of Sciences, No. 3 Zhongguancun South 1st Alley, Beijing 100190, China.
| | - Wei Zhang
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
| | - Zhongbing Lu
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
| | - Fang Zhang
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
| | - Wenjun Ding
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
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Lai KP, Cheung AHY, Tse WKF. DeubiquitinaseUsp18prevents cellular apoptosis from oxidative stress in liver cells. Cell Biol Int 2017; 41:914-921. [DOI: 10.1002/cbin.10799] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 05/25/2017] [Indexed: 12/26/2022]
Affiliation(s)
- Keng Po Lai
- Department of Biology and Chemistry; City University of Hong Kong; Hong Kong SAR China
| | - Angela Hoi Yan Cheung
- Department of Biology and Chemistry; City University of Hong Kong; Hong Kong SAR China
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Ulla A, Rahman MT, Habib ZF, Rahman MM, Subhan N, Sikder B, Reza HM, Hossain MH, Alam MA. Mango
peel powder supplementation prevents oxidative stress, inflammation, and fibrosis in carbon tetrachloride induced hepatic dysfunction in rats. J Food Biochem 2016. [DOI: 10.1111/jfbc.12344] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Anayt Ulla
- Department of Pharmaceutical Sciences; North South University; Dhaka Bangladesh
| | - Md Tariqur Rahman
- Department of Pharmaceutical Sciences; North South University; Dhaka Bangladesh
| | - Zaki Farhad Habib
- Department of Pharmaceutical Sciences; North South University; Dhaka Bangladesh
| | - Md Moshfequr Rahman
- Department of Pharmaceutical Sciences; North South University; Dhaka Bangladesh
| | - Nusrat Subhan
- Department of Pharmaceutical Sciences; North South University; Dhaka Bangladesh
| | - Biswajit Sikder
- Department of Pharmaceutical Sciences; North South University; Dhaka Bangladesh
| | - Hasan Mahmud Reza
- Department of Pharmaceutical Sciences; North South University; Dhaka Bangladesh
| | - Md Hemayet Hossain
- BCSIR Laboratories Bangladesh Council of Scientific and Industrial Research (BCSIR); Dhaka Bangladesh
| | - Md Ashraful Alam
- Department of Pharmaceutical Sciences; North South University; Dhaka Bangladesh
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Nishida T, Tsuneyama K, Fujimoto M, Nomoto K, Hayashi S, Miwa S, Nakajima T, Nakanishi Y, Hatta H, Imura J. Aberrant iron metabolism might have an impact on progression of diseases in Tsumura Suzuki obese diabetes mice, a model of spontaneous metabolic syndrome. Pathol Int 2016; 66:622-628. [DOI: 10.1111/pin.12466] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 08/31/2016] [Accepted: 09/08/2016] [Indexed: 12/30/2022]
Affiliation(s)
- Takeshi Nishida
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences; University of Toyama; Toyama Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences; Tokushima University Graduate School; Tokushima Japan
| | - Makoto Fujimoto
- Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences; University of Toyama; Toyama Japan
| | - Kazuhiro Nomoto
- Laboratory of Pathology; Kouseiren Takaoka Hospital; Takaoka Japan
| | - Shinichi Hayashi
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences; University of Toyama; Toyama Japan
| | - Shigeharu Miwa
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences; University of Toyama; Toyama Japan
| | - Takahiko Nakajima
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences; University of Toyama; Toyama Japan
| | - Yuko Nakanishi
- Department of Pathology; Toyama Prefectural Central Hospital; Toyama Japan
| | - Hideki Hatta
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences; University of Toyama; Toyama Japan
| | - Johji Imura
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences; University of Toyama; Toyama Japan
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35
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Sevcikova M, Modra H, Blahova J, Dobsikova R, Kalina J, Zitka O, Kizek R, Svobodova Z. Factors Affecting Antioxidant Response in Fish from a Long-term Mercury-Contaminated Reservoir. ARCHIVES OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY 2015; 69:431-439. [PMID: 26276034 DOI: 10.1007/s00244-015-0213-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 08/04/2015] [Indexed: 06/04/2023]
Abstract
The objective of this work was to evaluate antioxidant defence and oxidative damage in organs (liver, gills, kidney, and brain) of five fish species (Aspius aspius, Esox lucius, Sander lucioperca, Abramis brama, Rutilus rutilus) from the long-term mercury-contaminated Skalka Reservoir in the Czech Republic. Special emphasis was placed on a comprehensive assessment of the factors that may affect the antioxidant response to mercury in fish. Antioxidant enzymes (glutathione reductase, glutathione peroxidase, and glutathione-S-transferase) did not significantly respond to mercury contamination. Levels of the analysed enzymes and oxidative damage to lipids were predominantly determined by a separate organ factor or species factor, or by the combination of both (p < 0.001). Levels of total glutathione and the reduced/oxidized glutathione ratio were influenced by mercury contamination in combination with their specific organ distribution (p < 0.001). Our results suggest that species and type of organ alone or in combination are more important factors than chronic exposure to mercury contamination with respect to effects on antioxidant defence in fish under field conditions. Our findings suggest that the main antioxidant defensive mechanism in fish from the studied long-term mercury contaminated site was the inter-tissue distribution of glutathione.
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Affiliation(s)
- M Sevcikova
- Department of Veterinary Public Health and Animal Welfare, Faculty of Veterinary Hygiene and Ecology, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho tr. 1/3, 612 42, Brno, Czech Republic.
| | - H Modra
- Department of Veterinary Public Health and Animal Welfare, Faculty of Veterinary Hygiene and Ecology, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho tr. 1/3, 612 42, Brno, Czech Republic
| | - J Blahova
- Department of Veterinary Public Health and Animal Welfare, Faculty of Veterinary Hygiene and Ecology, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho tr. 1/3, 612 42, Brno, Czech Republic
| | - R Dobsikova
- Department of Veterinary Public Health and Animal Welfare, Faculty of Veterinary Hygiene and Ecology, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho tr. 1/3, 612 42, Brno, Czech Republic
| | - J Kalina
- Institute of Biostatistics and Analyses, Masaryk University, Kamenice 3, 625 000, Brno, Czech Republic
| | - O Zitka
- Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, 613 00, Brno, Czech Republic
| | - R Kizek
- Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, 613 00, Brno, Czech Republic
| | - Z Svobodova
- Department of Veterinary Public Health and Animal Welfare, Faculty of Veterinary Hygiene and Ecology, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho tr. 1/3, 612 42, Brno, Czech Republic
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Jung SB, Shin JH, Kim JY, Kwon O. Shinzami Korean purple-fleshed sweet potato extract prevents ischaemia-reperfusion-induced liver damage in rats. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2015; 95:2818-2823. [PMID: 25428031 DOI: 10.1002/jsfa.7021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Revised: 11/11/2014] [Accepted: 11/21/2014] [Indexed: 06/04/2023]
Abstract
BACKGROUND This study was designed to investigate the hepatoprotective effect of an extract from Shinzami, a variety of purple sweet potato, in rats injured by hepatic ischaemia-reperfusion (I/R). RESULTS Pretreatment with Shinzami extract decreased the aspirate aminotransferase and alanine aminotransferase serum levels in our hepatic I/R rat model. The glutathione level and superoxide dismutase activity level were significantly higher in the rats pretreated with the Shinzami extract compared with the hepatic I/R rats, and the glutathione peroxidase activity level was higher in pretreated rats. The total anthocyanins extracted from Shinzami, however, only increased the superoxide dismutase activity level in the hepatic I/R rats. Rats pretreated with the Shinzami extract or anthocyanins demonstrated attenuated hepatic pathological changes, such as hepatic distortion, haemorrhage, necrosis and inflammatory cell infiltration compared with the hepatic I/R control rats. CONCLUSION Shinzami extract and anthocyanins have a hepatoprotective effect on the liver damage induced by hepatic I/R by improving antioxidant status. Furthermore, the Shinzami extract may have a more potent effect on the antioxidant status compared with the Shinzami anthocyanins alone.
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Affiliation(s)
- Saet-Byeol Jung
- Department of Nutritional Science and Food Management, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Korea
| | - Jae-Ho Shin
- Department of Biomedical Laboratory Science, Eulji University, 553 Sansungdaero Seongnam-si, Kyeonggi-do 461-713, Korea
| | - Ji Yeon Kim
- Department of Food Science and Technology, Seoul National University of Science and Technology, 232, Gongneung-ro, Nowon-gu, Seoul 139-743, Korea
| | - Oran Kwon
- Department of Nutritional Science and Food Management, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Korea
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Shirai M, Matsuoka M, Makino T, Kai K, Teranishi M, Takasaki W. Hepatic glutathione contributes to attenuation of thioacetamide-induced hepatic necrosis due to suppression of oxidative stress in diet-induced obese mice. J Toxicol Sci 2015; 40:509-21. [PMID: 26165648 DOI: 10.2131/jts.40.509] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
We previously reported that hepatic necrosis induced by thioacetamide (TA), a hepatotoxicant, was attenuated in mice fed a high-fat diet (HFD mice) in comparison with mice fed a normal rodent diet (ND mice). In this study, we focused on investigation of the mechanism of the attenuation. Hepatic content of thiobarbituric acid reactive substances (TBARS), an oxidative stress marker, significantly increased in ND mice at 24 and 48 hr after TA administration in comparison to that in vehicle-treated ND mice. At these time points, severe hepatic necrosis was observed in ND mice. Treatment with an established antioxidant, butylated hydroxyanisole, attenuated the TA-induced hepatic necrosis in ND mice. In contrast, in HFD mice, hepatic TBARS content did not increase, and hepatic necrosis was attenuated in comparison with ND mice at 24 and 48 hr after TA dosing. Metabolomics analysis regarding hepatic glutathione, a biological antioxidant, revealed decreased glutathione and changes in the amount of glutathione metabolism-related metabolites, such as increased ophtalmate and decreased cysteine, and this indicated activation of glutathione synthesis and usage in HFD mice. Finally, after treatment with L-buthionine-S,R-sulfoxinine, an inhibitor of glutathione synthesis, TA-induced hepatic necrosis was enhanced and hepatic TBARS contents increased after TA dosing in HFD mice. These results suggested that activated synthesis and usage of hepatic GSH, which suppresses hepatic oxidative stress, is one of the factors that attenuate TA-induced hepatic necrosis in HFD mice.
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Affiliation(s)
- Makoto Shirai
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd
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Bilinsky LM, Reed MC, Nijhout HF. The role of skeletal muscle in liver glutathione metabolism during acetaminophen overdose. J Theor Biol 2015; 376:118-33. [PMID: 25890031 DOI: 10.1016/j.jtbi.2015.04.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Revised: 03/29/2015] [Accepted: 04/06/2015] [Indexed: 01/03/2023]
Abstract
Marked alterations in systemic glutamate-glutamine metabolism characterize the catabolic state, in which there is an increased breakdown and decreased synthesis of skeletal muscle protein. Among these alterations are a greatly increased net release of glutamine (Gln) from skeletal muscle into blood plasma and a dramatic depletion of intramuscular Gln. Understanding the catabolic state is important because a number of pathological conditions with very different etiologies are characterized by its presence; these include major surgery, sepsis, trauma, and some cancers. Acetaminophen (APAP) overdose is also accompanied by dramatic changes in systemic glutamate-glutamine metabolism including large drops in liver glutathione (for which glutamate is a precursor) and plasma Gln. We have constructed a mathematical model of glutamate and glutamine metabolism in rat which includes liver, blood plasma and skeletal muscle. We show that for the normal rat, the model solutions fit experimental data including the diurnal variation in liver glutathione (GSH). We show that for the rat chronically dosed with dexamethasone (an artificial glucocorticoid which induces a catabolic state) the model can be used to explain empirically observed facts such as the linear decline in intramuscular Gln and the drop in plasma glutamine. We show that for the Wistar rat undergoing APAP overdose the model reproduces the experimentally observed rebound of liver GSH to normal levels by the 24-h mark. We show that this rebound is achieved in part by the action of the cystine-glutamate antiporter, an amino acid transporter not normally expressed in liver but induced under conditions of oxidative stress. Finally, we explain why supplementation with Gln, a Glu precursor, assists in the preservation of liver GSH during APAP overdose despite the fact that under normal conditions only Cys is rate-limiting for GSH formation.
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Affiliation(s)
- L M Bilinsky
- Department of Mathematics, Duke University, United States.
| | - M C Reed
- Department of Mathematics, Duke University, United States
| | - H F Nijhout
- Department of Biology, Duke University, United States
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Vitex agnus-castus L. (Verbenaceae) Improves the Liver Lipid Metabolism and Redox State of Ovariectomized Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:212378. [PMID: 25954315 PMCID: PMC4411462 DOI: 10.1155/2015/212378] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Revised: 01/15/2015] [Accepted: 03/20/2015] [Indexed: 01/21/2023]
Abstract
Vitex agnus-castus (VAC) is a plant that has recently been used to treat the symptoms of menopause, by its actions on the central nervous system. However, little is known about its actions on disturbances in lipid metabolism and nonalcoholic fat liver disease (NAFLD), frequently associated with menopause. Ovariectomized (OVX) rats exhibit increased adiposity and NAFLD 13 weeks after ovary removal and were used as animal models of estrogen deficiency. The rats were treated with crude extract (CE) and a butanolic fraction of VAC (ButF) and displayed the beneficial effects of a reduction in the adiposity index and a complete reversion of NAFLD. NAFLD reversion was accompanied by a general improvement in the liver redox status. The activities of some antioxidant enzymes were restored and the mitochondrial hydrogen peroxide production was significantly reduced in animals treated with CE and the ButF. It can be concluded that the CE and ButF from Vitex agnus-castus were effective in preventing NAFLD and oxidative stress, which are frequent causes of abnormal liver functions in the postmenopausal period.
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Eroglu A, Dogan Z, Kanak EG, Atli G, Canli M. Effects of heavy metals (Cd, Cu, Cr, Pb, Zn) on fish glutathione metabolism. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2015; 22:3229-37. [PMID: 24793073 DOI: 10.1007/s11356-014-2972-y] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Accepted: 04/23/2014] [Indexed: 05/15/2023]
Abstract
The glutathione metabolism contains crucial antioxidant molecules to defend the organisms against oxidants. Thus, the aim of this study was to investigate the response of the glutathione metabolism in the liver of freshwater fish Oreochromis niloticus exposed to metals (Cu, Cd, Cr, Pb, Zn) in different periods. Fish were exposed to metals (as 1 μg/mL) individually for 1, 7, and 14 days and subsequently antioxidant enzymes (glutathione peroxidase, GPX; glutathione reductase, GR and glutathione S-transferase, GST) and glutathione levels (total glutathione, tGSH; reduced glutathione, rGSH; oxidized glutathione, GSSG and GSH/GSSG ratios) in the liver were measured. There was no fish mortality during the experiments, except Cu exposure. The antioxidant enzymes responded differently to metal exposures depending on metal types and exposure durations. GPX activity increased only after Cd exposure, while GST activity increased following 7 days of all metal exposures. However, GR activity did not alter in most cases. Total GSH and GSH/GSSG levels generally decreased, especially after 7 days. Data showed that metal exposures significantly altered the response of antioxidant system parameters, particularly at day 7 and some recovery occurred after 14 days. This study suggests that the response of antioxidant system could help to predict metal toxicity in the aquatic environments and be useful as an "early warning tool" in natural monitoring studies.
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Affiliation(s)
- A Eroglu
- Department of Biology, Faculty of Science and Letters, Cukurova University, 01330, Balcali, Adana, Turkey
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Heit C, Dong H, Chen Y, Shah YM, Thompson DC, Vasiliou V. Transgenic mouse models for alcohol metabolism, toxicity, and cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 815:375-87. [PMID: 25427919 PMCID: PMC4323349 DOI: 10.1007/978-3-319-09614-8_22] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Alcohol abuse leads to tissue damage including a variety of cancers; however, the molecular mechanisms by which this damage occurs remain to be fully understood. The primary enzymes involved in ethanol metabolism include alcohol dehydrogenase (ADH), cytochrome P450 isoform 2E1, (CYP2E1), catalase (CAT), and aldehyde dehydrogenases (ALDH). Genetic polymorphisms in human genes encoding these enzymes are associated with increased risks of alcohol-related tissue damage, as well as differences in alcohol consumption and dependence. Oxidative stress resulting from ethanol oxidation is one established pathogenic event in alcohol-induced toxicity. Ethanol metabolism generates free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), and has been associated with diminished glutathione (GSH) levels as well as changes in other antioxidant mechanisms. In addition, the formation of protein and DNA adducts associated with the accumulation of ethanol-derived aldehydes can adversely affect critical biological functions and thereby promote cellular and tissue pathology. Animal models have proven to be valuable tools for investigating mechanisms underlying pathogenesis caused by alcohol. In this review, we provide a brief discussion on several animal models with genetic defects in alcohol-metabolizing enzymes and GSH-synthesizing enzymes and their relevance to alcohol research.
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Affiliation(s)
- Claire Heit
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO, 80045, USA
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Moraes TB, Dalazen GR, Jacques CE, de Freitas RS, Rosa AP, Dutra-Filho CS. Glutathione metabolism enzymes in brain and liver of hyperphenylalaninemic rats and the effect of lipoic acid treatment. Metab Brain Dis 2014; 29:609-15. [PMID: 24488205 DOI: 10.1007/s11011-014-9491-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 01/16/2014] [Indexed: 01/22/2023]
Abstract
Phenylketonuria (PKU) is a disorder caused by a deficiency in phenylalanine hydroxylase activity, which converts phenylalanine (Phe) to tyrosine, leading to hyperphenylalaninemia (HPA) with accumulation of Phe in tissues of patients. The neuropathophysiology mechanism of disease remains unknown. However, recently the involvement of oxidative stress with decreased glutathione levels in PKU has been reported. Intracellular glutathione (GSH) levels may be maintained by the antioxidant action of lipoic acid (LA). The aim of this study was to evaluate the activity of the enzymes involved in the metabolism and function of GSH, such as glutathione peroxidase (GSH-Px), glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GR), glutamate-cysteine ligase (GCL), glutathione-S-transferase (GST) and GSH content in brain and liver of young rats subjected to a chemically induced model of HPA and the effect of LA for a week. In brain, the administration of Phe reduced the activity of the GSH-Px, GR and G6PD and LA prevented these effects totally or partially. GCL activity was increased by HPA and was not affect by LA antioxidant treatment. GST activity did not differ between groups. GSH content was increased by LA and decreased by HPA treatment in brain samples. Considering the liver, all parameters analyzed were increased in studied HPA animals and LA was able to hinder some effects except for the GCL, GST enzymes and GSH content. These results suggested that HPA model alter the metabolism of GSH in rat brain and liver, which may have an important role in the maintenance of GSH function in PKU although liver is not a directly affected organ in this disease. So, an antioxidant therapy with LA may be useful in the treatment of oxidative stress in HPA.
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Affiliation(s)
- Tarsila Barros Moraes
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil,
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Meng SL, Chen JZ, Hu GD, Song C, Fan LM, Qiu LP, Xu P. Effects of chronic exposure of methomyl on the antioxidant system in liver of Nile tilapia (Oreochromis niloticus). ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2014; 101:1-6. [PMID: 24507119 DOI: 10.1016/j.ecoenv.2013.10.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Revised: 10/17/2013] [Accepted: 10/18/2013] [Indexed: 06/03/2023]
Abstract
The chronic effect of methomyl on the antioxidant system in tilapia (Oreochromis niloticus) was investigated. Fish were exposed to sub-lethal concentrations of 0.2, 2, 20 and 200μgL(-1) for 30 days, and then transferred to methomyl-free water for 18 days. Hepatic antioxidant parameters, including Glutathione-S-transferase (GST), Glutathione peroxidase (GPx), Glutathione reductase (GR), Reduced glutathione (GSH) and oxidized glutathione (GSSG), were measured at 10min (day 0), 6, 12, 18, 24 and 30 days after starting the experiment and at 18 days after transferring to methomyl-free water. There were no significant changes in enzymatic activity and content of antioxidants in liver of tilapia exposed to 0.2μgL(-1) methomyl compared to controls. However, the results showed significant increases in activities of GST, GR, GPx and levels of GSSG accompanied by a decrease in GSH levels following methomyl exposure in tilapia to 2, 20 or 200μgL(-1) over the 30-day exposure period and the highest induction rates in GST, GR, GPx and GSSG were 150.87%, 163.21%, 189.76%, and 179.56% of the control respectively, and the highest inhibition rate in GSH was 50.67% of the control, suggesting the presence of oxidative stress. Thus it would appear that the 0.2μgL(-1) methomyl might be considered as the no observed adverse effect level (NOAEL). Recovery data showed that the effects produced by lower concentration of methomyl 20μgL(-1) were reversible but not at the higher 200μgL(-1) concentration.
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Affiliation(s)
- Shun Long Meng
- Wuxi Fishery College, Nanjing Agricultural University, Wuxi 214081, Jiangsu, China; Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences; Scientific Observing and Experimental Station of Fishery Resources and Environment in the Lower Reaches of the Changjiang River, Wuxi 214081, China
| | - Jia Zhang Chen
- Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences; Scientific Observing and Experimental Station of Fishery Resources and Environment in the Lower Reaches of the Changjiang River, Wuxi 214081, China
| | - Geng Dong Hu
- Wuxi Fishery College, Nanjing Agricultural University, Wuxi 214081, Jiangsu, China
| | - Chao Song
- Wuxi Fishery College, Nanjing Agricultural University, Wuxi 214081, Jiangsu, China
| | - Li Min Fan
- Wuxi Fishery College, Nanjing Agricultural University, Wuxi 214081, Jiangsu, China
| | - Li Ping Qiu
- Wuxi Fishery College, Nanjing Agricultural University, Wuxi 214081, Jiangsu, China
| | - Pao Xu
- Wuxi Fishery College, Nanjing Agricultural University, Wuxi 214081, Jiangsu, China; Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences; Scientific Observing and Experimental Station of Fishery Resources and Environment in the Lower Reaches of the Changjiang River, Wuxi 214081, China.
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Glutathione defense mechanism in liver injury: insights from animal models. Food Chem Toxicol 2013; 60:38-44. [PMID: 23856494 DOI: 10.1016/j.fct.2013.07.008] [Citation(s) in RCA: 169] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 07/01/2013] [Accepted: 07/03/2013] [Indexed: 12/11/2022]
Abstract
Glutathione (GSH) is the most abundant cellular thiol antioxidant and it exhibits numerous and versatile functions. Disturbances in GSH homeostasis have been associated with liver diseases induced by drugs, alcohol, diet and environmental pollutants. Until recently, our laboratories and others have developed mouse models with genetic deficiencies in glutamate-cysteine ligase (GCL), the rate-limiting enzyme in the GSH biosynthetic pathway. This review focuses on regulation of GSH homeostasis and, specifically, recent studies that have utilized such GSH-deficient mouse models to investigate the role of GSH in liver disease processes. These studies have revealed a differential hepatic response to distinct profiles of hepatic cellular GSH concentration. In particular, mice engineered to not express the catalytic subunit of GCL in hepatocytes [Gclc(h/h) mice] experience almostcomplete loss of hepatic GSH (to 5% of normal) and develop spontaneous liver pathologies characteristic of various clinical stages of liver injury. In contrast, mice globally engineered to not express the modifier subunit of GCL [Gclm⁻/⁻ mice] show a less severe hepatic GSH deficit (to ≈15% of normal) and exhibit overall protection against liver injuries induced by a variety of hepatic insults. Collectively, these transgenic mouse models provide interesting new insights regarding pathophysiological functions of GSH in the liver.
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Yokozawa T, Chen CP. Evidence suggesting a nitric oxide-scavenging activity for traditional crude drugs, and action mechanisms of Sanguisorbae Radix against oxidative stress and aging. J Am Aging Assoc 2013; 24:19-30. [PMID: 23604872 DOI: 10.1007/s11357-001-0003-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
In this series of experiments, we found that Sanguisorbae Radix extract possesses strong free radical-scavenging activity in vitro and in vivo. This crude drug protected against renal disease, which is closely associated with excessive generation of reactive oxygen species. We also showed that Sanguisorbae Radix extract can suppress lipid peroxidation and stimulate an antioxidant defense ability in SAM, suggesting that this crude drug may be an effective agent for ameliorating the pathological conditions related to excessive generation of free radicals and oxidant damage, particularly in the aging process.
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Affiliation(s)
- T Yokozawa
- Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama, 930-0194 Japan
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Yang J, Wang XY, Xue J, Gu ZL, Xie ML. Protective effect of apigenin on mouse acute liver injury induced by acetaminophen is associated with increment of hepatic glutathione reductase activity. Food Funct 2013; 4:939-43. [DOI: 10.1039/c3fo60071h] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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Chen Y, Krishan M, Nebert DW, Shertzer HG. Glutathione-deficient mice are susceptible to TCDD-Induced hepatocellular toxicity but resistant to steatosis. Chem Res Toxicol 2011; 25:94-100. [PMID: 22082335 DOI: 10.1021/tx200242a] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) generates both hepatocellular injury and steatosis, processes that involve oxidative stress. Herein, we evaluated the role of the antioxidant glutathione (GSH) in TCDD-induced hepatotoxicity. Glutamate-cysteine ligase (GCL), comprising catalytic (GCLC) and modifier (GCLM) subunits, is rate limiting in de novo GSH biosynthesis; GCLM maintains GSH homeostasis by optimizing the catalytic efficiency of GCL holoenzyme. Gclm(-/-) transgenic mice exhibit 10-20% of normal tissue GSH levels. Gclm(-/-) and Gclm(+/+) wild-type (WT) female mice received TCDD for 3 consecutive days and were then examined 21 days later. As compared with WT littermates, Gclm(-/-) mice were more sensitive to TCDD-induced hepatocellular toxicity, exhibiting lower reduction potentials for GSH, lower ATP levels, and elevated levels of plasma glutamic oxaloacetic transaminase (GOT) and γ-glutamyl transferase (GGT). However, the histopathology showed that TCDD-mediated steatosis, which occurs in WT mice, was absent in Gclm(-/-) mice. This finding was consistent with cDNA microarray expression analysis, revealing striking deficiencies in lipid biosynthesis pathways in Gclm(-/-) mice; qrt-PCR analysis confirmed that Gclm(-/-) mice are deficient in expression of several lipid metabolism genes including Srebp2, Elovl6, Fasn, Scd1/2, Ppargc1a, and Ppara. We suggest that whereas GSH protects against TCDD-mediated hepatocellular damage, GSH deficiency confers resistance to TCDD-induced steatosis due to impaired lipid metabolism.
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Affiliation(s)
- Ying Chen
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver , Aurora, Colorado 80045, United States
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Oral N-acetylcysteine rescues lethality of hepatocyte-specific Gclc-knockout mice, providing a model for hepatic cirrhosis. J Hepatol 2010; 53:1085-94. [PMID: 20810184 PMCID: PMC2970663 DOI: 10.1016/j.jhep.2010.05.028] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2009] [Revised: 05/11/2010] [Accepted: 05/25/2010] [Indexed: 01/28/2023]
Abstract
BACKGROUND & AIMS Certain liver diseases have been associated with depletion of glutathione (GSH), the major antioxidant in the liver. A recent report about Gclc(h/h) mice with a hepatocyte-specific ablation of Gclc (the gene encoding the catalytic subunit of the rate-limiting enzyme in GSH synthesis) has shown an essential role of GSH in hepatic function. Gclc(h/h) mice develop severe steatosis and die of liver failure within one month, due to ~95% depletion of hepatic GSH; mitochondria are the major affected organelles, displaying abnormal ultrastructure and impaired functioning. METHODS Gclc(h/h) mice were fed with L-N-acetylcysteine (NAC; 10 g/L) in drinking water, starting at postnatal day 18. RESULTS Gclc(h/h) mice were rescued by use of NAC supplementation, and survived until adulthood. NAC replenished the mitochondrial GSH pool and attenuated mitochondrial damage, with accompanying diminished hepatic steatosis; however, abnormal liver biochemical tests, hepatocyte death, and hepatic oxidative stress persisted in the rescued mice. At 50 days of age, the liver from rescued Gclc(h/h) mice started to display characteristics of fibrosis and at age 120 days, macronodular cirrhosis was observed. Immunohistostaining for liver-specific markers as well as the expression profile of hepatic cytokines indicated that the repopulation of hepatocytes in the cirrhotic nodules involved the expansion of oval cells. CONCLUSIONS Replenishment of mitochondrial GSH and restoration of mitochondrial function by NAC prevents mortality caused by the loss of hepatocyte GSH de novo synthesis, allowing steatosis to progress to a chronic stage. Thus, with NAC supplementation, Gclc(h/h) mice provide a model for the development of liver fibrosis and cirrhosis.
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Candiani G, Pezzoli D, Ciani L, Chiesa R, Ristori S. Bioreducible liposomes for gene delivery: from the formulation to the mechanism of action. PLoS One 2010; 5:e13430. [PMID: 20976172 PMCID: PMC2955545 DOI: 10.1371/journal.pone.0013430] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2010] [Accepted: 09/22/2010] [Indexed: 01/22/2023] Open
Abstract
Background A promising strategy to create stimuli-responsive gene delivery systems is to exploit the redox gradient between the oxidizing extracellular milieu and the reducing cytoplasm in order to disassemble DNA/cationic lipid complexes (lipoplexes). On these premises, we previously described the synthesis of SS14 redox-sensitive gemini surfactant for gene delivery. Although others have attributed the beneficial effects of intracellular reducing environment to reduced glutathione (GSH), these observations cannot rule out the possible implication of the redox milieu in its whole on transfection efficiency of bioreducible transfectants leaving the determinants of DNA release largely undefined. Methodology/Principal Findings With the aim of addressing this issue, SS14 was here formulated into binary and ternary 100 nm-extruded liposomes and the effects of the helper lipid composition and of the SS14/helper lipids molar ratio on chemical-physical and structural parameters defining transfection effectiveness were investigated. Among all formulations tested, DOPC/DOPE/SS14 at 25∶50∶25 molar ratio was the most effective in transfection studies owing to the presence of dioleoyl chains and phosphatidylethanolamine head groups in co-lipids. The increase in SS14 content up to 50% along DOPC/DOPE/SS14 liposome series yielded enhanced transfection, up to 2.7-fold higher than that of the benchmark Lipofectamine 2000, without altering cytotoxicity of the corresponding lipoplexes at charge ratio 5. Secondly, we specifically investigated the redox-dependent mechanisms of gene delivery into cells through tailored protocols of transfection in GSH-depleted and repleted vs. increased oxidative stress conditions. Importantly, GSH specifically induced DNA release in batch and in vitro. Conclusions/Significance The presence of helper lipids carrying unsaturated dioleoyl chains and phosphatidylethanolamine head groups significantly improved transfection efficiencies of DOPC/DOPE/SS14 lipoplexes. Most importantly, this study shows that intracellular GSH levels linearly correlated with transfection efficiency while oxidative stress levels did not, highlighting for the first time the pivotal role of GSH rather than oxidative stress in its whole in transfection of bioreducible vectors.
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Affiliation(s)
- Gabriele Candiani
- Department of Chemistry, Materials and Chemical Engineering Giulio Natta, Politecnico di Milano, Milan, Italy.
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Woodward KN. Adverse Drug Reactions in Dogs – Toxic Hepatic Responses. VETERINARY PHARMACOVIGILANCE 2009:423-452. [DOI: 10.1002/9781444322958.ch18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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