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Xie L, Huang L, Fang X, Zha J, Su Y. Assessing Liver Function in Rat Models of Acute Liver Failure Using Single-Photon Emission Computed Tomography and Cytokine Levels. PLoS One 2025; 20:e0323531. [PMID: 40333907 PMCID: PMC12057927 DOI: 10.1371/journal.pone.0323531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 04/10/2025] [Indexed: 05/09/2025] Open
Abstract
OBJECTIVE To evaluate liver function using dynamic hepatobiliary single-photon emission computed tomography (SPECT) in different rat models of acute liver failure. METHODS Twenty-four 6-8-week-old male Sprague-Dawley rats (weight 190-200 g) were evenly divided into four groups. Acute liver failure was induced by intraperitoneal injection of D-galactosamine (D-GalN, 600 mg/kg) and lipopolysaccharide (LPS, 10 µg/kg), common bile duct ligation surgery, and removing 70% of the liver mass. The fourth group served as the control without intervention. The time-activity curves for the liver and heart were generated from dynamic SPECT scans with 99mTc-ethylene hepatobiliary iminodiacetic acid (EHIDA). Image-derived functional parameters (5-minute heart/liver index [HLI5] and 15-minute receptor index [LHL15]) were calculated. Furthermore, correlations of image-derived parameters with serum interleukin-6 (IL-6) levels, liver aspartate aminotransferase (AST) and alanine transaminase (ALT) levels, and liver mRNA expression levels of tumor necrosis factor-α (TNF-α) and chemokine ligand-10 (CXCL-10) were analyzed. RESULTS All animals in the experimental groups exhibited varying degrees of liver damage. The SPECT images and indexes (HLI5 and LHL15) of the experimental groups significantly differed from those of the control group (P < 0.05). In the experimental groups, serum IL-6 levels and liver mRNA levels of TNF-α and CXCL-10 were significantly higher, while liver AST and ALT levels were significantly lower than those in the control group (P < 0.05). CONCLUSION Using SPECT with 99mTc-EHIDA, along with the calculated indexes and levels of various cytokines, presents a dependable method for assessing liver function.
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Affiliation(s)
- Long Xie
- Department of Nuclear Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Liqun Huang
- Department of Nuclear Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Xueting Fang
- Department of Pathology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Jinshun Zha
- Department of Nuclear Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Yingrui Su
- Department of Nuclear Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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Dassarma B, Mahapatra SK, Nandi DK, Gangopadhyay S, Samanta S. Protective role of butylated hydroxyanisole (BHA) and hydroxytoluene (BHT) against oxidative stress-induced inflammatory response in carbon tetrachloride-induced acute hepatorenal toxicity. Arch Physiol Biochem 2025:1-8. [PMID: 40272386 DOI: 10.1080/13813455.2025.2493105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 02/11/2025] [Accepted: 04/09/2025] [Indexed: 04/25/2025]
Abstract
BACKGROUND Any toxicity initially damages the hepatic system, followed by renal dysfunction. Previously, it was established that carbon tetrachloride (CCl4) intoxication severely damaged hepatocytes. Moreover, CCl4-mediated toxicity significantly impacted immune functions and influenced the inflammatory response, with mitochondrial dysfunction. The present study focused on the levels of inflammatory markers and mitochondrial dysfunction, as well as the protective role of BHA and BHT. METHODS In the present study, hepatorenal dysfunction was developed in experimental rats by applying a subcutaneous injection of CCl4 with a dose of 230 mg/kg bwt/rat/day. The level of immune toxicity was determined by measuring C-reactive protein (CRP), IL-6, 12, TNF-α, IL-10, and TGF-β in CCl4 intoxicated group and pretreated BHA and BHT groups. ROS generation and MMP were also measured in hepatic and renal cells using flow cytometric technique. RESULTS The level of toxicity was determined by a significant increase of CRP (407.29%), IL-6 (525.65%), IL-12 (1026.54%), and TNF-α (1007.33%) in CCl4 intoxicated group, while IL-10 and TGF-β were significantly decreased 84.65% and 66.36%, respectively. CCl4 intoxication caused decreased mitochondrial membrane potential and high levels of intracellular ROS generation. Pretreatment with BHA (0.5 mg/kg/bwt) and BHT (0.8 mg/kg/bwt) significantly (p<0.001, p<0.05) reduced inflammatory markers in the CCl4-treated group, restored mitochondrial membrane potential and decreased intracellular ROS levels. CONCLUSION BHA and BHT treatment could restrict the higher concentration of pro-inflammatory markers by scavenging ROS. Therefore, the study suggested that supplementation of BHA and BHT could be an alternative treatment for preventing hepatorenal dysfunctions.
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Affiliation(s)
- Barsha Dassarma
- Department of Physiology, Midnapore College, Midnapore, India
- Department of Physiology, Raja N.L. Khan Women's College (Autonomous), Midnapore, India
- Department of Physiology and Allied Sciences, Amity Institute of Health and Allied Sciences, Amity University Uttar Pradesh, Noida, India
| | - Santanu Kar Mahapatra
- Department of Paramedical and Allied Health Sciences, Midnapore City College, Midnapore, India
| | - Dilip Kumar Nandi
- Department of Physiology, Raja N.L. Khan Women's College (Autonomous), Midnapore, India
| | - Somnath Gangopadhyay
- Department of Physiology, Occupational Ergonomics Laboratory, University College of Science and Technology, University of Calcutta, Kolkata, India
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Lee YL, Lee JY, Park JW, Lee J, Lee HH, Lee DH. Protective Effects of Codium fragile Extract against Acetaminophen-Induced Liver Injury. J Microbiol Biotechnol 2024; 34:2675-2862. [PMID: 39473023 PMCID: PMC11729533 DOI: 10.4014/jmb.2409.09061] [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: 10/01/2024] [Revised: 10/10/2024] [Accepted: 10/12/2024] [Indexed: 12/31/2024]
Abstract
Acetaminophen (APAP) is a well-known analgesic used globally. Generally, APAP has been proven to be safe and effective at therapeutic doses; however, it can cause serious liver damage when administered at high levels. We prepared Codium fragile extract (CFE) using the seaweed C. fragile and confirmed that the CFE contains a substance called Loliolide with antioxidant activity. We performed the present study to determine whether CFE protects HEPG2 cells and BALB/c mice from oxidative stress-induced liver damage. We confirmed that CFE and Loliolide were non-cytotoxic and protected against liver damage by reducing the activities of ALT and AST, which were increased by APAP treatment, and that CFE reduced the mRNA expression of inflammatory cytokines TNF-α and IL-6 and inhibited the phosphorylation of ERK and p38 in HEPG2 cells as determined by RT-PCR and Western blot analyses. Furthermore, the TNF-α and IL-6 levels, which were increased after APAP treatment in BALB/c mice, decreased after CFE treatment. Therefore, we demonstrated that CFE exerts a protective effect against APAP-induced liver injury by suppressing the inflammatory response through anti-inflammatory activity. Our findings provide new perspectives for developing functional foods that utilize seaweeds to improve liver function.
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Affiliation(s)
- Yea-Lim Lee
- Nbio, Inc., Gangneung 25457, Republic of Korea
| | - Ji-Yun Lee
- Nbio, Inc., Gangneung 25457, Republic of Korea
| | | | - Jin Lee
- Biostream Co., Ltd., Suwon 10442, Republic of Korea
| | - Hyun-Hoo Lee
- Biostream Co., Ltd., Suwon 10442, Republic of Korea
| | - Dae-Hee Lee
- Nbio, Inc., Gangneung 25457, Republic of Korea
- Department of Marine Bio Food Science, Gangneung-Wonju National University, Gangneung 25457, Republic of Korea
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Chao S, Shan S, Liu Z, Liu Z, Wang S, Qiang Y, Ni W, Li H, Cheng D, Jia Q, Song F. Both TREM2-dependent macrophages and Kupffer cells play a protective role in APAP-induced acute liver injury. Int Immunopharmacol 2024; 141:112926. [PMID: 39159559 DOI: 10.1016/j.intimp.2024.112926] [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: 06/16/2024] [Revised: 07/22/2024] [Accepted: 08/09/2024] [Indexed: 08/21/2024]
Abstract
The inflammatory response is a significant factor in acetaminophen (APAP)-induced acute liver injury. And it can be mediated by macrophages of different origins. However, whether Kupffer cells and mononuclear-derived macrophages play an injury or protective role in APAP hepatotoxicity is still unclear. In this study, C57/BL6N mice were performed to establish the APAP acute liver injury model. Intervention experiments were also carried out using clodronate liposomes or TREM2 knockout. We found that APAP overdose triggered the activation of inflammatory factors and enhanced the expression of the RIPK1-MLKL pathway in mice's livers. Moreover, our study showed that inflammation-related protein expression was increased after clodronate liposome administration or TREM2 knockout. The RIPK1-MLKL-mediated necroptosis was also significantly activated after the elimination of Kupffer cells or the inhibition of mononuclear-derived macrophages. More importantly, clodronate liposomes treatment and TREM2 deficiency all worsen APAP-induced liver damage in mice. In conclusion, the results indicate that Kupffer cells and mononuclear macrophages play a protective role in APAP-induced liver injury by regulating necroptosis. Therefore, macrophages hold as a potential therapeutic target for APAP-induced liver damage.
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Affiliation(s)
- Shihua Chao
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, China; Qinghai Center for Disease Control and Prevention, No. 55, Bayi Middle Road, Chengdong District, Xining City, Qinghai Province 810000, China
| | - Shulin Shan
- Department of Health Test and Detection, Shandong Center for Disease Control and Prevention, 16992 Jingshi Road, Ji'nan, Shandong 250014, China
| | - Zhaoxiong Liu
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, China
| | - Zhidan Liu
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Science, Ji'nan 250062, China
| | - Shuai Wang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, China
| | - Yalong Qiang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, China
| | - Wenting Ni
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, China
| | - Hui Li
- Department of Health Test and Detection, Shandong Center for Disease Control and Prevention, 16992 Jingshi Road, Ji'nan, Shandong 250014, China
| | - Dong Cheng
- Department of Health Test and Detection, Shandong Center for Disease Control and Prevention, 16992 Jingshi Road, Ji'nan, Shandong 250014, China
| | - Qiang Jia
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Science, Ji'nan 250062, China
| | - Fuyong Song
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, China.
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Idrees M, Javaid S, Nadeem S, Khurshid F, Parveen A, Malik A, Ali Khan A, Akhtar S, Fatima S. Antimicrobial and Hepatoprotective Properties of Pods of Acacia nilotica (L.) Willd. ex Delile: In Vivo and In Silico Approaches. Dose Response 2024; 22:15593258241308998. [PMID: 39679261 PMCID: PMC11639031 DOI: 10.1177/15593258241308998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 11/15/2024] [Accepted: 11/29/2024] [Indexed: 12/17/2024] Open
Abstract
Background Acacia nilotica is a multipurpose plant known for its remedial properties but the antimicrobial and hepatoprotective activity of its pods remained unexplored. Objective This study aimed to evaluate the antimicrobial and hepatoprotective activity of n-hexane (ANPH) and methanol (ANPM) extracts of pods to scientifically validate their medicinal claims. Methods After the pharmacognostic evaluation of pods, in vitro tests were carried out to estimate phenolic and flavonoid content and antimicrobial potential. In vivo experiments involved testing of both extracts (250 and 500 mg/kg) paracetamol (PCM)-induced hepatotoxicity model in rats. The molecular docking studies explored insights into the potential binding capabilities of the ligands with the specific target proteins. Results ANPH and ANPM were enriched with phenols and flavonoids and showed antimicrobial effects. In the hepatoprotective test, the rats chronically treated with extracts had a dose-dependent hepatoprotection as markers of liver functionality were notably reduced (P < 0.05). The in silico studies revealed strong binding interactions of ergost-5-en-3-ol and oxiranyl methyl ester 9-octadecenoic acid with target proteins for antibacterial activity and hepatoprotective activity, respectively. Conclusion The antimicrobial and hepatoprotective potential of pods might be due to their phenols and flavonoids. The Pyrogallol, Ergost-5-en-3-and 9-octadecenoic acid might be bringing these remedial benefits through antioxidant and anti-inflammatory effects.
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Affiliation(s)
- Mehak Idrees
- Department of Pharmacognosy, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Sana Javaid
- Department of Pharmacy, The Women University, Multan, Pakistan
| | - Sumaira Nadeem
- Department of Pharmacy, The Women University, Multan, Pakistan
| | - Faria Khurshid
- Department of Pharmacology, Faculty of Pharmacy, University of Balochistan, Quetta, Pakistan
| | - Abida Parveen
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Abdul Malik
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Azmat Ali Khan
- Pharmaceutical Biotechnology Laboratory, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Suhail Akhtar
- Department of Biochemistry, A.T. Still University of Health Sciences, Kirksville, MO, USA
| | - Sabiha Fatima
- Department of Clinical Laboratory Science, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
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Laddha AP, Wu H, Manautou JE. Deciphering Acetaminophen-Induced Hepatotoxicity: The Crucial Role of Transcription Factors like Nuclear Factor Erythroid 2-Related Factor 2 as Genetic Determinants of Susceptibility to Drug-Induced Liver Injury. Drug Metab Dispos 2024; 52:740-753. [PMID: 38857948 DOI: 10.1124/dmd.124.001282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 05/20/2024] [Accepted: 06/06/2024] [Indexed: 06/12/2024] Open
Abstract
Acetaminophen (APAP) is the most commonly used over-the-counter medication throughout the world. At therapeutic doses, APAP has potent analgesic and antipyretic effects. The efficacy and safety of APAP are influenced by multifactorial processes dependent upon dosing, namely frequency and total dose. APAP poisoning by repeated ingestion of supratherapeutic doses, depletes glutathione stores in the liver and other organs capable of metabolic bioactivation, leading to hepatocellular death due to exhausted antioxidant defenses. Numerous genes, encompassing transcription factors and signaling pathways, have been identified as playing pivotal roles in APAP toxicity, with the liver being the primary organ studied due to its central role in APAP metabolism and injury. Nuclear factor erythroid 2-related factor 2 (NRF2) and its array of downstream responsive genes are crucial in counteracting APAP toxicity. NRF2, along with its negative regulator Kelch-like ECH-associated protein 1, plays a vital role in regulating intracellular redox homeostasis. This regulation is significant in modulating the oxidative stress, inflammation, and hepatocellular death induced by APAP. In this review, we provide an updated overview of the mechanisms through which NRF2 activation and signaling critically influence the threshold for developing APAP toxicity. We also describe how genetically modified rodent models for NRF2 and related genes have been pivotal in underscoring the significance of this antioxidant response pathway. While NRF2 is a primary focus, the article comprehensively explores other genetic factors involved in phase I and phase II metabolism of APAP, inflammation, oxidative stress, and related pathways that contribute to APAP toxicity, thereby providing a holistic understanding of the genetic landscape influencing susceptibility to this condition. SIGNIFICANCE STATEMENT: This review summarizes the genetic elements and signaling pathways underlying APAP-induced liver toxicity, focusing on the crucial protective role of the transcription factor NRF2. This review also delves into the genetic intricacies influencing APAP safety and potential liver harm. It also emphasizes the need for deeper insight into the molecular mechanisms of hepatotoxicity, especially the interplay of NRF2 with other pathways.
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Affiliation(s)
- Ankit P Laddha
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
| | - Hangyu Wu
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
| | - José E Manautou
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
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Kim DY, Park HJ, Eom JI, Han CH, Pan CH, Lee JK. Ethanol Extract of the Microalga Phaeodactylum tricornutum Shows Hepatoprotective Effects against Acetaminophen-Induced Acute Liver Injury in Mice. Int J Mol Sci 2024; 25:6247. [PMID: 38892435 PMCID: PMC11172906 DOI: 10.3390/ijms25116247] [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: 04/06/2024] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 06/21/2024] Open
Abstract
Acute liver failure is an infrequent yet fatal condition marked by rapid liver function decline, leading to abnormalities in blood clotting and cognitive impairment among individuals without prior liver ailments. The primary reasons for liver failure are infection with hepatitis virus or overdose of certain medicines, such as acetaminophen. Phaeodactylum tricornutum (PT), a type of microalgae known as a diatom species, has been reported to contain an active ingredient with anti-inflammatory and anti-obesity effects. In this study, we evaluated the preventive and therapeutic activities of PT extract in acute liver failure. To achieve our purpose, we used two different acute liver failure models: acetaminophen- and D-GalN/LPS-induced acute liver failure. PT extract showed protective activity against acetaminophen-induced acute liver failure through attenuation of the inflammatory response. However, we failed to demonstrate the protective effects of PT against acute liver injury in the D-GalN/LPS model. Although the PT extract did not show protective activity against two different acute liver failure animal models, this study clearly demonstrates the importance of considering the differences among animal models when selecting an acute liver failure model for evaluation.
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Affiliation(s)
- Dae Yoon Kim
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea;
| | - Hui Jin Park
- Department of Biology Education, College of Education, Chungbuk National University, Cheongju 28160, Republic of Korea;
| | - Jae-In Eom
- Microalgae Ask Us Co., Ltd., Gangneung 25441, Republic of Korea; (J.-I.E.); (C.-H.H.)
| | - Cheol-Ho Han
- Microalgae Ask Us Co., Ltd., Gangneung 25441, Republic of Korea; (J.-I.E.); (C.-H.H.)
| | - Cheol-Ho Pan
- Microalgae Ask Us Co., Ltd., Gangneung 25441, Republic of Korea; (J.-I.E.); (C.-H.H.)
| | - Jae Kwon Lee
- Department of Biology Education, College of Education, Chungbuk National University, Cheongju 28160, Republic of Korea;
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Salek A, Selmi M, Njim L, Umek P, Mejanelle P, Moussa F, Douki W, Hosni K, Baati T. Titanate nanotubes as an efficient oral detoxifying agent against drug overdose: application in rat acetaminophen poisoning. NANOSCALE ADVANCES 2023; 5:2950-2962. [PMID: 37260481 PMCID: PMC10228339 DOI: 10.1039/d2na00874b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 04/22/2023] [Indexed: 06/02/2023]
Abstract
Voluntary drug intoxication is mainly due to drug overdose or the interaction of several drugs. Coma and its associated complications such as hypoventilation, aspiration pneumopathy, and heart rhythm disorders are the main hallmarks of drug intoxication. Conventional detoxification treatments, including gastric lavage or vomiting, administration of ipecac or activated charcoal (CH), and the use of antidotes, have proven to be inefficient and are generally associated with severe adverse effects. To overcome these limitations, titanate nanotubes (TiNTs) are proposed as an efficient emerging detoxifying agent because of their tubular shape and high adsorption capacity. In the present study, the detoxifying ability of TiNTs was evaluated on paracetamol (PR)-intoxicated rats. Results indicate that the loading ability of PR into TiNTs (70%) was significantly higher than that recorded for CH (38.6%). In simulated intestinal medium, TiNTs showed a controlled drug release of less than 10% after 72 h of incubation. In PR-intoxicated rats, TiNTs treatment resulted in a 64% decrease of PR after 4 h of poisoning versus 40% for CH. Concomitantly, TiNTs efficiently reduced PR absorption by 90% after 24 h of poisoning, attenuated the elevated levels of biochemical markers (i.e., alanine aminotransferase, aspartate aminotransferase, creatinine, and TNF-α) and mitigated oxidative stress by increasing the activity of superoxide dismutase and reducing the oxidized glutathione/total glutathione ratio, suggesting a histoprotective effect of TiNTs against paracetamol-induced toxicity in rats. In addition to their safety and high stability in the entire gastro-intestinal tract, biodistribution analysis revealed that TiNTs exhibited low intestinal absorption owing to their large cluster size of compact aggregate nanomaterials across the intestinal villi hindering the absorption of paracetamol. Collectively, these data provide a new and promising solution for in vivo detoxification. TiNTs are expected to have great potential for the treatment of voluntary and accidental intoxication in emergency care.
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Affiliation(s)
- Abir Salek
- Laboratoire des Substances Naturelles, Institut National de Recherche et d'Analyse Physico-chimique, Biotechpôle Sidi Thabet 2020 Tunisia +216 71 537 688 +216 71 537 666
| | - Mouna Selmi
- Laboratoire des Substances Naturelles, Institut National de Recherche et d'Analyse Physico-chimique, Biotechpôle Sidi Thabet 2020 Tunisia +216 71 537 688 +216 71 537 666
| | - Leila Njim
- Service d'Anatomie Pathologique, EPS Fattouma Bourguiba de Monastir, Faculté de Médecine de Monastir, Université de Monastir 5000 Monastir Tunisia
| | - Polona Umek
- Jožef Stefan Institute Jamova cesta 39 SI-1000 Ljubljana Slovenia
| | - Philippe Mejanelle
- Département de chimie, IUT d'Orsay, Université Paris-Saclay 91190 Gif-sur-Yvette France
| | - Fathi Moussa
- Institut de Chimie Physique, CNRS UMR 8000, Université Paris-Saclay 91190 Gif-sur-Yvette France
| | - Wahiba Douki
- Laboratoire de Biochimie et de Toxicologie, EPS Fattouma Bourguiba de Monastir, Université de Monastir 5000 Monastir Tunisia
| | - Karim Hosni
- Laboratoire des Substances Naturelles, Institut National de Recherche et d'Analyse Physico-chimique, Biotechpôle Sidi Thabet 2020 Tunisia +216 71 537 688 +216 71 537 666
| | - Tarek Baati
- Laboratoire des Substances Naturelles, Institut National de Recherche et d'Analyse Physico-chimique, Biotechpôle Sidi Thabet 2020 Tunisia +216 71 537 688 +216 71 537 666
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Xu L, Wang H. A dual role of inflammation in acetaminophen-induced liver injury. LIVER RESEARCH 2023; 7:9-15. [PMID: 39959696 PMCID: PMC11791818 DOI: 10.1016/j.livres.2023.03.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/14/2023] [Accepted: 03/05/2023] [Indexed: 03/12/2023]
Abstract
In many affluent nations, acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure. The process of APAP-induced liver injury (AILI) is intimately tied to inflammation, including hepatocyte necrosis-caused initiation of inflammation, inflammation amplification that exacerbates liver injury, and the resolution of inflammation that triggers liver regeneration and repair. Excessive APAP metabolism in the liver eventually leads to hepatocyte necrosis and inflammation. Innate immune cells, such as neutrophils, eosinophils, monocytes, and gammadelta T cells, are recruited into the injured liver and release various cytokines. These immune cells and cytokines have been found to serve two purposes in AILI. In this review, we highlighted the dual role of inflammation, including inflammatory cytokines and inflammatory immune cells in AILI, and discussed possible explanations for contradictory findings.
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Affiliation(s)
- Long Xu
- School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Xu L, Yang Y, Jiang J, Wen Y, Jeong JM, Emontzpohl C, Atkins CL, Kim K, Jacobsen EA, Wang H, Ju C. Eosinophils protect against acetaminophen-induced liver injury through cyclooxygenase-mediated IL-4/IL-13 production. Hepatology 2023; 77:456-465. [PMID: 35714036 PMCID: PMC9758273 DOI: 10.1002/hep.32609] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/31/2022] [Accepted: 06/01/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND AIMS A better understanding of the underlying mechanism of acetaminophen (APAP)-induced liver injury (AILI) remains an important endeavor to develop therapeutic approaches. Eosinophils have been detected in liver biopsies of patients with APAP overdose. We recently demonstrated a profound protective role of eosinophils against AILI; however, the molecular mechanism had not been elucidated. APPROACH AND RESULTS In agreement with our previous data from experiments using genetic deletion of eosinophils, we found that depletion of eosinophils in wild-type (WT) mice by an anti-IL-15 antibody resulted in exacerbated AILI. Moreover, adoptive transfer of eosinophils significantly reduced liver injury and mortality rate in WT mice. Mechanistic studies using eosinophil-specific IL-4/IL-13 knockout mice demonstrated that these cytokines, through inhibiting interferon-γ, mediated the hepatoprotective function of eosinophils. Reverse phase protein array analyses and in vitro experiments using various inhibitors demonstrated that IL-33 stimulation of eosinophils activated p38 mitogen-activated protein kinase (MAPK), and in turn, cyclooxygenases (COX), which triggered NF-κB-mediated IL-4/IL-13 production. In vivo adoptive transfer experiments showed that in contrast to naive eosinophils, those pretreated with COX inhibitors failed to attenuate AILI. CONCLUSIONS The current study revealed that eosinophil-derived IL-4/IL-13 accounted for the hepatoprotective effect of eosinophils during AILI. The data demonstrated that the p38 MAPK/COX/NF-κB signaling cascade played a critical role in inducing IL-4/IL-13 production by eosinophils in response to IL-33.
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Affiliation(s)
- Long Xu
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
- School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, China
| | - Yang Yang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jiali Jiang
- School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, China
| | - Yankai Wen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jong-Min Jeong
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Christoph Emontzpohl
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Constance L. Atkins
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Kangho Kim
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Elizabeth A. Jacobsen
- Division of Allergy, Asthma and Clinical Immunology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
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El-Elimat T, Al-Tal BK, Al-Sawalha NA, Alsaggar M, Nusair SD, Al‐Qiam R, Al Sharie AH, El Hajji F, Hamadneh L. Sumc (Rhus coriaria L.) fruit ameliorates paracetamol-induced hepatotoxicity. FOOD BIOSCI 2023. [DOI: 10.1016/j.fbio.2023.102488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
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12
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Zhang S, Lu S, Li Z. Extrahepatic factors in hepatic immune regulation. Front Immunol 2022; 13:941721. [PMID: 36052075 PMCID: PMC9427192 DOI: 10.3389/fimmu.2022.941721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
The liver is a site of complex immune activity. The hepatic immune system tolerates harmless immunogenic loads in homeostasis status, shelters liver function, while maintaining vigilance against possible infectious agents or tissue damage and providing immune surveillance at the same time. Activation of the hepatic immunity is initiated by a diverse repertoire of hepatic resident immune cells as well as non-hematopoietic cells, which can sense "danger signals" and trigger robust immune response. Factors that mediate the regulation of hepatic immunity are elicited not only in liver, but also in other organs, given the dual blood supply of the liver via both portal vein blood and arterial blood. Emerging evidence indicates that inter-organ crosstalk between the liver and other organs such as spleen, gut, lung, adipose tissue, and brain is involved in the pathogenesis of liver diseases. In this review, we present the features of hepatic immune regulation, with particular attention to the correlation with factors from extrahepatic organ. We describe the mechanisms by which other organs establish an immune association with the liver and then modulate the hepatic immune response. We discuss their roles and distinct mechanisms in liver homeostasis and pathological conditions from the cellular and molecular perspective, highlighting their potential for liver disease intervention. Moreover, we review the available animal models and methods for revealing the regulatory mechanisms of these extrahepatic factors. With the increasing understanding of the mechanisms by which extrahepatic factors regulate liver immunity, we believe that this will provide promising targets for liver disease therapy.
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Affiliation(s)
- Shaoying Zhang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Shemin Lu
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, China
| | - Zongfang Li
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
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13
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El-Bahr SM, Elzoghby RR, Alfattah MA, Kandeel M, Hamouda AF. Aqueous Ginger ( Zingiber officinale) Extract Ameliorates the Harmful Effects of High-Dose Lornoxicam in Albino Male Rats. BIOMED RESEARCH INTERNATIONAL 2022; 2022:1546734. [PMID: 35958816 PMCID: PMC9363220 DOI: 10.1155/2022/1546734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/18/2022] [Indexed: 11/17/2022]
Abstract
Lornoxicam is a potent oxicam-class nonsteroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory, and antipyretic effects. Its impacts on many biological functions are not fully understood. We measured various biomarkers in male albino rats provided an oral aqueous ginger extract before IM administration of therapeutic and 2× the therapeutic doses of lornoxicam. The aqueous ginger plant extract was characterized by mass spectroscopy, and its effects were determined by examining free radical scavenging activity, blood parameters, renal and hepatic function, semen quality, proinflammatory cytokines, antioxidant markers, and histopathology. Rats administered lornoxicam had significantly higher liver and kidney function biomarker values, TNF-α, interleukin-6, and sperm abnormalities than the control rats. The overall erythrocyte count, packed cell volume, prostaglandin, and sperm counts were all considerably lower in the experimental animals. Histological changes were found in the liver, spleen, and testes of rats administered lornoxicam alone. In rats, pretreatment with ginger extract reduced the majority of the negative effects of conventional and high dosages of lornoxicam.
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Affiliation(s)
- Sabry M. El-Bahr
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia
- Department of Biochemistry, Faculty of Veterinary Medicine, Alexandria University, Alexandria 21523, Egypt
| | - Rabab R. Elzoghby
- Department of Pharmacology, Faculty of Veterinary Medicine, New Valley University, Egypt
| | | | - Mahmoud Kandeel
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafr Elsheikh University, Egypt
| | - Ahlam F. Hamouda
- Department of Forensic Medicine and Toxicology, Teaching Hospital, Faculty of Veterinary Medicine, Benha University, Benha 13736, Egypt
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Cai X, Cai H, Wang J, Yang Q, Guan J, Deng J, Chen Z. Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options. J Zhejiang Univ Sci B 2022; 23:265-285. [PMID: 35403383 DOI: 10.1631/jzus.b2100977] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Acetaminophen, also known as N-acetyl-p-aminophenol (APAP), is commonly used as an antipyretic and analgesic agent. APAP overdose can induce hepatic toxicity, known as acetaminophen-induced liver injury (AILI). However, therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting. Hence, there is a need to understand the potential pathological mechanisms underlying AILI. In this review, we summarize three main mechanisms involved in the pathogenesis of AILI: hepatocyte necrosis, sterile inflammation, and hepatocyte regeneration. The relevant factors are elucidated and discussed. For instance, N-acetyl-p-benzoquinone imine (NAPQI) protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis, danger-associated molecular patterns (DAMPs) are released to elicit sterile inflammation, and certain growth factors contribute to liver regeneration. Finally, we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists. This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future.
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Affiliation(s)
- Xiaopeng Cai
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Huiqiang Cai
- Department of Clinical Medicine, University of Aarhus, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark
| | - Jing Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qin Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jingwen Deng
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China. , .,Department of Pathology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. ,
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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15
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Elshal M, Abdelmageed ME. Diacerein counteracts acetaminophen-induced hepatotoxicity in mice via targeting NLRP3/caspase-1/IL-1β and IL-4/MCP-1 signaling pathways. Arch Pharm Res 2022; 45:142-158. [PMID: 35244883 PMCID: PMC8967791 DOI: 10.1007/s12272-022-01373-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 02/18/2022] [Indexed: 12/22/2022]
Abstract
The current study aims at repurposing the anti-arthritic drug diacerein (DCN) for the treatment of acetaminophen hepatotoxicity and investigating the potential underlying mechanisms. Mice were randomly divided into six groups receiving either no treatment (control group), 20 mg/kg DCN i.p, 400 mg/kg acetaminophen i.p, DCN 4 h before acetaminophen, DCN 2 h after acetaminophen, or 400 mg/kg N-acetylcysteine (NAC) i.p, 2 h after acetaminophen. Biomarkers of liver dysfunction, oxidative stress, and apoptosis were assessed. Hepatic necroinflammatory changes were evaluated along with hepatic expression of NF-κB and caspase-1. The levels of NLRP3, IL-1β, IL-4, MCP-1, and TNF-α in the liver, as well as CYP2E1 mRNA expression, were measured. Diacerein significantly reduced biomarkers of liver dysfunction, oxidative stress, hepatocyte necrosis, and infiltration of neutrophils and macrophages whether administered 4 h before or 2 h after acetaminophen. Further, the effects were comparable to those of NAC. Diacerein also counteracted acetaminophen-induced hepatocellular apoptosis by increasing Bcl-2 and decreasing Bax and caspase-3 expression levels. Moreover, DCN normalized hepatic TNF-α and significantly decreased NF-κB p65 expression. Accordingly, DCN can prevent or reverse acetaminophen hepatotoxicity in mice, suggesting potential utility as a repurposed drug for clinical treatment.
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Affiliation(s)
- Mahmoud Elshal
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Mansoura University, El Gomhoria Street, Eldakahlia, 35516 Egypt
| | - Marwa E. Abdelmageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Mansoura University, El Gomhoria Street, Eldakahlia, 35516 Egypt
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16
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Gong L, Liao L, Dai X, Xue X, Peng C, Li Y. The dual role of immune response in acetaminophen hepatotoxicity: Implication for immune pharmacological targets. Toxicol Lett 2021; 351:37-52. [PMID: 34454010 DOI: 10.1016/j.toxlet.2021.08.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 07/16/2021] [Accepted: 08/23/2021] [Indexed: 12/14/2022]
Abstract
Acetaminophen (APAP), one of the most widely used antipyretic and analgesic drugs, principally contributes to drug-induced liver injury when taken at a high dose. APAP-induced liver injury (AILI) results in extensive necrosis of hepatocytes along with the occurrence of multiple intracellular events such as metabolic activation, cell injury, and signaling pathway activation. However, the specific role of the immune response in AILI remains controversial for its complicated regulatory mechanisms. A variety of inflammasomes, immune cells, inflammatory mediators, and signaling transduction pathways are activated in AILI. These immune components play antagonistic roles in aggravating the liver injury or promoting regeneration. Recent experimental studies indicated that natural products showed remarkable therapeutic effects against APAP hepatotoxicity due to their favorable efficacy. Therefore, this study aimed to review the present understanding of the immune response in AILI and attempted to establish ties among a series of inflammatory cascade reactions. Also, the immune molecular mechanisms of natural products in the treatment of AILI were extensively reviewed, thus providing a fundamental basis for exploring the potential pharmacological targets associated with immune interventions.
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Affiliation(s)
- Lihong Gong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Li Liao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xuyang Dai
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xinyan Xue
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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17
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Wang B, Li J, Jiao J, Xu M, Luo Y, Wang F, Xia Q, Gao Y, Feng Y, Kong X, Sun X. Myeloid DJ-1 deficiency protects acetaminophen-induced acute liver injury through decreasing inflammatory response. Aging (Albany NY) 2021; 13:18879-18893. [PMID: 34289451 PMCID: PMC8351717 DOI: 10.18632/aging.203340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 07/09/2021] [Indexed: 02/05/2023]
Abstract
Background: DJ-1 (also known as PARK7), a noted protein implicated in modulating ROS production and immune response, has been observed to play critical roles in the pathogenesis of many forms of liver disease through multiple mechanisms. However, its role and specific mechanism in acetaminophen (APAP) -induced liver injury have not been explored. Results: In this present study, by employing an acute liver injury induced by APAP overdose mouse model, we demonstrated that DJ-1 knockout (DJ-1−/−) mice showed reduced liver injury and lower mortality. In accordance with these changes, there were also alleviating inflammatory responses in both the serum and the liver of the DJ-1−/− mice compared to those of the wild-type (WT) mice. Functional experiments showed that APAP metabolism did not affected by DJ-1 deficiency. In addition, to investigate DJ-1 modulates which kind of cell types during APAP-overdose-induced acute liver injury, hepatocyte-specific DJ-1-knockout (Alb-DJ-1−/−) and myeloid-specific DJ-1-knockout (Lysm-DJ-1−/−) mice were generated. Interestingly, hepatic deletion of DJ-1 did not protect APAP-overdose induced hepatotoxicity and inflammation, whereas Lysm-DJ-1−/− mice showed similar protective effects as DJ-1−/− mice which suggest that the protective effects of deletion of DJ-1 was through modulating myeloid cell function. Consistently, there were alleviated pro-inflammatory cells infiltration and reduced reactive oxygen species (ROS) production in the liver of Lysm-DJ-1−/− mice relative to control mice. Conclusion: our findings clearly defined that deletion of DJ-1 protects APAP-induced acute liver injury through decreasing inflammatory response, and suggest DJ-1 as a potential therapeutic and/or prophylactic target of APAP-induced acute liver injury.
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Affiliation(s)
- Bingrui Wang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Central Laboratory, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Jichang Li
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Junzhe Jiao
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Min Xu
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Yichun Luo
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Fang Wang
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yueqiu Gao
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Yu Feng
- Department of General Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoni Kong
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Xuehua Sun
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
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18
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Prego-Domínguez J, Takkouche B. Paracetamol Intake and Hematologic Malignancies: A Meta-Analysis of Observational Studies. J Clin Med 2021; 10:jcm10112429. [PMID: 34070784 PMCID: PMC8198062 DOI: 10.3390/jcm10112429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/12/2021] [Accepted: 05/27/2021] [Indexed: 11/16/2022] Open
Abstract
Hematologic malignancies cause more than half a million deaths every year worldwide. Analgesics were suggested as chemopreventive agents for several cancers but so far, results from individual studies about the relationship between paracetamol (acetaminophen) use and hematologic malignancies are conflicting. Therefore, we decided to perform a systematic review and meta-analysis. We retrieved studies published in any language by systematically searching Medline, Embase, Conference Proceedings Citation Index, Open Access Theses and Dissertations, and the five regional bibliographic databases of the World Health Organization until December 2020. Pooled odds ratios (OR) and their 95% confidence intervals (CI) were calculated according to the inverse of their variances. We performed separate analyses by histologic type. We also evaluated publication bias and assessed quality. A total of 17 study units met our inclusion criteria. The results show an association of hematologic malignancies with any paracetamol intake (OR 1.49, 95% CI 1.23-1.80) and with high paracetamol intake (OR 1.77, 95% CI 1.45-2.16). By subtype, risk was higher for multiple myeloma (OR 2.13, 95% CI 1.54-2.94) for any use and OR 3.16, 95% CI 1.96-5.10 for high intake, while risk was lower and non-significant for non-Hodgkin lymphoma. This meta-analysis provides evidence that paracetamol intake may be associated with hematologic malignancies and suggests that a dose-response effect is plausible. These results are unlikely to be due to publication bias or low quality of studies. Future research should focus on assessing the dose-response relationship.
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Affiliation(s)
- Jesús Prego-Domínguez
- Department of Preventive Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain;
| | - Bahi Takkouche
- Department of Preventive Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain;
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBER-ESP), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-881-812268; Fax: +34-981-572282
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Wei S, Ma W, Zhang B, Li W. NLRP3 Inflammasome: A Promising Therapeutic Target for Drug-Induced Toxicity. Front Cell Dev Biol 2021; 9:634607. [PMID: 33912556 PMCID: PMC8072389 DOI: 10.3389/fcell.2021.634607] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 03/18/2021] [Indexed: 12/13/2022] Open
Abstract
Drug-induced toxicity, which impairs human organ function, is a serious problem during drug development that hinders the clinical use of many marketed drugs, and the underlying mechanisms are complicated. As a sensor of infections and external stimuli, nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a key role in the pathological process of various diseases. In this review, we specifically focused on the role of NLRP3 inflammasome in drug-induced diverse organ toxicities, especially the hepatotoxicity, nephrotoxicity, and cardiotoxicity. NLRP3 inflammasome is involved in the initiation and deterioration of drug-induced toxicity through multiple signaling pathways. Therapeutic strategies via inhibiting NLRP3 inflammasome for drug-induced toxicity have made significant progress, especially in the protective effects of the phytochemicals. Growing evidence collected in this review indicates that NLRP3 is a promising therapeutic target for drug-induced toxicity.
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Affiliation(s)
- Shanshan Wei
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Wanjun Ma
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Wenqun Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
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20
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Acute liver injury following acetaminophen administration does not activate atrophic pathways in the mouse diaphragm. Sci Rep 2021; 11:6302. [PMID: 33737702 PMCID: PMC7973759 DOI: 10.1038/s41598-021-85859-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 03/04/2021] [Indexed: 11/09/2022] Open
Abstract
N-acetyl-para-amino phenol (APAP, usually named paracetamol), which is commonly used for its analgesic and antipyretic properties may lead to hepatotoxicity and acute liver damage in case of overdoses. Released cytokines and oxidative stress following acute liver damage may affect other organs' function notably the diaphragm, which is particularly sensitive to oxidative stress and circulating cytokines. We addressed this issue in a mouse model of acute liver injury induced by administration of APAP. C57BL/6J mice (each n = 8) were treated with N-acetyl-para-amino phenol (APAP) to induce acute drug caused liver injury and sacrificed 12 or 24 h afterwards. An untreated group served as controls. Key markers of inflammation, proteolysis, autophagy and oxidative stress were measured in diaphragm samples. In APAP treated animals, liver damage was proven by the enhanced serum levels of alanine aminotransferase and aspartate aminotransferase. In the diaphragm, besides a significant increase in IL 6 and lipid peroxidation, no changes were observed in key markers of the proteolytic, and autophagy signaling pathways, other inflammatory markers and fiber dimensions. The first 24 h of acute liver damage did not impair diaphragm atrophic pathways although it slightly enhanced IL-6 and lipid peroxidation. Whether longer exposure might affect the diaphragm needs to be addressed in future experiments.
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21
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Assis JB, Cogliati B, Esteves E, Capurro ML, Fonseca DM, Sá-Nunes A. Aedes aegypti mosquito saliva ameliorates acetaminophen-induced liver injury in mice. PLoS One 2021; 16:e0245788. [PMID: 33556084 PMCID: PMC7869984 DOI: 10.1371/journal.pone.0245788] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 01/07/2021] [Indexed: 02/07/2023] Open
Abstract
Acetaminophen (N-acetyl-p-aminophenol, APAP) overdose is the most common cause of drug-induced liver injury (DILI). Although the primary hepatic damage is induced by APAP-derived toxic intermediates resulting from cytochrome P450 metabolism, immune components also play an important role in DILI pathophysiology. Aedes aegypti saliva is a source of bioactive molecules with in vitro anti-inflammatory and immunomodulatory activities. However, evidences on the therapeutic use of Ae. aegypti salivary preparations in animal models of relevant clinical conditions are still scarce. Thus, the present study was designed to evaluate the protective role of Ae. aegypti saliva in a murine model of APAP-induced DILI. C57BL/6 mice were exposed to Ae. aegypti bites 2 hours after APAP overdose. Biochemical and immunological parameters were evaluated in blood and liver samples at different time points after APAP administration. Exposure to Ae. aegypti saliva attenuated liver damage, as demonstrated by reduced hepatic necrosis and serum levels of alanine aminotransferase in APAP-overdosed mice. The levels of hepatic CYP2E1, the major enzyme responsible for the bioactivation of APAP, were not changed in Ae. aegypti exposed animals, suggesting no effects in the generation of hepatotoxic metabolites. On the other hand, mice treated with Ae. aegypti saliva following APAP overdose presented lower serum concentration of TNF-α, IL-6, IL-1β and IL-10, as well as reduced frequency of inflammatory cell populations in the liver, such as NKT cells, macrophages and dendritic cells. These findings show that Ae. aegypti saliva has bioactive molecules with therapeutic properties and may represent a prospective source of new compounds in the management of DILI-associated inflammatory disorders and, perhaps, many other inflammatory/autoimmune diseases.
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Affiliation(s)
- Josiane B. Assis
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Bruno Cogliati
- Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, Brazil
| | - Eliane Esteves
- Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Margareth L. Capurro
- Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
- Instituto Nacional de Ciência e Tecnologia em Entomologia Molecular, Conselho Nacional de Desenvolvimento Científico e Tecnológico (INCT-EM/CNPq), Rio de Janeiro, Rio de Janeiro, Brazil
| | - Denise M. Fonseca
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Anderson Sá-Nunes
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
- Instituto Nacional de Ciência e Tecnologia em Entomologia Molecular, Conselho Nacional de Desenvolvimento Científico e Tecnológico (INCT-EM/CNPq), Rio de Janeiro, Rio de Janeiro, Brazil
- * E-mail:
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Ahmed LA, Abd El-Rhman RH, Gad AM, Hassaneen SK, El-Yamany MF. Dibenzazepine combats acute liver injury in rats via amendments of Notch signaling and activation of autophagy. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:337-348. [PMID: 32984915 DOI: 10.1007/s00210-020-01977-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 09/13/2020] [Indexed: 02/08/2023]
Abstract
Paracetamol is a commonly used over-the-counter analgesic and antipyretic drug. Nevertheless, an overdose of paracetamol leads to hepatic necrosis that can be lethal. This study aimed to assess the potential hepatoprotective effects of dibenzazepine, a Notch inhibitor, against acute liver injury in rats via interfering with oxidative stress, inflammation, apoptosis, autophagy, and Notch signaling. Silymarin (200 mg/kg, p.o.) or dibenzazepine (2 mg/kg, i.p.) were administered to rats for 5 days before a single hepatotoxic dose of paracetamol (800 mg/kg, i.p.). Pretreatment with silymarin and dibenzazepine significantly mitigated oxidative stress, inflammatory and apoptotic markers induced by paracetamol hepatotoxicity where dibenzazepine showed greater repression of inflammation. Furthermore, dibenzazepine was found to be significantly more efficacious than silymarin in inhibiting Notch signaling as represented by expression of Notch-1 and Hes-1. A significantly greater response was also demonstrated with dibenzazepine pretreatment with regard to the expression of autophagic proteins, Beclin-1 and LC-3. The aforementioned biochemical results were confirmed by histopathological examination. Autophagy and Notch signaling seem to play a significant role in protection provided by dibenzazepine for paracetamol-induced hepatotoxicity in rats, which could explain its superior results relative to silymarin. Graphical abstract.
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Affiliation(s)
- Lamiaa A Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Rana H Abd El-Rhman
- Department of Pharmacology, Egyptian Drug Authority formerly National Organization for Drug Control and Research, Giza, Egypt
| | - Amany M Gad
- Department of Pharmacology, Egyptian Drug Authority formerly National Organization for Drug Control and Research, Giza, Egypt
| | - Sherifa K Hassaneen
- Department of Pharmacology, Egyptian Drug Authority formerly National Organization for Drug Control and Research, Giza, Egypt
| | - Mohamad F El-Yamany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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23
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Adhyapok P, Fu X, Sluka JP, Clendenon SG, Sluka VD, Wang Z, Dunn K, Klaunig JE, Glazier JA. A computational model of liver tissue damage and repair. PLoS One 2020; 15:e0243451. [PMID: 33347443 PMCID: PMC7752149 DOI: 10.1371/journal.pone.0243451] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 11/22/2020] [Indexed: 01/09/2023] Open
Abstract
Drug induced liver injury (DILI) and cell death can result from oxidative stress in hepatocytes. An initial pattern of centrilobular damage in the APAP model of DILI is amplified by communication from stressed cells and immune system activation. While hepatocyte proliferation counters cell loss, high doses are still lethal to the tissue. To understand the progression of disease from the initial damage to tissue recovery or death, we computationally model the competing biological processes of hepatocyte proliferation, necrosis and injury propagation. We parametrize timescales of proliferation (α), conversion of healthy to stressed cells (β) and further sensitization of stressed cells towards necrotic pathways (γ) and model them on a Cellular Automaton (CA) based grid of lattice sites. 1D simulations show that a small α/β (fast proliferation), combined with a large γ/β (slow death) have the lowest probabilities of tissue survival. At large α/β, tissue fate can be described by a critical γ/β* ratio alone; this value is dependent on the initial amount of damage and proportional to the tissue size N. Additionally, the 1D model predicts a minimum healthy population size below which damage is irreversible. Finally, we compare 1D and 2D phase spaces and discuss outcomes of bistability where either survival or death is possible, and of coexistence where simulated tissue never completely recovers or dies but persists as a mixture of healthy, stressed and necrotic cells. In conclusion, our model sheds light on the evolution of tissue damage or recovery and predicts potential for divergent fates given different rates of proliferation, necrosis, and injury propagation.
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Affiliation(s)
- Priyom Adhyapok
- Biocomplexity Institute, Indiana University, Bloomington, IN, United States of America
- Department of Physics, Indiana University, Bloomington, IN, United States of America
- * E-mail:
| | - Xiao Fu
- The Francis Crick Institute, London, United Kingdom
| | - James P. Sluka
- Biocomplexity Institute, Indiana University, Bloomington, IN, United States of America
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, United States of America
| | - Sherry G. Clendenon
- Biocomplexity Institute, Indiana University, Bloomington, IN, United States of America
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, United States of America
| | - Victoria D. Sluka
- Biocomplexity Institute, Indiana University, Bloomington, IN, United States of America
| | - Zemin Wang
- School of Public Health, Indiana University, Bloomington, IN, United States of America
| | - Kenneth Dunn
- School of Medicine, Indiana University, Indianapolis, IN, United States of America
| | - James E. Klaunig
- School of Public Health, Indiana University, Bloomington, IN, United States of America
| | - James A. Glazier
- Biocomplexity Institute, Indiana University, Bloomington, IN, United States of America
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, United States of America
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24
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Kucukler S, Darendelioğlu E, Caglayan C, Ayna A, Yıldırım S, Kandemir FM. Zingerone attenuates vancomycin-induced hepatotoxicity in rats through regulation of oxidative stress, inflammation and apoptosis. Life Sci 2020; 259:118382. [PMID: 32898532 DOI: 10.1016/j.lfs.2020.118382] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/17/2020] [Accepted: 08/29/2020] [Indexed: 12/20/2022]
Abstract
AIM Vancomycin (VCM) is a glycopeptide antibiotic widely used to treat serious infections caused by methicillin-resistant Staphylococcus aureus and has been associated with some severe side effects such as hepatotoxicity and nephrotoxicity. However, the underlying mechanism of VCM-induced hepatotoxicity is not yet fully understood. Therefore, the current study was designed to evaluate the protective effects of zingerone (Zin) against VCM-induced hepatotoxicity in rats. MATERIALS AND METHODS VCM was intraperitoneally administered at a dose of 200 mg/kg body weight (b.w.) for 7 days alone and in combination with the orally administered Zin (25 and 50 mg/kg b.w). KEY FINDINGS Zin treatment significantly improved VCM-induced hepatic lipid peroxidation, glutathione depletion, reduced antioxidant enzyme (superoxide dismutase, catalase and glutathione peroxidase) activities and liver function markers (aspartate aminotransferase, alkaline phosphatase and alanine aminotransferase). Histopathological integrity and immunohistochemical expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the VCM-induced liver tissue were ameliorated after Zin administration. In addition, Zin reversed the changes in levels and/or activities of inflammatory and apoptotic parameters such as nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), p53, cysteine aspartate specific protease-3 (caspase-3), cysteine aspartate specific protease-8 (caspase-8), cytochrome c, Bcl-2 associated X protein (Bax) and B-cell lymphoma-2 (Bcl-2) in the VCM-induced hepatotoxicity. SIGNIFICANCE Collectively, these results reveal probable ameliorative role of Zin against VCM-induced hepatotoxicity.
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Affiliation(s)
- Sefa Kucukler
- Department of Biochemistry, Faculty of Veterinary Medicine, Ataturk University, 25240 Erzurum, Turkey.
| | - Ekrem Darendelioğlu
- Department of Molecular Biology and Genetics, Faculty of Science and Literature, Bingol University, 12000 Bingol, Turkey
| | - Cuneyt Caglayan
- Department of Biochemistry, Faculty of Veterinary Medicine, Bingol University, 12000 Bingol, Turkey.
| | - Adnan Ayna
- Department of Biochemistry, Faculty of Science and Literature, Bingol University, 12000 Bingol, Turkey
| | - Serkan Yıldırım
- Department of Pathology, Faculty of Veterinary Medicine, Ataturk University, 25240 Erzurum, Turkey
| | - Fatih Mehmet Kandemir
- Department of Biochemistry, Faculty of Veterinary Medicine, Ataturk University, 25240 Erzurum, Turkey
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25
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McMillin M, Grant S, Frampton G, Petrescu AD, Williams E, Jefferson B, DeMorrow S. The TGFβ1 Receptor Antagonist GW788388 Reduces JNK Activation and Protects Against Acetaminophen Hepatotoxicity in Mice. Toxicol Sci 2020; 170:549-561. [PMID: 31132129 DOI: 10.1093/toxsci/kfz122] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Acute liver failure is a serious consequence of acetaminophen (APAP)-induced hepatotoxic liver injury with high rates of morbidity and mortality. Transforming growth factor beta 1 (TGFβ1) is elevated during liver injury and influences hepatocyte senescence during APAP-induced hepatotoxicity. This study investigated TGFβ1 signaling in the context of inflammation, necrotic cell death, and oxidative stress during APAP-induced liver injury. Male C57Bl/6 mice were injected with 600 mg/kg APAP to generate liver injury in the presence or absence of the TGFβ receptor 1 inhibitor, GW788388, 1 h prior to APAP administration. Acetaminophen-induced liver injury was characterized using histological and biochemical measures. Transforming growth factor beta 1 expression and signal transduction were assessed using immunohistochemistry, Western blotting and ELISA assays. Hepatic necrosis, liver injury, cell proliferation, hepatic inflammation, and oxidative stress were assessed in all mice. Acetaminophen administration significantly induced necrosis and elevated serum transaminases compared with control mice. Transforming growth factor beta 1 staining was observed in and around areas of necrosis with phosphorylation of SMAD3 observed in hepatocytes neighboring necrotic areas in APAP-treated mice. Pretreatment with GW788388 prior to APAP administration in mice reduced hepatocyte cell death and stimulated regeneration. Phosphorylation of SMAD3 was reduced in APAP mice pretreated with GW788388 and this correlated with reduced hepatic cytokine production and oxidative stress. These results support that TGFβ1 signaling plays a significant role in APAP-induced liver injury by influencing necrotic cell death, inflammation, oxidative stress, and hepatocyte regeneration. In conclusion, targeting TGFβ1 or downstream signaling may be a possible therapeutic target for the management of APAP-induced liver injury.
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Affiliation(s)
- Matthew McMillin
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, Texas 78712.,Central Texas Veterans Health Care System, Austin, Texas, 78712.,Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504
| | - Stephanie Grant
- Central Texas Veterans Health Care System, Austin, Texas, 78712.,Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504.,Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas, 78712
| | - Gabriel Frampton
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, Texas 78712.,Central Texas Veterans Health Care System, Austin, Texas, 78712.,Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504
| | - Anca D Petrescu
- Central Texas Veterans Health Care System, Austin, Texas, 78712.,Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504.,Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas, 78712
| | - Elaina Williams
- Central Texas Veterans Health Care System, Austin, Texas, 78712.,Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504.,Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas, 78712
| | - Brandi Jefferson
- Central Texas Veterans Health Care System, Austin, Texas, 78712.,Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504
| | - Sharon DeMorrow
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, Texas 78712.,Central Texas Veterans Health Care System, Austin, Texas, 78712.,Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, 76504.,Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas, 78712
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26
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Omega-3 fatty acids protect against acetaminophen-induced hepatic and renal toxicity in rats through HO-1-Nrf2-BACH1 pathway. Arch Biochem Biophys 2020; 687:108387. [PMID: 32348741 DOI: 10.1016/j.abb.2020.108387] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 02/07/2023]
Abstract
Although acetaminophen (APAP) is a commonly used analgesic antipyretic drug, hepatotoxicity and nephrotoxicity are common after the overdose. The main mechanism of APAP toxicity is oxidative stress based. Stress may induce the production of heme oxygenase 1 (HO)-1 which is regulated by interleukin (IL)-10 and inhibit the production of tumor necrosis factor-alpha (TNF-α). HO-1 expression is further regulated by nuclear factor erythroid 2-related factor 2 (Nrf2) and the transcription factor BTB and CNC homology 1 (BACH1). Drug-induced toxicity can be relieved by several natural products, which are preferred due to their dietary nature and less adverse reactions. Of these natural products, omega-3 (ω-3) fatty acids are known for anti-inflammatory and antioxidant actions. However, effects of ω-3fatty acids on APAP-induced hepatic and renal toxicity are not well addressed. We designed this study to test the potential protecting actions of ω-3 fatty acids (270 mg/kg Eicosapentaenoic acid and 180 mg/kg docosahexaenoic acid, orally, for 7 days) in hepatotoxicity and nephrotoxicity induced by APAP (2 g/kg, once orally on day 7) in rats. Moreover, we focused on the molecular mechanism underlying APAP hepatotoxicity and nephrotoxicity. Pre-treatment with ω-3 fatty acids enhanced liver and kidney functions indicated by decreased serum aminotransferases activities and serum creatinine and urea concentrations. These results were further confirmed by histopathological examination. Moreover, ω-3 fatty acids showed antioxidant properties confirmed by decreased malondialdehyde level and increased total antioxidant capacity. Antioxidant Nrf2, its regulators (HO-1 and BACH1) and the anti-inflammatory cytokine (IL-10) were up-regulated by APAP administration as a compensatory mechanism and they were normalized by ω-3 fatty acids. ω-3 fatty acids showed anti-inflammatory actions through down-regulating nuclear factor kappa B (NF-ĸB) and its downstream TNF-α. Moreover, Western blot analysis showed that ω-3 fatty acids promoted Nrf2 translocation to the nucleus; BACH1 exit from the nucleus and inhibited NF-ĸB nuclear translocation. These findings suggested the protecting actions of ω-3 fatty acids against APAP-induced hepatic and renal toxicity through regulation of antioxidant Nrf2 and inflammatory NF-ĸB pathways.
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27
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Jaeschke H, Ramachandran A. Mechanisms and pathophysiological significance of sterile inflammation during acetaminophen hepatotoxicity. Food Chem Toxicol 2020; 138:111240. [PMID: 32145352 DOI: 10.1016/j.fct.2020.111240] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 02/26/2020] [Accepted: 02/28/2020] [Indexed: 02/07/2023]
Abstract
Acetaminophen (APAP) is a widely used analgesic drug, which can cause severe liver injury after an overdose. The intracellular signaling mechanisms of APAP-induced cell death such as reactive metabolite formation, mitochondrial dysfunction and nuclear DNA fragmentation have been extensively studied. Hepatocyte necrosis releases damage-associated molecular patterns (DAMPs) which activate cytokine and chemokine formation in macrophages. These signals activate and recruit neutrophils, monocytes and other leukocytes into the liver. While this sterile inflammatory response removes necrotic cell debris and promotes tissue repair, the capability of leukocytes to also cause tissue injury makes this a controversial topic. This review summarizes the literature on the role of various DAMPs, cytokines and chemokines, and the pathophysiological function of Kupffer cells, neutrophils, monocytes and monocyte-derived macrophages, and NK and NKT cells during APAP hepatotoxicity. Careful evaluation of results and experimental designs of studies dealing with the inflammatory response after APAP toxicity provide very limited evidence for aggravation of liver injury but support of the hypothesis that these leukocytes promote tissue repair. In addition, many cytokines and chemokines modulate tissue injury by affecting the intracellular signaling events of cell death rather than toxicity of leukocytes. Reasons for the controversial results in this area are also discussed.
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Affiliation(s)
- Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
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28
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Hewedy WA. Effects of treatment with sitagliptin on hepatotoxicity induced by acetaminophen in mice. BRAZ J PHARM SCI 2020. [DOI: 10.1590/s2175-97902019000418482] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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29
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30
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Mohammadi A, Kazemi S, Hosseini M, Najafzadeh Varzi H, Feyzi F, Morakabati P, Moghadamnia AA. Chrysin Effect in Prevention of Acetaminophen-Induced Hepatotoxicity in Rat. Chem Res Toxicol 2019; 32:2329-2337. [DOI: 10.1021/acs.chemrestox.9b00332] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Arezoo Mohammadi
- Student Research Committee, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Hosseini
- Department of Veterinary Parasitology, Babol-Branch, Islamic Azad University, Babol, Iran
| | - Hoseyn Najafzadeh Varzi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Farideh Feyzi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Payam Morakabati
- Student Research Committee, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Ali Akbar Moghadamnia
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
- Department of Pharmacology and Toxicology, Babol University of Medical Sciences, Babol, Iran
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31
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Auriculatone Sulfate Effectively Protects Mice Against Acetaminophen-Induced Liver Injury. Molecules 2019; 24:molecules24203642. [PMID: 31600996 PMCID: PMC6832223 DOI: 10.3390/molecules24203642] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/26/2019] [Accepted: 09/30/2019] [Indexed: 01/28/2023] Open
Abstract
Acetaminophen (APAP) overdose is very common worldwide and has been widely recognized as the leading cause of drug-induced liver injury in the Western world. In our previous investigation, auriculatone, a natural product firstly obtained from Aster auriculatus, has demonstrated a potent protective effect against APAP-induced hepatotoxicity in HL-7702 cells. However, the poor water solubility and low bioavailability restrict its application. Auriculatone sulfate (AS) is a sulfated derivative of auriculatone with highly improved water-solubility. Hepatoprotective effects against APAP-induced liver injury (AILI) showed that intragastric pretreatment with AS at 50 mg/kg almost completely prevented mice against APAP-induced increases of serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and ATPase. Histological results showed that AS could protect the liver tissue damage. In addition, AS pretreatment not only significantly retained hepatic malondialdehyde and the activities of glutathione, superoxide dismutase, and glutathione peroxidase at normal levels, but also markedly suppressed the increase of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 levels in mouse liver caused by overdose APAP. Immunohistochemical analysis showed that AS obviously attenuated the expression of CD45 and HNE in liver tissue. Further mechanisms of action investigation showed that inhibition of cytochrome P450 3A11 (CYP 3A11) and CYP2E1 enzymatic activities (but not that of CYP1A2) was responsible for APAP bioactivation. In conclusion, AS showed a hepatoprotective effect against AILI through alleviating oxidative stress and inflammation and inhibiting CYP-mediated APAP bioactivation. It may be an effective hepatoprotective agent for AILI and other forms of human liver disease.
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32
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Wang H, Zhang R, Zhu Y, Teng T, Cheng Y, Chowdhury A, Lu J, Jia Z, Song J, Yin X, Sun Y. Microsomal prostaglandin E synthase 2 deficiency is resistant to acetaminophen-induced liver injury. Arch Toxicol 2019; 93:2863-2878. [DOI: 10.1007/s00204-019-02543-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Accepted: 08/14/2019] [Indexed: 12/12/2022]
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33
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Manakkat Vijay GK, Hu C, Peng J, Garcia-Martinez I, Hoque R, Verghis RM, Ma Y, Mehal WZ, Shawcross DL, Wen L. Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9. Cell Mol Gastroenterol Hepatol 2019; 8:609-623. [PMID: 31401214 PMCID: PMC6889059 DOI: 10.1016/j.jcmgh.2019.08.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/31/2019] [Accepted: 08/02/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIM Ammonia is central in the pathogenesis of brain edema in acute liver failure (ALF) with infection and systemic inflammation expediting development of intracranial hypertension (ICH). Patients with acetaminophen-induced ALF have increased neutrophil TLR9 expression which can be induced by ammonia. We determined whether ammonia-induced brain edema and immune dysfunction are mediated by TLR9 and if this could be prevented in a TLR9-deficient mouse model. METHODS Ammonium acetate (NH4-Ac; 4mmol/kg) was injected intraperitoneally in wild type (WT), Tlr9-/- and Lysm-Cre Tlr9fl/fl mice (TLR9 absent in neutrophils and macrophages including Kupffer cells) and compared to controls. Six hours after NH4-Ac injection, intracellular cytokine production was determined in splenic macrophages, CD4+ and CD8+ T cells. Brain water (BW) and total plasma DNA (tDNA) were also measured. The impact of the TLR9 antagonist ODN2088 (50μg/mouse) was evaluated. RESULTS Following NH4-Ac injection, BW, macrophage and T cell cytokine production increased (P < .0001) in WT but not Tlr9-/- mice (P < .001). ODN2088 inhibited macrophage and T cell cytokine production (P < .05) and prevented an increase in BW (P < .0001). Following NH4-Ac injection, macrophage cytokine production and BW were ameliorated in Lysm-Cre Tlr9fl/fl mice compared to WT mice (P < .05) but there was no difference compared to Tlr9-/- mice. Following NH4-Ac injection, plasma tDNA levels increased in WT and Tlr9-/- mice (P < .05) suggesting that TLR9 may be activated by DNA released from ammonia-stimulated cells. CONCLUSION Ammonia-induced brain edema requires macrophage and T cell expression of TLR9. Amelioration of brain edema and lymphocyte cytokine production by ODN2088 supports exploration of TLR9 antagonism in early ALF to prevent progression to ICH.
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Affiliation(s)
- Godhev Kumar Manakkat Vijay
- Liver Sciences Department, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom,Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Changyun Hu
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Jian Peng
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Irma Garcia-Martinez
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Rafaz Hoque
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Rejina Mariam Verghis
- Welcome Wolfson Institute of Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queens University, Belfast, United Kingdom
| | - Yun Ma
- Liver Sciences Department, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Wajahat Zafar Mehal
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Debbie Lindsay Shawcross
- Liver Sciences Department, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom,Correspondence Address correspondence to: Debbie Lindsay Shawcross, BSc, MBBS, PhD, Liver Sciences Department, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital Campus, Denmark Hill, London, SE5 9RS United Kingdom. fax: +44 (0)20 3299 3167.
| | - Li Wen
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut,Li Wen, MD, PhD, Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, PO Box 208020, 333 Cedar Street, New Haven, Connecticut 06520. fax: (203) 737–5558.
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34
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Che J, Yang S, Qiao Z, Li H, Sun J, Zhuang W, Chen J, Wang C. Schisandra chinensis acidic polysaccharide partialy reverses acetaminophen-induced liver injury in mice. J Pharmacol Sci 2019; 140:248-254. [PMID: 31400930 DOI: 10.1016/j.jphs.2019.07.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 07/15/2019] [Accepted: 07/17/2019] [Indexed: 12/31/2022] Open
Abstract
Schisandra chinensis is a hepatoprotective herb that has been used for centuries in China. Polysaccharide is one of the major active components in S. chinensis, which has been reported to improve liver injuries induced by carbon tetrachloride, alcohol, or high-fat diet. In this study, we observed the effects and corresponding mechanisms of the secondary component of Schisandra polysaccharide (acidic polysaccharide, SCAP) on a murine model of severe acute liver injury induced by acetaminophen (APAP). SCAP significantly decreased the serum alanine aminotransferase (ALT), aspartate aminotransferas (AST), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels, and was found to alleviate hepatic pathological alterations in the mouse model. Meanwhile, SCAP revealed a protective effects on the liver injury-related enzymes and factors, such as significantly diminished malondialdehyde (MDA) levels and glutathione (GSH) depletion, reduced ratio of B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax)/Bcl-2, prohibited cleaved caspase-3 expression, and elevated the expression of p-AMPK, p-Akt, p-glycogen synthase kinase 3β (GSK 3β), nuclear factor erythroid 2-derived-like 2 (Nrf 2) and heme oxygenase-1 (HO-1) proteins in the liver tissues of the mouse model. In conclusion, we speculated that the protective activities of SCAP on the APAP-induced mouse model of acute liver injury might be related to its antioxidation, anti-inflammation and anti-apoptosis properties.
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Affiliation(s)
- Jinying Che
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, Jilin, 132013, China
| | - Shuo Yang
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, Jilin, 132013, China
| | - Zijing Qiao
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, Jilin, 132013, China
| | - He Li
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, Jilin, 132013, China
| | - Jinghui Sun
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, Jilin, 132013, China
| | - Wenyue Zhuang
- Department of Molecular Biology, College of Laboratory Medicine, Beihua University, Jilin, Jilin, 132002, China
| | - Jianguang Chen
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, Jilin, 132013, China.
| | - Chunmei Wang
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, Jilin, 132013, China.
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Hong L, Li Y, Liu Q, Chen Q, Chen L, Zhou D. The Hippo Signaling Pathway in Regenerative Medicine. Methods Mol Biol 2019; 1893:353-370. [PMID: 30565146 DOI: 10.1007/978-1-4939-8910-2_26] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The major role of Hippo signaling is to inhibit their downstream effectors YAP/TAZ for organ size control during development and regeneration (Nat Rev Drug Discov 13(1):63-79, 2014; Dev Cell 19(4):491-505, 2010; Cell 163(4):811-828, 2015). We and others have demonstrated that the genetic disruption of kinases Mst1 and Mst2 (Mst1/2), the core components of Hippo signaling, results in YAP activation and sustained liver growth, thereby leading to an eight- to tenfold increase in liver size within 3 months and occurrence of liver cancer within 5 months (Curr Biol 17(23):2054-2060, 2007; Cancer Cell 16(5):425-438, 2009; Cell 130(6):1120-1133, 2007; Cancer Cell 31(5):669-684 e667, 2017; Nat Commun 6:6239, 2015; Cell Rep 3(5):1663-1677, 2013). XMU-MP-1, an Mst1/2 inhibitor, is able to augment mouse liver and intestinal repair and regeneration in both acute and chronic injury mouse models (Sci Transl Med 8:352ra108, 2016).In addition, YAP-deficient mice show an impaired intestinal regenerative response after DSS treatment or gamma irradiation (Proc Natl Acad Sci U S A 108(49):E1312-1320, 2011; Nature 493(7430):106-110, 2013; Genes Dev 24(21):2383-2388, 2010; J Vis Exp (111), 2010). IBS008738, a TAZ activator, facilitates muscle repair after cardiotoxin-induced muscle injury (Mol Cell Biol. 2014;34(9):1607-21). Deletion of Salvador (Sav) in mouse hearts enhances cardiomyocyte regeneration with reduced fibrosis and recovery of pumping function after myocardial infarction (MI) or resection of mouse cardiac apex (Development 140(23):4683-4690, 2013; Sci Signal 8(375):ra41, 2015; Nature 550(7675):260-264, 2017). This chapter provides a detailed description of procedures and important considerations when performing the protocols for the respective assays used to determine the effects of Hippo signaling on tissue repair and regeneration.
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Affiliation(s)
- Lixin Hong
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Yuxi Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Qingxu Liu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Qinghua Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Lanfen Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Dawang Zhou
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
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A phospholipase D2 inhibitor, CAY10594, ameliorates acetaminophen-induced acute liver injury by regulating the phosphorylated-GSK-3β/JNK axis. Sci Rep 2019; 9:7242. [PMID: 31076618 PMCID: PMC6510900 DOI: 10.1038/s41598-019-43673-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 04/29/2019] [Indexed: 12/11/2022] Open
Abstract
We examined the role of phospholipase D2 (PLD2) on acetaminophen (APAP)-induced acute liver injury using a PLD2 inhibitor (CAY10594). 500 mg/kg of APAP challenge caused acute liver damage. CAY10594 administration markedly blocked the acute liver injury in a dose-dependent manner, showing almost complete inhibition with 8 mg/kg of CAY10594. During the pathological progress of acute liver injury, GSH levels are decreased, and this is significantly recovered upon the administration of CAY10594 at 6 hours post APAP challenge. GSK-3β (Serine 9)/JNK phosphorylation is mainly involved in APAP-induced liver injury. CAY10594 administration strongly blocked GSK-3β (Serine 9)/JNK phosphorylation in the APAP-induced acute liver injury model. Consistently, sustained JNK activation in the cytosol and mitochondria from hepatocytes were also decreased in CAY10594-treated mice. Many types of immune cells are also implicated in APAP-induced liver injury. However, neutrophil and monocyte populations were not different between vehicle- and CAY10594-administered mice which are challenged with APAP. Therapeutic administration of CAY10594 also significantly attenuated liver damage caused by the APAP challenge, eliciting an enhanced survival rate. Taken together, these results indicate that PLD2 is involved in the intrinsic response pathway of hepatocytes driving the pathogenesis of APAP-induced acute liver injury, and PLD2 may therefore represent an important therapeutic target for patients with drug-induced liver injury.
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Mitchell CM, El Jordi O, Yamamoto BK. Inflammatory mechanisms of abused drugs. ROLE OF INFLAMMATION IN ENVIRONMENTAL NEUROTOXICITY 2019. [DOI: 10.1016/bs.ant.2018.10.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Abdelrahman RS, Abdel-Rahman N. Dimethyl fumarate ameliorates acetaminophen-induced hepatic injury in mice dependent of Nrf-2/HO-1 pathway. Life Sci 2018; 217:251-260. [PMID: 30550888 DOI: 10.1016/j.lfs.2018.12.013] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 12/07/2018] [Accepted: 12/09/2018] [Indexed: 02/07/2023]
Abstract
Drug-induced liver toxicity is the most frequent cause of acute liver failure worldwide. Hepatotoxicity caused by acetaminophen (ACT) overdose is mediated by its metabolic product promoting oxidative stress and activation of inflammatory mediators. Nuclear factor erythroid-related factor-2 (Nrf-2) induces the release of cytoprotective enzymes in response to electrophilic or oxidative stress and is considered a promising therapeutic target. Dimethyl fumarate (DMF) is a potent activator of (Nrf-2), its anti-inflammatory and antioxidant properties of DMF have been highlighted recently. We designed this study to explore the effect of DMF (100 mg/kg, orally) administered once and twice on hepatotoxicity induced by acetaminophen (ACT, 500 mg/kg, i.p.) in mice. DMF administration enhanced ACT-induced parameters in liver function, inhibited apoptosis and ameliorated the antioxidant machinery and inflammatory markers in a Nrf-2-dependent fashion. DMF elevated Nrf-2 and HO-1 levels and ameliorated liver injury as indicated by lowered levels of serum aminotransferases, ALP, GGT and bilirubin levels. Hepatic (Bcl-2) was elevated whereas hepatic caspase-3, NFκ-B, TNF-α and MPO were reduced. Hepatic levels of GSH, SOD, MDA and NO were altered promoting the antioxidant machinery. Histological examination of liver has further supported these results. These findings suggest that DMF can be employed in the treatment ACT-induced liver injury acting primarily through targeting Nrf-2/HO-1 pathway.
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Affiliation(s)
- Rehab S Abdelrahman
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Noha Abdel-Rahman
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
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Cha H, Lee S, Lee JH, Park JW. Protective effects of p-coumaric acid against acetaminophen-induced hepatotoxicity in mice. Food Chem Toxicol 2018; 121:131-139. [DOI: 10.1016/j.fct.2018.08.060] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 08/03/2018] [Accepted: 08/23/2018] [Indexed: 12/16/2022]
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Markose D, Kirkland P, Ramachandran P, Henderson N. Immune cell regulation of liver regeneration and repair. ACTA ACUST UNITED AC 2018. [DOI: 10.1016/j.regen.2018.03.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Klopčič I, Markovič T, Mlinarič-Raščan I, Sollner Dolenc M. Endocrine disrupting activities and immunomodulatory effects in lymphoblastoid cell lines of diclofenac, 4-hydroxydiclofenac and paracetamol. Toxicol Lett 2018; 294:95-104. [DOI: 10.1016/j.toxlet.2018.05.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 05/11/2018] [Accepted: 05/15/2018] [Indexed: 12/27/2022]
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Anti-Inflammatory Effect of a Polyphenol-Enriched Fraction from Acalypha wilkesiana on Lipopolysaccharide-Stimulated RAW 264.7 Macrophages and Acetaminophen-Induced Liver Injury in Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:7858094. [PMID: 30159118 PMCID: PMC6109486 DOI: 10.1155/2018/7858094] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/22/2018] [Accepted: 07/12/2018] [Indexed: 12/11/2022]
Abstract
A polyphenol-enriched fraction (PEF) from Acalypha wilkesiana, whose leaves have been traditionally utilized for the treatment of diverse medical ailments, was investigated for the anti-inflammatory effect and molecular mechanisms by using lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages and acetaminophen- (APAP-) induced liver injury mouse model. Results showed that PEF significantly attenuated LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production and suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) in RAW 264.7 macrophages. PEF also reduced the secretion of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin- (IL-) 1β, and IL-6 in LPS-stimulated RAW 264.7 macrophages. Moreover, PEF potently inhibited LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs) as well as the activation of nuclear factor-κB (NF-κB) by preventing the degradation of inhibitor κB-α (IκB-α). In vivo, PEF pretreatment ameliorated APAP-induced liver injury and hepatic inflammation, as presented by decreased hepatic damage indicators and proinflammatory factors at both plasma and gene levels. Additionally, PEF pretreatment remarkably diminished Toll-like receptor 3 (TLR3) and TLR4 expression and the subsequent MAPKs and NF-κB activation. HPLC analysis revealed that two predominantly polyphenolic compounds present in PEF were geraniin and corilagin. These results indicated that PEF has an anti-inflammatory effect, and its molecular mechanisms may be involved in the inactivation of the TLR/MAPK/NF-κB signaling pathway, suggesting the therapeutic potential of PEF for inflammatory diseases.
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43
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Tsuchiya Y, Sakai H, Hirata A, Yanai T. Brazilian green propolis suppresses acetaminophen-induced hepatocellular necrosis by modulating inflammation-related factors in rats. J Toxicol Pathol 2018; 31:275-282. [PMID: 30393431 PMCID: PMC6206282 DOI: 10.1293/tox.2018-0027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 06/05/2018] [Indexed: 12/11/2022] Open
Abstract
Propolis is a resin-like material produced by honey bees from bud exudates and sap of plants and their own secretions. An ethanol extract of Brazilian green propolis (EEBGP) contains prenylated phenylpropanoids and flavonoids and has antioxidative and anti-inflammatory effects. Acetaminophen (N-acetyl-p-aminophenol; APAP) is a typical hepatotoxic drug, and APAP-treated rats are widely used as a model of drug-induced liver injury. Oxidative stress and inflammatory reactions cause APAP-induced hepatocellular necrosis and are also related to expansion of the lesion. In the present study, we investigated the preventive effects of EEBGP on APAP-induced hepatocellular necrosis in rats and the protective mechanism including the expression of antioxidative enzyme genes and inflammation-related genes. A histological analysis revealed that administration 0.3% EEBGP in the diet for seven days reduced centrilobular hepatocellular necrosis with inflammatory cell infiltration induced by oral administration of APAP (800 mg/kg) and significantly reduced the area of necrosis. EEBGP administration did not significantly change the mRNA expression levels of antioxidant enzyme genes in the liver of APAP-treated rats but decreased the mRNA expression of cytokines including Il10 and Il1b, with a significant difference in Il10 expression. In addition, the decrease in the mRNA levels of the Il1b and Il10 genes significantly correlated with the decrease in the percentage of hepatocellular necrosis. These findings suggest that EEBGP could suppress APAP-induced hepatocellular necrosis by modulating cytokine expression.
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Affiliation(s)
- Yuya Tsuchiya
- Nagaragawa Research Center, API Co., Ltd., 692-3 Nagara, Gifu-shi, Gifu 502-0071, Japan.,Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan
| | - Hiroki Sakai
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan
| | - Akihiro Hirata
- Division of Animal Experiment, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1194, Japan
| | - Tokuma Yanai
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan
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44
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Oppelt A, Kaschek D, Huppelschoten S, Sison-Young R, Zhang F, Buck-Wiese M, Herrmann F, Malkusch S, Krüger CL, Meub M, Merkt B, Zimmermann L, Schofield A, Jones RP, Malik H, Schilling M, Heilemann M, van de Water B, Goldring CE, Park BK, Timmer J, Klingmüller U. Model-based identification of TNFα-induced IKKβ-mediated and IκBα-mediated regulation of NFκB signal transduction as a tool to quantify the impact of drug-induced liver injury compounds. NPJ Syst Biol Appl 2018; 4:23. [PMID: 29900006 PMCID: PMC5995845 DOI: 10.1038/s41540-018-0058-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 04/16/2018] [Accepted: 05/04/2018] [Indexed: 02/07/2023] Open
Abstract
Drug-induced liver injury (DILI) has become a major problem for patients and for clinicians, academics and the pharmaceutical industry. To date, existing hepatotoxicity test systems are only poorly predictive and the underlying mechanisms are still unclear. One of the factors known to amplify hepatotoxicity is the tumor necrosis factor alpha (TNFα), especially due to its synergy with commonly used drugs such as diclofenac. However, the exact mechanism of how diclofenac in combination with TNFα induces liver injury remains elusive. Here, we combined time-resolved immunoblotting and live-cell imaging data of HepG2 cells and primary human hepatocytes (PHH) with dynamic pathway modeling using ordinary differential equations (ODEs) to describe the complex structure of TNFα-induced NFκB signal transduction and integrated the perturbations of the pathway caused by diclofenac. The resulting mathematical model was used to systematically identify parameters affected by diclofenac. These analyses showed that more than one regulatory module of TNFα-induced NFκB signal transduction is affected by diclofenac, suggesting that hepatotoxicity is the integrated consequence of multiple changes in hepatocytes and that multiple factors define toxicity thresholds. Applying our mathematical modeling approach to other DILI-causing compounds representing different putative DILI mechanism classes enabled us to quantify their impact on pathway activation, highlighting the potential of the dynamic pathway model as a quantitative tool for the analysis of DILI compounds.
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Affiliation(s)
- Angela Oppelt
- 1Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel Kaschek
- 2Institute of Physics, University of Freiburg, Freiburg, Germany
| | - Suzanna Huppelschoten
- 3Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Rowena Sison-Young
- 4MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Fang Zhang
- 4MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Marie Buck-Wiese
- 1Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Franziska Herrmann
- 1Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sebastian Malkusch
- 5Institute of Physical and Theoretical Chemistry, Single Molecule Biophysics, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Carmen L Krüger
- 5Institute of Physical and Theoretical Chemistry, Single Molecule Biophysics, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Mara Meub
- 5Institute of Physical and Theoretical Chemistry, Single Molecule Biophysics, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Benjamin Merkt
- 2Institute of Physics, University of Freiburg, Freiburg, Germany
| | - Lea Zimmermann
- 1Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Amy Schofield
- 4MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Robert P Jones
- 4MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.,6North Western Hepatobiliary Unit, Aintree University Hospital NHS Foundation Trust, Liverpool, UK
| | - Hassan Malik
- 6North Western Hepatobiliary Unit, Aintree University Hospital NHS Foundation Trust, Liverpool, UK
| | - Marcel Schilling
- 1Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mike Heilemann
- 5Institute of Physical and Theoretical Chemistry, Single Molecule Biophysics, Johann Wolfgang Goethe-University, Frankfurt, Germany.,7Bioquant, University of Heidelberg, Heidelberg, Germany
| | - Bob van de Water
- 3Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Christopher E Goldring
- 4MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - B Kevin Park
- 4MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Jens Timmer
- 2Institute of Physics, University of Freiburg, Freiburg, Germany.,8BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - Ursula Klingmüller
- 1Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Autophagy and acetaminophen-induced hepatotoxicity. Arch Toxicol 2018; 92:2153-2161. [PMID: 29876591 DOI: 10.1007/s00204-018-2237-5] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 06/04/2018] [Indexed: 12/15/2022]
Abstract
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. APAP overdose can induce acute liver injury in humans, which is responsible for approximately 50% of total cases of acute liver failure in the United States and some European countries. Currently, the metabolism of APAP in the body has been extensively investigated; however, the exact mechanisms for APAP hepatotoxicity are not well understood. Recent studies have shown that mitochondrial dysfunction, oxidative stress and inflammatory responses play a critical role in the pathogenesis of APAP hepatotoxicity. Autophagy is a catabolic machinery aimed at recycling cellular components and damaged organelles in response to a variety of stimuli, such as nutrient deprivation and toxic stress. Increasing evidence supports that autophagy is involved in the pathophysiological process of APAP-induced liver injury. In this review, we summarized the changes of autophagy in the liver following APAP intoxication and discussed the role and its possible mechanisms of autophagy in APAP hepatotoxicity. Furthermore, this review highlights the crosstalk between mitophagy, oxidative stress and inflammation in APAP-induced liver injury and presents some possible molecular mechanisms by which activated autophagy protects against APAP-induced liver injury.
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Yan XT, Sun YS, Ren S, Zhao LC, Liu WC, Chen C, Wang Z, Li W. Dietary α-Mangostin Provides Protective Effects against Acetaminophen-Induced Hepatotoxicity in Mice via Akt/mTOR-Mediated Inhibition of Autophagy and Apoptosis. Int J Mol Sci 2018; 19:ijms19051335. [PMID: 29723988 PMCID: PMC5983768 DOI: 10.3390/ijms19051335] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 04/25/2018] [Accepted: 04/26/2018] [Indexed: 12/11/2022] Open
Abstract
Acetaminophen overdose-induced hepatotoxicity is the most common cause of acute liver failure in many countries. Previously, alpha-mangostin (α-MG) has been confirmed to exert protective effects on a variety of liver injuries, but the protective effect on acetaminophen-induced acute liver injury (ALI) remains largely unknown. This work investigated the regulatory effect and underlying cellular mechanisms of α-MG action to attenuate acetaminophen-induced hepatotoxicity in mice. The increased serum aminotransferase levels and glutathione (GSH) content and reduced malondialdehyde (MDA) demonstrated the protective effect of α-MG against acetaminophen-induced hepatotoxicity. In addition, α-MG pretreatment inhibited increases in tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) caused by exposure of mice to acetaminophen. In liver tissues, α-MG inhibited the protein expression of autophagy-related microtubule-associated protein light chain 3 (LC3) and BCL2/adenovirus E1B protein-interacting protein 3 (BNIP3). Western blotting analysis of liver tissues also proved evidence that α-MG partially inhibited the activation of apoptotic signaling pathways via increasing the expression of Bcl-2 and decreasing Bax and cleaved caspase 3 proteins. In addition, α-MG could in part downregulate the increase in p62 level and upregulate the decrease in p-mTOR, p-AKT and LC3 II /LC3 I ratio in autophagy signaling pathways in the mouse liver. Taken together, our findings proved novel perspectives that detoxification effect of α-MG on acetaminophen-induced ALI might be due to the alterations in Akt/mTOR pathway in the liver.
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Affiliation(s)
- Xiao-Tong Yan
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China.
| | - Yin-Shi Sun
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China.
- Institute of Special Wild Economic Animals and Plant, CAAS, Changchun 132109, China.
| | - Shen Ren
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China.
| | - Li-Chun Zhao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530011, China.
| | - Wen-Cong Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China.
| | - Chen Chen
- School of Biomedical Sciences, University of Queensland, Brisbane 4072, Australia.
| | - Zi Wang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China.
| | - Wei Li
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China.
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Protective effect of an L-type calcium channel blocker, amlodipine, on paracetamol-induced hepatotoxicity in rats. Hum Exp Toxicol 2018; 37:1169-1179. [DOI: 10.1177/0960327118758382] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Paracetamol (P), one of the most popular and commonly used analgesic and antipyretic agents, causes hepatotoxicity in overdoses. Amlodipine (AML), an L-type calcium channel blocker, has been shown to have anti-inflammatory activity by reversing the effect of calcium in the inflammation pathogenesis. In this study, the hepatoprotective activity of AML on P-induced hepatotoxicity was evaluated. Thirty male albino Wistar rats were divided into five groups: (1) control, (2) 2 g/kg of P, (3) 2 g/kg of P + 5 mg/kg of AML, (4) 2 g/kg of P + 10 mg/kg of AML, and (5) 10 mg/kg of AML. Some liver enzymes, oxidative parameters, cytokine mRNA expressions, histopathology, and immunohistochemical studies were performed in liver and blood samples. The serum levels of alanine aminotransferase and aspartate aminotransferase and the mRNA expression of tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta in the liver tissues were significantly increased in the group treated with P. The superoxide dismutase and glutathione parameters decreased and malondialdehyde levels increased in the livers of the rats treated with P. All these parameters were increased with both doses of the AML similar to the control group. A histopathological examination of the liver showed that AML administration ameliorated the P-induced inflammatory liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the P group but not in other treatment groups when compared to the control. In conclusion, AML treatment showed significant protective effects against P-induced hepatotoxicity by increasing the activity of antioxidants and reducing inflammatory cytokines.
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Maes M, Crespo Yanguas S, Willebrords J, Weemhoff JL, da Silva TC, Decrock E, Lebofsky M, Pereira IVA, Leybaert L, Farhood A, Jaeschke H, Cogliati B, Vinken M. Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice. Toxicol Lett 2017; 278:30-37. [PMID: 28687253 PMCID: PMC5800489 DOI: 10.1016/j.toxlet.2017.07.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 06/27/2017] [Accepted: 07/01/2017] [Indexed: 02/07/2023]
Abstract
Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficacy of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5h. Sampling was performed 3, 6, 24 and 48h following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure.
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Affiliation(s)
- Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium.
| | - Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium.
| | - Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium.
| | - James L Weemhoff
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States.
| | - Tereza Cristina da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
| | - Elke Decrock
- Department of Basic Medical Sciences, Physiology Group, Ghent University, Ghent, Belgium.
| | - Margitta Lebofsky
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States.
| | - Isabel Veloso Alves Pereira
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
| | - Luc Leybaert
- Department of Basic Medical Sciences, Physiology Group, Ghent University, Ghent, Belgium.
| | - Anwar Farhood
- Department of Pathology, St. David's North Austin Medical Center, Austin, United States.
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States.
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium.
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Kim DE, Jang MJ, Kim YR, Lee JY, Cho EB, Kim E, Kim Y, Kim MY, Jeong WI, Kim S, Han YM, Lee SH. Prediction of drug-induced immune-mediated hepatotoxicity using hepatocyte-like cells derived from human embryonic stem cells. Toxicology 2017. [PMID: 28645575 DOI: 10.1016/j.tox.2017.06.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Drug-induced liver injury (DILI) is a leading cause of liver disease and a key safety factor during drug development. In addition to the initiation events of drug-specific hepatotoxicity, dysregulated immune responses have been proposed as major pathological events of DILI. Thus, there is a need for a reliable cell culture model with which to assess drug-induced immune reactions to predict hepatotoxicity for drug development. To this end, stem cell-derived hepatocytes have shown great potentials. Here we report that hepatocyte-like cells derived from human embryonic stem cells (hES-HLCs) can be used to evaluate drug-induced hepatotoxic immunological events. Treatment with acetaminophen significantly elevated the levels of inflammatory cytokines by hES-HLCs. Moreover, three human immune cell lines, Jurkat, THP-1, and NK92MI, were activated when cultured in conditioned medium obtained from acetaminophen-treated hES-HLCs. To further validate, we tested thiazolidinedione (TZD) class, antidiabetic drugs, including troglitazone withdrawn from the market because of severe idiosyncratic drug hepatotoxicity. We found that TZD drug treatment to hES-HLCs resulted in the production of pro-inflammatory cytokines and eventually associated immune cell activation. In summary, our study demonstrates for the first time the potential of hES-HLCs as an in vitro model system for assessment of drug-induced as well as immune-mediated hepatotoxicity.
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Affiliation(s)
- Dong Eon Kim
- Biomedical Science and Engineering Interdisciplinary Program, Daejeon, 34141, South Korea; Graduate School of Medical Science and Engineering, Biomedical Research Center, Daejeon, 34141, South Korea
| | - Mi-Jin Jang
- Department of Biological Sciences, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, South Korea
| | - Young Ran Kim
- Department of Biological Sciences, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, South Korea; Division of Life Science, Korea Basic Science Institute, Daejeon, 34133, South Korea
| | - Joo-Young Lee
- Department of Biological Sciences, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, South Korea
| | - Eun Byul Cho
- Biomedical Science and Engineering Interdisciplinary Program, Daejeon, 34141, South Korea
| | - Eunha Kim
- Department of Biological Sciences, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, South Korea
| | - Yeji Kim
- Department of Biological Sciences, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, South Korea
| | - Mi Young Kim
- Department of Biological Sciences, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, South Korea
| | - Won-Il Jeong
- Biomedical Science and Engineering Interdisciplinary Program, Daejeon, 34141, South Korea; Graduate School of Medical Science and Engineering, Biomedical Research Center, Daejeon, 34141, South Korea
| | - Seyun Kim
- Department of Biological Sciences, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, South Korea.
| | - Yong-Mahn Han
- Department of Biological Sciences, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, South Korea.
| | - Seung-Hyo Lee
- Biomedical Science and Engineering Interdisciplinary Program, Daejeon, 34141, South Korea; Graduate School of Medical Science and Engineering, Biomedical Research Center, Daejeon, 34141, South Korea.
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50
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Multi-targeted protection of acetaminophen-induced hepatotoxicity in mice by tannic acid. Int Immunopharmacol 2017; 47:95-105. [PMID: 28376392 DOI: 10.1016/j.intimp.2017.03.027] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2016] [Revised: 03/23/2017] [Accepted: 03/28/2017] [Indexed: 01/14/2023]
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