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Gurel M, Zomer H, McFetridge C, Murfee WL, McFetridge PS. Physiologically-Modeled Dynamic Stimulation and Growth Factors Induce Differentiation of Mesenchymal Stem Cells to a Vascular Endothelial Cell Phenotype. Microcirculation 2025; 32:e70007. [PMID: 40120632 PMCID: PMC12012511 DOI: 10.1111/micc.70007] [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: 08/13/2024] [Revised: 03/04/2025] [Accepted: 03/14/2025] [Indexed: 03/25/2025]
Abstract
OBJECTIVE Mesenchymal stem cells (MSCs) represent an attractive option as an endothelial cell (EC) source for regenerative medicine therapies. However, the differentiation of MSCs toward an ECs phenotype can be regulated by a complex and dynamic microenvironment, including specific growth factors as well as local mechanical cues. The objective of this work was to evaluate whether Physiologically-modeled dynamic stimulation (PMDS) characterized by continuous variability in pulse frequencies mimicking the dynamic temporal range of cardiac function would enhance MSC differentiation toward ECs compared to a constant frequency stimulation. METHODS Mesenchymal stem cells were grown in a complex growth factor cocktail versus standard culture media to initiate the endothelial differentiation process, then subsequently exposed to PMDS that vary in duration and constant flow (CF) at a fixed 10 dynes/cm2 shear stress and 1.3 Hz frequency. RESULTS Both PMDS and media type strongly influence cell differentiation and function. Cells were shown to significantly upregulate eNOS activity and displayed lower TNF-a induced leukocyte adhesion compared to cells cultured under CF, consistent with a more quiescent ECs phenotype that regulates anti-inflammatory and anti-thrombotic states. CONCLUSION These findings suggest that the dynamic microenvironment created by perfusion, in contrast to constant frequency, combined with growth factors, enhances MSCs differentiation toward a vascular endothelial-like phenotype.
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Affiliation(s)
- Mediha Gurel
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
- Biotechnology Research and Application Center, Cukurova University, Adana, Turkey
- Electronic and Automation Department, Bitlis Eren University, Bitlis, Turkey
| | - Helena Zomer
- Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA
| | - Calum McFetridge
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Walter L Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Peter S McFetridge
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
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Shi L, Chen H, Zhang Y, An D, Qin M, Yu W, Wen B, He D, Hao H, Xiong J. SLC13A2 promotes hepatocyte metabolic remodeling and liver regeneration by enhancing de novo cholesterol biosynthesis. EMBO J 2025; 44:1442-1463. [PMID: 39824985 PMCID: PMC11876347 DOI: 10.1038/s44318-025-00362-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 12/06/2024] [Accepted: 12/11/2024] [Indexed: 01/20/2025] Open
Abstract
Metabolic requirements of dividing hepatocytes are prerequisite for liver regeneration after injury. In contrast to transcriptional dynamics during liver repair, its metabolic dependencies remain poorly defined. Here, we screened metabolic genes differentially regulated during liver regeneration, and report that SLC13A2, a transporter for TCA cycle intermediates, is decreased in rapid response to partial hepatectomy in mice and recovered along restoration of liver mass and function. Liver-specific overexpression or depletion of SLC13A2 promoted or attenuated liver regeneration, respectively. SLC13A2 increased cleavage of SREBP2, and expression of cholesterol metabolism genes, including LDLR and HMGCR. Mechanistically, SLC13A2 promotes import of citrate into hepatocytes, serving as building block for ACLY-dependent acetyl-CoA formation and de novo synthesis of cholesterol. In line, the pre-administration of the HMGCR inhibitor lovastatin abolished SLC13A2-mediated liver regeneration. Similarly, ACLY inhibition suppressed SLC13A2-promoted cholesterol synthesis for hepatocellular proliferation and liver regeneration in vivo. In sum, this study demonstrates that citrate transported by SLC13A2 acts as an intermediate metabolite to restore the metabolic homeostasis during liver regeneration, suggesting SLC13A2 as a potential drug target after liver damage.
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Affiliation(s)
- Li Shi
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China
| | - Hao Chen
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China
| | - Yuxin Zhang
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China
| | - Donghao An
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China
| | - Mengyao Qin
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China
| | - Wanting Yu
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China
| | - Bin Wen
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China
| | - Dandan He
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China
| | - Haiping Hao
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.
| | - Jing Xiong
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.
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Ortega-Ribera M, Zhuang Y, Brezani V, Joshi RS, Zsengeller Z, Nagesh PT, Datta A, Szabo G. Gasdermin D deletion prevents liver injury and exacerbates extrahepatic damage in a murine model of alcohol-induced ACLF. EGASTROENTEROLOGY 2025; 3:e100151. [PMID: 40134717 PMCID: PMC11934631 DOI: 10.1136/egastro-2024-100151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 02/27/2025] [Indexed: 03/27/2025]
Abstract
Background Gasdermin D (GSDM-D), a key executor of pyroptosis, is increased in various liver diseases and contributes to disease progression. Alcohol induces inflammasome activation and cell death, which are both linked to GSDM-D activation. However, its role in alcohol-induced acute-on-chronic liver failure (ACLF) remains unclear. Methods ACLF was induced in GSDM-D-deficient or wild-type (WT) mice by 28-day bile duct ligation surgery plus a single 5 g/kg alcohol binge leading to acute decompensation. Nine hours after the alcohol binge, blood, liver, kidney and cerebellum specimens were collected for analysis. Results Active GSDM-D was significantly increased in humans and mice ACLF livers compared with both healthy controls and cirrhotic livers. GSDM-D-deficient mice with ACLF showed decreased inflammation, neutrophil infiltration and fibrosis in the liver, together with a reduction in pyroptotic, apoptotic and necroptotic death, compared with WT ACLF mice. Notably, GSDM-D-deficient mice also showed decreased liver regeneration and hepatocyte function. This was associated with an increase in senescence and expression of stem-like/cholangiocyte markers in the liver. Interestingly, in the kidney, GSDM-D-deficient mice showed an increase in histopathological damage score, decreased function and increased expression of necroptosis-related genes. In the cerebellum, GSDM-D deficiency increased the expression of neuroinflammation markers, astrocyte activation and apoptosis-related genes. Conclusion Our data indicate that GSDM-D deficiency has organ-specific effects in ACLF. While it reduces inflammation, neutrophil activation, cell death and fibrosis in the liver, GSDM-D deficiency impairs the synthetic function and increases senescence in hepatocytes. GSDM-D deficiency also increases kidney injury and neuroinflammation in ACLF.
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Affiliation(s)
- Martí Ortega-Ribera
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Yuan Zhuang
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Veronika Brezani
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Radhika S Joshi
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Zsuzsanna Zsengeller
- Department of Medicine, Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Prashanth Thevkar Nagesh
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Aditi Datta
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Gyongyi Szabo
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute, Cambridge, Massachusetts, USA
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Zhang S, Yu M, Wang F, Li S, Li X, Hu H, Zhang Z, Zhu X, Tian W. Salidroside promotes liver regeneration after partial hepatectomy in mice by modulating NLRP3 inflammasome-mediated pyroptosis pathway. Biochem Biophys Res Commun 2024; 735:150678. [PMID: 39270555 DOI: 10.1016/j.bbrc.2024.150678] [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: 05/14/2024] [Revised: 07/26/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024]
Abstract
Insufficient residual liver tissue after partial hepatectomy (PH) may lead to serious complications such as hepatic failure and small-for-size syndrome. Salidroside (SAL) is obtained from Rhodiola rosea through modernized separation and extraction and has been validated for treating various liver diseases. It's yet unknown, nevertheless, how SAL affects liver regeneration after PH. This study aimed to determine whether SAL could promote liver regeneration after PH in mice. We demonstrated that SAL could attenuate liver injury after PH and promote hepatocyte proliferation and liver mass recovery. Mechanistically, SAL inhibited the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, attenuating pyroptosis. RNA-seq analysis indicated that SAL downregulated the transcription of NLRP3 and GSDMD genes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the NOD-like receptor signaling pathway was significantly enriched in down-regulated signaling pathways. Notably, SAL in combination with the NLRP3 inhibitor MCC950 did not further inhibit NLRP3 inflammasome and promote liver mass recovery. In summary, our findings proved that SAL could be a potential agent for improving liver function and promoting liver regeneration after PH.
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Affiliation(s)
- Saiya Zhang
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Meilu Yu
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Fen Wang
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Sha Li
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Xuefei Li
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Hongyu Hu
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Zhen Zhang
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Xiangpeng Zhu
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Weiqian Tian
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China.
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Huang C, Gan J, Mo X, Li Q, Liao L, Wang B, Wu X, Liang H, Xie C, Peng T, Lei Y, Zhuang B, Zeng M, Peng Y, Chen Y, Liu C, Zhou J, Wang K, Li C. Accumulation of polyunsaturated lipids fuels ferroptosis to promote liver failure after extended hepatectomy in mice. Free Radic Res 2024; 58:733-747. [PMID: 39514464 DOI: 10.1080/10715762.2024.2423691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 09/07/2024] [Accepted: 10/19/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Post-hepatectomy liver failure (PHLF) is a fatal complication of hepatectomy. However, the mechanism of hepatocyte injury in PHLF remains elusive. METHODS PHLF was induced by extended 86% hepatectomy (eHx) in mice. Lipidomics was performed to investigate the eHx-induced lipid alteration in the residual liver. Ferroptosis was assessed to screen the hepatocyte injury induced by eHx. The therapeutic effects of ferrostatin-1 (Fer-1) on PHLF were evaluated. RESULTS PHLF was induced by eHx with elevation in markers of hepatocyte injury and mortality in mice within 48 h after surgery. eHx-induced hepatocyte injury was manifested by hepatocyte enlargement and hepatocyte death with glycogen depletion and lipid accumulation. Lipidomics revealed that eHx induced the accumulation of ferroptosis-favored polyunsaturated lipids. Ferroptosis was found to mediate the eHx-induced hepatocyte death in the residual liver during the development of PHLF. Fer-1 could attenuate the eHx-induced ferroptotic hepatocyte death and PHLF in mice. CONCLUSIONS Ferroptosis partly mediates the eHx-induced hepatocyte injury during the development of PHLF. Accumulation of polyunsaturated lipids in hepatocytes may promote eHx-induced ferroptosis, and targeting lipid peroxidation is a potential therapeutic strategy for PHLF.
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Affiliation(s)
- Can Huang
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Gan
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiangyue Mo
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qingping Li
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Leyi Liao
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Biao Wang
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xianqiu Wu
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hanbiao Liang
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chen Xie
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tianzhou Peng
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Lei
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Baoxiong Zhuang
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Minghui Zeng
- Institute of Scientific Research, Southern Medical University, Guangzhou, China
| | - Yonghong Peng
- Central Laboratory, Southern Medical University, Guangzhou, China
| | - Yisi Chen
- Central Laboratory, Southern Medical University, Guangzhou, China
| | - Cuiting Liu
- Central Laboratory, Southern Medical University, Guangzhou, China
| | - Jie Zhou
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kai Wang
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chuanjiang Li
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Wen GL, Wang JL. Combined preoperative albumin bilirubin score and hepatectomy percentage for evaluate the liver regeneration after partial hepatectomy. World J Gastroenterol 2024; 30:4376-4379. [PMID: 39494096 PMCID: PMC11525867 DOI: 10.3748/wjg.v30.i40.4376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 09/13/2024] [Accepted: 09/27/2024] [Indexed: 10/16/2024] Open
Abstract
Surgical resection is a pivotal therapeutic approach for addressing hepatic space-occupying lesions, with liver volume restoration and hepatic functional recovery being crucial for assessing surgical prognosis. The preoperative albumin-bilirubin (ALBI) score, encompassing serum albumin and bilirubin levels, can be determined via blood analysis, effectively mitigating human error and providing an accurate depiction of liver function. The hepatectomy ratio, which is the proportion of the liver volume removed to the total liver volume, is critical in preserving an adequate liver tissue volume to ensure postoperative hepatic functional compensation, minimize surgical complications, and reduce mortality rates. Incorporating the preoperative ALBI score and hepatectomy ratio aids surgeons in assessing the optimal timing and extent of partial hepatectomy. The introduction of preoperative albumin bilirubin score and hepatectomy percentage is beneficial for the surgeons to evaluate the timing and magnitude of partial liver resection.
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Affiliation(s)
- Gao-Lin Wen
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University of Chinese Medicine, Nanjing 210008, Jiangsu Province, China
| | - Jing-Lin Wang
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Nanjing 210008, Jiangsu Province, China
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Hayıroğlu Mİ, Altay S. Overlap Between Nutritional Indices in Patients with Acute Coronary Syndrome: A Focus on Albumin. Balkan Med J 2024; 41:324-325. [PMID: 39086257 PMCID: PMC11588916 DOI: 10.4274/balkanmedj.galenos.2024.190724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2024] Open
Affiliation(s)
- Mert İlker Hayıroğlu
- Department of Cardiology University of Health Sciences Türkiye, Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, İstanbul, Türkiye
| | - Servet Altay
- Department of Cardiology Trakya University Faculty of Medicine, Edirne, Türkiye
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8
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Cheng CK, Yi M, Wang L, Huang Y. Role of gasdermin D in inflammatory diseases: from mechanism to therapeutics. Front Immunol 2024; 15:1456244. [PMID: 39253076 PMCID: PMC11381298 DOI: 10.3389/fimmu.2024.1456244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 08/08/2024] [Indexed: 09/11/2024] Open
Abstract
Inflammatory diseases compromise a clinically common and diverse group of conditions, causing detrimental effects on body functions. Gasdermins (GSDM) are pore-forming proteins, playing pivotal roles in modulating inflammation. Belonging to the GSDM family, gasdermin D (GSDMD) actively mediates the pathogenesis of inflammatory diseases by mechanistically regulating different forms of cell death, particularly pyroptosis, and cytokine release, in an inflammasome-dependent manner. Aberrant activation of GSDMD in different types of cells, such as immune cells, cardiovascular cells, pancreatic cells and hepatocytes, critically contributes to the persistent inflammation in different tissues and organs. The contributory role of GSDMD has been implicated in diabetes mellitus, liver diseases, cardiovascular diseases, neurodegenerative diseases, and inflammatory bowel disease (IBD). Clinically, alterations in GSDMD levels are potentially indicative to the occurrence and severity of diseases. GSDMD inhibition might represent an attractive therapeutic direction to counteract the progression of inflammatory diseases, whereas a number of GSDMD inhibitors have been shown to restrain GSDMD-mediated pyroptosis through different mechanisms. This review discusses the current understanding and future perspectives on the role of GSDMD in the development of inflammatory diseases, as well as the clinical insights of GSDMD alterations, and therapeutic potential of GSDMD inhibitors against inflammatory diseases. Further investigation on the comprehensive role of GSDM shall deepen our understanding towards inflammation, opening up more diagnostic and therapeutic opportunities against inflammatory diseases.
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Affiliation(s)
- Chak Kwong Cheng
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Min Yi
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR, China
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9
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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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10
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Yuan X, Chen P, Luan X, Yu C, Miao L, Zuo Y, Liu A, Sun T, Di G. NLRP3 deficiency protects against acetaminophen‑induced liver injury by inhibiting hepatocyte pyroptosis. Mol Med Rep 2024; 29:61. [PMID: 38391117 PMCID: PMC10902631 DOI: 10.3892/mmr.2024.13185] [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: 09/22/2023] [Accepted: 01/23/2024] [Indexed: 02/24/2024] Open
Abstract
Acetaminophen (APAP) overdose is the primary cause of drug‑induced acute liver failure in numerous Western countries. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation serves a pivotal role in the pathogenesis of various forms of acute liver injury. However, the cellular source for NLRP3 induction and its involvement during APAP‑induced hepatotoxicity have not been thoroughly investigated. In the present study, hematoxylin and eosin staining was performed to assess histopathological changes of liver tissue. Immunohistochemistry staining(NLRP3, Caspase‑1, IL‑1β, GSDMD and Caspase‑3), western blotting (NLRP3, Caspase‑1, IL‑1β, GSDMD and Caspase‑3) and RT‑qPCR (NLRP3, Caspase‑1 and IL‑1β) were performed to assess the expression of NLRP3/GSDMD signaling pathway. TUNEL staining was performed to assess apoptosis of liver tissue. The serum expression levels of inflammatory factors (IL‑6, IL‑18, IL‑1β and TNF‑α) were assessed using ELISA and inflammation of liver tissue was assessed using immunohistochemistry (Ly6G and CD68) and RT‑qPCR (TNF‑α, Il‑6, Mcp‑1, Cxcl‑1, Cxcl‑2). A Cell Counting Kit‑8 was performed to assess cell viability and apoptosis. Protein and gene expression were analyzed by western blotting (PCNA, CCND1) and RT‑qPCR (CyclinA2, CyclinD1 and CyclinE1). Through investigation of an APAP‑induced acute liver injury model (AILI), the present study demonstrated that APAP overdose induced activation of NLRP3 and cleavage of gasdermin D (GSDMD) in hepatocytes, both in vivo and in vitro. Additionally, mice with hepatocyte‑specific knockout of Nlrp3 exhibited reduced liver injury and lower mortality following APAP intervention, accompanied by decreased infiltration of inflammatory cells and attenuated inflammatory response. Furthermore, pharmacological blockade of NLRP3/GSDMD signaling using MCC950 or disulfiram significantly ameliorated liver injury and reduced hepatocyte death. Notably, hepatocyte Nlrp3 deficiency promoted liver recovery by enhancing hepatocyte proliferation. Collectively, the present study demonstrated that inhibition of the NLRP3 inflammasome protects against APAP‑induced acute liver injury by reducing hepatocyte pyroptosis and suggests that targeting NLRP3 may hold therapeutic potential for treating AILI.
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Affiliation(s)
- Xinying Yuan
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Peng Chen
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
- Institute of Stem Cell and Regenerative Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xiaoyu Luan
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Chaoqun Yu
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Longyu Miao
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Yaru Zuo
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Anxu Liu
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Tianyi Sun
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Guohu Di
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
- Institute of Stem Cell and Regenerative Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
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11
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Zhang C, Sun C, Zhao Y, Ye B, Yu G. Signaling pathways of liver regeneration: Biological mechanisms and implications. iScience 2024; 27:108683. [PMID: 38155779 PMCID: PMC10753089 DOI: 10.1016/j.isci.2023.108683] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2023] Open
Abstract
The liver possesses a unique regenerative ability to restore its original mass, in this regard, partial hepatectomy (PHx) and partial liver transplantation (PLTx) can be executed smoothly and safely, which has important implications for the treatment of liver disease. Liver regeneration (LR) can be the very complicated procedure that involves multiple cytokines and transcription factors that interact with each other to activate different signaling pathways. Activation of these pathways can drive the LR process, which can be divided into three stages, namely, the initiation, progression, and termination stages. Therefore, it is important to investigate the pathways involved in LR to elucidate the mechanism of LR. This study reviews the latest research on the key signaling pathways in the different stages of LR.
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Affiliation(s)
- Chunyan Zhang
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Caifang Sun
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Yabin Zhao
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Bingyu Ye
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - GuoYing Yu
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
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12
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Mulla J, Katti R, Scott MJ. The Role of Gasdermin-D-Mediated Pyroptosis in Organ Injury and Its Therapeutic Implications. Organogenesis 2023; 19:2177484. [PMID: 36967609 PMCID: PMC9980590 DOI: 10.1080/15476278.2023.2177484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 02/03/2023] [Indexed: 02/25/2023] Open
Abstract
Gasdermin-D (GSDMD) belongs to the Gasdermin family (GSDM), which are pore-forming effector proteins that facilitate inflammatory cell death, also known as pyroptosis. This type of programmed cell death is dependent on inflammatory caspase activation, which cleaves gasdermin-D (GSDMD) to form membrane pores and initiates the release of pro-inflammatory cytokines. Pyroptosis plays an important role in achieving immune regulation and homeostasis within various organ systems. The role of GSDMD in pyroptosis has been extensively studied in recent years. In this review, we summarize the role of GSDMD in cellular and organ injury mediated by pyroptosis. We will also provide an outlook on GSDMD therapeutic targets in various organ systems.
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Affiliation(s)
- Joud Mulla
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Rohan Katti
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Melanie J. Scott
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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13
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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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14
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Chen S, Gong Y, Li S, Yang D, Zhang Y, Liu Q. Hydra gasdermin-gated pyroptosis signalling regulates tissue regeneration. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 149:104904. [PMID: 37543221 DOI: 10.1016/j.dci.2023.104904] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/02/2023] [Accepted: 08/02/2023] [Indexed: 08/07/2023]
Abstract
Pyroptosis, an inflammatory form of programmed cell death, is directly executed by gasdermin (GSDM) depending on its N-terminal pore-forming fragment-mediated membrane-disrupting, triggering intracellular contents release, which plays important roles in mammalian anti-infection and anti-tumor immune responses. However, whether pyroptosis engages in the regulation of tissue regeneration remains largely unknown. Here, utilizing Hydra vulgaris as the research model, we found that an HyCARD2-HyGSDME-mediated pyroptosis signalling is activated in both head and foot regenerated tips after amputation. Impeding pyroptosis by knocking down the expression of either HyGSDME or HyCARD2 significantly hampered both head and foot regeneration in Hydra. Mechanistically, the activation of HyCARD2-HyGSDME axis at wound sites is dependent of intracellular mitochondrial reactive oxygen species (mtROS), the removing of which hindered Hydra head regeneration. Moreover, the HyCARD2-HyGSDME axis-gated pyroptosis was found to enhance the initial secretion and upregulated expression of Wnt3. Collectively, these findings indicate that gasdermin-gated pyroptosis is critical for the evoking of Wnt signalling to facilitate Hydra tissue regeneration, which provides insights into functional diversification within the gasdermin family in the animal kingdom.
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Affiliation(s)
- Shouwen Chen
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, East China University of Science and Technology, Shanghai, 200237, China
| | - Yuxin Gong
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, East China University of Science and Technology, Shanghai, 200237, China
| | - Shuxin Li
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, East China University of Science and Technology, Shanghai, 200237, China
| | - Dahai Yang
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, East China University of Science and Technology, Shanghai, 200237, China
| | - Yuanxing Zhang
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, 519000, China; Shanghai Engineering Research Center of Marine Cultured Animal Vaccines, Shanghai, 200237, China
| | - Qin Liu
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, East China University of Science and Technology, Shanghai, 200237, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, 519000, China; Shanghai Engineering Research Center of Marine Cultured Animal Vaccines, Shanghai, 200237, China.
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15
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Lv X, Lin Y, Zhu X, Cai X. Isoalantolactone suppresses gallbladder cancer progression via inhibiting the ERK signalling pathway. PHARMACEUTICAL BIOLOGY 2023; 61:556-567. [PMID: 36994917 PMCID: PMC10064832 DOI: 10.1080/13880209.2023.2191645] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 03/09/2023] [Accepted: 03/12/2023] [Indexed: 06/19/2023]
Abstract
CONTEXT Gallbladder cancer (GBC) is the most common malignant tumour of the biliary tract. Isoalantolactone (IAL), an active sesquiterpene lactone compound isolated from the roots of Inula helenium L. (Asteraceae), has antitumour effects. OBJECTIVE This study investigates the effects of IAL on GBC. MATERIALS AND METHODS In vitro, NOZ and GBC-SD cells were treated with IAL (0, 10, 20 and 40 μM) for 24 h. The DMSO-treated cells were selected as a control. Cell proliferation, migration, invasion and apoptosis were measured by the CCK-8 assay, transwell assay, flow cytometry and western blot. In vivo, subcutaneous tumour xenografts were constructed by injecting nude mice (BALB/C) with 5 × 106 NOZ cells. Mice were divided into the control group (equal amount of DMSO), the IAL group (10 mg/kg/day) and the IAL + Ro 67-7476 group (IAL, 10 mg/kg/day; Ro 67-7476, 4 mg/kg/day). The study duration was 30 days. RESULTS Compared with the DMSO group, cell proliferation of NOZ (IC50 15.98 μM) and GBC-SD (IC50 20.22 μM) was inhibited by about 70% in the IAL 40 μM group. Migration and invasion were suppressed by about 80%. Cell apoptosis rate was increased about three-fold. The phosphorylation level of ERK was decreased to 30-35%. Tumour volume and weight (about 80% reduction) were suppressed by IAL in vivo. Moreover, the effects of IAL were abolished by Ro 67-7476 in vitro and in vivo. DISCUSSION AND CONCLUSIONS Our findings indicate that IAL could inhibit GBC progression in vitro and in vivo by inhibiting the ERK signalling pathway.
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Affiliation(s)
- Xingyu Lv
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuqi Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xi Zhu
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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16
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Chen Y, Li P, Chen T, Liu H, Wang P, Dai X, Zou Q. Ronidazole Is a Superior Prodrug to Metronidazole for Nitroreductase-Mediated Hepatocytes Ablation in Zebrafish Larvae. Zebrafish 2023. [PMID: 37229597 DOI: 10.1089/zeb.2022.0066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2023] Open
Abstract
The liver plays a very important role in physiological processes of the human body. Liver regeneration has developed into an important area of study in liver disease. The Mtz (metronidazole)/NTR (nitroreductase)-mediated cell ablation system has been widely used to study the processes and mechanisms of liver injury and regeneration. However, high concentrations and toxic side effects of Mtz severely limit the application of the Mtz/NTR system. Therefore, screening new analogs to replace Mtz has become an important means to optimize the NTR ablation system. In this study, we screened five Mtz analogs including furazolidone, ronidazole, ornidazole, nitromide, and tinidazole. We compared their toxicity on the transgenic fish line Tg(fabp10a: mCherry-NTR) and their specific ablation ability on liver cells. The results showed that Ronidazole at a lower concentration (2 mM) had the same ability to ablate liver cells comparable with that of Mtz (10 mM), almost without toxic side effects on juvenile fish. Further study found that zebrafish hepatocyte injury caused by the Ronidazole/NTR system achieved the same liver regenerative effect as the Mtz/NTR system. The above results show that Ronidazole can replace Mtz with NTR to achieve superior damage and ablation effects in zebrafish liver.
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Affiliation(s)
- Yuhang Chen
- Schools of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Peipei Li
- Schools of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Ting Chen
- Schools of Biosciences and Technology, Chengdu Medical College, Chengdu, China
| | - Hanjie Liu
- Schools of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Peijian Wang
- Department of Cardiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
- Key Laboratory of Aging and Vascular Homeostasis of Sichuan Higher Education Institutes, Chengdu, China
| | - Xiaozhen Dai
- Schools of Biosciences and Technology, Chengdu Medical College, Chengdu, China
| | - Qingliang Zou
- Department of Cardiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
- Key Laboratory of Aging and Vascular Homeostasis of Sichuan Higher Education Institutes, Chengdu, China
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