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Aloufi MF, Hazem SH, Abdelaziz RR, Suddek GM. Roflumilast counteracts high-dose dexamethasone-induced steatohepatitis, metabolic abnormalities and aortic injury via inhibiting TNF-α/NF-κB, NLRP3/IL-1β and ER stress sensors. Life Sci 2025; 372:123634. [PMID: 40233857 DOI: 10.1016/j.lfs.2025.123634] [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: 02/10/2025] [Revised: 03/28/2025] [Accepted: 04/12/2025] [Indexed: 04/17/2025]
Abstract
INTRODUCTION High-dose dexamethasone (DEX) is used for management of severe conditions. However, the multisystem adverse effects induced by glucocorticoids represent a hindering stone toward the effective clinical use of such agents. Various initiatives have been taken to ameliorate these complications with limited success. AIM The present study aims to explore the beneficial effects of roflumilast (ROF), a phosphodiesterase-4 (PDE-4) inhibitor, to combat DEX-induced steatohepatitis, metabolic abnormalities and aortic degeneration. RESULTS The application of ROF (2.5 and 5 mg/kg) has reverted the hepatic and aortic histopathological abnormalities as well as the rise in serum liver enzymes induced by DEX. Such palliative effect is probably attributed to PDE-4 inhibition (↑cAMP) that subsequently regulates multiple effectors. The chemotaxis of inflammatory cells (MCP-1) was inhibited by ROF treatments which was linked to inhibition of extracellular ROS production (MDA and NO) as well as restoration of cellular antioxidant defense (GSH). DEX challenge was associated with activation of the inflammatory pathways including TNF-α/NF-κB and NLRP3/IL-1β that were significantly dampened in the ROF groups. The oxidative stress as well as activation of inflammatory pathways exerted by DEX has contributed to the activation of endoplasmic reticulum stress (CHOP and PERK) posing more threats to the insulted cells, however, fortunately, ROF treatments showed inhibited activation of ER stress sensors and thereby abstaining the cells from inevitable damage. The metabolic abnormalities induced by DEX including elevated fasting insulin and heightened AUC of blood glucose level upon application of oral glucose tolerance test were significantly improved by ROF treatment. CONCLUSION The findings of our study depicted the hepatoprotective and metabolic regulating potentials of ROF in a rat model of DEX- induced steatohepatitis. Thereby, enhancing the overall efficacy and safety of DEX use in management of various disorders.
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Affiliation(s)
- Mohammed Fulayyih Aloufi
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Sara H Hazem
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Rania R Abdelaziz
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Ghada M Suddek
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
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Lei J, Zhai J, Zhang Y, Qi J, Sun C. Supervised Machine Learning Models for Predicting Sepsis-Associated Liver Injury in Patients With Sepsis: Development and Validation Study Based on a Multicenter Cohort Study. J Med Internet Res 2025; 27:e66733. [PMID: 40418571 DOI: 10.2196/66733] [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: 09/22/2024] [Revised: 12/15/2024] [Accepted: 04/29/2025] [Indexed: 05/27/2025] Open
Abstract
BACKGROUND Sepsis-associated liver injury (SALI) is a severe complication of sepsis that contributes to increased mortality and morbidity. Early identification of SALI can improve patient outcomes; however, sepsis heterogeneity makes timely diagnosis challenging. Traditional diagnostic tools are often limited, and machine learning techniques offer promising solutions for predicting adverse outcomes in patients with sepsis. OBJECTIVE This study aims to develop an explainable machine learning model, incorporating stacking techniques, to predict the occurrence of liver injury in patients with sepsis and provide decision support for early intervention and personalized treatment strategies. METHODS This retrospective multicenter cohort study adhered to the TRIPOD+AI (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis, Extended for Artificial Intelligence) guidelines. Data from 8834 patients with sepsis in the Medical Information Mart for Intensive Care IV (MIMIC-IV) database were used for training and internal validation, while data from 4236 patients in the eICU-Collaborative Research Database (eICU-CRD) database were used for external validation. SALI was defined as an international normalized ratio >1.5 and total bilirubin >2 mg/dL within 1 week of intensive care unit admission. Nine machine learning models-decision tree, random forest (RF), extreme gradient boosting (XGBoost), light gradient boosting machine (LightGBM), support vector machine, elastic net, logistic regression, multilayer perceptron, and k-nearest neighbors-were trained. A stacking ensemble model, using LightGBM, XGBoost, and RF as base learners and Lasso regression as the meta-model, was optimized via 10-fold cross-validation. Hyperparameters were tuned using grid search and Bayesian optimization. Model performance was evaluated using accuracy, balanced accuracy, Brier score, detection prevalence, F1-score, Jaccard index, κ coefficient, Matthews correlation coefficient, negative predictive value, positive predictive value, precision, recall, area under the receiver operating characteristic curve (ROC-AUC), precision-recall AUC, and decision curve analysis. Shapley additive explanations (SHAP) values were used to quantify feature importance. RESULTS In the training set, LightGBM, XGBoost, and RF demonstrated the best performance among all models, with ROC-AUCs of 0.9977, 0.9311, and 0.9847, respectively. These models exhibited minimal variance in cross-validation, with tightly clustered ROC-AUC and precision-recall area under the curve distributions. In the internal validation set, LightGBM (ROC-AUC 0.8401) and XGBoost (ROC-AUC 0.8403) outperformed all other models, while RF achieved an ROC-AUC of 0.8193. In the external validation set, LightGBM (ROC-AUC 0.7077), XGBoost (ROC-AUC 0.7169), and RF (ROC-AUC 0.7081) maintained strong performance, although with slight decreases in ROC-AUC compared with the training set. The stacking model achieved ROC-AUCs of 0.995, 0.838, and 0.721 in the training, internal validation, and external validation sets, respectively. Key predictors-total bilirubin, lactate, prothrombin time, and mechanical ventilation status-were consistently identified across models, with SHAP analysis highlighting their significant contributions to the model's predictions. CONCLUSIONS The stacking ensemble model developed in this study yields accurate and robust predictions of SALI in patients with sepsis, demonstrating potential clinical utility for early intervention and personalized treatment strategies.
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Affiliation(s)
- Jingchao Lei
- Third Xiangya Hospital of Central South University, Changsha, China
| | - Jia Zhai
- Third Xiangya Hospital of Central South University, Changsha, China
| | - Yao Zhang
- Third Xiangya Hospital of Central South University, Changsha, China
| | - Jing Qi
- Third Xiangya Hospital of Central South University, Changsha, China
| | - Chuanzheng Sun
- Third Xiangya Hospital of Central South University, Changsha, China
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Deng Q, Qu Y, Luo Y, Zhang X. An immune-liver microphysiological system method for evaluation and quality control of hepatotoxicity induced by Polygonum multiflorum thunb. Extract. JOURNAL OF ETHNOPHARMACOLOGY 2025; 345:119633. [PMID: 40086609 DOI: 10.1016/j.jep.2025.119633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 02/22/2025] [Accepted: 03/12/2025] [Indexed: 03/16/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Clinical applications of Polygonum multiflorum Thunb. (PMT) have occasionally reported adverse effects on liver function, linking these instances of hepatotoxicity to PMT samples. Evaluating the hepatotoxicity of PMT, given its intricate composition and mechanisms, presents a notable challenge. Notably, three toxic components display additive/synergistic effects, further complicating the establishment of a toxicological quality control method. AIM OF THE STUDY This study aims to develop a biology-based quality control method that can reflect the multi-mechanistic hepatotoxicity of PMT. MATERIALS AND METHODS We designed a microphysiological system tailored for the immune-liver interplay, termed the i-LOC, featuring three-cell channels. This i-LOC integrates hepatic cells with two distinct immune cell types to mimic inflammatory cell infiltration. As a control, a liver-on-chip devoid of immune cells was utilized to characterize hepatotoxicity induced by inflammatory stress. RESULTS The i-LOC system exhibited remarkable sensitivity in detecting both direct and inflammation-mediated hepatotoxic effects of the three PMT toxic components. This system significantly reduced the sample size requirements by thousandfold compared to animal models, presenting a cost-effective and attractive alternative for PMT toxicological assessments. Intriguingly, the system identified the present of previously unknown PMT compounds with potential hepatotoxic properties, emphasizing the need for a comprehensive biological evaluation method. CONCLUSION This study successfully developed an i-LOC method for effectively evaluating PMT's hepatotoxicity, overcoming the complexities posed by its intricate composition and mechanisms.
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Affiliation(s)
- Quanfeng Deng
- Jiangsu Key Laboratory of Neuropsychiatric Disease and College of Pharmaceutical Science, Suzhou Medical College, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, Soochow University, 215127, Suzhou, Jiangsu Province, China; Intensive Care Unit, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518031, China
| | - Yueyang Qu
- Jiangsu Key Laboratory of Neuropsychiatric Disease and College of Pharmaceutical Science, Suzhou Medical College, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, Soochow University, 215127, Suzhou, Jiangsu Province, China
| | - Yong Luo
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, 116024, Dalian, Liaoning Province, China.
| | - Xiuli Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Disease and College of Pharmaceutical Science, Suzhou Medical College, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, Soochow University, 215127, Suzhou, Jiangsu Province, China.
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Iwata H, Horino T, Osakabe Y, Inotani S, Yoshida K, Mitani K, Hatakeyama Y, Miura Y, Terada Y, Kawano T. Urinary [TIMP-2]•[IGFBP7], TIMP-2, IGFBP7, NGAL, and L-FABP for the prediction of acute kidney injury following cardiovascular surgery in Japanese patients. Clin Exp Nephrol 2025:10.1007/s10157-025-02671-2. [PMID: 40195176 DOI: 10.1007/s10157-025-02671-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 03/25/2025] [Indexed: 04/09/2025]
Abstract
BACKGROUND Acute kidney injury (AKI) following cardiac surgery is common and is associated with poor outcomes. The combination of urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) is a strong predictor of AKI after cardiac surgery. However, most studies have focused on non-Asian populations, and comparisons with other AKI biomarkers or the optimal timing for measurement have yet to be explored. METHODS We prospectively enrolled adult patients at Kochi Medical School Hospital in Kochi, Japan, to assess the predictive values of [TIMP-2]•[IGFBP7], TIMP-2, IGFBP7, neutrophil gelatinase-associated lipocalin (NGAL), and liver fatty acid-binding protein (L-FABP) measured preoperatively and at 2, 4, 6, and 8 h, as well as on day 1 and day 2 after postoperative intensive care unit (ICU) admission, using receiver operating characteristic curve (ROC) analysis. RESULTS Of the 38 patients, 13 (34.2%) developed AKI: seven (18.4%) with stage 1, four (10.5%) with stage 2, and two (5.2%) with stage 3. ROC analysis showed that the area under the curve (AUC) for predicting any stage of AKI peaked at 0-4 h, with the highest value at 2 h after ICU admission. Among the biomarkers, [TIMP-2]•[IGFBP7] showed the best AUC at 2 h after ICU admission, followed by TIMP-2, IGFBP7, L-FABP, and NGAL. CONCLUSIONS Our study demonstrated the good predictive performance of urine biomarkers, including [TIMP-2]•[IGFBP7], TIMP-2, IGFBP7, NGAL, and L-FABP, for any stage of cardiac surgery-associated AKI (CSA-AKI). The combination of TIMP-2 and IGFBP7 measured 2 h after postoperative ICU admission effectively predicted CSA-AKI, identifying patients at higher risk.
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Affiliation(s)
- Hideki Iwata
- Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Taro Horino
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
| | - Yuki Osakabe
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Satoshi Inotani
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Keisuke Yoshida
- Department of Cardiovascular Surgery, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Keita Mitani
- Centre of Medical Information Science, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Yutaka Hatakeyama
- Centre of Medical Information Science, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Yujiro Miura
- Department of Cardiovascular Surgery, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Yoshio Terada
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Takashi Kawano
- Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
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Ye H, Zhang X, Li P, Wang M, Liu R, Yang D. Novel insights into the molecular mechanisms of sepsis-associated acute kidney injury: an integrative study of GBP2, PSMB8, PSMB9 genes and immune microenvironment characteristics. BMC Nephrol 2025; 26:160. [PMID: 40155864 PMCID: PMC11954279 DOI: 10.1186/s12882-025-04069-4] [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: 11/26/2024] [Accepted: 03/13/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND Sepsis-associated acute kidney injury (SA-AKI) is a prevalent and severe complication of sepsis, but its complex pathogenesis remains unclear. This study aims to identify potential biomarkers for SA-AKI by elucidating its molecular mechanisms through bioinformatics methods. METHODS Transcriptional data related to SA-AKI were obtained from the Gene Expression Omnibus (GEO) database. We used differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) to identify characteristic genes associated with SA-AKI and conducted enrichment analyses. Hub genes were determined using protein-protein interaction (PPI) network analysis and the Least Absolute Shrinkage and Selection Operator (LASSO). Additionally, ROC curves were plotted to assess the diagnostic value of these core genes. Immune cell infiltration was analyzed using the CIBERSORT algorithm, and potential associations between the hub genes and clinicopathological features were explored based on the Nephroseq database. Finally, a murine model of SA-AKI was induced with lipopolysaccharide (LPS) to validate the findings, and mRNA abundance and protein production levels of pivotal genes were confirmed via RT-qPCR, Western blotting, and immunohistochemical methods. RESULTS We identified 268 characteristic genes associated with SA-AKI that are enriched in immune and inflammation-related pathways. Utilizing machine learning techniques, three key genes were screened: GBP2, PSMB8 and PSMB9. The expression patterns of these three genes were well-validated through animal experiments and databases. Correlation between these genes and clinical indicators was confirmed using the Nephroseq database. Furthermore, immune infiltration analysis provided additional insights into their potential functions. CONCLUSION GBP2, PSMB8, and PSMB9 are promising candidate genes for SA-AKI, providing a novel perspective on its pathological mechanisms. Further exploration of the biological roles of these genes in the pathogenesis of SA-AKI is needed in the future.
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Affiliation(s)
- Haiting Ye
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Transfusion, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, China
| | - Xiang Zhang
- Department of Clinical Laboratory, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pengyan Li
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mei Wang
- Department of Transfusion, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, China
| | - Ruolan Liu
- Department of Transfusion, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, China
| | - Dingping Yang
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.
- Nephrology and Urology Research Institute of Wuhan University, Wuhan, China.
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Tang X, Ning J, Zhao Y, Feng S, Shao L, Liu T, Miao H, Zhang Y, Wang C. Intestine-derived fibroblast growth factor 19 alleviates lipopolysaccharide-induced liver injury by regulating bile acid homeostasis and directly improving oxidative stress. JOURNAL OF INTENSIVE MEDICINE 2025; 5:79-88. [PMID: 39872844 PMCID: PMC11763227 DOI: 10.1016/j.jointm.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 05/17/2024] [Accepted: 06/11/2024] [Indexed: 01/30/2025]
Abstract
Background Cholestasis plays a critical role in sepsis-associated liver injury (SALI). Intestine-derived fibroblast growth factor 19 (FGF19) is a key regulator for bile acid homeostasis. However, the roles and underlying mechanisms of FGF19 in SALI are still unclear. Methods We conducted a case-control study that included 58 pediatric patients aged from 1 month to 14-years-old diagnosed with sepsis at Shanghai Children's Hospital from January to December 2018 and 30 healthy individuals. The serum FGF19 levels of these patients with sepsis were analyzed and compared with those of healthy controls. Recombinant human FGF19 was intravenously injected in mice once a day for 7 days at a dose of 0.1 mg/kg body weight before lipopolysaccharide (LPS) treatment. Liver bile acid profiles and the gene expression involved in bile acid homeostasis were investigated in the mice groups. Metabolomic data were further integrated and analyzed using Ingenuity Pathways Analysis (IPA) software. In the in vitro analysis using HepG2 cells, the influence of FGF19 pretreatment on reactive oxygen species (ROS) production and mitochondrial dysfunction was analyzed. Compound C (CC), an inhibitor of AMP-activated protein kinase (AMPK) activation, was used to confirm the roles of AMPK activation in FGF19-mediated hepatoprotective effects. Results Serum FGF19 levels were significantly lower in children with sepsis than in healthy controls (115 pg/mL vs. 79 pg/mL, P=0.03). Pre-administration of recombinant human FGF19 alleviated LPS-induced acute liver injury (ALI) and improved LPS-induced cholestasis in mice. Moreover, FGF19 directly reversed LPS-induced intracellular ROS generation and LPS-decreased mitochondrial membrane potential in vitro and in vivo, resulting in hepatoprotection against LPS-induced apoptosis. More importantly, the inhibition of AMPK activity partially blocked the protective effects of FGF19 against LPS-induced oxidative stress and mitochondrial dysfunction. Conclusions Intestine-derived FGF19 alleviates LPS-induced ALI via improving bile acid homeostasis and directly suppressing ROS production via activating the AMPK signaling pathway.
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Affiliation(s)
- Xiaomeng Tang
- Department of Critical Care Medicine, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Laboratory of Critical Care Translational Medicine, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingjing Ning
- Department of Critical Care Medicine, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Laboratory of Critical Care Translational Medicine, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yilin Zhao
- Department of Critical Care Medicine, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Laboratory of Critical Care Translational Medicine, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuyun Feng
- Department of Critical Care Medicine, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Laboratory of Critical Care Translational Medicine, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lujing Shao
- Department of Critical Care Medicine, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Laboratory of Critical Care Translational Medicine, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tiantian Liu
- Department of Critical Care Medicine, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Laboratory of Critical Care Translational Medicine, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huijie Miao
- Department of Critical Care Medicine, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Laboratory of Critical Care Translational Medicine, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University, Shanghai, China
| | - Yucai Zhang
- Department of Critical Care Medicine, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Laboratory of Critical Care Translational Medicine, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University, Shanghai, China
| | - Chunxia Wang
- Department of Critical Care Medicine, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Laboratory of Critical Care Translational Medicine, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University, Shanghai, China
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Jaeschke H, Ramachandran A. Ferroptosis and Intrinsic Drug-induced Liver Injury by Acetaminophen and Other Drugs: A Critical Evaluation and Historical Perspective. J Clin Transl Hepatol 2024; 12:1057-1066. [PMID: 39649034 PMCID: PMC11622198 DOI: 10.14218/jcth.2024.00324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 10/07/2024] [Accepted: 10/11/2024] [Indexed: 12/10/2024] Open
Abstract
Drug-induced hepatotoxicity is a significant clinical issue worldwide. Given the limited treatment options for these liver injuries, understanding the mechanisms and modes of cell death is crucial for identifying novel therapeutic targets. For the past 60 years, reactive oxygen species and iron-dependent lipid peroxidation (LPO) have been hypothesized to be involved in many models of acute drug-induced liver injury. However, this mechanism of toxicity was largely abandoned when apoptosis became the primary focus of cell death research. More recently, ferroptosis-a novel, non-apoptotic form of cell death-was identified in NRAS-mutant HT-1080 fibrosarcoma cells exposed to erastin and other NRLs. Ferroptosis is characterized by glutathione depletion and the impairment of glutathione peroxidase 4 activity, which hinders the detoxification of lipid hydroperoxides. These hydroperoxides then serve as substrates for iron-dependent LPO propagation. This cell death mechanism is now receiving widespread attention, extending well beyond its original identification in cancer research, including in the field of drug-induced liver injury. However, concerns arise when such mechanisms are applied across different cell types and disease states without sufficient validation. This review critically evaluated the historical evidence for iron-dependent LPO as a mechanism of drug-induced hepatotoxicity and explored how these earlier findings have led to the current concept of ferroptosis. Overall, the published data support the idea that multi-layered endogenous antioxidant defense mechanisms in the liver limit the occurrence of pathophysiologically relevant LPO under normal conditions. Only when these defense mechanisms are severely compromised does ferroptosis become a significant mode of drug-induced cell death.
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Affiliation(s)
- Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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Fan JH, Li XM. Mesangial cell-derived CircRNAs in chronic glomerulonephritis: RNA sequencing and bioinformatics analysis. Ren Fail 2024; 46:2371059. [PMID: 38946402 PMCID: PMC467094 DOI: 10.1080/0886022x.2024.2371059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 06/17/2024] [Indexed: 07/02/2024] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) have been shown to play critical roles in the initiation and progression of chronic glomerulonephritis (CGN), while their role from mesangial cells in contributing to the pathogenesis of CGN is rarely understood. Our study aims to explore the potential functions of mesangial cell-derived circRNAs using RNA sequencing (RNA-seq) and bioinformatics analysis. METHODS Mouse mesangial cells (MMCs) were stimulated by lipopolysaccharide (LPS) to establish an in vitro model of CGN. Pro-inflammatory cytokines and cell cycle stages were detected by Enzyme-linked immunosorbent assay (ELISA) and Flow Cytometry experiment, respectively. Subsequently, differentially expressed circRNAs (DE-circRNAs) were identified by RNA-seq. GEO microarrays were used to identify differentially expressed mRNAs (DE-mRNAs) between CGN and healthy populations. Weighted co-expression network analysis (WGCNA) was utilized to explore clinically significant modules of CGN. CircRNA-associated CeRNA networks were constructed by bioinformatics analysis. The hub mRNAs from CeRNA network were identified using LASSO algorithms. Furthermore, utilizing protein-protein interaction (PPI), gene ontology (GO), pathway enrichment (KEGG), and GSEA analyses to explore the potential biological function of target genes from CeRNA network. In addition, we investigated the relationships between immune cells and hub mRNAs from CeRNA network using CIBERSORT. RESULTS The expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α was drastically increased in LPS-induced MMCs. The number of cells decreased significantly in the G1 phase but increased significantly in the S/G2 phase. A total of 6 DE-mRNAs were determined by RNA-seq, including 4 up-regulated circRNAs and 2 down-regulated circRNAs. WGCNA analysis identified 1747 DE-mRNAs of the turquoise module from CGN people in the GEO database. Then, the CeRNA networks, including 6 circRNAs, 38 miRNAs, and 80 mRNAs, were successfully constructed. The results of GO and KEGG analyses revealed that the target mRNAs were mainly enriched in immune, infection, and inflammation-related pathways. Furthermore, three hub mRNAs (BOC, MLST8, and HMGCS2) from the CeRNA network were screened using LASSO algorithms. GSEA analysis revealed that hub mRNAs were implicated in a great deal of immune system responses and inflammatory pathways, including IL-5 production, MAPK signaling pathway, and JAK-STAT signaling pathway. Moreover, according to an evaluation of immune infiltration, hub mRNAs have statistical correlations with neutrophils, plasma cells, monocytes, and follicular helper T cells. CONCLUSIONS Our findings provide fundamental and novel insights for further investigations into the role of mesangial cell-derived circRNAs in CGN pathogenesis.
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Affiliation(s)
- Ji Hui Fan
- Department of Nephrology, Huaibei People’s Hospital, Huaibei, China
| | - Xiao Min Li
- Department of Nephrology, Huaibei People’s Hospital, Huaibei, China
- Department of Traditional Chinese Medicine, Huaibei People’s Hospital, Huaibei, China
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Rasmussen SB, Boyko Y, Ranucci M, de Somer F, Ravn HB. Cardiac surgery-Associated acute kidney injury - A narrative review. Perfusion 2024; 39:1516-1530. [PMID: 37905794 DOI: 10.1177/02676591231211503] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
Cardiac Surgery-Associated Acute Kidney Injury (CSA-AKI) is a serious complication seen in approximately 20-30% of cardiac surgery patients. The underlying pathophysiology is complex, often involving both patient- and procedure related risk factors. In contrast to AKI occurring after other types of major surgery, the use of cardiopulmonary bypass comprises both additional advantages and challenges, including non-pulsatile flow, targeted blood flow and pressure as well as the ability to manipulate central venous pressure (congestion). With an increasing focus on the impact of CSA-AKI on both short and long-term mortality, early identification and management of high-risk patients for CSA-AKI has evolved. The present narrative review gives an up-to-date summary on definition, diagnosis, underlying pathophysiology, monitoring and implications of CSA-AKI, including potential preventive interventions. The review will provide the reader with an in-depth understanding of how to identify, support and provide a more personalized and tailored perioperative management to avoid development of CSA-AKI.
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Affiliation(s)
- Sebastian Buhl Rasmussen
- Department of Anaesthesiology and Intensive Care, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Yuliya Boyko
- Department of Anaesthesiology and Intensive Care, Odense University Hospital, Odense, Denmark
| | - Marco Ranucci
- Department of Cardiovascular Anaesthesiology and Intensive Care, IRCCS Policlinico San Donato, Milan, Italy
| | | | - Hanne Berg Ravn
- Department of Anaesthesiology and Intensive Care, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Luyendyk JP, Morozova E, Copple BL. Good Cells Go Bad: Immune Dysregulation in the Transition from Acute Liver Injury to Liver Failure After Acetaminophen Overdose. Drug Metab Dispos 2024; 52:722-728. [PMID: 38050055 PMCID: PMC11257689 DOI: 10.1124/dmd.123.001280] [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: 09/11/2023] [Revised: 11/12/2023] [Accepted: 11/27/2023] [Indexed: 12/06/2023] Open
Abstract
The role of inflammatory cells and other components of the immune system in acetaminophen (APAP)-induced liver injury and repair has been extensively investigated. Although this has resulted in a wealth of information regarding the function and regulation of immune cells in the liver after injury, apparent contradictions have fueled controversy around the central question of whether the immune system is beneficial or detrimental after APAP overdose. Ultimately, this may not be a simple assignment of "good" or "bad." Clinical studies have clearly demonstrated an association between immune dysregulation and a poor outcome in patients with severe liver damage/liver failure induced by APAP overdose. To date, studies in mice have not uniformly replicated this connection. The apparent disconnect between clinical and experimental studies has perhaps stymied progress and further complicated investigation of the immune system in APAP-induced liver injury. Mouse models are often dismissed as not recapitulating the clinical scenario. Moreover, clinical investigation is most often focused on the most severe APAP overdose patients, those with liver failure. Notably, recent studies have made it apparent that the functional role of the immune system in the pathogenesis of APAP-induced liver injury is highly context dependent and greatly influenced by the experimental conditions. In this review, we highlight some of these recent findings and suggest strategies seeking to resolve and build on existing disconnects in the literature. SIGNIFICANCE STATEMENT: Acetaminophen overdose is the most frequent cause of acute liver failure in the United States. Studies indicate that dysregulated innate immunity contributes to the transition from acute liver injury to acute liver failure. In this review, we discuss the evidence for this and the potential underlying causes.
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Affiliation(s)
- James P Luyendyk
- Departments of Pathobiology and Diagnostic Investigation (J.P.L., E.M.) and Pharmacology and Toxicology (B.L.C.), Michigan State University, East Lansing, Michigan
| | - Elena Morozova
- Departments of Pathobiology and Diagnostic Investigation (J.P.L., E.M.) and Pharmacology and Toxicology (B.L.C.), Michigan State University, East Lansing, Michigan
| | - Bryan L Copple
- Departments of Pathobiology and Diagnostic Investigation (J.P.L., E.M.) and Pharmacology and Toxicology (B.L.C.), Michigan State University, East Lansing, Michigan
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11
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Balogun O, Shao D, Carson M, King T, Kosar K, Zhang R, Zeng G, Cornuet P, Goel C, Lee E, Patel G, Brooks E, Monga SP, Liu S, Nejak-Bowen K. Loss of β-catenin reveals a role for glutathione in regulating oxidative stress during cholestatic liver disease. Hepatol Commun 2024; 8:e0485. [PMID: 38967587 PMCID: PMC11227358 DOI: 10.1097/hc9.0000000000000485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 04/22/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Cholestasis is an intractable liver disorder that results from impaired bile flow. We have previously shown that the Wnt/β-catenin signaling pathway regulates the progression of cholestatic liver disease through multiple mechanisms, including bile acid metabolism and hepatocyte proliferation. To further explore the impact of these functions during intrahepatic cholestasis, we exposed mice to a xenobiotic that causes selective biliary injury. METHODS α-naphthylisothiocyanate (ANIT) was administered to liver-specific knockout (KO) of β-catenin and wild-type mice in the diet. Mice were killed at 6 or 14 days to assess the severity of cholestatic liver disease, measure the expression of target genes, and perform biochemical analyses. RESULTS We found that the presence of β-catenin was protective against ANIT, as KO mice had a significantly lower survival rate than wild-type mice. Although serum markers of liver damage and total bile acid levels were similar between KO and wild-type mice, the KO had minor histological abnormalities, such as sinusoidal dilatation, concentric fibrosis around ducts, and decreased inflammation. Notably, both total glutathione levels and expression of glutathione-S-transferases, which catalyze the conjugation of ANIT to glutathione, were significantly decreased in KO after ANIT. Nuclear factor erythroid-derived 2-like 2, a master regulator of the antioxidant response, was activated in KO after ANIT as well as in a subset of patients with primary sclerosing cholangitis lacking activated β-catenin. Despite the activation of nuclear factor erythroid-derived 2-like 2, KO livers had increased lipid peroxidation and cell death, which likely contributed to mortality. CONCLUSIONS Loss of β-catenin leads to increased cellular injury and cell death during cholestasis through failure to neutralize oxidative stress, which may contribute to the pathology of this disease.
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Affiliation(s)
- Oluwashanu Balogun
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Daniel Shao
- Case-Western Reserve University, Departments of Biochemistry and Computer Science, Cleveland, Ohio, USA
| | - Matthew Carson
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Thalia King
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Karis Kosar
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Rong Zhang
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Gang Zeng
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Pamela Cornuet
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Chhavi Goel
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Elizabeth Lee
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Garima Patel
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Eva Brooks
- Duquesne University, School of Science and Engineering, Department of Biotechnology, Pittsburgh, Pennsylvania, USA
| | - Satdarshan P. Monga
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Medicine, Hepatology and Nutrition, Division of Gastroenterology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Silvia Liu
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Kari Nejak-Bowen
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Ng KTP, Pang L, Wang JQ, She WH, Tsang SHY, Lo CM, Man K, Cheung TT. Indications of pro-inflammatory cytokines in laparoscopic and open liver resection for early-stage hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2024; 23:257-264. [PMID: 37903711 DOI: 10.1016/j.hbpd.2023.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 10/06/2023] [Indexed: 11/01/2023]
Abstract
BACKGROUND Our clinical practice of laparoscopic liver resection (LLR) had achieved better short-term and long-term benefits for patients with hepatocellular carcinoma (HCC) over open liver resection (OLR), but the underlying mechanisms are not clear. This study was to find out whether systemic inflammation plays an important role. METHODS A total of 103 patients with early-stage HCC under liver resection were enrolled (LLR group, n = 53; OLR group, n = 50). The expression of 9 inflammatory cytokines in patients at preoperation, postoperative day 1 (POD1) and POD7 was quantified by Luminex Multiplex assay. The relationships of the cytokines and the postoperative outcomes were compared between LLR and OLR. RESULTS Seven of the circulating cytokines were found to be significantly upregulated on POD1 after LLR or OLR compared to their preoperative levels. Compared to OLR, the POD1 levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1) in the LLR group were significantly lower. Higher POD1 levels of these cytokines were significantly correlated with longer operative time and higher volume of blood loss during operation. The levels of these cytokines were positively associated with postoperative liver injury, and the length of hospital stay. Importantly, a high level of IL-6 at POD1 was a risk factor for HCC recurrence and poor disease-free survival after liver resection. CONCLUSIONS Significantly lower level of GM-CSF, IL-6, IL-8, and MCP-1 after liver resection represented a milder systemic inflammation which might be an important mechanism to offer better short-term and long-term outcomes in LLR over OLR.
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Affiliation(s)
- Kevin Tak-Pan Ng
- Department of Surgery, HKU-SZH & School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Li Pang
- Department of Surgery, HKU-SZH & School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jia-Qi Wang
- Department of Surgery, HKU-SZH & School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wong Hoi She
- Department of Surgery, HKU-SZH & School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Simon Hing-Yin Tsang
- Department of Surgery, HKU-SZH & School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Chung Mau Lo
- Department of Surgery, HKU-SZH & School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kwan Man
- Department of Surgery, HKU-SZH & School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Tan To Cheung
- Department of Surgery, HKU-SZH & School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
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13
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Deng RM, Zhou J. Targeting NF-κB in Hepatic Ischemia-Reperfusion Alleviation: from Signaling Networks to Therapeutic Targeting. Mol Neurobiol 2024; 61:3409-3426. [PMID: 37991700 DOI: 10.1007/s12035-023-03787-w] [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: 09/15/2023] [Accepted: 11/09/2023] [Indexed: 11/23/2023]
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a major complication of liver trauma, resection, and transplantation that can lead to liver dysfunction and failure. Scholars have proposed a variety of liver protection methods aimed at reducing ischemia-reperfusion damage, but there is still a lack of effective treatment methods, which urgently needs to find new effective treatment methods for patients. Many studies have reported that signaling pathway plays a key role in HIRI pathological process and liver function recovery mechanism, among which nuclear transfer factor-κB (NF-κB) signaling pathway is one of the signal transduction closely related to disease. NF-κB pathway is closely related to HIRI pathologic process, and inhibition of this pathway can delay oxidative stress, inflammatory response, cell death, and mitochondrial dysfunction. In addition, NF-κB can also interact with PI3K/Akt, MAPK, and Nrf2 signaling pathways to participate in HIRI regulation. Based on the role of NF-κB pathway in HIRI, it may be a potential target pathway for HIRI. This review emphasizes the role of inhibiting the NF-κB signaling pathway in oxidative stress, inflammatory response, cell death, and mitochondrial dysfunction in HIRI, as well as the effects of related drugs or inhibitors targeting NF-κB on HIRI. The objective of this review is to elucidate the role and mechanism of NF-κB pathway in HIRI, emphasize the important role of NF-κB pathway in the prevention and treatment of HIRI, and provide a theoretical basis for the target NF-κB pathway as a therapy for HIRI.
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Affiliation(s)
- Rui-Ming Deng
- Department of Anesthesiology, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China
- The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China
| | - Juan Zhou
- The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China.
- Department of Thyroid and Breast Surgery, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China.
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Ligeron C, Saenz J, Evrard B, Drouin M, Merieau E, Mary C, Biteau K, Wilhelm E, Batty C, Gauttier V, Baccelli I, Poirier N, Chiffoleau E. CLEC-1 Restrains Acute Inflammatory Response and Recruitment of Neutrophils following Tissue Injury. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1178-1187. [PMID: 38353642 DOI: 10.4049/jimmunol.2300479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 01/17/2024] [Indexed: 03/20/2024]
Abstract
The inflammatory response is a key mechanism for the elimination of injurious agents but must be tightly controlled to prevent additional tissue damage and progression to persistent inflammation. C-type lectin receptors expressed mostly by myeloid cells play a crucial role in the regulation of inflammation by recognizing molecular patterns released by injured tissues. We recently showed that the C-type lectin receptor CLEC-1 is able to recognize necrotic cells. However, its role in the acute inflammatory response following tissue damage had not yet been investigated. We show in this study, in a mouse model of liver injury induced by acetaminophen intoxication, that Clec1a deficiency enhances the acute immune response with increased expression of Il1b, Tnfa, and Cxcl2 and higher infiltration of activated neutrophils into the injured organ. Furthermore, we demonstrate that Clec1a deficiency exacerbates tissue damage via CXCL2-dependent neutrophil infiltration. In contrast, we observed that the lack of CLEC-1 limits CCL2 expression and the accumulation, beyond the peak of injury, of monocyte-derived macrophages. Mechanistically, we found that Clec1a-deficient dendritic cells increase the expression of Il1b, Tnfa, and Cxcl2 in response to necrotic cells, but decrease the expression of Ccl2. Interestingly, treatment with an anti-human CLEC-1 antagonist mAb recapitulates the exacerbation of acute immunopathology observed by genetic loss of Clec1a in a preclinical humanized mouse model. To conclude, our results demonstrate that CLEC-1 is a death receptor limiting the acute inflammatory response following injury and represents a therapeutic target to modulate immunity.
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Affiliation(s)
- Camille Ligeron
- OSE Immunotherapeutics, Nantes, France
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Javier Saenz
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Berangere Evrard
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Marion Drouin
- OSE Immunotherapeutics, Nantes, France
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Emmanuel Merieau
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | | | | | | | | | | | | | | | - Elise Chiffoleau
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
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15
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Jaeschke H, Ramachandran A. Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury. ANNUAL REVIEW OF PATHOLOGY 2024; 19:453-478. [PMID: 38265880 PMCID: PMC11131139 DOI: 10.1146/annurev-pathmechdis-051122-094016] [Citation(s) in RCA: 47] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2024]
Abstract
Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance of animal models, APAP is mechanistically the most studied drug. This review covers intracellular signaling events starting with drug metabolism and the central role of mitochondrial dysfunction involving oxidant stress and peroxynitrite. Mitochondria-derived endonucleases trigger nuclear DNA fragmentation, the point of no return for cell death. In addition, adaptive mechanisms that limit cell death are discussed including autophagy, mitochondrial morphology changes, and biogenesis. Extensive evidence supports oncotic necrosis as the mode of cell death; however, a partial overlap with signaling events of apoptosis, ferroptosis, and pyroptosis is the basis for controversial discussions. Furthermore, an update on sterile inflammation in injury and repair with activation of Kupffer cells, monocyte-derived macrophages, and neutrophils is provided. Understanding these mechanisms of cell death led to discovery of N-acetylcysteine and recently fomepizole as effective antidotes against APAP toxicity.
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Affiliation(s)
- Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA; ,
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA; ,
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Nakatake R, Okuyama T, Ishizaki M, Yanagida H, Kitade H, Yoshizawa K, Nishizawa M, Sekimoto M. Hepatoprotection of a Standardized Extract of Cultured Lentinula edodes Mycelia against Liver Injury Induced by Ischemia-Reperfusion and Partial Hepatectomy. Nutrients 2024; 16:256. [PMID: 38257149 PMCID: PMC10820669 DOI: 10.3390/nu16020256] [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: 12/06/2023] [Revised: 01/08/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
A standardized extract of cultured Lentinula edodes mycelia (ECLM, AHCC®) has been shown to have beneficial effects on organ metabolism. ECLM has been indicated to have liver protective properties by suppressing inflammatory responses. The pathogenesis of hepatic ischemia-reperfusion injury is thought to involve the induction of inflammatory mediators. However, whether ECLM affects inflammatory mediators caused by warm hepatic ischemia-reperfusion injury and partial hepatectomy (HIRI+PH) has not been clarified. In this study, we evaluated the protective effects of ECLM against liver damage caused by HIRI+PH. Rats were fed a normal diet (HIRI+PH) or a normal diet with 2% ECLM (HIRI+PH and ECLM) for ten days, then the liver and duodenal ligament were clamped and subjected to 15 min of hepatic ischemia. After 70% hepatectomy, the inflow occlusion was released, and liver and blood samples were collected at 3, 6, and 24 h. The effect of ECLM on mortality induced by 30 min of ischemia and hepatectomy was evaluated. The results showed that ECLM attenuated pathological liver damage, including apoptosis, in the rats treated with HIRI+PH, and decreased serum aminotransferase activity; ECLM decreased mRNA levels of the inflammation-related genes inducible nitric oxide synthase and C-X-C motif chemokine ligand 1, and increased mRNA levels of interleukin 10, an anti-inflammatory cytokine; ECLM increased hepatocyte growth factor mRNA levels and Ki-67 labeled nuclei in the liver at 24 h; ECLM significantly reduced HIRI+PH-induced mortality. In conclusion, ECLM may prevent HIRI+PH-induced liver injury in part by suppressing various inflammatory responses and promoting liver regeneration.
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Affiliation(s)
- Richi Nakatake
- Department of Surgery, Kansai Medical University, Hirakata 573-1010, Osaka, Japan; (T.O.)
| | - Tetsuya Okuyama
- Department of Surgery, Kansai Medical University, Hirakata 573-1010, Osaka, Japan; (T.O.)
| | - Morihiko Ishizaki
- Department of Surgery, Kansai Medical University, Hirakata 573-1010, Osaka, Japan; (T.O.)
| | - Hidesuke Yanagida
- Department of Surgery, Kansai Medical University, Hirakata 573-1010, Osaka, Japan; (T.O.)
| | - Hiroaki Kitade
- Department of Surgery, Kansai Medical University, Hirakata 573-1010, Osaka, Japan; (T.O.)
| | - Katsuhiko Yoshizawa
- Department of Innovative Food Sciences, School of Food Sciences and Nutrition, Mukogawa Women’s University, 6-46 Ikebiraki-cho, Nishinomiya 663-8558, Hyogo, Japan;
| | - Mikio Nishizawa
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu 525-8577, Shiga, Japan;
| | - Mitsugu Sekimoto
- Department of Surgery, Kansai Medical University, Hirakata 573-1010, Osaka, Japan; (T.O.)
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Wang Y, Piao C, Liu T, Lu X, Ma Y, Zhang J, Liu G, Wang H. Effects of the exosomes of adipose-derived mesenchymal stem cells on apoptosis and pyroptosis of injured liver in miniature pigs. Biomed Pharmacother 2023; 169:115873. [PMID: 37979374 DOI: 10.1016/j.biopha.2023.115873] [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: 07/25/2023] [Revised: 11/07/2023] [Accepted: 11/07/2023] [Indexed: 11/20/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a complication of hepatectomy that affects the functional recovery of the remnant liver, which has been demonstrated to be associated with pyroptosis and apoptosis. Mesenchymal stem cells (MSCs) can protect against HIRI in rodents. Paracrine mechanisms of MSCs indicated that MSCs-derived exosomes (MSCs-exo) are one of the important components within the paracrine substances of MSCs. Moreover, miniature pigs are ideal experimental animals in comparative medicine compared to rodents. Accordingly, this study aimed to investigate whether hepatectomy combined with HIRI in miniature pigs would induce pyroptosis and whether adipose-derived MSCs (ADSCs) and their exosomes (ADSCs-exo) could positively mitigate apoptosis and pyroptosis. The study also compared the differences in the effects and the role of ADSCs and ADSCs-exo in pyroptosis and apoptosis. Results showed that severe ultrastructure damage occurred in liver tissues and systemic inflammatory response was induced after surgery, with TLR4/MyD88/NFκB/HMGB1 activation, NLRP3-ASC-Caspase1 complex generation, GSDMD revitalization, and IL-1β, IL-18, and LDH elevation in the serum. Furthermore, expression of Fas-Fasl-Caspase8 and CytC-APAF1-Caspase9 was increased in the liver. The ADSCs or ADSCs-exo intervention could inhibit the expression of these indicators and improve the ultrastructural pathological changes and systemic inflammatory response. There was no significant difference between the two intervention groups. In summary, ADSCs-exo could effectively inhibit pyroptosis and apoptosis similar to ADSCs and may be considered a safe and effective cell-free therapy to protect against liver injury.
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Affiliation(s)
- Yue Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Chenxi Piao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Tao Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xiangyu Lu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yajun Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jiantao Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Guodong Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Hongbin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
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Zhang X, Yi Y, Jiang Y, Liao J, Yang R, Deng X, Zhang L. Targeted Therapy of Acute Liver Injury via Cryptotanshinone-Loaded Biomimetic Nanoparticles Derived from Mesenchymal Stromal Cells Driven by Homing. Pharmaceutics 2023; 15:2764. [PMID: 38140104 PMCID: PMC10747007 DOI: 10.3390/pharmaceutics15122764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/16/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Acute liver injury (ALI) has the potential to compromise hepatic function rapidly, with severe cases posing a considerable threat to human health and wellbeing. Conventional treatments, such as the oral administration of antioxidants, can inadvertently lead to liver toxicity and other unwanted side effects. Mesenchymal stromal cells (MSCs) can target therapeutic agents directly to inflammatory sites owing to their homing effect, and they offer a promising avenue for the treatment of ALI. However, the efficacy and feasibility of these live cell products are hampered by challenges associated with delivery pathways and safety concerns. Therefore, in this work, MSC membranes were ingeniously harnessed as protective shells to encapsulate synthesized PLGA nanoparticle cores (PLGA/MSCs). This strategic approach enabled nanoparticles to simulate endogenous substances and yielded a core-shell nano-biomimetic structure. The biomimetic nanocarrier remarkably maintained the homing ability of MSCs to inflammatory sites. In this study, cryptotanshinone (CPT)-loaded PLGA/MSCs (CPT@PLGA/MSC) were prepared. These nanoparticles can be effectively internalized by LO2 cells. They reduced cellular oxidative stress and elevated inflammatory levels. In vivo results suggested that, after intravenous administration, CPT@PLGA/MSCs significantly reduced uptake by the reticuloendothelial system and immune recognition compared to PLGA nanoparticles without MSC membrane coatings, subsequently resulting in their targeted and enhanced accumulation in the liver. The effectiveness of CPT@PLGA/MSCs in alleviating carbon tetrachloride-induced oxidative stress and inflammation in a mouse model was unequivocally demonstrated through comprehensive histological examination and liver function tests. This study introduces a pioneering strategy with substantial potential for ALI treatment.
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Affiliation(s)
- Xin Zhang
- College of Science, Sichuan Agricultural University, Ya’an 625014, China; (X.Z.); (Y.Y.); (Y.J.); (X.D.)
| | - Yao Yi
- College of Science, Sichuan Agricultural University, Ya’an 625014, China; (X.Z.); (Y.Y.); (Y.J.); (X.D.)
| | - Yuanyuan Jiang
- College of Science, Sichuan Agricultural University, Ya’an 625014, China; (X.Z.); (Y.Y.); (Y.J.); (X.D.)
| | - Jinqiu Liao
- College of Life Science, Sichuan Agricultural University, Ya’an 625014, China; (J.L.); (R.Y.)
| | - Ruiwu Yang
- College of Life Science, Sichuan Agricultural University, Ya’an 625014, China; (J.L.); (R.Y.)
| | - Xuexue Deng
- College of Science, Sichuan Agricultural University, Ya’an 625014, China; (X.Z.); (Y.Y.); (Y.J.); (X.D.)
| | - Li Zhang
- College of Science, Sichuan Agricultural University, Ya’an 625014, China; (X.Z.); (Y.Y.); (Y.J.); (X.D.)
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Maspero M, Yilmaz S, Cazzaniga B, Raj R, Ali K, Mazzaferro V, Schlegel A. The role of ischaemia-reperfusion injury and liver regeneration in hepatic tumour recurrence. JHEP Rep 2023; 5:100846. [PMID: 37771368 PMCID: PMC10523008 DOI: 10.1016/j.jhepr.2023.100846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 06/20/2023] [Accepted: 07/01/2023] [Indexed: 09/30/2023] Open
Abstract
The risk of cancer recurrence after liver surgery mainly depends on tumour biology, but preclinical and clinical evidence suggests that the degree of perioperative liver injury plays a role in creating a favourable microenvironment for tumour cell engraftment or proliferation of dormant micro-metastases. Understanding the contribution of perioperative liver injury to tumour recurrence is imperative, as these pathways are potentially actionable. In this review, we examine the key mechanisms of perioperative liver injury, which comprise mechanical handling and surgical stress, ischaemia-reperfusion injury, and parenchymal loss leading to liver regeneration. We explore how these processes can trigger downstream cascades leading to the activation of the immune system and the pro-inflammatory response, cellular proliferation, angiogenesis, anti-apoptotic signals, and release of circulating tumour cells. Finally, we discuss the novel therapies under investigation to decrease ischaemia-reperfusion injury and increase regeneration after liver surgery, including pharmaceutical agents, inflow modulation, and machine perfusion.
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Affiliation(s)
- Marianna Maspero
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
| | - Sumeyye Yilmaz
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Beatrice Cazzaniga
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Roma Raj
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Khaled Ali
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Vincenzo Mazzaferro
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | - Andrea Schlegel
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
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20
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Yang H, Chen J, Li J. Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure. Front Immunol 2023; 14:1243220. [PMID: 37744328 PMCID: PMC10513107 DOI: 10.3389/fimmu.2023.1243220] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Acute liver failure (ALF) is a high-mortality syndrome for which liver transplantation is considered the only effective treatment option. A shortage of donor organs, high costs and surgical complications associated with immune rejection constrain the therapeutic effects of liver transplantation. Recently, mesenchymal stem cell (MSC) therapy was recognized as an alternative strategy for liver transplantation. Bone marrow mesenchymal stem cells (BMSCs) have been used in clinical trials of several liver diseases due to their ease of acquisition, strong proliferation ability, multipotent differentiation, homing to the lesion site, low immunogenicity and anti-inflammatory and antifibrotic effects. In this review, we comprehensively summarized the harvest and culture expansion strategies for BMSCs, the development of animal models of ALF of different aetiologies, the critical mechanisms of BMSC therapy for ALF and the challenge of clinical application.
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Affiliation(s)
| | | | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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21
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Nguyen NT, Umbaugh DS, Smith S, Adelusi OB, Sanchez-Guerrero G, Ramachandran A, Jaeschke H. Dose-dependent pleiotropic role of neutrophils during acetaminophen-induced liver injury in male and female mice. Arch Toxicol 2023; 97:1397-1412. [PMID: 36928416 PMCID: PMC10680445 DOI: 10.1007/s00204-023-03478-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 03/02/2023] [Indexed: 03/18/2023]
Abstract
Acetaminophen (APAP) overdose is the leading cause of acute liver failure in western countries. APAP can cause extensive hepatocellular necrosis, which triggers an inflammatory response involving neutrophil and monocyte recruitment. Particularly the role of neutrophils in the injury mechanism of APAP hepatotoxicity has been highly controversial. Thus, the objective of the current study was to assess whether a potential contribution of neutrophils was dependent on the APAP dose and the sex of the animals. Male and female C57BL/6 J mice were treated with 300 or 600 mg/kg APAP and the injury and inflammatory cell recruitment was evaluated between 6 and 48 h. In both male and female mice, ALT plasma levels and the areas of necrosis peaked at 12-24 h after both doses with more severe injury at the higher dose. In addition, Ly6g-positive neutrophils started to accumulate in the liver at 6 h and peaked at 6-12 h after 300 mg/kg and 12-24 h after 600 mg/kg for both sexes; however, the absolute numbers of hepatic neutrophils in the liver were significantly higher after the 600 mg/kg dose. Neutrophil infiltration correlated with mRNA levels of the neutrophil chemoattractant Cxcl2 in the liver. Treating mice with an anti-Cxcl2 antibody at 2 h after APAP significantly reduced neutrophil accumulation at 24 h after both doses and in both sexes. However, the injury was significantly reduced only after the high overdose. Thus, neutrophils, recruited through Cxcl2, have no effect on APAP-induced liver injury after 300 mg/kg but aggravate the injury only after severe overdoses.
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Affiliation(s)
- Nga T Nguyen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA
| | - David S Umbaugh
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA
| | - Sawyer Smith
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA
| | - Olamide B Adelusi
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA
| | - Giselle Sanchez-Guerrero
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, 66160, USA.
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22
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Press AT, Ungelenk L, Medyukhina A, Pennington SA, Nietzsche S, Kan C, Lupp A, Dahmen U, Wang R, Settmacher U, Wetzker R, Figge MT, Clemens MG, Bauer M. Sodium thiosulfate refuels the hepatic antioxidant pool reducing ischemia-reperfusion-induced liver injury. Free Radic Biol Med 2023; 204:151-160. [PMID: 37105418 DOI: 10.1016/j.freeradbiomed.2023.04.012] [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: 03/23/2023] [Revised: 04/18/2023] [Accepted: 04/24/2023] [Indexed: 04/29/2023]
Abstract
Ischemia-reperfusion injury is a critical liver condition during hepatic transplantation, trauma, or shock. An ischemic deprivation of antioxidants and energy characterizes liver injury in such cases. In the face of increased reactive oxygen production, hepatocytes are vulnerable to the reperfusion driving ROS generation and multiple cell-death mechanisms. In this study, we investigate the importance of hydrogen sulfide as part of the liver's antioxidant pool and the therapeutic potency of the hydrogen sulfide donors sodium sulfide (Na2S, fast releasing) and sodium thiosulfate (STS, Na2S2O3, slow releasing). The mitoprotection and toxicity of STS and Na2S were investigated on isolated mitochondria and a liver perfusion oxidative stress model by adding text-butyl hydroperoxide and hydrogen sulfide donors. The respiratory capacity of mitochondria, hepatocellular released LDH, glutathione, and lipid-peroxide levels were quantified. In addition, wild-type and cystathionine-γ-lyase knockout mice were subjected to warm selective ischemia-reperfusion injury by clamping the main inflow for 1 h followed by reperfusion of 1 or 24 h. A subset of animals was treated with STS shortly before reperfusion. Glutathione, plasma ALT, and lipid-peroxide levels were investigated alongside mitochondrial changes in structure (electron microscopy) and function (intravital microscopy). Liver tissue necrosis quantified 24 h after reperfusion indicates the net effects of the treatment on the organ. STS refuels and protects the endogenous antioxidant pool during liver ischemia-reperfusion injury. In addition, STS-mediated ROS scavenging significantly reduced lipid peroxidation and mitochondrial damage, resulting in better molecular and histopathological preservation of the liver tissue architecture. STS prevents tissue damage in liver ischemia-reperfusion injury by increasing the liver's antioxidant pool, thereby protecting mitochondrial integrity.
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Affiliation(s)
- Adrian T Press
- Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Jena, Germany; Jena University Hospital, Medical Faculty, Jena, Germany.
| | - Luisa Ungelenk
- Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Jena, Germany; Jena University Hospital, Medical Faculty, Jena, Germany
| | - Anna Medyukhina
- Applied Systems Biology, HKI-Center for Systems Biology of Infection, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute (HKI), Jena, Germany
| | - Samantha A Pennington
- Department of Biological Sciences, University of North Carolina, Charlotte, NC, USA; Pfeiffer University, Department of Natural and Health Sciences, Misenheimer, NC, USA
| | - Sandor Nietzsche
- Jena University Hospital, Electron Microscopy Center, Jena, Germany
| | - Chunyi Kan
- Jena University Hospital, Department of General, Visceral and Vascular Surgery, Experimental Transplantation Surgery, Jena, Germany
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
| | - Uta Dahmen
- Jena University Hospital, Department of General, Visceral and Vascular Surgery, Experimental Transplantation Surgery, Jena, Germany
| | - Rui Wang
- Department of Biology, York University, Toronto, Canada
| | - Utz Settmacher
- Jena University Hospital, Department of General, Visceral and Vascular Surgery, Experimental Transplantation Surgery, Jena, Germany
| | - Reinhard Wetzker
- Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Jena, Germany
| | - Marc Thilo Figge
- Applied Systems Biology, HKI-Center for Systems Biology of Infection, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute (HKI), Jena, Germany; Institute of Microbiology, Faculty of Biological Sciences, Friedrich-Schiller-University, Jena, Germany
| | - Mark G Clemens
- Department of Biological Sciences, University of North Carolina, Charlotte, NC, USA
| | - Michael Bauer
- Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Jena, Germany
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23
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Sun H, Wang XK, Li JR, Tang M, Li H, Lei L, Li HY, Jiang J, Li JY, Dong B, Jiang JD, Peng ZG. Establishment and application of a high-throughput screening model for cell adhesion inhibitors. Front Pharmacol 2023; 14:1140163. [PMID: 36909195 PMCID: PMC9995855 DOI: 10.3389/fphar.2023.1140163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 02/10/2023] [Indexed: 02/25/2023] Open
Abstract
The cell adhesion between leukocytes and endothelial cells plays an important balanced role in the pathophysiological function, while excessive adhesion caused by etiological agents is associated with the occurrence and development of many acute and chronic diseases. Cell adhesion inhibitors have been shown to have a potential therapeutic effect on these diseases, therefore, efficient and specific inhibitors against cell adhesion are highly desirable. Here, using lipopolysaccharide-induced human umbilical vein endothelial cells (HUVECs) and calcein-AM-labeled human monocytic cell THP-1, we established a high-throughput screening model for cell adhesion inhibitors with excellent model evaluation parameters. Using the drug repurposing strategy, we screened out lifitegrast, a potent cell adhesion inhibitor, which inhibited cell adhesion between HUVEC and THP-1 cells by directly interrupting the adhesion interaction between HUVEC and THP-1 cells and showed a strong therapeutic effect on the mouse acute liver injury induced by poly (I:C)/D-GalN. Therefore, the screening model is suitable for screening and validating cell adhesion inhibitors, which will promote the research and development of inhibitors for the treatment of diseases caused by excessive cell adhesion.
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Affiliation(s)
- Han Sun
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xue-Kai Wang
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jian-Rui Li
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mei Tang
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hu Li
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei Lei
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong-Ying Li
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Jiang
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jia-Yu Li
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Biao Dong
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jian-Dong Jiang
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zong-Gen Peng
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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24
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Enniatin B and beauvericin affect intestinal cell function and hematological processes in Atlantic salmon (Salmo salar) after acute exposure. Food Chem Toxicol 2023; 172:113557. [PMID: 36526092 DOI: 10.1016/j.fct.2022.113557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/05/2022] [Accepted: 12/11/2022] [Indexed: 12/15/2022]
Abstract
Unintentional use of mold-infested plant-based feed ingredients are sources of mycotoxins in fish feeds. The presence of the emerging mycotoxins ENNB and BEA in Norwegian commercial fish feeds and plant-based feed ingredients has raised concerns regarding the health effects on farmed Atlantic salmon (Salmon salar). Atlantic salmon pre-smolts were exposed to non-lethal doses of BEA and ENNB (ctrl, 50 and 500 μg/kg feed for 12 h), after which total RNA sequencing of the intestine and liver was carried out to evaluate gut health and identify possible hepatological changes after acute dietary exposure. ENNB and BEA did not trigger acute toxicity, however ENNB caused the onset of pathways linked to acute intestinal inflammation and BEA exposures caused the onset of hepatic hematological disruption. The prevalence and concentration of ENNB found in today's commercial feed could affect the fish health if consumed over a longer time-period.
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25
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Kaden T, Noerenberg A, Boldt J, Sagawe C, Johannssen T, Rennert K, Raasch M, Evenburg T. Generation & characterization of expandable human liver sinusoidal endothelial cells and their application to assess hepatotoxicity in an advanced in vitro liver model. Toxicology 2023; 483:153374. [PMID: 36396002 DOI: 10.1016/j.tox.2022.153374] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/08/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022]
Abstract
Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells forming the hepatic sinusoidal wall. Besides their high endocytic potential, LSECs have been demonstrated to markedly contribute to liver homeostasis and immunity, and may partially explain unexpected hepatotoxicity of drug candidates. However, their use for in vitro investigations is compromised by poor cell yields and a limited proliferation capacity. Here, we report the transient expansion of primary human LSECs from three donors by lentiviral transduction. Transduced ("upcyte®") LSECs were able to undergo at least 25 additional population doublings (PDs) before growth arrest due to senescence. Expanded upcyte® LSECs maintained several characteristics of primary LSECs, including expression of surface markers such as MMR and LYVE-1 as well as rapid uptake of acetylated LDL and ovalbumin. We further investigated the suitability of expanded upcyte® LSECs and proliferating upcyte® hepatocytes for detecting acetaminophen toxicity at millimolar concentrations (0, 0.5, 1, 2, 5, 10 mM) in static 2D cultures and a microphysiological 3D model. upcyte® LSECs exhibited a higher sensitivity to acetaminophen-induced toxicity compared to upcyte® hepatocytes in 2D culture, however, culturing upcyte® LSECs together with upcyte® hepatocytes in a co-culture reduced APAP-induced toxicity compared to 2D monocultures. A perfused Dynamic42 3D model was more sensitive to acetaminophen than the 2D co-culture model. Cytotoxicity in the 3D model was evident by decreased cellular viability, elevated LDH release, reduced nuclei counts and impaired cell morphology. Taken together, our data demonstrate that transient expansion of LSECs represents a suitable method for generation of large quantities of cells while maintaining many characteristics of primary cells and responsiveness to acetaminophen.
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Chen L, Zhen X, Jiang X. Activatable Optical Probes for Fluorescence and Photoacoustic Imaging of Drug‐Induced Liver Injury. ADVANCED NANOBIOMED RESEARCH 2022. [DOI: 10.1002/anbr.202200097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Linrong Chen
- MOE Key Laboratory of High Performance Polymer Materials and Technology and Department of Polymer Science & Engineering School of Chemistry & Chemical Engineering Nanjing University Nanjing 210093 P.R. China
| | - Xu Zhen
- MOE Key Laboratory of High Performance Polymer Materials and Technology and Department of Polymer Science & Engineering School of Chemistry & Chemical Engineering Nanjing University Nanjing 210093 P.R. China
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development School of Chemistry and Molecular Engineering East China Normal University Shanghai 200062 P.R. China
| | - Xiqun Jiang
- MOE Key Laboratory of High Performance Polymer Materials and Technology and Department of Polymer Science & Engineering School of Chemistry & Chemical Engineering Nanjing University Nanjing 210093 P.R. China
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27
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Ahmad A. Prophylactic Treatment with Hydrogen Sulphide Can Prevent Renal Ischemia-Reperfusion Injury in L-NAME Induced Hypertensive Rats with Cisplatin-Induced Acute Renal Failure. Life (Basel) 2022; 12:1819. [PMID: 36362975 PMCID: PMC9695289 DOI: 10.3390/life12111819] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/01/2022] [Accepted: 11/03/2022] [Indexed: 08/26/2023] Open
Abstract
(Background and Objectives): Renal ischemia perfusion injury is one of the major issues in kidney transplant. The aim of the study was to investigate the hypothesis that prophylactic treatment-with a hydrogen sulphide donor to an acute renal failure case of hypertensive rats-can minimize the ischemia reperfusion injury of the kidney which is beneficial for kidney transplant. To check this hypothesis, the present study was designed to investigate the effect of chronic administration of a hydrogen sulphide (H2S) donor and sodium hydrosulfide (NaHS) on nuclear factor kappa B (NF-kB) and inter cellular adhesion molecule-1 (ICAM-1) concentration in non-renal failure (NRF) and acute renal failure (ARF) rats in the ischemia-reperfusion injury (IRI) model of the kidney in both normotensive WKY and hypertensive rats (L-nitro arginine methyl ester (L-NAME-induced); (Materials and Methods): A total number of 48 Sprague-Dawley rats were recruited into eight groups each consisting of six animals. Each of these eight groups was used to measure systemic and renal parameters, H2S, antioxidant parameters in plasma, plasma concentration of NF-kB and ICAM-1 and renal cortical blood pressure. ARF was induced by single intraperitoneal (i.p.) cisplatin injection (5 mg/kg). Hypertension was induced by oral administration of L-NAME in drinking water for four weeks at 40 mg/kg/day. NaHS was administered (i.p) at 56 µmol/kg for five weeks while dL-propargylglycine (PAG), a H2S generation inhibitor, was administered as a single intra-peritoneal injection (50 mg/kg). An acute surgical experiment was performed for the induction of renal ischemia for 30 min by renal artery clamping followed by reperfusion for three hours; (Results): Chronic administration of NaHS attenuated the severity of ARF in both normotensive and hypertensive animals (L-NAME) along with lowering the blood pressure in hypertensive groups. NaHS improved the oxidative stress parameters such as total superoxide dismutase (T-SOD), glutathione (GSH) and reduced the malondialdehyde (MDA) concentration along with reduction of NF-kB and ICAM-1 following renal IRI; Conclusions: These findings demonstrate that H2S not only reduced the severity of cisplatin induced ARF but also reduced the severity of renal IRI by upregulating antioxidants along with decreased concentrations of NF-kB and ICAM-1 in normotensive and L-NAME induced hypertensive rats.
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Affiliation(s)
- Ashfaq Ahmad
- Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al Batin, Hafr Al Batin 39524, Saudi Arabia
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28
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Woolbright BL, Nguyen NT, McGill MR, Sharpe MR, Curry SC, Jaeschke H. Generation of pro-and anti-inflammatory mediators after acetaminophen overdose in surviving and non-surviving patients. Toxicol Lett 2022; 367:59-66. [PMID: 35905941 PMCID: PMC9849076 DOI: 10.1016/j.toxlet.2022.07.813] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 07/17/2022] [Accepted: 07/25/2022] [Indexed: 01/21/2023]
Abstract
Acetaminophen (APAP) overdose causes liver injury in animals and humans. Although well-studied in animals, limited longitudinal data exist on cytokine release after APAP overdose in patients. The purpose of this study was to quantify concentrations of cytokines in APAP overdose patients to determine if early cytokine or complement measurements can distinguish between surviving and non-surviving patients. Plasma was obtained from healthy controls, APAP overdose patients with no increase in liver transaminases, and surviving and non-surviving APAP overdose patients with severe liver injury. Interleukin-10 (IL-10), and CC chemokine ligand-2 (CCL2, MCP-1) were substantially elevated in surviving and non-surviving patients, whereas IL-6 and CXC chemokine ligand-8 (CXCL8, IL-8) had early elevations in a subset of patients only with liver injury. Day 1 IL-10 and IL-6 levels, and Day 2 CCL2, levels correlated positively with survival. There was no significant increase in IL-1α, IL-1β or TNF-α in any patient during the first week after APAP. Monitoring cytokines such as CCL2 may be a good indicator of patient prognosis; furthermore, these data indicate the inflammatory response after APAP overdose in patients is not mediated by a second phase of inflammation driven by the inflammasome.
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Affiliation(s)
| | - Nga T Nguyen
- Department of Pharmacology, Toxicology & Therapeutics, USA
| | | | - Matthew R Sharpe
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Steven C Curry
- Department of Medical Toxicology, Banner Good Samaritan Medical Center, Phoenix, AZ, USA; Department of Medicine, and Center for Toxicology and Pharmacology Education and Research, University of Arizona College of Medicine, Phoenix, AZ, USA
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29
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Kaltenmeier C, Wang R, Popp B, Geller D, Tohme S, Yazdani HO. Role of Immuno-Inflammatory Signals in Liver Ischemia-Reperfusion Injury. Cells 2022; 11:cells11142222. [PMID: 35883665 PMCID: PMC9323912 DOI: 10.3390/cells11142222] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/09/2022] [Accepted: 07/13/2022] [Indexed: 02/01/2023] Open
Abstract
Ischemia reperfusion injury (IRI) is a major obstacle in liver resection and liver transplantation. The initial step of IRI is mediated through ischemia which promotes the production of reactive oxygen species in Kupffer cells. This furthermore promotes the activation of pro-inflammatory signaling cascades, including tumor necrosis factor-alpha, IL-6, interferon, inducible nitric oxide synthase, TLR9/nuclear-factor kappa B pathway, and the production of damage-associated molecular patterns (DAMPs), such as ATP, histone, high mobility group box 1 (HMGB1), urate, mitochondrial formyl peptides and S100 proteins. With ongoing cell death of hepatocytes during the ischemic phase, DAMPs are built up and released into the circulation upon reperfusion. This promotes a cytokines/chemokine storm that attracts neutrophils and other immune cells to the site of tissue injury. The effect of IRI is further aggravated by the release of cytokines and chemokines, such as epithelial neutrophil activating protein (CXCL5), KC (CXCL1) and MIP-2 (CXCL2), the complement proteins C3a and C5a, mitochondrial-derived formyl peptides, leukotriene B4 and neutrophil extracellular traps (NETs) from migrating neutrophils. These NETs can also activate platelets and form Neutrophil-platelet microthrombi to further worsen ischemia in the liver. In this review we aim to summarize the current knowledge of mediators that promote liver IRI, and we will discuss the role of neutrophils and neutrophil extracellular traps in mediating IRI.
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Affiliation(s)
- Christof Kaltenmeier
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
| | - Ronghua Wang
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
| | - Brandon Popp
- Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA;
| | - David Geller
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
| | - Samer Tohme
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
| | - Hamza O. Yazdani
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
- Correspondence:
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Li Y, Palmer A, Lupu L, Huber-Lang M. Inflammatory response to the ischaemia-reperfusion insult in the liver after major tissue trauma. Eur J Trauma Emerg Surg 2022; 48:4431-4444. [PMID: 35831749 DOI: 10.1007/s00068-022-02026-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 05/28/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Polytrauma is often accompanied by ischaemia-reperfusion injury to tissues and organs, and the resulting series of immune inflammatory reactions are a major cause of death in patients. The liver is one of the largest organs in the body, a characteristic that makes it the most vulnerable organ after multiple injuries. In addition, the liver is an important digestive organ that secretes a variety of inflammatory mediators involved in local as well as systemic immune inflammatory responses. Therefore, this review considers the main features of post-traumatic liver injury, focusing on the immuno-pathophysiological changes, the interactions between liver organs, and the principles of treatment deduced. METHODS We focus on the local as well as systemic immune response involving the liver after multiple injuries, with emphasis on the pathophysiological mechanisms. RESULTS An overview of the mechanisms underlying the pathophysiology of local as well as systemic immune responses involving the liver after multiple injuries, the latest research findings, and the current mainstream therapeutic approaches. CONCLUSION Cross-reactivity between various organs and cascade amplification effects are among the main causes of systemic immune inflammatory responses after multiple injuries. For the time being, the pathophysiological mechanisms underlying this interaction remain unclear. Future work will continue to focus on identifying potential signalling pathways as well as target genes and intervening at the right time points to prevent more severe immune inflammatory responses and promote better and faster recovery of the patient.
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Affiliation(s)
- Yang Li
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Annette Palmer
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Ludmila Lupu
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany.
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Gao F, Qiu X, Wang K, Shao C, Jin W, Zhang Z, Xu X. Targeting the Hepatic Microenvironment to Improve Ischemia/Reperfusion Injury: New Insights into the Immune and Metabolic Compartments. Aging Dis 2022; 13:1196-1214. [PMID: 35855339 PMCID: PMC9286916 DOI: 10.14336/ad.2022.0109] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 01/09/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatic ischemia/reperfusion injury (IRI) is mainly characterized by high activation of immune inflammatory responses and metabolic responses. Understanding the molecular and metabolic mechanisms underlying development of hepatic IRI is critical for developing effective therapies for hepatic IRI. Recent advances in research have improved our understanding of the pathogenesis of IRI. During IRI, hepatocyte injury and inflammatory responses are mediated by crosstalk between the immune cells and metabolic components. This crosstalk can be targeted to treat or reverse hepatic IRI. Thus, a deep understanding of hepatic microenvironment, especially the immune and metabolic responses, can reveal new therapeutic opportunities for hepatic IRI. In this review, we describe important cells in the liver microenvironment (especially non-parenchymal cells) that regulate immune inflammatory responses. The role of metabolic components in the diagnosis and prevention of hepatic IRI are discussed. Furthermore, recent updated therapeutic strategies based on the hepatic microenvironment, including immune cells and metabolic components, are highlighted.
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Affiliation(s)
- Fengqiang Gao
- 1Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,6Zhejiang University School of Medicine, Hangzhou, China
| | - Xun Qiu
- 1Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,6Zhejiang University School of Medicine, Hangzhou, China
| | - Kai Wang
- 1Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chuxiao Shao
- 7Department of Hepatobiliary and Pancreatic Surgery, Affiliated Lishui Hospital, Zhejiang University School of Medicine, Lishui, China
| | - Wenjian Jin
- 8Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Zhen Zhang
- 6Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Xu
- 1Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,2Zhejiang University Cancer Center, Hangzhou, China.,3Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,4NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.,5Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
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Gastrodin Alleviates Acetaminophen-Induced Liver Injury in a Mouse Model Through Inhibiting MAPK and Enhancing Nrf2 Pathways. Inflammation 2022; 45:1450-1462. [PMID: 35474551 DOI: 10.1007/s10753-021-01557-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/25/2021] [Indexed: 11/05/2022]
Abstract
Gastrodin is a major active phenolic glycoside extract from Gastrodia elata, an important herb used in traditional medicine. Previous research has reported that gastrodin possesses anti-inflammatory and anti-oxidant properties. Therefore, we aimed to investigate its hepatoprotective effects and mechanisms on acetaminophen (APAP)-induced liver injury in a mouse model. Mice included in this study were intraperitoneally administered with a hepatotoxic APAP dose (300 mg/kg). At 30 min after APAP administration, gastrodin was intraperitoneally injected at concentrations of 0, 15, 30, and 45 mg/kg. Then, all mice were sacrificed at 16 h after APAP injection for further analysis. The results showed that gastrodin treatment ameliorated acute liver injury caused by APAP, as indicated by serum alanine aminotransferase level, hepatic myeloperoxidase activity, and cytokine (TNF-α, IL-1β, and IL-6) production. It also significantly decreased hepatic malondialdehyde activity but increased superoxide dismutase activity. In addition, gastrodin decreased ERK/JNK MAPK expression but promoted Nrf2 expression. These results demonstrated that gastrodin may be a potential therapeutic target for the prevention of APAP-induced hepatotoxicity via amelioration of the inflammatory response and oxidative stress, inhibition of ERK/JNK MAPK signaling pathways, and activation of Nrf2 expression levels.
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Liver ischaemia-reperfusion injury: a new understanding of the role of innate immunity. Nat Rev Gastroenterol Hepatol 2022; 19:239-256. [PMID: 34837066 DOI: 10.1038/s41575-021-00549-8] [Citation(s) in RCA: 193] [Impact Index Per Article: 64.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/29/2021] [Indexed: 02/08/2023]
Abstract
Liver ischaemia-reperfusion injury (LIRI), a local sterile inflammatory response driven by innate immunity, is one of the primary causes of early organ dysfunction and failure after liver transplantation. Cellular damage resulting from LIRI is an important risk factor not only for graft dysfunction but also for acute and even chronic rejection and exacerbates the shortage of donor organs for life-saving liver transplantation. Hepatocytes, liver sinusoidal endothelial cells and Kupffer cells, along with extrahepatic monocyte-derived macrophages, neutrophils and platelets, are all involved in LIRI. However, the mechanisms underlying the responses of these cells in the acute phase of LIRI and how these responses are orchestrated to control and resolve inflammation and achieve homeostatic tissue repair are not well understood. Technological advances allow the tracking of cells to better appreciate the role of hepatic macrophages and platelets (such as their origin and immunomodulatory and tissue-remodelling functions) and hepatic neutrophils (such as their selective recruitment, anti-inflammatory and tissue-repairing functions, and formation of extracellular traps and reverse migration) in LIRI. In this Review, we summarize the role of macrophages, platelets and neutrophils in LIRI, highlight unanswered questions, and discuss prospects for innovative therapeutic regimens against LIRI in transplant recipients.
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Ntamo Y, Ziqubu K, Chellan N, Nkambule BB, Nyambuya TM, Mazibuko-Mbeje SE, Gabuza KB, Orlando P, Tiano L, Dludla PV. Clinical use of N-acetyl cysteine during liver transplantation: Implications of oxidative stress and inflammation as therapeutic targets. Biomed Pharmacother 2022; 147:112638. [DOI: 10.1016/j.biopha.2022.112638] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/05/2022] [Accepted: 01/12/2022] [Indexed: 02/09/2023] Open
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Jaeschke H, Ramachandran A. Targeting the sterile inflammatory response during acetaminophen hepatotoxicity with natural products. Toxicol Lett 2022; 355:170-171. [PMID: 34801638 PMCID: PMC8702449 DOI: 10.1016/j.toxlet.2021.11.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/16/2021] [Indexed: 02/03/2023]
Abstract
The sterile inflammatory response observed after hepatic necrosis caused by an acetaminophen (APAP) overdose has been a controversial topic for years. In a recent review, Gong et al. (2021) provided a list of studies investigating the mechanisms of inflammation during APAP-induced injury and recovery as well as those using natural products as anti-inflammatory intervention strategies in this context. However, the review lacks a critical assessment of the cited literature, which leads to the amplification of questionable mechanistic conclusions. We feel it is necessary to express our concerns regarding such superficial reviews of a scientific field, which hamper progress and are not helpful in advancing the field.
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Affiliation(s)
- Hartmut Jaeschke
- Corresponding author at: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, 3901Rainbow Blvd, MS1018, Kansas City, KS 66160, USA. Tel.: +1 913 588 7969,
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Guo Z, Chen J, Zeng Y, Wang Z, Yao M, Tomlinson S, Chen B, Yuan G, He S. Complement Inhibition Alleviates Cholestatic Liver Injury Through Mediating Macrophage Infiltration and Function in Mice. Front Immunol 2022; 12:785287. [PMID: 35069557 PMCID: PMC8777082 DOI: 10.3389/fimmu.2021.785287] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/14/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND AIMS Cholestatic liver injury (CLI), which is associated with inflammatory reactions and oxidative stress, is a serious risk factor for postoperative complications. Complement system is involved in a wide range of liver disorders, including cholestasis. The present study assessed the role of complement in CLI and the therapeutic effect of the site-targeted complement inhibitor CR2-Crry in CLI. METHODS Wild-type and complement gene deficient mice underwent common bile duct ligation (BDL) to induce CLI or a sham operation, followed by treatment with CR2-Crry or GdCl3. The roles of complement in CLI and the potential therapeutic effects of CR2-Crry were investigated by biochemical analysis, flow cytometry, immunohistochemistry, ELISA, and quantitative RT-PCR. RESULTS C3 deficiency and CR2-Crry significantly reduced liver injuries in mice with CLI, and also markedly decreasing the numbers of neutrophils and macrophages in the liver. C3 deficiency and CR2-Crry also significantly reduced neutrophil expression of Mac-1 and liver expression of VCAM-1. More importantly, C3 deficiency and CR2-Crry significantly inhibited M1 macrophage polarization in these mice. Intravenous injection of GdCl3 inhibited macrophage infiltration and activation in the liver. However, the liver injury increased significantly. BDL significantly increased the level of lipopolysaccharide (LPS) in portal blood, but not in peripheral blood. GdCl3 significantly increased LPS in peripheral blood, suggesting that macrophages clear portal blood LPS. Oral administration of ampicillin to in GdCl3 treated mice reduced LPS levels in portal blood and alleviated liver damage. In contrast, intraperitoneal injection LPS increased portal blood LPS and reversed the protective effect of ampicillin. Interestingly, C3 deficiency did not affect the clearance of LPS. CONCLUSIONS Complement is involved in CLI, perhaps mediating the infiltration and activation of neutrophils and macrophage M1 polarization in the liver. C3 deficiency and CR2-Crry significantly alleviated CLI. Inhibition of complement could preserve the protective function of macrophages in clearing LPS, suggesting that complement inhibition could be useful in treating CLI.
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Affiliation(s)
- Zhenya Guo
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, China
| | - Junze Chen
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, China
| | - Yonglian Zeng
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, China
| | - Zefeng Wang
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Mei Yao
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, China
| | - Stephen Tomlinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Bin Chen
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, China
| | - Guandou Yuan
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, China
| | - Songqing He
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, China
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Liu D, Liu DC, Fan H, Wang Y. Lactobacillus fermentum CQPC08 Attenuates Exercise-Induced Fatigue in Mice Through Its Antioxidant Effects and Effective Intervention of Galactooligosaccharide. Drug Des Devel Ther 2021; 15:5151-5164. [PMID: 34992351 PMCID: PMC8714972 DOI: 10.2147/dddt.s317456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/18/2021] [Indexed: 12/02/2022] Open
Abstract
Aim The purpose of this study is to study the antioxidant effect of Lactobacillus fermentum CQPC08 (CQPC08) on exercise-induced fatigue, and the beneficial intervention of GOS on CQPC08. Methods We use the treadmill to establish a fatigue model caused by exercise, and perform drug treatment after exercise. We tested the exhaustive exercise time of mice; investigated the changes of mice body weight, liver index, histopathology, serum biochemical indicators and mRNA expression levels of oxidative and inflammation-related genes; and assessed the potential fatigue inhibitory effect of CQPC08, and the anti-oxidation effect of the combination of GOS and CQPC08. Results The results suggest that CQPC08 and combination with GOS reduces fatigue-induced oxidative damage of the liver, and it decreases blood urea nitrogen (BUN), lactic acid (LA), glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), malonaldehyde (MDA), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in serum. Higher levels of serum catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were found. Treatment with the CQPC08 and combination with GOS correlates with lower relative mRNA expression levels of neuronal NOS (nNOS), iNOS, and TNF-α, and with higher mRNA expression levels of catalase and copper/zinc (Cu/Zn) and manganese (Mn) SOD enzymes in the liver and muscles. Conclusion These results suggest that CQPC08 can resolve exercise-induced fatigue by improving antioxidant ability in mice, and the combination of GOS and CQPC08 enhances this ability of CQPC08.
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Affiliation(s)
- Dong Liu
- Development Chongqing University of Education, Chongqing, People’s Republic of China
- Education Major in Physical Education, University of Perpetual Help System DALTA Las Pinas, Manila, Philippines
| | - Da Chuan Liu
- Student Affairs Department, Jiangmen Preschool Education College, Jiangmen, Guangdong, People’s Republic of China
| | - Hao Fan
- School of Tourism and Service Management, Chongqing University of Education, Chongqing, People’s Republic of China
- Cultural Industries and Cultural Policy, Yuan Ze University, Taoyuan, Taiwan
| | - Yu Wang
- Orthopedics Department, General Hospital of Northern Theatre Command, Liaoning Province, People’s Republic of China
- Correspondence: Yu Wang Orthopedics Department, General Hospital of Northern Theatre Command, No. 83 Wenhua Road, Shenhe District, Shenyang, Liaoning Province, 110016, People’s Republic of ChinaTel +86-18609886338 Email
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Jaeschke H, Adelusi OB, Akakpo JY, Nguyen NT, Sanchez-Guerrero G, Umbaugh DS, Ding WX, Ramachandran A. Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls. Acta Pharm Sin B 2021; 11:3740-3755. [PMID: 35024303 PMCID: PMC8727921 DOI: 10.1016/j.apsb.2021.09.023] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/22/2021] [Accepted: 09/10/2021] [Indexed: 02/07/2023] Open
Abstract
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is safe at therapeutic doses but can cause severe liver injury and even liver failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As a result, this clinically relevant model is frequently used to study mechanisms of drug-induced liver injury and even more so to test potential therapeutic interventions. However, the complexity of the model requires a thorough understanding of the pathophysiology to obtain valid results and mechanistic information that is translatable to the clinic. However, many studies using this model are flawed, which jeopardizes the scientific and clinical relevance. The purpose of this review is to provide a framework of the model where mechanistically sound and clinically relevant data can be obtained. The discussion provides insight into the injury mechanisms and how to study it including the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response. In addition, the most frequently made mistakes when using this model are discussed. Thus, considering these recommendations when studying APAP hepatotoxicity will facilitate the discovery of more clinically relevant interventions.
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Key Words
- AIF, apoptosis-inducing factor
- AMPK, AMP-activated protein kinase
- APAP, acetaminophen
- ARE, antioxidant response element
- ATG, autophagy-related genes
- Acetaminophen hepatotoxicity
- Apoptosis
- Autophagy
- BSO, buthionine sulfoximine
- CAD, caspase-activated DNase
- CYP, cytochrome P450 enzymes
- DAMPs, damage-associated molecular patterns
- DMSO, dimethylsulfoxide
- Drug metabolism
- EndoG, endonuclease G
- FSP1, ferroptosis suppressing protein 1
- Ferroptosis
- GPX4, glutathione peroxidase 4
- GSH, glutathione
- GSSG, glutathione disulfide
- Gclc, glutamate–cysteine ligase catalytic subunit
- Gclm, glutamate–cysteine ligase modifier subunit
- HMGB1, high mobility group box protein 1
- HNE, 4-hydroxynonenal
- Innate immunity
- JNK, c-jun N-terminal kinase
- KEAP1, Kelch-like ECH-associated protein 1
- LAMP, lysosomal-associated membrane protein
- LC3, light chain 3
- LOOH, lipid hydroperoxides
- LPO, lipid peroxidation
- MAP kinase, mitogen activated protein kinase
- MCP-1, monocyte chemoattractant protein-1
- MDA, malondialdehyde
- MPT, mitochondrial permeability transition
- Mitochondria
- MnSOD, manganese superoxide dismutase
- NAC, N-acetylcysteine
- NAPQI, N-acetyl-p-benzoquinone imine
- NF-κB, nuclear factor κB
- NQO1, NAD(P)H:quinone oxidoreductase 1
- NRF2
- NRF2, nuclear factor erythroid 2-related factor 2
- PUFAs, polyunsaturated fatty acids
- ROS, reactive oxygen species
- SMAC/DIABLO, second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI
- TLR, toll like receptor
- TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling
- UGT, UDP-glucuronosyltransferases
- mTORC1, mammalian target of rapamycin complex 1
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Affiliation(s)
- Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Olamide B. Adelusi
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Jephte Y. Akakpo
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Nga T. Nguyen
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Giselle Sanchez-Guerrero
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - David S. Umbaugh
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Wen-Xing Ding
- 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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Yang L, Bi L, Jin L, Wang Y, Li Y, Li Z, He W, Cui H, Miao J, Wang L. Geniposide Ameliorates Liver Fibrosis Through Reducing Oxidative Stress and Inflammatory Respose, Inhibiting Apoptosis and Modulating Overall Metabolism. Front Pharmacol 2021; 12:772635. [PMID: 34899328 PMCID: PMC8651620 DOI: 10.3389/fphar.2021.772635] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/05/2021] [Indexed: 12/15/2022] Open
Abstract
Liver fibrosis is a progressive liver damage condition caused by various factors and may progress toward liver cirrhosis, and even hepatocellular carcinoma. Many studies have found that the disfunction in metabolism could contribute to the development of liver fibrosis. Geniposide, derived from Gardenia jasminoides J. Ellis, has been demonstrated with therapeutic effects on liver fibrosis. However, the exact molecular mechanisms of such liver-protection remain largely unknown. The aim of this study was to explored the effect of geniposide on metabolic regulations in liver fibrosis. We used carbon tetrachloride (CCl4) to construct a mouse model of liver fibrosis and subsequently administered geniposide treatment. Therapeutic effects of geniposide on liver fibrosis were accessed through measuring the levels of hepatic enzymes in serum and the pathological changes in liver. We also investigated the effects of geniposide on inflammatory response, oxidative stress and apoptosis in liver. Furthermore, serum untargeted metabolomics were used to explore the metabolic regulatory mechanisms behind geniposide on liver fibrosis. Our results demonstrated that geniposide could reduce the levels of hepatic enzymes in serum and ameliorate the pathological changes in liver fibrosis mice. Geniposide enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased methane dicarboxylic aldehyde (MDA) levels in liver. Geniposide treatment also decreased the levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-a) in liver tissue homogenate. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining demonstrated that geniposide could reduce the apoptosis of hepatocytes. Geniposide increased the protein expression of B-cell lymphoma-2 (Bcl-2) and downregulated the protein expression of Bcl-2 Associated X (Bax), cleaved-Caspase 3, and cleaved-Caspase 9. Serum untargeted metabolomics analysis demonstrated that geniposide treatment improved the metabolic disorders including glycerophospholipid metabolism, arginine and proline metabolism, and arachidonic acid (AA) metabolism. In conclusion, our study demonstrated the protective effects of geniposide on liver fibrosis. We found that geniposide could treat liver fibrosis by inhibiting oxidative stress, reducing inflammatory response and apoptosis in the liver, and modulating glycerophospholipid, and arginine, proline, and AA metabolism processes.
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Affiliation(s)
- Lu Yang
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Second People’s Hospital, Tianjin, China
| | - Liping Bi
- Tianjin Second People’s Hospital, Tianjin, China
| | - Lulu Jin
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuming Wang
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuting Li
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zixuan Li
- Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, China
| | - Wenju He
- Tianjin First Central Hospital, Tianjin, China
| | - Huantian Cui
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Jing Miao
- Tianjin Second People’s Hospital, Tianjin, China
| | - Li Wang
- Tianjin Second People’s Hospital, Tianjin, China
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Association between immunologic markers and cirrhosis in individuals with chronic hepatitis B. Sci Rep 2021; 11:21194. [PMID: 34782638 PMCID: PMC8593047 DOI: 10.1038/s41598-021-00455-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 09/23/2021] [Indexed: 12/20/2022] Open
Abstract
Host immune response and chronic inflammation associated with chronic hepatitis B virus (HBV) infection play a key role in the pathogenesis of liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). We sampled 175 HCC, 117 cirrhotic and 165 non-cirrhotic controls from a prospective cohort study of chronically HBV-infected individuals. Multivariable polytomous logistic regression and canonical discriminant analysis (CDA) were used to compare baseline plasma levels for 102 markers in individuals who developed cirrhosis vs. controls and those who developed HCC vs. cirrhosis. Leave-one-out cross validation was used to generate receiver operating characteristic curves to compare the predictive ability of marker groups. After multivariable adjustment, HGF (Q4v1OR: 3.74; p-trend = 0.0001), SLAMF1 (Q4v1OR: 4.07; p-trend = 0.0001), CSF1 (Q4v1OR: 3.00; p-trend = 0.002), uPA (Q4v1OR: 3.36; p-trend = 0.002), IL-8 (Q4v1OR: 2.83; p-trend = 0.004), and OPG (Q4v1OR: 2.44; p-trend = 0.005) were all found to be associated with cirrhosis development compared to controls; these markers predicted cirrhosis with 69% accuracy. CDA analysis identified a nine marker model capable of predicting cirrhosis development with 79% accuracy. No markers were significantly different between HCC and cirrhotic participants. In this study, we assessed immunologic markers in relation to liver disease in chronically-HBV infected individuals. While validation in required, these findings highlight the importance of immunologic processes in HBV-related cirrhosis.
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Getachew A, Hussain M, Huang X, Li Y. Toll-like receptor 2 signaling in liver pathophysiology. Life Sci 2021; 284:119941. [PMID: 34508761 DOI: 10.1016/j.lfs.2021.119941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 08/19/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022]
Abstract
Chronic liver diseases (CLD) are among the major cause of mortality and morbidity worldwide. Despite current achievements in the area of hepatitis virus, chronic alcohol abuse and high-fat diet are still fueling an epidemic of severe liver disease, for which, an effective therapy has yet not been discovered. In particular, the therapeutic regimens that could prevent the progression of fibrosis and, in turn, aid cirrhotic liver to develop a robust regenerative capability are intensively needed. To this context, a better understanding of the signaling pathways regulating hepatic disease development may be of critical value. In general, the liver responds to various insults with an orchestrated healing process involving variety of signaling pathways. One such pathway is the TLR2 signaling pathway, which essentially regulates adult liver pathogenesis and thus has emerged as an attractive target to treat liver disease. TLR2 is expressed by different liver cells, including Kupffer cells (KCs), hepatocytes, and hepatic stellate cells (HSCs). From a pathologic perspective, the crosstalk between antigens and TLR2 may preferentially trigger a distinctive set of signaling mechanisms in these liver cells and, thereby, induce the production of inflammatory and fibrogenic cytokines that can initiate and prolong liver inflammation, ultimately leading to fibrosis. In this review, we summarize the currently available evidence regarding the role of TLR2 signaling in hepatic disease progression. We first elaborate its pathological involvement in liver-disease states, such as inflammation, fibrosis, and cirrhosis. We then discuss how therapeutic targeting of this pathway may help to alleviate its disease-related functioning.
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Affiliation(s)
- Anteneh Getachew
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Muzammal Hussain
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xinping Huang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yinxiong Li
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China.
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Hashmi SF, Rathore HA, Sattar MA, Johns EJ, Gan CY, Chia TY, Ahmad A. Hydrogen Sulphide Treatment Prevents Renal Ischemia-Reperfusion Injury by Inhibiting the Expression of ICAM-1 and NF-kB Concentration in Normotensive and Hypertensive Rats. Biomolecules 2021; 11:1549. [PMID: 34680182 PMCID: PMC8534271 DOI: 10.3390/biom11101549] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 01/13/2023] Open
Abstract
Our main objective was to investigate the effect of chronic administration of hydrogen sulphide donor (sodium hydrosulphide) on the expression of intercellular adhesion molecule-1 (ICAM-1) and concentration of nuclear factor-kappa B (NF-kB) in a renal ischemia-reperfusion injury (IRI) model of WKY and L-nitro-arginine-methyl-ester (L-NAME)-induced hypertensive rats. Sodium hydrosulphide (NaHS) was administered intraperitoneally (i.p.) for 35 days while cystathionine gamma lyase (CSE) inhibitor dL-propargylglycine (PAG) was administered at a single dose of 50 mg/kg. Animals were anesthetised using sodium pentobarbitone (60 mg/kg) and then prepared to induce renal ischemia by clamping the left renal artery for 30 min followed by 3 h of reperfusion. Pre-treatment with NaHS improved the renal functional parameters in both WKY and L-NAME-induced hypertensive rats along with reduction of blood pressure in hypertensive groups. Oxidative stress markers like malondialdehyde (MDA), total superoxide dismutase (T-SOD) and glutathione (GSH) were also improved by NaHS treatment following renal IRI. Levels of ICAM-1 and NF-kB concentration were reduced by chronic treatment with NaHS and increased by PAG administration after renal IRI in plasma and kidney. Treatment with NaHS improved tubular morphology and glomerulus hypertrophy. Pre-treatment with NaHS reduced the degree of renal IRI by potentiating its antioxidant and anti-inflammatory mechanism, as evidenced by decreased NF-kB concentration and downregulation of ICAM-1 expression.
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Affiliation(s)
- Syed F. Hashmi
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia; (S.F.H.); (H.A.R.); (M.A.S.)
| | - Hassaan Anwer Rathore
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia; (S.F.H.); (H.A.R.); (M.A.S.)
| | - Munavvar A. Sattar
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia; (S.F.H.); (H.A.R.); (M.A.S.)
| | - Edward J. Johns
- Department of Physiology, University College Cork, T12 K8AF Cork, Ireland;
| | - Chee-Yuen Gan
- Analytical Biochemistry Research Centre (ABrC), Universiti Sains Malaysia (USM), Lebuh Bukit Jambul, Penang 11900, Malaysia;
| | - Tan Yong Chia
- Analytical Biochemistry Research Centre (ABrC), Universiti Sains Malaysia (USM), Lebuh Bukit Jambul, Penang 11900, Malaysia;
| | - Ashfaq Ahmad
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia; (S.F.H.); (H.A.R.); (M.A.S.)
- Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 31991, Saudi Arabia
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Wang Z, Zhang X. Adenovirus vector-attributed hepatotoxicity blocks clinical application in gene therapy. Cytotherapy 2021; 23:1045-1052. [PMID: 34548241 DOI: 10.1016/j.jcyt.2021.07.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 02/07/2023]
Abstract
Adenoviruses (Ads), common self-limiting pathogens in humans and animals, usually cause conjunctivitis, mild upper respiratory tract infection or gastroenteritis in humans and hepatotoxicity syndrome in chickens and dogs, posing great threats to public health and livestock husbandry. Artificially modified Ads, which wipe out virulence-determining genes, are the most frequently used viral vectors in gene therapy, and some Ad vector (AdV)-related medicines and vaccines have been licensed and applied. Inherent liver tropism enables AdVs to specifically deliver drugs/genes to the liver; however, AdVs are closely associated with acute hepatotoxicity in immunocompromised individuals, and the side effects of AdVs, which stimulate a strong inflammatory reaction in the liver and cause acute hepatotoxicity, have largely limited clinical application. Therefore, this review systematically elucidates the intimate relationship between AdVs and hepatotoxicity in terms of virus and host and precisely illustrates the accumulated understanding in this field over the past decades. This review demonstrates the liver tropism of AdVs and molecular mechanism of AdV-induced hepatotoxicity and looks at the studies on AdV-mediated animal hepatotoxicity, which will undoubtedly deepen the understanding of AdV-caused liver injury and be of benefit in the further safe development of AdVs.
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Affiliation(s)
- Zeng Wang
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China.
| | - Xiaozhan Zhang
- College of Veterinary Medicine, Henan University of Animal Husbandry and Economy, Zhengzhou, China
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How Machine Perfusion Ameliorates Hepatic Ischaemia Reperfusion Injury. Int J Mol Sci 2021; 22:ijms22147523. [PMID: 34299142 PMCID: PMC8307386 DOI: 10.3390/ijms22147523] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 07/07/2021] [Accepted: 07/11/2021] [Indexed: 02/07/2023] Open
Abstract
The increasing disparity between the number of patients listed for transplantation and the number of suitable organs has led to the increasing use of extended criteria donors (ECDs). ECDs are at increased risk of developing ischaemia reperfusion injury and greater risk of post-transplant complications. Ischaemia reperfusion injury is a major complication of organ transplantation defined as the inflammatory changes seen following the disruption and restoration of blood flow to an organ—it is a multifactorial process with the potential to cause both local and systemic organ failure. The utilisation of machine perfusion under normothermic (37 degrees Celsius) and hypothermic (4–10 degrees Celsius) has proven to be a significant advancement in organ preservation and restoration. One of the key benefits is its ability to optimise suboptimal organs for successful transplantation. This review is focused on examining ischaemia reperfusion injury and how machine perfusion ameliorates the graft’s response to this.
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Lv S, Yu H, Liu X, Gao X. The Study on the Mechanism of Hugan Tablets in Treating Drug-Induced Liver Injury Induced by Atorvastatin. Front Pharmacol 2021; 12:683707. [PMID: 34262454 PMCID: PMC8275032 DOI: 10.3389/fphar.2021.683707] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/12/2021] [Indexed: 01/12/2023] Open
Abstract
Atorvastatin is a widely used lipid-lowering drug in the clinic. Research shows that taking long-term atorvastatin has the risk of drug-induced liver injury (DILI) in most patients. Hugan tablets, a commonly used drug for liver disease, can effectively lower transaminase and protect the liver. However, the underlying mechanism of Hugan tablets alleviating atorvastatin-induced DILI remains unclear. To address this problem, comprehensive chemical profiling and network pharmacology methods were used in the study. First, the strategy of "compound-single herb-TCM prescription" was applied to characterize the ingredients of Hugan tablets. Then, active ingredients and potential targets of Hugan tablets in DILI treatment were screened using network pharmacology, molecular docking, and literature research. In the end, the mechanism of Hugan tablets in treating atorvastatin-induced DILI was elucidated. The results showed that Hugan tablets can effectively alleviate DILI induced by atorvastatin in model rats, and 71 compounds were characterized from Hugan tablets. Based on these compounds, 271 potential targets for the treatment of DILI were predicted, and 10 key targets were chosen by characterizing protein-protein interactions. Then, 30 potential active ingredients were screened through the molecular docking with these 10 key targets, and their biological activity was explained based on literature research. Finally, the major 19 active ingredients of Hugan tablets were discovered. In addition, further enrichment analysis of 271 targets indicated that the PI3K-Akt, TNF, HIF-1, Rap1, and FoxO signaling pathways may be the primary pathways regulated by Hugan tablets in treating DILI. This study proved that Hugan tablets could alleviate atorvastatin-induced DILI through multiple components, targets, and pathways.
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Affiliation(s)
| | | | | | - Xiaoyan Gao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Baseline Values and Kinetics of IL-6, Procalcitonin, and TNF- α in Landrace-Large White Swine Anesthetized with Propofol-Based Total Intravenous Anesthesia. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6672573. [PMID: 34250089 PMCID: PMC8238574 DOI: 10.1155/2021/6672573] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 05/01/2021] [Accepted: 05/22/2021] [Indexed: 01/01/2023]
Abstract
The baseline levels of various inflammatory mediators and their changes during anesthesia in swine are not known. The aim of this animal study was to measure the baseline values and kinetics of interleukin-6, procalcitonin, and tumor necrosis factor-alpha in healthy Landrace-Large White swine anesthetized with propofol-based total intravenous anesthesia. We included 8 healthy male pigs with an average weight of 19 ± 2 kg (aged 10-15 weeks) that were subjected to propofol-based total intravenous anesthesia for 8 hours. Complete blood count, serum chemistry, and serum levels of interleukin-6, procalcitonin, and tumor necrosis factor-alpha were analyzed, and serum levels were quantified hourly. Blood was also collected for bacterial culturing. Baseline values of interleukin-6 and procalcitonin were 18 pg/ml and 21 ng/ml, respectively, while tumor necrosis factor-alpha was not detectable during collection of baseline samples. A statistically significant difference was observed in interleukin-6 levels between time points (p < 0.0001). Procalcitonin increased with time, but there were no significant differences between time points (p = 0.152). Tumor necrosis factor-alpha increased until the 3rd hour of propofol-based total intravenous anesthesia, while after the 4th hour, it gradually decreased, reaching its baseline undetectable values by the 7th hour (p < 0.001). Our results can serve as the basis for further translational research.
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Guan Y, Yao W, Yi K, Zheng C, Lv S, Tao Y, Hei Z, Li M. Nanotheranostics for the Management of Hepatic Ischemia-Reperfusion Injury. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2021; 17:e2007727. [PMID: 33852769 DOI: 10.1002/smll.202007727] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/21/2021] [Indexed: 06/12/2023]
Abstract
Hepatic ischemia-reperfusion injury (IRI), in which an insufficient oxygen supply followed by reperfusion leads to an inflammatory network and oxidative stress in disease tissue to cause cell death, always occurs after liver transplantations and sections. Although pharmacological treatments favorably prevent or protect the liver against experimental IRI, there have been few successes in clinical applications for patient benefits because of the incomprehension of complicated IRI-induced signaling events as well as short blood circulation time, poor solubility, and severe side reactions of most antioxidants and anti-inflammatory drugs. Nanomaterials can achieve targeted delivery and controllable release of contrast agents and therapeutic drugs in desired hepatic IRI regions for enhanced imaging sensitivity and improved therapeutic effects, emerging as novel alternative approaches for hepatic IRI diagnosis and therapy. In this review, the application of nanotechnology is summarized in the management of hepatic IRI, including nanomaterial-assisted hepatic IRI diagnosis, nanoparticulate systems-mediated remission of reactive oxygen species-induced tissue injury, and nanoparticle-based targeted drug delivery systems for the alleviation of IRI-related inflammation. The current challenges and future perspectives of these nanoenabled strategies for hepatic IRI treatment are also discussed.
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Affiliation(s)
- Yu Guan
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Weifeng Yao
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Ke Yi
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Chunxiong Zheng
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, China
| | - Shixian Lv
- Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, China
| | - Ziqing Hei
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, China
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Zhou H, Xu J, Huang S, He Y, He X, Guo L, Yin S, Lu S. Blocking the Hepatic Branch of the Vagus Aggravates Hepatic Ischemia-Reperfusion Injury via Inhibiting the Expression of IL-22 in the Liver. J Immunol Res 2021; 2021:6666428. [PMID: 34514001 PMCID: PMC8429033 DOI: 10.1155/2021/6666428] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/20/2021] [Accepted: 04/27/2021] [Indexed: 12/02/2022] Open
Abstract
Liver ischemia-reperfusion injury (IRI) is an inevitable process during liver transplantation, hemorrhagic shock, resection, and other liver surgeries. It is an important cause of postoperative liver dysfunction and increased medical costs. The protective effects of the vagus nerve on hepatic IRI have been reported, but the underlying mechanism has not been fully understood. We established a hepatic vagotomy (Hv) mouse model to study the effect of the vagus on liver IRI and to explore the underlying mechanism. Liver IRI was more serious in mice with Hv, which showed higher serum ALT and AST activities and histopathological changes. Further experiments confirmed that Hv significantly downregulated the expression of IL-22 protein and mRNA in the liver, blocking the activation of the STAT3 pathway. The STAT3 pathway in the livers of Hv mice was significantly activated, and liver injury was clearly alleviated after treatment with exogenous IL-22 recombinant protein. In conclusion, Hv can aggravate hepatic IRI, and its mechanism may be related to inhibition of IL-22 expression and downregulation of the STAT3 pathway in the liver.
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Affiliation(s)
- Heng Zhou
- Department of Pharmacy, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, China
| | - Juling Xu
- Medical School of Huzhou University, Huzhou 313000, China
| | - Sanxiong Huang
- Department of Hepatobiliary Surgery, The First People's Hospital of Huzhou, Huzhou 313000, China
| | - Ying He
- Zhejiang Provincial Key Laboratory of Media Biology and Pathogenic Control, Central Laboratory, First Affiliated Hospital of Huzhou University, Huzhou 313000, China
| | - Xiaowei He
- Department of Pharmacy, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, China
| | - Lu Guo
- Department of Pharmacy, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, China
| | - Shi Yin
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Sheng Lu
- Department of Pharmacy, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, China
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Frissen M, Liao L, Schneider KM, Djudjaj S, Haybaeck J, Wree A, Rolle-Kampczyk U, von Bergen M, Latz E, Boor P, Trautwein C. Bidirectional Role of NLRP3 During Acute and Chronic Cholestatic Liver Injury. Hepatology 2021; 73:1836-1854. [PMID: 32748971 DOI: 10.1002/hep.31494] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 05/29/2020] [Accepted: 06/08/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Cholestatic liver injury leads to cell death and subsequent inflammation and fibrosis. As shown for primary biliary cholangitis (PBC), the mechanisms and circuits between different cell death pathways leading to disease progression are incompletely defined. Common bile duct ligation (BDL) is a well-established murine model to mimic cholestatic liver injury. Here, we hypothesized that pyroptotic cell death by the Nucleotide-Binding Domain, Leucine-Rich-Containing Family, Pyrin Domain-Containing-3 (Nlrp3) inflammasome plays an essential role during human and murine cholestasis. APPROACH AND RESULTS NLRP3 activation was analyzed in humans with cholestatic liver injury. Wild-type (WT) and Nlrp3-/- mice were subjected to BDL for 2 or 28 days. Chronic cholestasis in humans and mice is associated with NLRP3 activation and correlates with disease activity. Acute BDL in Nlrp3-deficient mice triggered increased inflammation as well as liver injury, associated with stronger apoptotic and necroptotic cell death. In contrast, NLRP3 deletion led to decreased liver injury and inflammation in chronic cholestasis. Moreover, bridging fibrosis was observed in WT, but not in NLRP3 knockout, mice 28 days after BDL. In contrast, lack of NLRP3 expression attenuated kidney injury and fibrosis after acute and chronic BDL. Importantly, administration of MCC950, an NLRP3 small molecule inhibitor, reduced BDL-induced disease progression in WT mice. CONCLUSIONS NLRP3 activation correlates with disease activity in patients with PBC. NLRP3 has a differential role during acute and chronic cholestatic liver injury in contrast to kidney injury. Disease progression during chronic cholestasis can be targeted through small molecules and thus suggests a potential clinical benefit for humans, attenuating liver and kidney injury.
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Affiliation(s)
- Mick Frissen
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Lijun Liao
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Kai Markus Schneider
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Sonja Djudjaj
- Institute of Pathology, RWTH Aachen University, Aachen, Germany
| | - Johannes Haybaeck
- Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, Graz, Austria.,Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.,Department of Pathology, Neuropathology, and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexander Wree
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulrike Rolle-Kampczyk
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Eicke Latz
- Institute for Innate Immunity, University Clinic Bonn, Bonn, Germany
| | - Peter Boor
- Institute of Pathology, RWTH Aachen University, Aachen, Germany.,Department of Nephrology and Immunology, RWTH Aachen University, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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Gerussi A, Natalini A, Antonangeli F, Mancuso C, Agostinetto E, Barisani D, Di Rosa F, Andrade R, Invernizzi P. Immune-Mediated Drug-Induced Liver Injury: Immunogenetics and Experimental Models. Int J Mol Sci 2021; 22:4557. [PMID: 33925355 PMCID: PMC8123708 DOI: 10.3390/ijms22094557] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI) is a challenging clinical event in medicine, particularly because of its ability to present with a variety of phenotypes including that of autoimmune hepatitis or other immune mediated liver injuries. Limited diagnostic and therapeutic tools are available, mostly because its pathogenesis has remained poorly understood for decades. The recent scientific and technological advancements in genomics and immunology are paving the way for a better understanding of the molecular aspects of DILI. This review provides an updated overview of the genetic predisposition and immunological mechanisms behind the pathogenesis of DILI and presents the state-of-the-art experimental models to study DILI at the pre-clinical level.
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Affiliation(s)
- Alessio Gerussi
- Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (C.M.); (D.B.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Ambra Natalini
- Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), 00185 Rome, Italy; (A.N.); (F.A.); (F.D.R.)
| | - Fabrizio Antonangeli
- Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), 00185 Rome, Italy; (A.N.); (F.A.); (F.D.R.)
| | - Clara Mancuso
- Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (C.M.); (D.B.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Elisa Agostinetto
- Academic Trials Promoting Team, Institut Jules Bordet, L’Universite’ Libre de Bruxelles (ULB), 1050 Brussels, Belgium;
- Medical Oncology and Hematology Unit, Humanitas Clinical and Research Center—IRCCS, Humanitas Cancer Center, Rozzano, 20089 Milan, Italy
- Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, Pieve Emanuele, 20090 Milan, Italy
| | - Donatella Barisani
- Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (C.M.); (D.B.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Francesca Di Rosa
- Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), 00185 Rome, Italy; (A.N.); (F.A.); (F.D.R.)
| | - Raul Andrade
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), UGC Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29016 Málaga, Spain;
| | - Pietro Invernizzi
- Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (C.M.); (D.B.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
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