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Lim JJ, Klaassen CD, Cui JY. Deciphering the cell type-specific and zonal distribution of drug-metabolizing enzymes, transporters, and transcription factors in livers of mice using single-cell transcriptomics. Drug Metab Dispos 2025; 53:100029. [PMID: 39919554 DOI: 10.1016/j.dmd.2024.100029] [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: 08/12/2024] [Accepted: 11/08/2024] [Indexed: 02/09/2025] Open
Abstract
The liver contains multiple cell types, including resident cell types and immune cells. The liver is also categorized into 3 zones: periportal (zone 1), midzonal (zone 2), and centrilobular (zone 3). The goal of this study was to characterize the distribution of drug-processing genes (DPGs) in mouse liver using published single-cell and nuclei transcriptomic datasets, which were subjected to zonal deconvolution. Filtering, normalization, clustering, and differential expression analyses were performed using Seurat V5 in R. Hepatocytes were assigned to 3 zones based on known zonal markers and validated with published spatial transcriptomics data. Among the 195 DPGs profiled, most were expressed highest in hepatocytes (61.3%). Interestingly, certain DPGs were expressed most highly in nonparenchymal cells, such as in cholangiocytes (11.2%, eg, carboxylesterase [Ces] 2e, Ces2g), endothelial cells (7.2%, eg, aldo-keto reductase [Akr] 1c19, Akr1e1), Kupffer cells (5.3%, eg, Akr1a1, Akr1b10), stellate cells (5.1%, eg, retinoic acid receptor [Rar] α, Rarβ), myofibroblasts (2.9%, RAR-related orphan receptor [Rar] α), and a few were expressed in immune cell types. In hepatocytes, 72.4% of phase-I enzymes were enriched in zone 3. Phase-II conjugation enzymes such as UDP-glucuronosyltransferases (75%) were enriched in zone 3, whereas sulfotransferases (40%) were enriched in zone 1. Hepatic xenobiotic transporters were enriched in zone 3. The xenobiotic biotransformation-regulating transcription factors were enriched in zone 3 hepatocytes. The enrichment of DPGs in liver cell types, including non-parenchymal cells and zone 1 hepatocytes, may serve as an additional repertoire for xenobiotic biotransformation. SIGNIFICANCE STATEMENT: Our study is among the first to systematically characterize the baseline mRNA enrichment of important drug-processing genes in different cell types and zones in the liver. This finding will aid in further understanding the mechanisms of chemical-induced liver injury with improved resolution and precision.
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Affiliation(s)
- Joe Jongpyo Lim
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington; Environmental Health and Microbiome Research Center (EHMBRACE), Seattle, Washington
| | - Curtis Dean Klaassen
- Department of Pharmacology, Toxicology, and Therapeutics, School of Medicine, University of Kansas, Kansas City, Kanas.
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington; Environmental Health and Microbiome Research Center (EHMBRACE), Seattle, Washington.
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Zhang H, Gao M, Wang H, Zhang J, Wang L, Dong G, Ma Q, Li C, Dai J, Li Z, Yan F, Xiong H. Atractylenolide I prevents acute liver failure in mouse by regulating M1 macrophage polarization. Sci Rep 2025; 15:4015. [PMID: 39893238 PMCID: PMC11787394 DOI: 10.1038/s41598-025-86977-x] [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: 07/23/2024] [Accepted: 01/15/2025] [Indexed: 02/04/2025] Open
Abstract
Acute liver failure (ALF) is a life-threatening clinical syndrome with a substantial risk of mortality. A murine model of lipopolysaccharide (LPS)- and D-galactosamine (D-GalN)-induced ALF is widely used to investigate the underlying mechanisms and potential therapeutic drugs for human liver failure. Atractylenolide I (ATR-I) is an active component of the Atractylodes macrocephala rhizome and possesses various pharmacological activities, including anti-tumor, anti-inflammatory, and anti-oxidant properties. Given the key role of oxidative stress and inflammation in ALF pathogenesis, this study investigates the protective effects of ATR-I on LPS/D-GalN-induced ALF in mice. The results suggest that ATR-I pretreatment significantly ameliorates ALF, as evidenced by decreased serum aminotransferase levels and prolonged mice survival. Additionally, ATR-I pretreatment inhibits oxidative stress. Furthermore, the ATR-I pretreatment markedly suppresses M1 macrophage activation in hepatic mononuclear cells. In vitro experiments with bone marrow-derived macrophages indicate that ATR-I regulates macrophage polarization through the mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF) signaling pathways. Collectively, ATR-I pretreatment protects mice from LPS/D-GalN-induced ALF partially by regulating M1 macrophage polarization.
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Affiliation(s)
- Hui Zhang
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Min Gao
- Clinical Laboratory, Jining First People's Hospital, Jining, Shandong, China
| | - Haiyan Wang
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Junfeng Zhang
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Lin Wang
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Guanjun Dong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Qun Ma
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Chunxia Li
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Jun Dai
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Zhihua Li
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China
| | - Fenglian Yan
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China.
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China.
| | - Huabao Xiong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China.
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, Shandong, China.
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Lim HJ, Kwak HJ. Selective PPARδ Agonist GW501516 Protects Against LPS-Induced Macrophage Inflammation and Acute Liver Failure in Mice via Suppressing Inflammatory Mediators. Molecules 2024; 29:5189. [PMID: 39519830 PMCID: PMC11547330 DOI: 10.3390/molecules29215189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Inflammation is critical in the development of acute liver failure (ALF). Peroxisome proliferator-activated receptor delta (PPARδ) regulates anti-inflammatory responses and is protective in several diseases such as obesity and cancer. However, the beneficial effects and underlying mechanisms of PPARδ agonist GW501516 in ALF remain unclear. This study investigated the molecular mechanisms underlying the anti-inflammatory effects of GW501516 in macrophages and assessed its protective potential against lipopolysaccharide (LPS)/galactosamine (GalN)-induced ALF. In vivo administration of GW501516 significantly reduced LPS/GalN-induced hepatotoxicity, as evidenced by lower mortality, decreased liver damage, and attenuated secretion of IL-1β, IL-6, and TNF-α. GW501516 treatment also decreased LPS-induced nitric oxide synthase 2 (NOS2) expression and nitric oxide (NO) production in RAW264.7 cells, an effect reversed by PPARδ siRNA. Additionally, GW501516 inhibited LPS-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), suggesting that inactivation of these MAPKs contributes to its effects. The secretion of IL-6, TNF-α, and NF-κB DNA-binding activity were also suppressed by GW501516, while the nuclear translocation of the NF-κB p65 subunit was unaffected. In conclusion, our findings suggest that GW501516 exerts protective effects in ALF by inhibiting the production of inflammatory mediators. Therefore, GW501516 may act as a potential agent for developing anti-inflammatory therapies for ALF.
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Affiliation(s)
- Hyun-Joung Lim
- Division of Cardiovascular Diseases Research, Department of Chronic Diseases Convergence, National Institute of Health, Cheongju 28159, Republic of Korea;
| | - Hyun Jeong Kwak
- Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Republic of Korea
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El-Kashef DH, Abdel-Rahman N, Sharawy MH. Apocynin alleviates thioacetamide-induced acute liver injury: Role of NOX1/NOX4/NF-κB/NLRP3 pathways. Cytokine 2024; 183:156747. [PMID: 39236429 DOI: 10.1016/j.cyto.2024.156747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 07/01/2024] [Accepted: 08/28/2024] [Indexed: 09/07/2024]
Abstract
The liver has a distinctive capacity to regenerate, yet severe acute injury can be life-threatening if not treated appropriately. Inflammation and oxidative stress are central processes implicated in the pathophysiology of acute livery injury. NOX isoforms are important enzymes for ROS generation, NF-κB and NLRP3 activation, its inhibition could be vital in alleviating acute liver injury (ALI). Here in our study, we used apocynin, a natural occurring potent NOX inhibitor, to exploreits potential protective effect against thioacetamide (TAA)-induced ALI through modulating crucial oxidative and inflammatory pathways. Rats were injected once with TAA (500 mg/kg/i.p) and treated with apocynin (10 mg/kg/i.p) twice before TAA challenge. Sera and hepatic tissues were collected for biochemical, mRNA expression, western blot analysis and histopathological assessments. Pretreatment with apocynin improved liver dysfunction evidenced by decreased levels of aminotransferases, ALP, GGT and bilirubin. Apocynin reduced mRNA expression of NOX1 and NOX4 which in turn alleviated oxidative stress, as shown by reduction in MDA and NOx levels, and elevation in GSH levels andcatalase and SOD activities. Moreover, apocynin significantly reduced MPO gene expression. We also demonstrate that apocynin ameliorated inflammation through activating IκBα and suppressing IKKα, IKKβ, NF-κBp65 and p-NF-κBp65, IL-6 andTNF-α. Additionally, apocynin potentiated the gene expression of anti-inflammatory IL-10 and reduced levels of hepatic NLRP3, Caspase-1 and IL-1β. These results suggest that apocynin protects against ALI in association with the inhibition of NOX1 and NOX4 and regulating oxidative and inflammatory pathways.
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Affiliation(s)
- Dalia H El-Kashef
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Noha Abdel-Rahman
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
| | - Maha H Sharawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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Lei ZY, Li ZH, Lin DN, Cao J, Chen JF, Meng SB, Wang JL, Liu J, Zhang J, Lin BL. Med1 inhibits ferroptosis and alleviates liver injury in acute liver failure via Nrf2 activation. Cell Biosci 2024; 14:54. [PMID: 38678227 PMCID: PMC11056072 DOI: 10.1186/s13578-024-01234-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 04/12/2024] [Indexed: 04/29/2024] Open
Abstract
BACKGROUND Extensive hepatocyte mortality and the absence of specific medical therapy significantly contribute to the unfavorable prognosis of acute liver failure (ALF). Ferroptosis is a crucial form of cell death involved in ALF. In this study, we aimed to determine the impact of Mediator complex subunit 1 (Med1) on ferroptosis and its potential hepatoprotective effects in ALF. RESULTS Med1 expression is diminished in the liver of lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALF mice, as well as in hepatocytes damaged by H2O2 or TNF-α/D-GalN in vitro. Med1 overexpression mitigates liver injury and decreases the mortality rate of ALF mice by ferroptosis inhibition. The mechanism by which Med1 inhibits erastin-induced ferroptosis in hepatocytes involves the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes heme oxygenase-1 (HO-1), glutamate cysteine ligase catalytic (GCLC), and NAD(P)H quinone oxidoreductase 1 (NQO1). Furthermore, Med1 overexpression suppresses the transcription of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the liver of mice with LPS/D-GalN-induced ALF. CONCLUSION Overall, our research findings indicate that Med1 suppresses ferroptosis and alleviates liver injury in LPS/D-GalN-induced ALF through the activation of Nrf2. These findings substantiate the therapeutic viability of targeting the Med1-Nrf2 axis as a means of treating individuals afflicted with ALF.
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Affiliation(s)
- Zi-Ying Lei
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Zhi-Hui Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Deng-Na Lin
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China
| | - Jing Cao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jun-Feng Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Shi-Bo Meng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jia-Lei Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jing Liu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China.
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
| | - Jing Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China.
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
| | - Bing-Liang Lin
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China.
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China.
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Diao J, Fan H, Zhang J, Fu X, Liao R, Zhao P, Huang W, Huang S, Liao H, Yu J, Pan D, Wang M, Xiao W, Wen X. Activation of APE1 modulates Nrf2 protected against acute liver injury by inhibit hepatocyte ferroptosis and promote hepatocyte autophagy. Int Immunopharmacol 2024; 128:111529. [PMID: 38244516 DOI: 10.1016/j.intimp.2024.111529] [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: 11/16/2023] [Revised: 01/02/2024] [Accepted: 01/08/2024] [Indexed: 01/22/2024]
Abstract
BACKGROUND Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) plays a crucial role in DNA base excision repair, cell apoptosis, cell signaling, and the regulation of transcription factors through redox modulation and the control of reactive oxygen species (ROS). However, the connection between APE1 and acute liver injury (ALI) remains enigmatic. This study aims to unravel the molecular mechanisms underlying ALI and shed light on the role of APE1 in this context. METHOD We induced acute liver injury (ALI) in mice by lipopolysaccharide/D-galactosamine (LPS/GalN) and intervened with the APE1 inhibitor E3330. We examined the expression of APE1 in ALI mice and ALI patient tissues after E3330 intervention, Additionally, we measured hepatic oxidative stress, ferroptosis, and autophagy marker proteins and genes. In establishing an AML-12 liver cell injury model, we utilized the Nrf2 activator tert-butylhydroquinone (TBHQ) as an intervention and examined APE1, Nrf2, ferroptosis-related proteins, and autophagy marker proteins and mRNA. RESULTS Both ALI patients and ALI mice exhibited reduced APE1 expression levels. After E3330 intervention, there was a significant exacerbation of liver injury, oxidative stress, and a reduction in the expression of proteins, including GPX4, X-CT, ATG3, ATG5, and LC3 (LC3I/II). Consistent results were also observed in AML-12 cells. With TBHQ intervention, Nrf2 expression increased, along with the expression of proteins associated with iron death and autophagy. Mechanistically, APE1 activation regulates Nrf2 to inhibit ferroptosis and promote autophagy in hepatocytes. CONCLUSION The data suggest that APE1 is a pivotal player in ALI, closely linked to its regulation of Nrf2. Strategies involving APE1 activation to modulate Nrf2, thereby inhibiting hepatocyte ferroptosis and promoting autophagy, may represent innovative therapeutic approaches for ALI. Additionally, tert-butylhydroquinone (TBHQ) holds significant promise in the treatment of acute liver injury.
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Affiliation(s)
- Jianxin Diao
- Center of TCM Preventive Treatment, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Huijie Fan
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Traditional Chinese Medicine, People's Hospital of Yangjiang, Yangjiang 529500, China
| | - Jia Zhang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Xiuqiong Fu
- School of Chinese Medicine, Consun Chinese Medicines Research Centre for Renal Diseases, Hong Kong Baptist University, Hong Kong, China
| | - Rongxin Liao
- Center of TCM Preventive Treatment, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
| | - Peng Zhao
- Center of TCM Preventive Treatment, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
| | - Wei Huang
- Center of TCM Preventive Treatment, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
| | - Shiying Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Huajun Liao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Jieying Yu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Dongmei Pan
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Ming Wang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China; Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510515, China.
| | - Wei Xiao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, China.
| | - Xiaomin Wen
- Center of TCM Preventive Treatment, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
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Yang H, Chen J, Li J. Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure. Front Immunol 2023; 14:1243220. [PMID: 37744328 PMCID: PMC10513107 DOI: 10.3389/fimmu.2023.1243220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Acute liver failure (ALF) is a high-mortality syndrome for which liver transplantation is considered the only effective treatment option. A shortage of donor organs, high costs and surgical complications associated with immune rejection constrain the therapeutic effects of liver transplantation. Recently, mesenchymal stem cell (MSC) therapy was recognized as an alternative strategy for liver transplantation. Bone marrow mesenchymal stem cells (BMSCs) have been used in clinical trials of several liver diseases due to their ease of acquisition, strong proliferation ability, multipotent differentiation, homing to the lesion site, low immunogenicity and anti-inflammatory and antifibrotic effects. In this review, we comprehensively summarized the harvest and culture expansion strategies for BMSCs, the development of animal models of ALF of different aetiologies, the critical mechanisms of BMSC therapy for ALF and the challenge of clinical application.
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Affiliation(s)
| | | | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Hassan GS, Flores Molina M, Shoukry NH. The multifaceted role of macrophages during acute liver injury. Front Immunol 2023; 14:1237042. [PMID: 37736102 PMCID: PMC10510203 DOI: 10.3389/fimmu.2023.1237042] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/15/2023] [Indexed: 09/23/2023] Open
Abstract
The liver is situated at the interface of the gut and circulation where it acts as a filter for blood-borne and gut-derived microbes and biological molecules, promoting tolerance of non-invasive antigens while driving immune responses against pathogenic ones. Liver resident immune cells such as Kupffer cells (KCs), a subset of macrophages, maintain homeostasis under physiological conditions. However, upon liver injury, these cells and others recruited from circulation participate in the response to injury and the repair of tissue damage. Such response is thus spatially and temporally regulated and implicates interconnected cells of immune and non-immune nature. This review will describe the hepatic immune environment during acute liver injury and the subsequent wound healing process. In its early stages, the wound healing immune response involves a necroinflammatory process characterized by partial depletion of resident KCs and lymphocytes and a significant infiltration of myeloid cells including monocyte-derived macrophages (MoMFs) complemented by a wave of pro-inflammatory mediators. The subsequent repair stage includes restoring KCs, initiating angiogenesis, renewing extracellular matrix and enhancing proliferation/activation of resident parenchymal and mesenchymal cells. This review will focus on the multifaceted role of hepatic macrophages, including KCs and MoMFs, and their spatial distribution and roles during acute liver injury.
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Affiliation(s)
- Ghada S. Hassan
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Manuel Flores Molina
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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Kahan R, Cray PL, Abraham N, Gao Q, Hartwig MG, Pollara JJ, Barbas AS. Sterile inflammation in liver transplantation. Front Med (Lausanne) 2023; 10:1223224. [PMID: 37636574 PMCID: PMC10449546 DOI: 10.3389/fmed.2023.1223224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/17/2023] [Indexed: 08/29/2023] Open
Abstract
Sterile inflammation is the immune response to damage-associated molecular patterns (DAMPs) released during cell death in the absence of foreign pathogens. In the setting of solid organ transplantation, ischemia-reperfusion injury results in mitochondria-mediated production of reactive oxygen and nitrogen species that are a major cause of uncontrolled cell death and release of various DAMPs from the graft tissue. When properly regulated, the immune response initiated by DAMP-sensing serves as means of damage control and is necessary for initiation of recovery pathways and re-establishment of homeostasis. In contrast, a dysregulated or overt sterile inflammatory response can inadvertently lead to further injury through recruitment of immune cells, innate immune cell activation, and sensitization of the adaptive immune system. In liver transplantation, sterile inflammation may manifest as early graft dysfunction, acute graft failure, or increased risk of immunosuppression-resistant rejection. Understanding the mechanisms of the development of sterile inflammation in the setting of liver transplantation is crucial for finding reliable biomarkers that predict graft function, and for development of therapeutic approaches to improve long-term transplant outcomes. Here, we discuss the recent advances that have been made to elucidate the early signs of sterile inflammation and extent of damage from it. We also discuss new therapeutics that may be effective in quelling the detrimental effects of sterile inflammation.
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Affiliation(s)
| | | | | | | | | | | | - Andrew S. Barbas
- Duke Ex-Vivo Organ Lab (DEVOL)—Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
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Hrynkiewicz R, Niedźwiedzka-Rystwej P. Etiology of viral induced acute liver failure and defensins as potential therapeutic agents in ALF treatment. Front Immunol 2023; 14:1153528. [PMID: 37153560 PMCID: PMC10160486 DOI: 10.3389/fimmu.2023.1153528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 04/12/2023] [Indexed: 05/09/2023] Open
Abstract
Acute liver failure (ALF) is a rare and severe disease, which, despite continuous advances in medicine, is still characterized by high mortality (65-85%). Very often, a liver transplant is the only effective treatment for ALF. Despite the implementation of prophylactic vaccinations in the world, the viral background of ALF is still a problem and leads to many deaths. Depending on the cause of ALF, it is sometimes possible to reverse this condition with appropriate therapies, which is why the search for effective antiviral agents seems to be a very desirable direction of research. Defensins, which are our natural antimicrobial peptides, have a very high potential to be used as therapeutic agents for infectious liver diseases. Previous studies on the expression of human defensins have shown that increased expression of human α and β-defensins in HCV and HBV infections is associated with a better response to treatment. Unfortunately, conducting clinical trials for ALF is very difficult due to the severity of the disease and the low incidence, therefore animal models are important for the development of new therapeutic strategies. One of the best animal models that has real reference to research on acute liver failure (ALF) is rabbit hemorrhagic disease in rabbits caused by the Lagovirus europaeus virus. So far, there have been no studies on the potential of defensins in rabbits infected with Lagovirus europaeus virus.
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Yuan C, Fan J, Jiang L, Ye W, Chen Z, Wu W, Huang Q, Qian L. Integrated Analysis of Gut Microbiome and Liver Metabolome to Evaluate the Effects of Fecal Microbiota Transplantation on Lipopolysaccharide/D-galactosamine-Induced Acute Liver Injury in Mice. Nutrients 2023; 15:nu15051149. [PMID: 36904149 PMCID: PMC10005546 DOI: 10.3390/nu15051149] [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: 11/24/2022] [Revised: 02/16/2023] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
Acute liver failure (ALF) refers to the occurrence of massive hepatocyte necrosis in a short time, with multiple complications, including inflammatory response, hepatic encephalopathy, and multiple organ failure. Additionally, effective therapies for ALF are lacking. There exists a relationship between the human intestinal microbiota and liver, so intestinal microbiota modulation may be a strategy for therapy of hepatic diseases. In previous studies, fecal microbiota transplantation (FMT) from fit donors has been used to modulate intestinal microbiota widely. Here, we established a mouse model of lipopolysaccharide (LPS)/D-galactosamine (D-gal) induced ALF to explore the preventive and therapeutic effects of FMT, and its mechanism of action. We found that FMT decreased hepatic aminotransferase activity and serum total bilirubin levels, and decreased hepatic pro-inflammatory cytokines in LPS/D-gal challenged mice (p < 0.05). Moreover, FMT gavage ameliorated LPS/D-gal induced liver apoptosis and markedly reduced cleaved caspase-3 levels, and improved histopathological features of the liver. FMT gavage also restored LPS/D-gal-evoked gut microbiota dysbiosis by modifying the colonic microbial composition, improving the abundance of unclassified_o_Bacteroidales (p < 0.001), norank_f_Muribaculaceae (p < 0.001), and Prevotellaceae_UCG-001 (p < 0.001), while reducing that of Lactobacillus (p < 0.05) and unclassified_f_Lachnospiraceae (p < 0.05). Metabolomics analysis revealed that FMT significantly altered LPS/D-gal induced disordered liver metabolites. Pearson's correlation revealed strong correlations between microbiota composition and liver metabolites. Our findings suggest that FMT ameliorate ALF by modulating gut microbiota and liver metabolism, and can used as a potential preventive and therapeutic strategy for ALF.
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Affiliation(s)
- Chunchun Yuan
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jinghui Fan
- Hangzhou Academy of Agricultural Sciences, Hangzhou 310004, China
| | - Lai Jiang
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wenxin Ye
- Hainan Institute of Zhejiang University, Sanya 572025, China
| | - Zhuo Chen
- Hainan Institute of Zhejiang University, Sanya 572025, China
| | - Wenzi Wu
- Hainan Institute of Zhejiang University, Sanya 572025, China
| | - Qixin Huang
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Lichun Qian
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
- Correspondence: ; Tel.: +86-571-88982171
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12
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Lu W, Tang H, Li S, Bai L, Chen Y. Extracellular vesicles as potential biomarkers and treatment options for liver failure: A systematic review up to March 2022. Front Immunol 2023; 14:1116518. [PMID: 36911706 PMCID: PMC9992400 DOI: 10.3389/fimmu.2023.1116518] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
Introduction Extracellular vesicles (EVs) carrying functional cargoes are emerging as biomarkers and treatment strategies in multiple liver diseases. Nevertheless, the potential of EVs in liver failure remains indistinct. In this systematic review, we comprehensively analyzed the potential of EVs as biomarkers of liver failure and the therapeutic effects and possible mechanisms of EVs for liver failure. Methods We conducted a systematic review by comprehensively searching the following electronic databases: PubMed, Web of Science, Embase and Cochrane Central Register of Controlled Trials from inception to March 2022. The used text words (synonyms and word variations) and database-specific subject headings included "Extracellular Vesicles", "Exosomes", "Liver Failure", "Liver Injury", etc. Results A total of 1479 studies were identified. After removing 680 duplicate studies and 742 irrelevant studies, 57 studies were finally retained and analyzed. Fourteen studies revealed EVs with functional cargoes could be used to make the diagnosis of liver failure and provide clues for early warning and prognostic assessment of patients with liver failure. Forty-three studies confirmed the administration of EVs from different sources alleviated hepatic damage and improved survival through inhibiting inflammatory response, oxidative stress as well as apoptosis or promoting hepatocyte regeneration and autophagy. Conclusions EVs and their cargoes can be used not only as superior biomarkers of early warning, early diagnosis and prognostic assessments for liver failure, but also as potentially effective treatment options for liver failure. In the future, large-scale studies are urgently needed to verify the diagnostic, predictive and therapeutic value of EVs for liver failure.
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Affiliation(s)
- Wang Lu
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Huixin Tang
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Shanshan Li
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Li Bai
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Yu Chen
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
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13
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Li P, Guo X, Liu T, Liu Q, Yang J, Liu G. Evaluation of Hepatoprotective Effects of Piperlongumine Derivative PL 1-3-Loaded Albumin Nanoparticles on Lipopolysaccharide/d-Galactosamine-Induced Acute Liver Injury in Mice. Mol Pharm 2022; 19:4576-4587. [PMID: 35971845 DOI: 10.1021/acs.molpharmaceut.2c00215] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In recent years, piperlongumine (PL) having specific cytotoxicity has attracted considerable attention for anticancer activity. Through structural modification, the active derivative PL 1-3 shows potential anti-inflammatory activity and low cytotoxicity, but its water solubility is low. Here, PL 1-3-loaded bovine serum albumin nanoparticles (1-3 NPs) were prepared and characterized, which can improve the dissolution. 1-3 NPs exhibited effective hepatoprotective effects on lipopolysaccharide/d-galactosamine-induced acute liver injury of mice, which was similar to liver injury in clinical settings. 1-3 NPs treatment can inhibit inflammation, oxidative stress, and apoptosis via the downregulation of NF-κB signaling pathways, the activation of Nrf2/HO-1 signaling pathways, and the inhibition of expression of Bax and caspase 3 proteins. The above results demonstrated that PL 1-3-loaded bovine serum albumin nanoparticles possessed potential value in intervention of inflammation-based liver injury.
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Affiliation(s)
- Pengxiao Li
- School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China
| | - Xiaoyuan Guo
- School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China
| | - Ting Liu
- School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China
| | - Qing Liu
- School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China
| | - Jie Yang
- School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China
| | - Guoyun Liu
- School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China
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14
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Oliaei R, Keshtmand Z, Shabani R. The effect of <em>Lactobacillus casei</em> and <em>Bacillus coagulans</em> probiotics on liver damage induced by silver nanoparticles and expression of Bax, Bcl2 and Caspase 3 genes in male rats. Eur J Transl Myol 2022; 33:10673. [PMID: 36101996 PMCID: PMC10141749 DOI: 10.4081/ejtm.2022.10673] [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: 06/13/2022] [Accepted: 06/21/2022] [Indexed: 11/23/2022] Open
Abstract
In this study, we aimed to evaluate the effect of Bacillus coagulans and Lactobacillus casei probiotics on liver damage induced by silver nanoparticles and expression of Bax, Bcl2 and Caspase 3 genes in rats. 32 adult male Wistar rats were divided into four healthy groups (control), the group receiving silver nanoparticles treated with L. casei, the group receiving silver nanoparticles treated with B. coagulans and the group receiving only silver nanoparticles. The effect of nanoparticles was induced by intraperitoneal injection of silver nanoparticles prepared from nettle at a dose of 50 mg/kg and entered the liver tissue through the bloodstream. Two days after injection, probiotic treatment with 109 CFU was performed by gavage for 30 days. One day after the last gavage, rat liver tissue weight was assessed. Also, the total amount of RNA was extracted from treated, and healthy tissues, as well as induced silver nanoparticles tissues, then evaluated by Real Time PCR. Data were evaluated using one-way Anova, Tukey test. Based on the biochemical results of this study, exposure of rats to different concentrations of silver nanoparticles compared with the control group caused a significant increase in the serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), alkaline phosphatase (ALP), especially at high concentrations. Evaluation of damage and histopathological lesions showed that silver nanoparticles in different concentrations caused different damage to liver tissue, so that, necrosis, inflammatory cell infiltration and vascular degeneration were observed at different concentrations by silver nanoparticles. In the present study, the effects of L. casei cell extract on increasing the expression of Bax proapoptotic gene and decreasing Bcl2 gene expression in cancer cells and inducing programmed cell death were shown. In this study, the expression of Bax, Bcl-2 and Caspase-3 genes in the group receiving silver nanoparticles and in the groups treated with probiotics showed significant changes compared to the control group. It can be concluded that the function of silver nanoparticles and the effects of relative improvement of probiotics are from the internal route of apoptosis and factors such as dose, nanoparticle size and nanoparticle coating have an important role in the toxicity of silver nanoparticles, thus the destructive effects on liver tissue could be increased by increasing the concentration of silver nanoparticles.
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Affiliation(s)
- Reyhaneh Oliaei
- Department of Biology, Central Tehran Branch, Islamic Azad University, Tehran.
| | - Zahra Keshtmand
- Department of Biology, Central Tehran Branch, Islamic Azad University, Tehran.
| | - Ronak Shabani
- Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran.
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15
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Wang X, Sun Y, Fu Y, Wu H, Chen Y, Ye Y, Zhou Q, He L, Zhou E, Wang J, Yang Z. Lysine specific demethylase 1 inhibitor alleviated lipopolysaccharide/D-galactosamine-induced acute liver injury. Eur J Pharmacol 2022; 932:175227. [PMID: 36007605 DOI: 10.1016/j.ejphar.2022.175227] [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: 05/04/2022] [Revised: 08/08/2022] [Accepted: 08/17/2022] [Indexed: 11/19/2022]
Abstract
Acute liver injury is a severe clinical syndrome with markedly high mortality and poor prognosis. An accumulating body of evidence has demonstrated that epigenetic mechanisms have essential roles in the pathogenesis of acute liver injury. Lysine-specific demethylase 1 (LSD1) belongs to the amine oxidase superfamily of flavin adenine dinucleotide (FAD)-dependent enzymes, specifically demethylates H3 lysine 4. In the study, we investigated the effects and mechanisms of LSD1 in lipopolysaccharide (LPS)/D-Galactosamine (D-Gal)-induced acute liver injury in mice. Western blot analysis showed that LSD1 phosphorylation and di-methylated histone H3 on lysine 4 (H3K4me2) protein expression were significantly increased after LPS/D-Gal treatment (2.3 and 2.4 times higher than control respectively). GSK-LSD1 2HCl is an irreversible and selective LSD1 inhibitor. Pre-treatment with LSD1 inhibitor alleviated LPS/D-Gal-induced liver damage, decreased serum levels of alanine transaminase and aspartate aminotransferase in mice. Moreover, the LSD1 phosphorylation level in low, medium, and high LSD1 inhibitor groups was lower by a factor of 1.6, 1.9, and 2.0 from the LPS/D-Gal group, respectively. Mechanistically, LSD1 inhibitor further inhibited NF-κB signaling cascades and subsequently inhibited the production of pro-inflammatory cytokine TNF-α, IL-6, and IL-1β induced by LPS/D-Gal in liver tissues. Furthermore, LSD1 inhibitor upregulated the protein expression of Nrf2/HO-1 signaling pathways, and the activities of related antioxidant enzymes were enhanced. Collectively, our data demonstrated that LSD1 inhibitor protected against the LPS/D-Gal-induced acute liver injury via inhibiting inflammation and oxidative stress, and targeting the epigenetic marker may be a potent therapeutic strategy for acute liver injury.
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Affiliation(s)
- Xia Wang
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Youpeng Sun
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Yiwu Fu
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Hanpeng Wu
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Yichun Chen
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Yingrong Ye
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Qingqing Zhou
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Li He
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Ershun Zhou
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China
| | - Jingjing Wang
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China.
| | - Zhengtao Yang
- College of Life Science and Engineering, Foshan University, Foshan, Guangdong, 528231, People's Republic of China.
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16
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Exosomes Derived from Baicalin-Pretreated Mesenchymal Stem Cells Alleviate Hepatocyte Ferroptosis after Acute Liver Injury via the Keap1-NRF2 Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8287227. [PMID: 35910831 PMCID: PMC9334037 DOI: 10.1155/2022/8287227] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 06/30/2022] [Indexed: 12/12/2022]
Abstract
Acute liver injury (ALI) is characterized as a severe metabolic dysfunction caused by extensive damage to liver cells. Ferroptosis is a type of cell death dependent on iron and oxidative stress, which differs from classical cell death, such as apoptosis and necrosis. Ferroptosis has unique morphological features, which mainly include mitochondrial dissolution and mitochondrial outline reduction. Furthermore, the intracellular accumulation of lipid peroxides directly affects the occurrence of ferroptosis. Baicalin, the main compound isolated from Scutellaria baicalensis, has anti-inflammatory and antioxidative effects. Recently, exosomes derived from preconditioned mesenchymal stem cells (MSCs) have shown great potential in the treatment of various diseases including ALI. This study investigates the ability of exosomes derived from baicalin-pretreated MSCs (Ba-Exo) to promote liver function recovery in mice with ALI compared with those without pretreatment. Through in vivo and in vitro experiments, this study demonstrates for the first time that Ba-Exo greatly attenuates D-galactosamine and lipopolysaccharide (D-GaIN/LPS)-induced liver damage and inhibits reactive oxygen species (ROS) production and lipid peroxide-induced ferroptosis. Moreover, P62 was significantly upregulated in Ba-Exo, whereas its downregulation in Ba-Exo counteracted the beneficial effect of Ba-Exo. P62 regulates hepatocyte ferroptosis by activating the Keap1-NRF2 pathway. The beneficial effect of Ba-Exo in inhibiting ferroptosis was also attenuated after the NRF2 pathway was inhibited. Therefore, baicalin pretreatment is an effective and promising approach to optimize the therapeutic efficacy of MSC-derived exosomes in ALI.
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17
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Shi C, Jiao F, Wang Y, Chen Q, Wang L, Gong Z. SIRT3 inhibitor 3-TYP exacerbates thioacetamide-induced hepatic injury in mice. Front Physiol 2022; 13:915193. [PMID: 35923224 PMCID: PMC9340259 DOI: 10.3389/fphys.2022.915193] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/29/2022] [Indexed: 11/28/2022] Open
Abstract
The purpose of the study was to explore the effects of SIRT3 inhibitor 3-TYP on acute liver failure (ALF) in mice and its underlying mechanism. The mice were treated with thioacetamide (TAA, 300 mg/kg) for inducing ALF model. 3-TYP (50 mg/kg) was administered 2 h prior to TAA. The liver histological changes were measured by HE staining. Blood samples were collected for analysis of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). MDA and GSH were used to evaluate the oxidative stress of liver. The expression levels of inflammatory cytokines (TNF-α and IL-1β) were measured by ELISA and Western blotting. The cell type expression of IL-1β in liver tissue was detected by immunofluorescent staining. The expression of SIRT3, MnSOD, ALDH2, MAPK, NF-κB, Nrf2/HO-1, p-elF2α/CHOP, and cleaved caspase 3 was determined by Western blotting. TUNEL staining was performed to detect the apoptosis cells of liver tissues. 3-TYP exacerbated the liver injury of ALF mice. 3-TYP increased the inflammatory responses and activation of MAPK and NF-κB pathways. In addition, 3-TYP administration enhanced the damage of oxidative stress, endoplasmic reticulum stress, and promoted hepatocyte apoptosis in ALF mice. 3-TYP exacerbates thioacetamide-induced hepatic injury in mice. Activation of SIRT3 could be a promising target for the treatment of ALF.
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Affiliation(s)
- Chunxia Shi
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fangzhou Jiao
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qian Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Luwen Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zuojiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Zuojiong Gong,
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18
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Jin X, Li Y, Li J, Cheng L, Yao Y, Shen H, Wang B, Ren J, Ying H, Xu J. Acute bone damage through liver-bone axis induced by thioacetamide in rats. BMC Pharmacol Toxicol 2022; 23:29. [PMID: 35526079 PMCID: PMC9080193 DOI: 10.1186/s40360-022-00568-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 04/25/2022] [Indexed: 11/24/2022] Open
Abstract
Background Thioacetamide (TAA) is used in various fields, such as synthetic drugs, organic chemical synthesis, and materials chemistry. TAA is mainly used to establish animal liver injury models and other organ damage models to explore their mechanisms for helping patients with liver disease. Liver damage can lead to abnormal expression of some enzymes in the serum, so we detected the appropriate enzyme levels in the serum of SD rats to verify the damage of TAA to the liver. More importantly, TAA caused bone damage is barely understood. Therefore, our research aims to establish a rat model reflecting the acute bone damage injury caused by TAA. Methods The SD rats were intraperitoneally injected with normal saline (0.9%) or TAA (200 mg/kg, 400 mg/kg) for 1 month (once the other day). After the last intraperitoneal injection, serum samples from rats were used for biochemical tests. Masson staining is used to detect liver damage, and micro-CT is used to detect the changes in bone. Moreover, the three-point bending experiment was used to detect the force range of the hind limbs of SD rats. Results Compared with the control group, after the intraperitoneal injection of TAA, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), uric acid (UA), total bile acid (TBA), alkaline phosphatase (ALP), carbamide (UREA) and creatinine (CREA) rose sharply, while the levels of serum content of total protein (TP), lactate dehydrogenase (LDH), calcium (Ca) and phosphorus (P) were severely reduced. After TAA administration, collagen fibers were deposited and liver fibrosis was obvious. Micro-CT results showed that the bone surface, tissue surface, bone volume, and tissue volume of rats with an intraperitoneal injection of TAA were significantly reduced. In addition, the bones of rats with an intraperitoneal injection of TAA can resist less pressure and are prone to fractures. Conclusions TAA can cause liver damage in SD rats, which is explained by the changes in serum biochemical indicators and the deposition of liver collagen. More importantly, TAA can reduce bone mineral density and increase the separation of bone trabeculae in SD rats, and finally lead to bone injury. This suggests that TAA may become an ideal model to investigate abnormal bone metabolism after liver injury.
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Affiliation(s)
- Xiaoli Jin
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yang Li
- FUDAN University, school of basic medical sciences, Shanghai, 200433, PR China
| | - Jianghua Li
- Department of The Third Orthopaedic, The First Affiliated Hospital of Shihezi University School of Medicine Xinjiang Shihezi, Shihezi, 832008, China
| | - Linyan Cheng
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yetao Yao
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hao Shen
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Bili Wang
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jun Ren
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hang Ying
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jian Xu
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
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Mu W, Wang Q, Jia M, Dong S, Li S, Yang J, Liu G. Hepatoprotective Effects of Albumin-Encapsulated Nanoparticles of a Curcumin Derivative COP-22 against Lipopolysaccharide/D-Galactosamine-Induced Acute Liver Injury in Mice. Int J Mol Sci 2022; 23:ijms23094903. [PMID: 35563293 PMCID: PMC9102161 DOI: 10.3390/ijms23094903] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/21/2022] [Accepted: 04/26/2022] [Indexed: 01/27/2023] Open
Abstract
Acute liver injury (ALI) is a severe syndrome and can further develop into acute liver failure (ALF) which can lead to high mortality and cause irreversible liver injuries in the clinic. Liver transplantation is the most common treatment; however, liver donors are lacking, and the progression of ALF is rapid. Nanoparticles can increase the bioavailability and the targeted accumulation of drugs in the liver, so as to significantly improve the therapeutic effect of ALI. Curcumin derivative COP-22 exhibits low cytotoxicity and effective anti-inflammatory activity; however, it has poor water solubility. In this study, COP-22-loaded bovine serum albumin (BSA) nanoparticles (22 NPs) were prepared and characterized. They exhibit effective hepatoprotective effects by inhibiting inflammation, oxidative stress, and apoptosis on Lipopolysaccharide/D-Galactosamine-induced acute liver injury of mice. The anti-inflammatory activity of 22 NPs is related to the regulation of the NF-κB signaling pathways; the antioxidant activity is related to the regulation of the Nrf2 signaling pathways; and the apoptosis activity is related to mitochondrial pathways, involving Bcl-2 family and Caspase-3 protein. These three cellular pathways are interrelated and affected each other. Moreover, 22 NPs could be passively targeted to accumulate in the liver through the retention effect and are more easily absorbed than 22.HCl salt in the liver.
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Affiliation(s)
| | | | | | | | | | - Jie Yang
- Correspondence: (J.Y.); (G.L.); Tel.: +86-15063505132 (L.G.)
| | - Guoyun Liu
- Correspondence: (J.Y.); (G.L.); Tel.: +86-15063505132 (L.G.)
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20
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Bębnowska D, Niedźwiedzka-Rystwej P. The Interplay between Autophagy and Virus Pathogenesis-The Significance of Autophagy in Viral Hepatitis and Viral Hemorrhagic Fevers. Cells 2022; 11:871. [PMID: 35269494 PMCID: PMC8909602 DOI: 10.3390/cells11050871] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 12/17/2022] Open
Abstract
Autophagy is a process focused on maintaining the homeostasis of organisms; nevertheless, the role of this process has also been widely documented in viral infections. Thus, xenophagy is a selective form of autophagy targeting viruses. However, the relation between autophagy and viruses is ambiguous-this process may be used as a strategy to fight with a virus, but is also in favor of the virus's replication. In this paper, we have gathered data on autophagy in viral hepatitis and viral hemorrhagic fevers and the relations impacting its viral pathogenesis. Thus, autophagy is a potential therapeutic target, but research is needed to fully understand the mechanisms by which the virus interacts with the autophagic machinery. These studies must be performed in specific research models other than the natural host for many reasons. In this paper, we also indicate Lagovirus europaeus virus as a potentially good research model for acute liver failure and viral hemorrhagic disease.
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Affiliation(s)
- Dominika Bębnowska
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland
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21
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Huang S, Wang Y, Xie S, Lai Y, Mo C, Zeng T, Kuang S, Deng G, Zhou C, Chen Y, Huang S, Gao L, Lv Z. Hepatic TGFβr1 Deficiency Attenuates Lipopolysaccharide/D-Galactosamine-Induced Acute Liver Failure Through Inhibiting GSK3β-Nrf2-Mediated Hepatocyte Apoptosis and Ferroptosis. Cell Mol Gastroenterol Hepatol 2022; 13:1649-1672. [PMID: 35202887 PMCID: PMC9046809 DOI: 10.1016/j.jcmgh.2022.02.009] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 02/11/2022] [Accepted: 02/11/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Acute liver failure (ALF) is a condition with high mortality and morbidity, characterized by glutathione depletion, oxidative stress, and mitochondrial dysfunction. Ferroptosis may be involved in ALF. Indeed, emerging studies have shown that ferroptosis plays a significant role in ALF. However, the mechanism of ferroptosis in hepatocytes during ALF remains unknown. METHODS Hepatic-specific transforming growth factor β receptor 1 knockout (TGFβr1Δhep-CKO) mice and nuclear factor erythroid 2-related factor 2 knockout (Nrf2-/-) mice were generated and subjected to ALF. Electron microscopy was used to detect mitochondrial and other cell substructure changes during ALF. RESULTS In this study, we noticed that lipopolysaccharide (LPS)/D-galactosamine (D-GalN) induced caspases-mediated apoptosis as current research reported, we also found lipid peroxidation, reactive oxygen species accumulation, and glutathione, co-enzyme Q10 system inhibition mediated ferroptosis during LPS/D-GalN-induced ALF. Rescue studies have shown that ferrostatin-1 (Fer-1) and deferoxamine mesylate (DFOM), the inhibitor of ferroptosis, could alleviate LPS/D-GalN-induced ALF. In addition, we noticed that TGFβ1 was increased during ALF, while ALF was relieved in TGFβr1Δhep-CKO mice. We also noticed that liver TGFβr1 deficiency alleviated LPS/D-GalN-induced apoptosis and ferroptosis by affecting the phosphorylation of glycogen synthase kinase 3β and Nrf2, a key antioxidant factor, by up-regulating the levels of glutathione peroxidase 4 (GPX4), glutamine antiporter xCT (XCT), dihydroorotate dehydrogenase (DHODH), and ferroptosis suppressor protein 1 (FSP1), and down-regulating transferrin receptor (TFR), prostaglandin-endoperoxide synthase (Ptgs2), chaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1), and cytochrome P450 reductase (POR) expression. The further supplemental experiment showed that ferroptosis was aggravated significantly in Nrf2-/- mice compared with its wild-type controls and reversed by ferrostatin-1. CONCLUSIONS This study shows that TGFβr1 plays a critical role in mediating LPS/D-GalN-induced ALF by promoting apoptosis and ferroptosis.
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Affiliation(s)
- Sha Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China,Shaohui Huang, Zhiping Lv, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
| | - Yuhua Wang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Shunwen Xie
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuqi Lai
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Chan Mo
- Medical Laboratory, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Ting Zeng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Shanshan Kuang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Guanghui Deng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China,Guangdeng Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, 510515, China
| | - Chuying Zhou
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuyao Chen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Shaohui Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Lei Gao
- ZhuJiang Hospital of Southern Medical University, Guangzhou, Guangdong, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, China,Correspondence Corresponding author address: Lei Gao, ZhuJiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510285, China.
| | - Zhiping Lv
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China,Shaohui Huang, Zhiping Lv, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
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22
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Murase K, Kashiwagi N, Tomiyama N. Quantitative evaluation of simultaneous spatial and temporal regularization in dynamic contrast-enhanced MRI of the liver using Gd-EOB-DTPA. Magn Reson Imaging 2022; 88:25-37. [PMID: 35007694 DOI: 10.1016/j.mri.2022.01.006] [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: 10/04/2021] [Revised: 01/02/2022] [Accepted: 01/04/2022] [Indexed: 02/07/2023]
Abstract
The purpose of this study was to quantitatively evaluate the usefulness of simultaneous spatial and temporal regularization using total variation (TV), total generalized variation (TGV), a combination of low-rank decomposition (LRD) and TV (LRD+TV), a combination of LRD and TGV (LRD+TGV), and nuclear norm (NN) when applied to dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in rats with concanavalin A (ConA)-induced acute hepatic injury. The rats were divided into three groups: normal control (NC) (n = 10), ConA10 (n = 8), and ConA20 (n = 7). Rats in the ConA10 and ConA20 groups were intravenously injected with 10 and 20 mg/kg of ConA, respectively; those in the NC group were intravenously injected with the same volume of saline. DCE-MRI studies were performed using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA; 0.025 mmol Gd/kg) as a contrast agent (CA), 24 h after the ConA or saline injection. After the DCE-MRI study, we generated zero-filled and undersampled k-space data from the original images using a pseudoradial sampling scheme with 4 to 64 spokes. We subsequently reconstructed images from these data using the above regularizers and calculated the signal-to-error ratio (SERimg) and structural similarity index (SSIM) using the original and reconstructed images. We also calculated the area under the curve (AUC), rate of CA washout (λw), maximum relative enhancement (REmax), and time to REmax (Tmax) from time-intensity curves using an empirical mathematical model (EMM) and the signal-to-error ratio for curve fitting (SERfit) from the original and fit curves. We also compared the parameters obtained using the pseudoradial and Cartesian sampling schemes in the NC group. When using LRD+TV and LRD+TGV, both SERimg and SSIM were greater than those for the other regularizers at all spoke numbers studied; the SERfit for TGV was the greatest. When using TGV and LRD+TGV, in the majority of cases the AUCs did not significantly differ from those obtained from the original images, whereas those for LRD+TV and NN were significantly less at several spoke numbers. The λw for NN was significantly greater at numerous spoke numbers in the NC group; the REmax values for LRD+TV and NN were significantly less at several spoke numbers in all groups. The Tmax values for TV, TGV, and LRD+TGV were significantly greater at numerous spoke numbers in the NC group. Although there were significant differences in SERimg and SSIM between the pseudoradial and Cartesian sampling schemes, the kinetic parameters obtained by the EMM did not significantly differ between the two sampling schemes, with certain exceptions. In conclusion, our results suggest that simultaneous spatial and temporal regularization using TGV or LRD+TGV is useful for accelerating DCE-MRI without significant reduction in the accuracy of the kinetic parameter estimation, even at extremely low sampling factors.
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Affiliation(s)
- Kenya Murase
- Department of Future Diagnostic Radiology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
| | - Nobuo Kashiwagi
- Department of Future Diagnostic Radiology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Noriyuki Tomiyama
- Department of Diagnostic and Interventional Radiology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
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23
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Deng Y, Xia B, Chen Z, Wang F, Lv Y, Chen G. Stem Cell-based Therapy Strategy for Hepatic Fibrosis by Targeting Intrahepatic Cells. Stem Cell Rev Rep 2021; 18:77-93. [PMID: 34668120 DOI: 10.1007/s12015-021-10286-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2021] [Indexed: 12/11/2022]
Abstract
The whole liver transplantation is the most effective treatment for end-stage fibrosis. However, the lack of available donors, immune rejection and total cost of surgery remain as the key challenges in advancing liver fibrosis therapeutics. Due to the multi-differentiation and low immunogenicity of stem cells, treatment of liver fibrosis with stem cells has been considered as a valuable new therapeutic modality. The pathological progression of liver fibrosis is closely related to the changes in the activities of intrahepatic cells. Damaged hepatocytes, activated Kupffer cells and other inflammatory cells lead to hepatic stellate cells (HSCs) activation, further promoting apoptosis of damaged hepatocytes, while stem cells can work on fibrosis-related intrahepatic cells through relevant transduction pathways. Herein, this article elucidates the phenomena and the mechanisms of the crosstalk between various types of stem cells and intrahepatic cells including HSCs and hepatocytes in the treatment of liver fibrosis. Then, the important influences of chemical compositions, mechanical properties and blood flow on liver fibrosis models with stem cell treatment are emphasized. Clinical trials on stem cell-based therapy for liver fibrosis are also briefly summarized. Finally, continuing challenges and future directions of stem cell-based therapy for hepatic fibrosis are discussed. In short, stem cells play an important advantage and have a great potential in treating liver fibrosis by interacting with intrahepatic cells. Clarifying how stem cells interact with intrahepatic cells to change the progression of liver fibrosis is of great significance for a deeper understanding of liver fibrosis mechanisms and targeted therapy.
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Affiliation(s)
- Yaxin Deng
- School of Pharmacy and Bioengineering, Chongqing University of Technology, No. 69 Hongguang Avenue, Banan District, Chongqing, 400054, People's Republic of China.,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, People's Republic of China
| | - Bin Xia
- Engineering Research Center for Waste Oil Recovery Technology and Equipment, Ministry of Education, Chongqing Technology and Business University, Chongqing, 400067, People's Republic of China
| | - Zhongmin Chen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, No. 69 Hongguang Avenue, Banan District, Chongqing, 400054, People's Republic of China.,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, People's Republic of China
| | - Fuping Wang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, No. 69 Hongguang Avenue, Banan District, Chongqing, 400054, People's Republic of China.,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, People's Republic of China
| | - Yonggang Lv
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing, 400044, People's Republic of China.,State Key Laboratory of New Textile Materials and Advanced Processing Technologies, Wuhan Textile University, Wuhan, 430200, People's Republic of China
| | - Guobao Chen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, No. 69 Hongguang Avenue, Banan District, Chongqing, 400054, People's Republic of China. .,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, People's Republic of China.
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24
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Stephen Robert J, Peddha MS, Srivastava AK. Effect of Silymarin and Quercetin in a Miniaturized Scaffold in Wistar Rats against Non-alcoholic Fatty Liver Disease. ACS OMEGA 2021; 6:20735-20745. [PMID: 34423182 PMCID: PMC8374897 DOI: 10.1021/acsomega.1c00555] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 07/26/2021] [Indexed: 05/02/2023]
Abstract
Silymarin and quercetin (SQ) are known antioxidants with substantial free radical scavenging activities. The efficacy of SQ activity is restricted due to poor absorption and availability. This study aims to increase the hepatoprotective activity of SQ by a newer delivery technique. We have optimized a technique, miniaturized scaffold (MS), for the delivery of active compounds of SQ. SQ molecules were embedded in MS and characterized by morphology, particle size, miniaturization efficiency, and functional group. Further, the hepatoprotective effects of MSQ were investigated through in vitro and in vivo methods. Hepatotoxicity was induced in rats by carbon tetrachloride (CCl4), and subsequently, hepatotoxic rats were treated with the miniaturized scaffold of SQ (MSQ) for 8 weeks. The body weight were significantly high in groups fed with MSQ. A substantial decrease in triglyceride, total cholesterol, low-density lipoprotein, alanine aminotransferase, and aspartate aminotransferase activities were observed in rats treated with MSQ. Similarly, rats treated with MSQ exhibited lower lipid accumulation in the hepatocytes. The experiments clearly demonstrated the efficacy of MSQ as a superior hepatoprotective agent against non-alcoholic fatty liver disease simulated through toxicity induced by CCl4.
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Affiliation(s)
- Jaisheela
Marry Stephen Robert
- Department
of Food Safety and Analytical Quality Control Laboratory, CSIR- Central Food Technological Research Institute, Mysuru, Karnataka 570 020, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Muthukumar Serva Peddha
- Department
of Biochemistry, CSIR- Central Food Technological
Research Institute, Mysuru, 570 020 Karnataka, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Alok Kumar Srivastava
- Department
of Food Safety and Analytical Quality Control Laboratory, CSIR- Central Food Technological Research Institute, Mysuru, Karnataka 570 020, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
- .
Phone: 91-821-2514972. Fax: 91-821-2517233
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25
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Vukićević D, Rovčanin B, Gopčević K, Stanković S, Vučević D, Jorgačević B, Mladenović D, Vesković M, Samardžić J, Ješić R, Radosavljević T. The Role of MIF in Hepatic Function, Oxidative Stress, and Inflammation in Thioacetamide-induced Liver Injury in Mice: Protective Effects of Betaine. Curr Med Chem 2021; 28:3249-3268. [PMID: 33148149 DOI: 10.2174/0929867327666201104151025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 09/25/2020] [Accepted: 09/27/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that contributes to the inflammatory response to chemical liver injury. This cytokine exhibits pro- and anti-inflammatory effects depending on the etiology and stage of liver disease. OBJECTIVE Our study aimed to investigate the role of MIF in oxidative stress and inflammation in the liver, and modulatory effects of betaine on MIF in thioacetamide (TAA)-induced chronic hepatic damage in mice. METHODS The experiment was performed on wild type and knockout MIF-/- C57BL/6 mice. They were divided into the following groups: control; Bet-group that received betaine (2% wt/v dissolved in drinking water); MIF-/- mice group; MIF-/-+Bet; TAA-group that received TAA (200 mg/kg b.w.), intraperitoneally, 3x/week/8 weeks); TAA+Bet; MIF-/-+TAA, and MIF-/-+TAA+Bet. In TAA- and Bet-treated groups, animals received the same doses. After eight weeks of treatment, blood samples were collected for biochemical analysis, and liver specimens were prepared for the assessment of parameters of oxidative stress and inflammation. RESULTS In MIF-/-mice, TAA reduced transaminases, γ-glutamyltranspeptidase, bilirubin, malondialdehyde (MDA), oxidative protein products (AOPP), total oxidant status (TOS), C-reactive protein (CRP), IL-6, IFN-γ, and increased thiols and total antioxidant status (TAS). Betaine attenuated the mechanism of MIF and mediated effects in TAA-induced liver injury, reducing transaminases, γ-glutamyltranspeptidase, bilirubin, MDA, AOPP, TOS, CRP, IL-6, IFN-g, and increasing thiols. CONCLUSION MIF is a mediator in hepatotoxic, pro-oxidative, and proinflammatoryeffects of TAA-induced liver injury. MIF-targeted therapy can potentially mitigate oxidative stress and inflammation in the liver, but the exact mechanism of its action requires further investigation. Betaine increases anti-oxidative defense and attenuates hepatotoxic effects of MIF, suggesting that betaine can be used for the prevention and treatment of liver damage.
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Affiliation(s)
- Dušan Vukićević
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Branislav Rovčanin
- Center for Endocrine Surgery, Clinical Center of Serbia, Belgrade, Serbia
| | - Kristina Gopčević
- Institute of Chemistry in Medicine "Prof. Dr. Petar Matavulj", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Sanja Stanković
- Centre of Medical Biochemistry, Clinical Centre of Serbia, Belgrade, Serbia
| | - Danijela Vučević
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Bojan Jorgačević
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dušan Mladenović
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milena Vesković
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Janko Samardžić
- Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Dr. Subotica 9, 11000 Belgrade, Serbia
| | - Rada Ješić
- Institute of Digestive Diseases, Clinical Centre of Serbia, Belgrade, Serbia
| | - Tatjana Radosavljević
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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26
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Sepehrinezhad A, Shahbazi A, Sahab Negah S, Joghataei MT, Larsen FS. Drug-induced-acute liver failure: A critical appraisal of the thioacetamide model for the study of hepatic encephalopathy. Toxicol Rep 2021; 8:962-970. [PMID: 34026559 PMCID: PMC8122178 DOI: 10.1016/j.toxrep.2021.04.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/17/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) following acute and chronic liver failure is defined as a complex of neuropsychiatric abnormalities, such as discrete personal changes, sleep disorder, forgetfulness, confusion, and decreasing the level of consciousness to coma. The use and design of suitable animal models that represent clinical features and pathological changes of HE are valuable to map the molecular mechanisms that result in HE. Among different types of animal models, thioacetamide (TAA) has been used extensively for the induction of acute liver injury and HE. This agent is not directly hepatotoxic but its metabolites induce liver injury through the induction of oxidative stress and produce systemic inflammation similar to that seen in acute HE patients. In this short review article, we shortly review the most important pathological findings in animal models of acute HE following the administration of TAA.
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Key Words
- ALT, alanine aminotransferase
- AQP4, aquaporin 4 water channel
- AST, aspartate aminotransferase
- Acute liver failure
- Animal model
- B7, B7 molecules (CD80+CD86)
- BBB, blood-brain barrier
- CBF, cerebral blood flow
- CCL2, chemokine ligand 2
- CNS, central nervous system
- CTLA4, Cytotoxic T-lymphocyte-associated Protein 4
- CYP2E1, Cytochrome P450 family 2 subfamily E member 1
- GFAP, glial fibrillary acidic protein
- HE, hepatic encephalopathy
- Hepatic encephalopathy
- IL-6, interleukin 6
- IL-β, interleukin 1 β
- Iba1, ionized calcium-binding adaptor molecule 1
- JNK, c-Jun N-terminal kinase
- NAC, N-acetylcysteine
- NF-κB, nuclear factor κB
- OA, L-ornithine-l-aspartate
- ROS, reactive oxygen species
- TAA, thioacetamide
- TASO, thioacetamide sulfoxide
- TASO2, thioacetamide sulfdioxide
- TLR-2, toll-like receptor 2
- TLR-4, toll-like receptor 4
- TNFα, tumor necrosis factor α
- Thioacetamide
- Toxicity pathway
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Taghi Joghataei
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Fin Stolze Larsen
- Department of Hepatology CA-3163, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
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27
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Jia F, Deng F, Xu P, Li S, Wang X, Hu P, Ren H, Tong S, Yin W. NOD1 Agonist Protects Against Lipopolysaccharide and D-Galactosamine-Induced Fatal Hepatitis Through the Upregulation of A20 Expression in Hepatocytes. Front Immunol 2021; 12:603192. [PMID: 33746949 PMCID: PMC7969647 DOI: 10.3389/fimmu.2021.603192] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 02/17/2021] [Indexed: 01/13/2023] Open
Abstract
Increasing evidence suggests that NODs are involved in liver diseases; however, the underlying mechanisms remain obscure. In the present study, we analyzed the effect of NOD1 agonist pretreatment on acute liver failure induced by lipopolysaccharide (LPS) in D-galactosamine (D-GalN)-sensitized mice. We found that pretreatment with the NOD1 agonist markedly reduced LPS/D-GalN-induced mortality, elevation of serum ALT levels, and hepatocyte apoptosis. The protective effect of NOD1 agonist was independent of tumor necrosis factor (TNF)-α inhibition. NOD1 agonist pretreatment also attenuated TNF-α/D-GalN-induced apoptotic liver damage. The anti-apoptotic protein A20 expression was more pronounced in NOD1 agonist pretreated mice than in controls, and knockdown of A20 abrogated the protective effect of NOD1 agonist on LPS/D-GalN-induced liver injury and hepatocyte apoptosis. Further experiments showed that NOD1 agonist-induced A20 upregulation required the presence of kupffer cells and TNF-α. Taken together, our data strongly indicate that NOD1 is involved in the regulation of liver injury and could be a potential therapeutic target for liver diseases.
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Affiliation(s)
- Fang Jia
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Endocrinology, The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), Xi'an Jiaotong University, Xi'an, China
| | - Fuxue Deng
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), Xi'an Jiaotong University, Xi'an, China
| | - Pan Xu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shiying Li
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xuefu Wang
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shiwen Tong
- Department of Clinical Nutrition, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenwei Yin
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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28
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Avni D, Harikumar KB, Sanyal AJ, Spiegel S. Deletion or inhibition of SphK1 mitigates fulminant hepatic failure by suppressing TNFα-dependent inflammation and apoptosis. FASEB J 2021; 35:e21415. [PMID: 33566377 PMCID: PMC8491138 DOI: 10.1096/fj.202002540r] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/15/2021] [Accepted: 01/20/2021] [Indexed: 12/13/2022]
Abstract
Acute liver failure (ALF) causes severe liver dysfunction that can lead to multi-organ failure and death. Previous studies suggest that sphingosine kinase 1 (SphK1) protects against hepatocyte injury, yet not much is still known about its involvement in ALF. This study examines the role of SphK1 in D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced ALF, which is a well-established experimental mouse model that mimics the fulminant hepatitis. Here we report that deletion of SphK1, but not SphK2, dramatically decreased GalN/LPS-induced liver damage, hepatic apoptosis, serum alanine aminotransferase levels, and mortality rate compared to wild-type mice. Whereas GalN/LPS treatment-induced hepatic activation of NF-κB and JNK in wild-type and SphK2-/- mice, these signaling pathways were reduced in SphK1-/- mice. Moreover, repression of ALF in SphK1-/- mice correlated with decreased expression of the pro-inflammatory cytokine TNFα. Adoptive transfer experiments indicated that SphK1 in bone marrow-derived infiltrating immune cells but not in host liver-resident cells, contribute to the development of ALF. Interestingly, LPS-induced TNFα production was drastically suppressed in SphK1-deleted macrophages, whereas IL-10 expression was markedly enhanced, suggesting a switch to the anti-inflammatory phenotype. Finally, treatment with a specific SphK1 inhibitor ameliorated inflammation and protected mice from ALF. Our findings suggest that SphK1 regulates TNFα secretion from macrophages and inhibition or deletion of SphK1 mitigated ALF. Thus, a potent inhibitor of SphK1 could potentially be a therapeutic agent for fulminant hepatitis.
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Affiliation(s)
- Dorit Avni
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Kuzhuvelil B. Harikumar
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Arun J. Sanyal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
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Ansari MA, Raish M, Bin Jardan YA, Ahmad A, Shahid M, Ahmad SF, Haq N, Khan MR, Bakheet SA. Sinapic acid ameliorates D-galactosamine/lipopolysaccharide-induced fulminant hepatitis in rats: Role of nuclear factor erythroid-related factor 2/heme oxygenase-1 pathways. World J Gastroenterol 2021; 27:592-608. [PMID: 33642831 PMCID: PMC7901048 DOI: 10.3748/wjg.v27.i7.592] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/30/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sinapic acid (SA) has been shown to have various pharmacological properties such as antioxidant, antifibrotic, anti-inflammatory, and anticancer activities. Its mechanism of action is dependent upon its ability to curb free radical production and protect against oxidative stress-induced tissue injuries. AIM To study the hepatoprotective effects of SA against lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver failure (ALF) in rats. METHODS Experimental ALF was induced with an intraperitoneal (i.p.) administration of 8 μg LPS and 800 mg/kg D-GalN in normal saline. SA was administered orally once daily starting 7 d before LPS/D-GalN treatment. RESULTS Data showed that SA ameliorates acute liver dysfunction, decreases serum levels of alanine transaminase (ALT), and aspartate aminotransferase (AST), as well as malondialdehyde (MDA) and NO levels in ALF model rats. However, pretreatment with SA (20 mg/kg and 40 mg/kg) reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and levels of inflammatory cytokines (tumor necrosis factor-α and interleukin 6). Also, SA increased the activity of the nuclear factor erythroid-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway. CONCLUSION In conclusion, SA offers significant protection against LPS/D-GalN-induced ALF in rats by upregulating Nrf2/HO-1 and downregulating NF-κB.
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Affiliation(s)
- Mushtaq Ahmad Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad Raish
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Yousef A Bin Jardan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ajaz Ahmad
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mudassar Shahid
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sheikh Fayaz Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Nazrul Haq
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad Rashid Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Saleh A Bakheet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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Mohammadi H, Heidari R, Niknezhad SV, Jamshidzadeh A, Farjadian F. In vitro and in vivo Evaluation of Succinic Acid-Substituted Mesoporous Silica for Ammonia Adsorption: Potential Application in the Management of Hepatic Encephalopathy. Int J Nanomedicine 2020; 15:10085-10098. [PMID: 33363368 PMCID: PMC7754271 DOI: 10.2147/ijn.s271883] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 11/20/2020] [Indexed: 12/21/2022] Open
Abstract
Purpose Hepatic encephalopathy (HE) is a critical situation in which liver failure affects brain function. HE could result in a state of coma and death. The liver is the main organ for ammonium ion (NH4 +) metabolism. Hence, acute and/or chronic liver failure could lead to hyperammonemia. NH4 + is the most suspected neurotoxic agent in HE. Thus, finding new therapeutic options to decrease plasma and brain NH4 + levels has a significant clinical value. Mesoporous silica (MS) particles have revolutionized many aspects of pharmaceutical sciences, including drug delivery systems. Moreover, recently, MS has been applied as agents for the detoxification of chemicals (eg, drugs and poisons). Methods First, MS particles containing amine groups (MS-NH2) were synthesized in co-condensation processes. Then, the structure was modified by succinic anhydride to have MS-SA. The MS-SA was characterized (FT-IR, XRD, X-ray photoelectron spectroscopy (XPS), DLS-Zeta FESEM-EDX, and HRTEM). Then, the potential of MS-NH2 and MS-SA particles in adsorption of NH4 + was investigated in vitro and in vivo. MS-NH2 and MS-SA were incubated with increasing concentrations (0.1-10 mM) of NH4 +, and the scavenging capacity of the investigated particles was evaluated. On the other hand, different doses (1 and 5 mg/kg per day) of nanoparticles were administered to a hyperammonemia animal model. Results It was figured out that both MS-NH2 and MS-SA significantly scavenged NH4 + in the in vitro model. However, the NH4 + scavenging capability of MS-SA was more significant. Administration of MS-NH2 and MS-SA also considerably decreased the level of ammonium in plasma and brain and improved cognitive and locomotor activity in hyperammonemic animals. The effects of MS-SA were more significant than MS-NH2 in the HE animal model. Conclusion Collectively, our data suggest that MS particles, especially succinic acid-functionalized MS, could act as special ancillary treatment in HE as a critical clinical complication.
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Affiliation(s)
- Hamidreza Mohammadi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyyed Vahid Niknezhad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Akram Jamshidzadeh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Farjadian
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Jin Y, Wang H, Yi K, Lv S, Hu H, Li M, Tao Y. Applications of Nanobiomaterials in the Therapy and Imaging of Acute Liver Failure. NANO-MICRO LETTERS 2020; 13:25. [PMID: 34138224 PMCID: PMC8187515 DOI: 10.1007/s40820-020-00550-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 10/22/2020] [Indexed: 05/02/2023]
Abstract
This review focuses on the therapeutic mechanisms, targeting strategies of various nanomaterials in acute liver failure, and recent advances of diverse nanomaterials for acute liver failure therapy, diagnosis, and imaging. This review provides an outlook on the applications of nanomaterials, especially on the new horizons in acute liver failure therapy, and inspires broader interests across various disciplines. Acute liver failure (ALF), a fatal clinical disease featured with overwhelming hepatocyte necrosis, is a grand challenge in global health. However, a satisfactory therapeutic option for curing ALF is still absent, other than liver transplantation. Nanobiomaterials are currently being developed for the diagnosis and treatment of ALF. The liver can sequester most of nanoparticles from blood circulation, which becomes an intrinsic superiority for nanobiomaterials targeting hepatic diseases. Nanobiomaterials can enhance the bioavailability of free drugs, thereby significantly improving the therapeutic effects in ALF. Nanobiomaterials can also increase the liver accumulation of therapeutic agents and enable more effective targeting of the liver or specific liver cells. In addition, stimuli-responsive, optical, or magnetic nanomaterials exhibit great potential in the therapeutical, diagnostic, and imaging applications in ALF. Therefore, therapeutic agents in combination with nanobiomaterials increase the specificity of ALF therapy, diminish adverse systemic effects, and offer a multifunctional theranostic platform. Nanobiomaterial holds excellent significance and prospects in ALF theranostics. In this review, we summarize the therapeutic mechanisms and targeting strategies of various nanobiomaterials in ALF. We highlight recent developments of diverse nanomedicines for ALF therapy, diagnosis, and imaging. Furthermore, the challenges and future perspectives in the theranostics of ALF are also discussed.
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Affiliation(s)
- Yuanyuan Jin
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People's Republic of China
| | - Haixia Wang
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People's Republic of China
| | - Ke Yi
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People's Republic of China
| | - Shixian Lv
- Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA
| | - Hanze Hu
- Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People's Republic of China.
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People's Republic of China.
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Koblihová E, Mrázová I, Vaňourková Z, Maxová H, Ryska M, Froněk J. Sex-linked differences in the course of thioacetamide-induced acute liver failure in Lewis rats. Physiol Res 2020; 69:835-845. [PMID: 32901492 DOI: 10.33549/physiolres.934499] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Acute liver failure (ALF) is a clinical syndrome with high mortality rate, resulting from widespread hepatocyte damage. Its pathophysiological background is still poorly understood and preclinical studies evaluating pathophysiology and new potential therapeutic measures are needed. The model of ALF induced by administration of thioacetamide (TAA) in Lewis rats is recommended as optimal; however, the limitation of previous studies was that they were performed predominantly in male rats. In view of the growing recognition that sex as a biological variable should be taken into consideration in preclinical research, we examined its role in the development of TAA-induced ALF in Lewis rats. We found that, first, intact male Lewis rats showed lower survival rate than their female counterparts, due to augmented liver injury documented by higher plasma ammonia, and bilirubin levels and alanine aminotransferase activity. Second, in female rats castration did not alter the course of TAA-induced ALF whereas in the male gonadectomy improved the survival rate and attenuated liver injury, reducing it to levels observed in their female counterparts. In conclusion, we found that Lewis rats show a remarkable sexual dimorphism with respect to TAA-induced ALF, and male rats display dramatically poorer prognosis as compared with the females. We showed that testosterone is responsible for the deterioration of the course of TAA-induced ALF in male rats. In most general terms, our findings indicate that in the preclinical studies of the pathophysiology and treatment of ALF (at least of the TAA-induced form) the sex-linked differences should be seriously considered.
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Affiliation(s)
- E Koblihová
- Department of Surgery, Second Faculty of Medicine, Charles University and Central Military Hospital, Prague, Czech Republic.
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Mohammed SAA, Khan RA, El-Readi MZ, Emwas AH, Sioud S, Poulson BG, Jaremko M, Eldeeb HM, Al-Omar MS, Mohammed HA. Suaeda vermiculata Aqueous-Ethanolic Extract-Based Mitigation of CCl 4-Induced Hepatotoxicity in Rats, and HepG-2 and HepG-2/ADR Cell-Lines-Based Cytotoxicity Evaluations. PLANTS 2020; 9:plants9101291. [PMID: 33003604 PMCID: PMC7601535 DOI: 10.3390/plants9101291] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 12/16/2022]
Abstract
Suaeda vermiculata, an edible halophytic plant, used by desert nomads to treat jaundice, was investigated for its hepatoprotective bioactivity and safety profile on its mother liquor aqueous-ethanolic extract. Upon LC-MS (Liquid Chromatography-Mass Spectrometry) analysis, the presence of several constituents including three major flavonoids, namely quercetin, quercetin-3-O-rutinoside, and kaempferol-O-(acetyl)-hexoside-pentoside were confirmed. The aqueous-ethanolic extract, rich in antioxidants, quenched the DPPH (1,1-diphenyl-2-picrylhydrazyl) radicals, and also showed noticeable levels of radical scavenging capacity in ABTS (2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid) assay. For the hepatoprotective activity confirmation, the male rat groups were fed daily, for 7 days (n = 8/group, p.o.), either carboxyl methylcellulose (CMC) 0.5%, silymarin 200 mg/kg, the aqueous-ethanolic extract of the plant Suaeda vermiculata (100, 250, and 500 mg/kg extract), or quercetin (100 mg/kg) alone, and on day 7 of the administrations, all the animal groups, excluding a naïve (250 mg/kg aqueous-ethanolic extract-fed), and an intact animal group were induced hepatotoxicity by intraperitoneally administering carbon tetrachloride (CCl4). All the animals were sacrificed after 24 h, and aspartate transaminase and alanine transaminase serum levels were observed, which were noted to be significantly decreased for the aqueous-ethanolic extract, silymarin, and quercetin-fed groups in comparison to the CMC-fed group (p < 0.0001). No noticeable adverse effects were observed on the liver, kidney, or heart's functions of the naïve (250 mg/kg) group. The aqueous-ethanolic extract was found to be safe in the acute toxicity (5 g/kg) test and showed hepatoprotection and safety at higher doses. Further upon, the cytotoxicity testings in HepG-2 and HepG-2/ADR (Adriamycin resistant) cell-lines were also investigated, and the IC50 values were recorded at 56.19±2.55 µg/mL, and 78.40±0.32 µg/mL (p < 0.001, Relative Resistance RR 1.39), respectively, while the doxorubicin (Adriamycin) IC50 values were found to be 1.3±0.064, and 4.77±1.05 µg/mL (p < 0.001, RR 3.67), respectively. The HepG-2/ADR cell-lines when tested in a combination of the aqueous-ethanolic extract with doxorubicin, a significant reversal in the doxorubicin's IC50 value by 2.77 folds (p < 0.001, CI = 0.56) was noted as compared to the cytotoxicity test where the extract was absent. The mode of action for the reversal was determined to be synergistic in nature indicating the role of the aqueous-ethanolic extract.
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Affiliation(s)
- Salman A. A. Mohammed
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia;
- Correspondence: (S.A.A.M.); (R.A.K.); (H.A.M.); Tel.: +966-(0)530309899 (S.A.A.M.); +966-(0)508384296 (R.A.K.); +966-(0)566176074 (H.A.M.)
| | - Riaz A. Khan
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia;
- Correspondence: (S.A.A.M.); (R.A.K.); (H.A.M.); Tel.: +966-(0)530309899 (S.A.A.M.); +966-(0)508384296 (R.A.K.); +966-(0)566176074 (H.A.M.)
| | - Mahmoud Z. El-Readi
- Department of Clinical Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
- Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt
| | - Abdul-Hamid Emwas
- King Abdullah University of Science and Technology (KAUST), Core Labs, Thuwal 23955-6900, Saudi Arabia; (A.-H.E.); (S.S.)
| | - Salim Sioud
- King Abdullah University of Science and Technology (KAUST), Core Labs, Thuwal 23955-6900, Saudi Arabia; (A.-H.E.); (S.S.)
| | - Benjamin G. Poulson
- King Abdullah University of Science and Technology (KAUST), Biological and Environmental Sciences and Engineering Division (BESE), Thuwal, 23955-6900, Saudi Arabia; (B.G.P); (M.J.)
| | - Mariusz Jaremko
- King Abdullah University of Science and Technology (KAUST), Biological and Environmental Sciences and Engineering Division (BESE), Thuwal, 23955-6900, Saudi Arabia; (B.G.P); (M.J.)
| | - Hussein M. Eldeeb
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia;
- Department of Biochemistry, Faculty of Medicine, Al-Azhar University, Assiut, 71524, Egypt
| | - Mohsen S. Al-Omar
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia;
- Medicinal Chemistry and Pharmacognosy Department, Faculty of Pharmacy, JUST, Irbid 22110, Jordan
| | - Hamdoon A. Mohammed
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia;
- Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Cairo, 11371, Egypt
- Correspondence: (S.A.A.M.); (R.A.K.); (H.A.M.); Tel.: +966-(0)530309899 (S.A.A.M.); +966-(0)508384296 (R.A.K.); +966-(0)566176074 (H.A.M.)
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Rousta AM, Mirahmadi SMS, Shahmohammadi A, Ramzi S, Baluchnejadmojarad T, Roghani M. S-allyl cysteine, an active ingredient of garlic, attenuates acute liver dysfunction induced by lipopolysaccharide/ d-galactosamine in mouse: Underlying mechanisms. J Biochem Mol Toxicol 2020; 34:e22518. [PMID: 32453893 DOI: 10.1002/jbt.22518] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 03/31/2020] [Accepted: 04/23/2020] [Indexed: 12/15/2022]
Abstract
In the present study, beneficial effect of S-allyl cysteine (SAC) was evaluated in the lipopolysaccharide/d-galactosamine (LPS/d-Gal) model of acute liver injury (ALI). To mimic ALI, LPS and d-Gal (50 μg/kg and 400 mg/kg, respectively) were intraperitoneally administered and animals received SAC per os (25 or 100 mg/kg/d) for 3 days till 1 hour before LPS/d-Gal injection. Pretreatment of LPS/d-Gal group with SAC-lowered activities of alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase and partially reversed inappropriate alterations of hepatic oxidative stress- and inflammation-related biomarkers including liver reactive oxygen species, malondialdehyde, and hepatic activity of the defensive enzyme superoxide dismutase, ferric reducing antioxidant power (FRAP), toll-like receptor-4 (TLR4), cyclooxygenase 2, NLR family pyrin domain containing 3 (NLRP3), caspase 1, nuclear factor κB (NF-κB), interleukin 1β (IL-1β), IL-6, tumor necrosis factor-α, and myeloperoxidase activity. Additionally, SAC was capable to ameliorate apoptotic biomarkers including caspase 3 and DNA fragmentation. In summary, SAC can protect liver against LPS/d-Gal by attenuation of neutrophil infiltration, oxidative stress, inflammation, apoptosis, and pyroptosis which is partly linked to its suppression of TLR4/NF-κB/NLRP3 signaling.
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Affiliation(s)
| | | | | | - Samira Ramzi
- Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mehrdad Roghani
- Neurophysiology Research Center, Shahed University, Tehran, Iran
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Memon A, Pyao Y, Jung Y, Lee JI, Lee WK. A Modified Protocol of Diethylnitrosamine Administration in Mice to Model Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:ijms21155461. [PMID: 32751728 PMCID: PMC7432842 DOI: 10.3390/ijms21155461] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/27/2020] [Accepted: 07/28/2020] [Indexed: 12/24/2022] Open
Abstract
We aimed to create an animal model for hepatocellular carcinoma (HCC) with a short time, a high survival rate, as well as a high incidence of HCC in both males and females than previously reported. The Diethylnitrosamine (DEN) model has an age-related effect. A single dose of DEN treatment is not enough in young mice up to 50 weeks. The same pattern is shown in an adult with multiple-dose trials whether or not there is some promotion agent. In this study, two-week old C57BL6 mice were given a total of eight doses of DEN, initially 20mg/kg body weight, and then 30mg/kg in the third week, followed by 50mg/kg for the last six weeks. The first group is DEN treatment only and the other two groups received thioacetamide (TAA) treatment for four or eight weeks after one week of rest from the last DEN treatment. An autopsy was performed after 24 weeks of the initial dose of DEN in each group. The cellular arrangement of HCC in the entire group was well-differentiated carcinoma and tumor presence with no significant impact on the survival of mice. Increased levels of the biochemical markers in serum, loss of tissue architecture, hepatocyte death, and proliferation were highly activated in all tumor-induced groups. This finding demonstrates an improved strategy to generate an animal model with a high occurrence of tumors combined with cirrhosis in a short time regardless of sex for researchers who want to investigate liver cancer-related.
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Affiliation(s)
- Azra Memon
- Department of Biomedical Sciences, School of Medicine, Inha University, Incheon 22212, Korea; (A.M.); (Y.P.); (Y.J.)
| | - Yuliya Pyao
- Department of Biomedical Sciences, School of Medicine, Inha University, Incheon 22212, Korea; (A.M.); (Y.P.); (Y.J.)
| | - Yerin Jung
- Department of Biomedical Sciences, School of Medicine, Inha University, Incheon 22212, Korea; (A.M.); (Y.P.); (Y.J.)
| | - Jung Il Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea;
| | - Woon Kyu Lee
- Department of Biomedical Sciences, School of Medicine, Inha University, Incheon 22212, Korea; (A.M.); (Y.P.); (Y.J.)
- Correspondence: ; Tel.:+82-32-860-9882; Fax: +82-32-885-8302
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Mohammadi H, Sayad A, Mohammadi M, Niknahad H, Heidari R. N-acetyl cysteine treatment preserves mitochondrial indices of functionality in the brain of hyperammonemic mice. Clin Exp Hepatol 2020; 6:106-115. [PMID: 32728627 PMCID: PMC7380475 DOI: 10.5114/ceh.2020.95814] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 02/20/2020] [Indexed: 12/11/2022] Open
Abstract
AIM OF THE STUDY Acute or chronic live failure could result in hyperammonemia and hepatic encephalopathy (HE). HE is a clinical complication characterized by severe cognitive dysfunction and coma. The ammonium ion (NH4 +) is the most suspected toxic molecule involved in the pathogenesis of HE. NH4 + is a neurotoxic agent. Different mechanisms, including oxidative/nitrosative stress, inflammatory response, excitotoxicity, and mitochondrial impairment, are proposed for NH4 +-induced neurotoxicity. N-acetyl cysteine (NAC) is a well-known thiol-reductant and antioxidant agent. Several investigations also mentioned the positive effects of NAC on mitochondrial function. In the current study, the effect of NAC treatment on brain mitochondrial indices and energy status was investigated in an animal model of HE. MATERIAL AND METHODS Acetaminophen (APAP)-induced acute liver failure was induced by a single dose of the drug (800 mg/kg, i.p.) to C57BL/6J mice. Plasma and brain levels of NH4 + were measured. Then, brain mitochondria were isolated, and several indices, including mitochondrial depolarization, ATP level, lipid peroxidation, glutathione content, mitochondrial permeabilization, and dehydrogenase activity, were assessed. RESULTS A significant increase in plasma and brain NH4 + was evident in APAP-treated animals. Moreover, mitochondrial indices of functionality were impaired, and mitochondrial oxidative stress biomarkers were significantly increased in APAP-treated mice. It was found that NAC treatment (100, 200, and 400 mg/kg, i.p.) significantly mitigated mitochondrial impairment in the brain of APAP-treated animals. CONCLUSIONS These data suggest the effects of NAC on brain mitochondrial function and energy status as a pivotal mechanism involved in its neuroprotective properties during HE.
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Affiliation(s)
- Hamidreza Mohammadi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abolfazl Sayad
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohsen Mohammadi
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Hossein Niknahad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Crespo I, Fernández-Palanca P, San-Miguel B, Álvarez M, González-Gallego J, Tuñón MJ. Melatonin modulates mitophagy, innate immunity and circadian clocks in a model of viral-induced fulminant hepatic failure. J Cell Mol Med 2020; 24:7625-7636. [PMID: 32468679 PMCID: PMC7339179 DOI: 10.1111/jcmm.15398] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/23/2020] [Accepted: 04/27/2020] [Indexed: 12/12/2022] Open
Abstract
The haemorrhagic disease virus (RHDV) is a non‐cultivable virus that promotes in rabbits an acute disease which accomplishes many characteristics of an animal model of fulminant hepatic failure (FHF). Beneficial effects of melatonin have been reported in RHDV‐infected rabbits. This study investigated whether protection against viral‐derived liver injury by melatonin is associated with modulation of mitophagy, innate immunity and clock signalling. Rabbits were experimentally infected with 2 × 104 haemagglutination units of a RHDV isolate and killed at 18, 24 and 30 hours after infection (hpi). Melatonin (20 mg/kg body weight ip) was administered at 0, 12 and 24 hpi. RHDV infection induced mitophagy, with the presence of a high number of mitophagosomes in hepatocytes and increased expression of mitophagy genes. Greater expression of main innate immune intermediaries and inflammasome components was also found in livers with RHDV‐induced FHF. Both mitophagy and innate immunity activation was significantly hindered by melatonin. FHF induction also elicited an early dysregulation in clock signalling, and melatonin was able to prevent such circadian disruption. Our study discloses novel molecular routes contributing to RHDV‐induced damage progression and supports the potential of melatonin as a promising therapeutic option in human FHF.
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Affiliation(s)
- Irene Crespo
- Institute of Biomedicine (IBIOMED), University of León, León, Spain.,Department of Functional Biology, University of Oviedo, Oviedo, Spain
| | | | | | | | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), University of León, León, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - María Jesús Tuñón
- Institute of Biomedicine (IBIOMED), University of León, León, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
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Frank D, Savir S, Gruenbaum BF, Melamed I, Grinshpun J, Kuts R, Knyazer B, Zlotnik A, Vinokur M, Boyko M. Inducing Acute Liver Injury in Rats via Carbon Tetrachloride (CCl4) Exposure Through an Orogastric Tube. J Vis Exp 2020. [PMID: 32420997 DOI: 10.3791/60695] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Acute liver injury (ALI) plays a crucial role in the development of hepatic failure, which is characterized by severe liver dysfunction including complications such as hepatic encephalopathy and impaired protein synthesis. Appropriate animal models are vital to test the mechanism and pathophysiology of ALI and investigate different hepatoprotective strategies. Due to its ability to perform chemical transformations, carbon tetrachloride (CCl4) is widely used in the liver to induce ALI through the formation of reactive oxygen species. CCl4 exposure can be performed intraperitoneally, by inhalation, or through a nasogastric or orogastric tube. Here, we describe a rodent model, in which ALI is induced by CCl4 exposure through an orogastric tube. This method is inexpensive, easily performed, and has minimal hazard risk. The model is highly reproducible and can be widely used to determine the efficacy of potential hepatoprotective strategies and assess markers of liver injury.
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Affiliation(s)
- Dmitry Frank
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev
| | - Shiri Savir
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev
| | | | - Israel Melamed
- Department of Neurosurgery, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev
| | - Julia Grinshpun
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev
| | - Ruslan Kuts
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev
| | - Boris Knyazer
- Department of Ophthalmology, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev
| | - Alexander Zlotnik
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev
| | - Max Vinokur
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev
| | - Matthew Boyko
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev;
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Pasqua M, Pereira U, Messina A, de Lartigue C, Vigneron P, Dubart-Kupperschmitt A, Legallais C. HepaRG Self-Assembled Spheroids in Alginate Beads Meet the Clinical Needs for Bioartificial Liver. Tissue Eng Part A 2020; 26:613-622. [PMID: 31914890 DOI: 10.1089/ten.tea.2019.0262] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
In liver tissue engineering, cell culture in spheroids is now well recognized to promote the maintenance of hepatic functions. However, the process leading to spheroids formation is time consuming, costly, and not easy to scale-up for further use in human bioartificial liver (BAL) applications. In this study, we encapsulated HepaRG cells (precursors of hepatocyte-like cells) in 1.5% alginate beads without preforming spheroids. Starting from a given hepatic biomass, we analyzed cell differentiation and metabolic performance for further use in a fluidized-bed BAL. We observed that cells self-rearranged as aggregates within the beads and adequately differentiated over time, in the absence of any differentiating factors classically used. On day 14 postencapsulation, cells displayed a wide range of hepatic features necessary for the treatment of a patient in acute liver failure. These activities include albumin synthesis, ammonia and lactate detoxification, and the efficacy of the enzymes involved in the xenobiotic metabolism (such as CYP1A1/2). Impact statement It has been recognized that culturing cells in spheroids (SPHs) is advantageous as they better reproduce the three-dimensional physiological microenvironment. This approach can be exploited in bioartificial liver applications, where obtaining a functional hepatic biomass is the major challenge. Our study describes an original method for culturing hepatic cells in alginate beads that makes possible the autonomous formation of SPHs after 3 days of culture. In turn, the cells differentiate adequately and display a wide range of hepatic features. They are also capable of treating a pathological plasma model. Finally, this setup can easily be scaled-up to treat acute liver failure.
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Affiliation(s)
- Mattia Pasqua
- UMR CNRS 7338 Biomechanics & Bioengineering, Université de Technologie de Compiègne, Alliance Sorbonne Université, Compiègne, France
| | - Ulysse Pereira
- UMR CNRS 7338 Biomechanics & Bioengineering, Université de Technologie de Compiègne, Alliance Sorbonne Université, Compiègne, France
| | - Antonietta Messina
- DHU Hépatinov, Villejuif, France.,UMR_S1193 Inserm/Paris-Saclay University, Villejuif, France
| | - Claire de Lartigue
- UMR CNRS 7338 Biomechanics & Bioengineering, Université de Technologie de Compiègne, Alliance Sorbonne Université, Compiègne, France
| | - Pascale Vigneron
- UMR CNRS 7338 Biomechanics & Bioengineering, Université de Technologie de Compiègne, Alliance Sorbonne Université, Compiègne, France
| | | | - Cecile Legallais
- UMR CNRS 7338 Biomechanics & Bioengineering, Université de Technologie de Compiègne, Alliance Sorbonne Université, Compiègne, France.,DHU Hépatinov, Villejuif, France
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Wang X, Yang L, Wang J, Zhang Y, Dong R, Wu X, Yang CS, Zhang Z, Zhang J. A mouse model of subacute liver failure with ascites induced by step-wise increased doses of (-)-epigallocatechin-3-gallate. Sci Rep 2019; 9:18102. [PMID: 31792332 PMCID: PMC6888815 DOI: 10.1038/s41598-019-54691-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Accepted: 11/18/2019] [Indexed: 12/20/2022] Open
Abstract
Acute liver failure is divided into hyperacute, acute and subacute liver failure. Ascites is a common complication of subacute liver failure. Although animal models of acute liver failure have been established, the study of the pathogenesis of subacute liver failure with ascites complication is hampered by the lack of experimental animal model. The present study aimed at providing a mouse model of subacute liver failure with ascites complication. Kunming mice were intraperitoneally injected with (-)-epigallocatechin-3-gallate (EGCG), a redox-active polyphenol from green tea, for 32 consecutive days with step-wise increased dosage. The EGCG treatment resulted in liver failure as evidenced by extensive hepatocyte necrosis observed histologically along with significant elevation of serum alanine aminotransferase, aspartate aminotransferase, total bilirubin and direct bilirubin levels as well as significant reduction of serum albumin. Liver fibrosis was not observed by Masson staining and fibrosis-associated proteins were not increased. The mortality was less than 12% and the survival mice developed noticeable ascites. Hepatic thioredoxin and glutathione systems were activated by the EGCG. These adaptive responses might render most mice tolerable to the EGCG treatment. The EGCG treatment significantly up-regulated renal urea transporter A1 and promoted its trafficking to apical membrane. These alterations, known to increase water reabsorption, may be responsible, at least in part, for the formation of the ascites. Overall, the mice treated with gradually elevated doses of EGCG exhibits some of the features observed in patients with subacute liver failure, especially ascites. This mouse model is a useful tool for investigating the pathogenesis of subacute liver failure with ascites complication.
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Affiliation(s)
- Xiaoxiao Wang
- State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui, China
| | - Lumin Yang
- State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui, China
| | - Jiajia Wang
- State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui, China
| | - Yafei Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, P.R. China
| | - Ruixia Dong
- Department of Forestry and Technology, Lishui Vocational and Technical College, Lishui, Zhejiang, China
| | - Ximing Wu
- State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui, China
| | - Chung S Yang
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
- International Joint Research Laboratory of Tea Chemistry and Health Effects, Anhui Agricultural University, Hefei, Anhui, China
| | - Zhenhua Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, P.R. China.
| | - Jinsong Zhang
- State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui, China.
- International Joint Research Laboratory of Tea Chemistry and Health Effects, Anhui Agricultural University, Hefei, Anhui, China.
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Yu W, Lan X, Cai J, Wang X, Liu X, Ye X, Yang Q, Su Y, Xu B, Chen T, Li L, Sun H. Critical role of IL-1β in the pathogenesis of Agrocybe aegerita galectin-induced liver injury through recruiting T cell to liver. Biochem Biophys Res Commun 2019; 521:449-456. [PMID: 31676068 DOI: 10.1016/j.bbrc.2019.10.087] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 10/10/2019] [Indexed: 12/27/2022]
Abstract
Acute liver failure (ALF) can be the consequence of various etiologies, which immune response plays a pivotal role in the pathogenesis. For the diversity of etiologies, more animal models are still needed in this field. Here, we developed a new acute liver injury mouse model induced by a fungal lectin AAGL (Agrocybe aegerita galectin). Intravenous injection of AAGL could induce the infiltration and activation of T, NKT and NK cells in liver and T cell played an important role in the pathogenesis. However, compared with the widely used concanavalin A model, AAGL model showed different immune mechanism. Transcriptome analysis of live tissue suggested that inflammation mediated by chemokine and cytokine signaling pathway was different between AAGL and Con A model. Fluorescent quantitative PCR verification assay showed that IL-1β was expressed much higher in AAGL-treated mice and anti-IL-1β could ameliorate AAGL-induced liver injury by inhibiting NF-κB and p38 signaling pathway. The expression of CXCL9 which was responsible for T cell infiltration in liver was also inhibited in AAGL model. We found a critical role of IL-1β in the pathogenesis of AAGL model through recruiting T cells to liver, which highlighted that IL-1β antibody might be a candidate therapy for ALF.
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Affiliation(s)
- Wenhui Yu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Xianqing Lan
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Jie Cai
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Xueqing Wang
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Xiaomei Liu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Xiangdong Ye
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Qing Yang
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Yanting Su
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Bo Xu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Tielong Chen
- Department of Infections, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430072, China
| | - Lingyun Li
- Department of Immunology, College of Medicine, Shenzhen University, Shenzhen, 518061, China.
| | - Hui Sun
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China; Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University, Wuhan, 430072, China.
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Zhao S, Liu Y, Pu Z. Bone marrow mesenchymal stem cell-derived exosomes attenuate D-GaIN/LPS-induced hepatocyte apoptosis by activating autophagy in vitro. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:2887-2897. [PMID: 31695322 PMCID: PMC6707369 DOI: 10.2147/dddt.s220190] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 08/02/2019] [Indexed: 12/20/2022]
Abstract
Background Acute liver failure is an inflammation-mediated hepatocyte injury. Mesenchymal stem cell (MSC) transplantation is currently considered to be an effective treatment strategy for acute liver failure. Exosomes are an important paracrine factor that can be used as a direct therapeutic agent. However, the use of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) in the treatment of acute liver failure has not been reported. Purpose Here, we established a model of hepatocyte injury and apoptosis induced by D-galactosamine and lipopolysaccharide (D-GalN/LPS) to study the protective effect of BMSC-Exos on hepatocyte apoptosis, and further explored its protective mechanism. Methods BMSC-Exos was identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blot. Laser confocal microscopy was used to observe the uptake of Dil-Exos by hepatocytes. D-GalN/LPS-induced primary hepatocytes were pretreated with BMSC-Exos in vitro, and then the cells were harvested. The apoptosis of hepatocytes was observed by TUNEL staining, flow cytometry and Western blot. Electron microscopy and mRFP-GFP-LC3 and Western blot was used to observe autophagy. Results BMSC-Exos increased the expression of autophagy marker proteins LC3 and Beclin-1 and promoted the formation of autophagosomes. After BMSC-Exos treatment, the expression levels of the proapoptotic proteins Bax and cleaved caspase-3 were significantly decreased, while the expression level of the anti-apoptotic protein Bcl-2 was upregulated. However, when the autophagy inhibitor 3MA was present, the effect of BMSC-Exos on inhibiting apoptosis was significantly reversed. Conclusions Our results showed for the first time that BMSC-Exos had the potential to reduce hepatocyte apoptosis after acute liver failure. In particular, we found that BMSC-Exos attenuated hepatocyte apoptosis by promoting autophagy.
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Affiliation(s)
- Shuxian Zhao
- Medical College of Qingdao University, Qingdao 266071, Shandong, People's Republic of China.,Department of Infectious Disease, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, People's Republic of China
| | - Yan Liu
- Department of Infectious Disease, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, People's Republic of China
| | - Zenghui Pu
- Department of Infectious Disease, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, People's Republic of China
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van der Helm D, Barnhoorn MC, de Jonge-Muller ESM, Molendijk I, Hawinkels LJAC, Coenraad MJ, van Hoek B, Verspaget HW. Local but not systemic administration of mesenchymal stromal cells ameliorates fibrogenesis in regenerating livers. J Cell Mol Med 2019; 23:6238-6250. [PMID: 31245923 PMCID: PMC6714167 DOI: 10.1111/jcmm.14508] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/29/2019] [Accepted: 06/01/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic liver injury leads to the accumulation of myofibroblasts resulting in increased collagen deposition and hepatic fibrogenesis. Treatments specifically targeting fibrogenesis are not yet available. Mesenchymal stromal cells (MSCs) are fibroblast-like stromal (stem) cells, which stimulate tissue regeneration and modulate immune responses. In the present study we assessed whether liver fibrosis and cirrhosis can be reversed by treatment with MSCs or fibroblasts concomitant to partial hepatectomy (pHx)-induced liver regeneration. After carbon tetrachloride-induced fibrosis and cirrhosis, mice underwent a pHx and received either systemically or locally MSCs in one of the two remaining fibrotic/cirrhotic liver lobes. Eight days after treatment, liver fibrogenesis was evaluated by Sirius-red staining for collagen deposition. A significant reduction of collagen content in the locally treated lobes of the regenerated fibrotic and cirrhotic livers was observed in mice that received high dose MSCs. In the non-MSC-treated counterpart liver lobes no changes in collagen deposition were observed. Local fibroblast administration or intravenous administration of MSCs did not ameliorate fibrosis. To conclude, local administration of MSCs after pHx, in contrast to fibroblasts, results in a dose-dependent on-site reduction of collagen deposition in mouse models for liver fibrosis and cirrhosis.
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Affiliation(s)
- Danny van der Helm
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marieke C Barnhoorn
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Ilse Molendijk
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Luuk J A C Hawinkels
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Minneke J Coenraad
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Hein W Verspaget
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
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Potential Effect of 1,25 Dihydroxyvitamin D 3 on Thioacetamide-Induced Hepatotoxicity in Rats. J Surg Res 2019; 243:165-172. [PMID: 31177036 DOI: 10.1016/j.jss.2019.05.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/12/2019] [Accepted: 05/08/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND 1,25 Dihydroxyvitamin D3 (1,25(OH)2D3) modulates inflammation and immune responses. Deficiency of 1,25(OH)2D3 was found to be associated with the risk of cancer, cardiovascular disease, osteoarthritis, infections, and autoimmune diseases. This study evaluated the effect of 1,25 dihydroxyvitamin D3 1,25(OH)2D3 on thioacetamide (TAA)-induced acute liver injury in rats. MATERIALS AND METHODS Rats were treated with either saline or 1,25(OH)2D3 (0.30 μg/kg; orogastrically) for 15 d. Starting from day 13, TAA (200 mg/kg; intraperitoneally) was given for 3 d. On day 15, all rats were euthanized. Liver and blood samples were collected. RESULTS TAA caused severe damage, increased lipid peroxidation with reductions in endogenous antioxidants, increased apoptosis, increased production of reactive oxygen species, and elevated inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NF-κB) expression in liver. Extent of damage was decreased by 1,25(OH)2D3 (P < 0.01). 1,25(OH)2D3 attenuated the increase in malondialdehyde (P < 0.01), increase in myeloperoxidase (P < 0.01), increase in chemiluminescence levels (P < 0.05) and apoptotic activity (P < 0.001). Elevated liver iNOS and NF-κB expression in TAA group was also reduced by 1,25(OH)2D3 (P < 0.001, for iNOS; P < 0.001, for NF-κB). TAA group revealed high serum aspartate transaminase and alanine transaminase (ALT) activities (P < 0.01, for aspartate transaminase; P = 0.08, for ALT) and reduced albumin levels (P < 0.01) compared with control. 1,25(OH)2D3 had no statistically significant effect on these parameters. CONCLUSIONS 1,25(OH)2D3 provides protection against hepatic injury in a rat model of TAA-induced hepatotoxicity via suppression of inflammatory reaction, oxidative stress, and apoptosis.
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A novel evaluation system for whole-organ-engineered liver graft by ex vivo application to a highly reproducible hepatic failure rat model. J Artif Organs 2019; 22:222-229. [PMID: 31076904 DOI: 10.1007/s10047-019-01106-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 05/01/2019] [Indexed: 10/26/2022]
Abstract
In recent years, studies on liver graft construction using the decellularized liver as a template for transplantation therapy have attracted much attention. However, the therapeutic effect of constructed liver grafts in hepatic failure has not been evaluated. Therefore, we aimed to develop a novel evaluation system demonstrating the curative effect of a constructed liver graft in animals with hepatic failure. First, we developed a highly reproducible rat model of hepatic failure by combining 80% partial hepatectomy with warm ischemia. In this model, severity could be controlled by the warm ischemic period. We also constructed a liver graft by recellularization of decellularized liver, and confirmed the ammonia metabolic function in the graft in vitro as one of the most important functions for recovery from hepatic failure. The graft was then applied to our developed hepatic failure rat model using a blood extracorporeal circulation system. In this application, the graft metabolized the ammonia in the blood of animals with hepatic failure and was thus suggested to be effective for the treatment of hepatic failure. In summary, a novel evaluation system for whole-organ-engineered liver graft as a preliminary stage of transplantation was developed. This system was expected to provide much information about the curative effect of a constructed liver graft.
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Wang CY, Yang YP, Liu CY, Lu KH, Liu YY, Wu WW, Chen KH, Chang YL, Lee SD, Lin HC. Nanoparticle-delivery system enhanced the improvement and recovery in toxicity-induced acute hepatic failure. J Chin Med Assoc 2019; 82:363-367. [PMID: 31058711 DOI: 10.1097/jcma.0000000000000066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND The major curative remedy for advanced liver failure is hepatic transplantation. However, the conventional medicine still shows the limitations and obstacles for liver regeneration. Importantly, it is unclear whether we can get a rapid and high efficacy platform to facilitate to reprogram hepatic capability. The main work of this study was to develop a platform for a nanomedicine-based gene-delivery platform of novel nanoparticles (NNPs) to efficiently facilitate the liver function recovery. METHODS In this study, we studied the feasibility and efficiency of NNP and produced the multiple abilities of NNPs for a potential platform of gene transduction. We showed that NNPs played an important role in hepatic protection. The cytoprotective effects of NNPs in toxic-hepatic cells were investigated and evaluated by cell viability, reactive oxygen species production, in vitro cell abilities, and in vivo animal studies. RESULTS We demonstrated that NNPs possess the abilities to protect the cell after toxic-stress both in vitro and in vivo. Under the stress condition, our result showed that cell viabilities can be improved by NNP-carried hepatocyte nuclear factor 3 (HNF3) gene (NNP-HNF3), which is a famous hepatic transcriptional factor and regenerative marker to modulate essential molecular pathways activating various hepatic-specific markers. Importantly, compared to control and NNP-control, NNP-HNF3 exhibited the cytoprotective effects that prevented toxic-induced oxidative stress and cell damage in vitro as well as in vivo. Notably, our data showed that NNP-HNF3 treatment may improve toxic-induced hepatic encephalopathy. CONCLUSION Herein, we demonstrated that novel nanoparticle, such as NNP-HNF3, serves as a key regulator for protecting the damaged hepatic cell and the bioproduct-based source for the new therapeutics of hepatic failure.
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Affiliation(s)
- Chien-Ying Wang
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Division of Trauma, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Ping Yang
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chao-Yu Liu
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Division of Thoracic Surgery, Far-Eastern Memorial Hospital, New Taipei City, Taiwan, ROC
- Department of Surgery, Far-Eastern Memorial Hospital, New Taipei City, Taiwan, ROC
| | - Kai-Hsi Lu
- Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC
| | - Yung-Yang Liu
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Department of Chest, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Wai-Wah Wu
- Division of Gastroenterology, Department of Internal Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC
| | - Kuan-Hsuan Chen
- Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yuh-Lih Chang
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shou-Dong Lee
- Division of Gastroenterology, Department of Internal Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC
- Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC
| | - Hsin-Chi Lin
- Division of Gastroenterology, Department of Internal Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC
- Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC
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Tang F, Fan K, Wang K, Bian C. Amygdalin attenuates acute liver injury induced by D-galactosamine and lipopolysaccharide by regulating the NLRP3, NF-κB and Nrf2/NQO1 signalling pathways. Biomed Pharmacother 2018; 111:527-536. [PMID: 30597306 DOI: 10.1016/j.biopha.2018.12.096] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 12/19/2018] [Accepted: 12/19/2018] [Indexed: 12/11/2022] Open
Abstract
Acute liver injury (ALI) is a life-threatening syndrome accompanied by overwhelming inflammation. Amygdalin (AGD) has been reported to possess various biological activities, particularly anti-inflammatory activity. The current study was designed to assess the protective effects and underlying mechanisms of AGD against ALI induced by d-galactosamine (GalN) and lipopolysaccharide (LPS) in mice. The results indicated that AGD treatment effectively reduced the lethality, ameliorated the histopathological liver changes, reduced the malondialdehyde (MDA) and myeloperoxidase (MPO) levels, and decreased the alanine transaminase (ALT) and aspartate aminotransferase (AST) levels resulting from LPS/GalN challenge. Moreover, AGD significantly inhibited LPS/GalN-induced inflammatory responses in mice with ALI by reducing not only the secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 but also the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Additionally, our results demonstrated that the inhibitory effect of AGD was due to the suppressed activation of nuclear factor-kappa B (NF-κB) and nucleotide-binding domain (NOD-)like receptor protein 3 (NLRP3) inflammasome activity. Furthermore, AGD treatment substantially increased nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and enhanced NAD (P) H: quinoneoxidoreductase 1 protein expression, which was reversed by a Nrf2 inhibitor, in HepG2 cells. In summary, our investigations suggested that the ability of AGD to ameliorate LPS/GalN-induced ALI may involve the inhibition of the NLRP3 inflammasome and NF-κB signalling pathways and the upregulation of the Nrf2/NQO1 signalling pathway.
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Affiliation(s)
- Fayin Tang
- College of pharmaceutical Engineering, Henan University of Husbandry and Economy, Zhengzhou, 450046, Henan Province, China; College of Veterinary Medicine, Jilin University, Xi'an Road 5333#, Changchun 130062, China
| | - Kefeng Fan
- College of pharmaceutical Engineering, Henan University of Husbandry and Economy, Zhengzhou, 450046, Henan Province, China
| | - Kunli Wang
- College of pharmaceutical Engineering, Henan University of Husbandry and Economy, Zhengzhou, 450046, Henan Province, China
| | - Chuanzhou Bian
- College of pharmaceutical Engineering, Henan University of Husbandry and Economy, Zhengzhou, 450046, Henan Province, China.
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Mesenchymal stromal cells prevent progression of liver fibrosis in a novel zebrafish embryo model. Sci Rep 2018; 8:16005. [PMID: 30375438 PMCID: PMC6207680 DOI: 10.1038/s41598-018-34351-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 10/12/2018] [Indexed: 12/22/2022] Open
Abstract
Chronic liver damage leads to the onset of fibrogenesis. Rodent models for liver fibrosis have been widely used, but are less suitable for screening purposes. Therefore the aim of our study was to design a novel model for liver fibrosis in zebrafish embryos, suitable for high throughput screening. Furthermore, we evaluated the efficacy of mesenchymal stromal cells (MSCs) to inhibit the fibrotic process and thereby the applicability of this model to evaluate therapeutic responses. Zebrafish embryos were exposed to TAA or CCL4 and mRNA levels of fibrosis-related genes (Collagen-1α1, Hand-2, and Acta-2) and tissue damage-related genes (TGF-β and SDF-1a, SDF-1b) were determined, while Sirius-red staining was used to estimate collagen deposition. Three days after start of TAA exposure, MSCs were injected after which the fibrotic response was determined. In contrast to CCL4, TAA resulted in an upregulation of the fibrosis-related genes, increased extracellular matrix deposition and decreased liver sizes suggesting the onset of fibrosis. The applicability of this model to evaluate therapeutic responses was shown by local treatment with MSCs which resulted in decreased expression of the fibrosis-related RNA markers. In conclusion, TAA induces liver fibrosis in zebrafish embryos, thereby providing a promising model for future mechanistic and therapeutic studies.
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Qinna NA, Ghanim BY. Chemical induction of hepatic apoptosis in rodents. J Appl Toxicol 2018; 39:178-190. [PMID: 30350376 DOI: 10.1002/jat.3740] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Accepted: 09/13/2018] [Indexed: 12/13/2022]
Abstract
The urge of identifying new pharmacological interventions to prevent or attenuate liver injury is of critical importance and needs an expanded experimental toolbox. Hepatocyte injury and cellular death is a prominent feature behind the pathology of liver diseases. Several research activities focused on identifying chemicals and hepatotoxicants that induce cell death by apoptosis, in addition to presenting its corresponding signaling pathway. Although such efforts provided further understanding of the mechanisms of cell death, it has also raised confusion concerning identifying the involvement of several modes of cell death including apoptosis, necrosis and fibrosis. The current review highlights the ability of several chemicals and potential hepatotoxicants to induce liver damage in rodents by means of apoptosis while the probable involvement of other modes of cell death is also exposed. Thus, several chemical substances including hepatotoxins, mycotoxins, hyperglycemia inducers, metallic nanoparticles and immunosuppressant drugs are reviewed to explore the hepatic cytotoxic spectrum they could exert on hepatocytes of rodents. In addition, the current review address the mechanism by which hepatotoxicity is initiated in hepatocytes in different rodents aiding the researcher in choosing the right animal model for a better research outcome.
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Affiliation(s)
- Nidal A Qinna
- University of Petra Pharmaceutical Center (UPPC), Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
| | - Bayan Y Ghanim
- University of Petra Pharmaceutical Center (UPPC), Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
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El-Sayed AEKB, Aboulthana WM, El-Feky AM, Ibrahim NE, Seif MM. Bio and phyto-chemical effect of Amphora coffeaeformis extract against hepatic injury induced by paracetamol in rats. Mol Biol Rep 2018; 45:2007-2023. [DOI: 10.1007/s11033-018-4356-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 09/03/2018] [Indexed: 02/07/2023]
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