S-Adenosylmethionine Inhibits Plasminogen-Activating Inhibitor-1 and Protects Male Mice from FOLFOX-Induced Liver InjurySummary
Background & Aims: FOLFOX, often used in patients with colorectal liver metastases, can cause sinusoidal obstruction syndrome (SOS) hindering subsequent treatment. S-adenosylmethionine (SAMe) is hepatoprotective and here we investigated whether it protects against FOLFOX-induced hepatotoxici...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X25000542 |
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| author | Alexandra Gangi Tony W.H. Li Youngyi Lim Swati Chandla Andrea Floris Arash Khangholi Maria Lauda Tomasi Shelly C. Lu |
| author_facet | Alexandra Gangi Tony W.H. Li Youngyi Lim Swati Chandla Andrea Floris Arash Khangholi Maria Lauda Tomasi Shelly C. Lu |
| author_sort | Alexandra Gangi |
| collection | DOAJ |
| description | Background & Aims: FOLFOX, often used in patients with colorectal liver metastases, can cause sinusoidal obstruction syndrome (SOS) hindering subsequent treatment. S-adenosylmethionine (SAMe) is hepatoprotective and here we investigated whether it protects against FOLFOX-induced hepatotoxicity and defined the underlying mechanisms. Methods: A murine model of FOLFOX-induced SOS examined the effect of SAMe and plasminogen-activating inhibitor-1 (PAI-1). In vitro studies included primary mouse and human hepatocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal endothelial cells. Results: SAMe cotreatment completely blocked the induction of markers increased in FOLFOX-induced SOS and protected against liver injury. The most up-regulated gene was Serpine1, which encodes for PAI-1. SAMe blocked FOLFOX-induced expression and activation of nuclear factor (NF)-κB, which is known to activate SERPINE1/Serpine1 promoters. Interestingly, FOLFOX failed to activate hepatic NF-κB or cause liver injury in Serpine1 knockout male mice. Treatment of mouse hepatocytes with recombinant PAI-1 induced NF-κB activation; conditioned media from recombinant PAI-1 or interleukin-1β-treated hepatocytes, but not exosomes, increased the expression of proinflammatory cytokines and Cd31 in Kupffer cells and liver sinusoidal endothelial cells, respectively, which were blocked by SAMe. FOLFOX and interleukin-1β induced interaction between PAI-1 with urokinase plasminogen activator receptor in mouse liver and hepatocytes, respectively, which was blocked by SAMe. Recombinant PAI-1 requires interaction with uPA for full activation of NF-κB in hepatocytes. Neutralizing antibody against PAI-1 blocked interleukin-1β-mediated p65/PAI-1 activation in hepatocytes. Conclusions: FOLFOX treatment increased hepatocyte PAI-1 expression and liver injury, which were not observed in germline PAI-1 deficiency. Hepatocytes secrete PAI-1 to exert autocrine and paracrine effects to activate Kupffer cells and liver sinusoidal endothelial cells. SAMe protects against FOLFOX-mediated liver injury in part by inhibiting NF-κB activation and PAI-1 induction. |
| format | Article |
| id | doaj-art-f6a0d25d13724867a7b8d912079c6515 |
| institution | Kabale University |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-f6a0d25d13724867a7b8d912079c65152025-08-20T03:24:33ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-0119810151310.1016/j.jcmgh.2025.101513S-Adenosylmethionine Inhibits Plasminogen-Activating Inhibitor-1 and Protects Male Mice from FOLFOX-Induced Liver InjurySummaryAlexandra Gangi0Tony W.H. Li1Youngyi Lim2Swati Chandla3Andrea Floris4Arash Khangholi5Maria Lauda Tomasi6Shelly C. Lu7Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CaliforniaKarsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CaliforniaKarsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CaliforniaKarsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CaliforniaKarsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CaliforniaKarsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CaliforniaKarsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; Correspondence Address correspondence to: Maria Lauda Tomasi, PhD, Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Davis Building, Room #2093, 8700 Beverly Boulevard, Los Angeles, California 90048.Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; Shelly C. Lu, MD, Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Davis Building, Room #2097, 8700 Beverly Boulevard, Los Angeles, California 90048.Background & Aims: FOLFOX, often used in patients with colorectal liver metastases, can cause sinusoidal obstruction syndrome (SOS) hindering subsequent treatment. S-adenosylmethionine (SAMe) is hepatoprotective and here we investigated whether it protects against FOLFOX-induced hepatotoxicity and defined the underlying mechanisms. Methods: A murine model of FOLFOX-induced SOS examined the effect of SAMe and plasminogen-activating inhibitor-1 (PAI-1). In vitro studies included primary mouse and human hepatocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal endothelial cells. Results: SAMe cotreatment completely blocked the induction of markers increased in FOLFOX-induced SOS and protected against liver injury. The most up-regulated gene was Serpine1, which encodes for PAI-1. SAMe blocked FOLFOX-induced expression and activation of nuclear factor (NF)-κB, which is known to activate SERPINE1/Serpine1 promoters. Interestingly, FOLFOX failed to activate hepatic NF-κB or cause liver injury in Serpine1 knockout male mice. Treatment of mouse hepatocytes with recombinant PAI-1 induced NF-κB activation; conditioned media from recombinant PAI-1 or interleukin-1β-treated hepatocytes, but not exosomes, increased the expression of proinflammatory cytokines and Cd31 in Kupffer cells and liver sinusoidal endothelial cells, respectively, which were blocked by SAMe. FOLFOX and interleukin-1β induced interaction between PAI-1 with urokinase plasminogen activator receptor in mouse liver and hepatocytes, respectively, which was blocked by SAMe. Recombinant PAI-1 requires interaction with uPA for full activation of NF-κB in hepatocytes. Neutralizing antibody against PAI-1 blocked interleukin-1β-mediated p65/PAI-1 activation in hepatocytes. Conclusions: FOLFOX treatment increased hepatocyte PAI-1 expression and liver injury, which were not observed in germline PAI-1 deficiency. Hepatocytes secrete PAI-1 to exert autocrine and paracrine effects to activate Kupffer cells and liver sinusoidal endothelial cells. SAMe protects against FOLFOX-mediated liver injury in part by inhibiting NF-κB activation and PAI-1 induction.http://www.sciencedirect.com/science/article/pii/S2352345X25000542Colorectal Liver MetastasisNF-κBSinusoidal Obstruction Syndrome |
| spellingShingle | Alexandra Gangi Tony W.H. Li Youngyi Lim Swati Chandla Andrea Floris Arash Khangholi Maria Lauda Tomasi Shelly C. Lu S-Adenosylmethionine Inhibits Plasminogen-Activating Inhibitor-1 and Protects Male Mice from FOLFOX-Induced Liver InjurySummary Cellular and Molecular Gastroenterology and Hepatology Colorectal Liver Metastasis NF-κB Sinusoidal Obstruction Syndrome |
| title | S-Adenosylmethionine Inhibits Plasminogen-Activating Inhibitor-1 and Protects Male Mice from FOLFOX-Induced Liver InjurySummary |
| title_full | S-Adenosylmethionine Inhibits Plasminogen-Activating Inhibitor-1 and Protects Male Mice from FOLFOX-Induced Liver InjurySummary |
| title_fullStr | S-Adenosylmethionine Inhibits Plasminogen-Activating Inhibitor-1 and Protects Male Mice from FOLFOX-Induced Liver InjurySummary |
| title_full_unstemmed | S-Adenosylmethionine Inhibits Plasminogen-Activating Inhibitor-1 and Protects Male Mice from FOLFOX-Induced Liver InjurySummary |
| title_short | S-Adenosylmethionine Inhibits Plasminogen-Activating Inhibitor-1 and Protects Male Mice from FOLFOX-Induced Liver InjurySummary |
| title_sort | s adenosylmethionine inhibits plasminogen activating inhibitor 1 and protects male mice from folfox induced liver injurysummary |
| topic | Colorectal Liver Metastasis NF-κB Sinusoidal Obstruction Syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X25000542 |
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