Antagonizing Activin A/p15<sup>INK4b</sup> Signaling as Therapeutic Strategy for Liver Disease
Background/Aim: Activin A is involved in the pathogenesis of human liver diseases, but its therapeutic targeting is not fully explored. Here, we tested the effect of novel, highly specific small-molecule-based activin A antagonists (NUCC-474/555) in improving liver regeneration following partial hep...
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| Format: | Article |
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MDPI AG
2024-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/13/7/649 |
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| author | Sowmya Mekala Ravi Rai Samantha Loretta Reed Bill Bowen George K. Michalopoulos Joseph Locker Reben Raeman Michael Oertel |
| author_facet | Sowmya Mekala Ravi Rai Samantha Loretta Reed Bill Bowen George K. Michalopoulos Joseph Locker Reben Raeman Michael Oertel |
| author_sort | Sowmya Mekala |
| collection | DOAJ |
| description | Background/Aim: Activin A is involved in the pathogenesis of human liver diseases, but its therapeutic targeting is not fully explored. Here, we tested the effect of novel, highly specific small-molecule-based activin A antagonists (NUCC-474/555) in improving liver regeneration following partial hepatectomy and halting fibrosis progression in models of chronic liver diseases (CLDs). Methods: Cell toxicity of antagonists was determined in rat hepatocytes and Huh-7 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Hepatocytes and hepatic stellate cells (HSCs) were treated with activin A and NUCC-555 and analyzed by reverse transcription–polymerase chain reaction and immunohistochemistry. Partial hepatectomized Fisher (F)344 rats were treated with NUCC-555, and bromodeoxyuridine (BrdU) incorporation was determined at 18/24/36/120/240 h. NUCC-555 was administered into thioacetamide- or carbon tetrachloride-treated F344 rats or C57BL/6 mice, and the fibrosis progression was studied. Results: NUCC-474 showed higher cytotoxicity in cultured hepatic cells; therefore, NUCC-555 was used in subsequent studies. Activin A-stimulated overexpression of cell cycle-/senescence-related genes (e.g., <i>p15<sup>INK4b</sup></i>, <i>DEC1</i>, <i>Glb1</i>) was near-completely reversed by NUCC-555 in hepatocytes. Activin A-mediated HSC activation was blocked by NUCC-555. In partial hepatectomized rats, antagonizing activin A signaling resulted in a 1.9-fold and 2.3-fold increase in BrdU<sup>+</sup> cells at 18 and 24 h, respectively. Administration of NUCC-555 in rats and mice with progressing fibrosis significantly reduced collagen accumulation (7.9-fold), HSC activation indicated by reduced alpha smooth muscle actin<sup>+</sup> and vimentin<sup>+</sup> cells, and serum aminotransferase activity. Conclusions: Our studies demonstrate that activin A antagonist NUCC-555 promotes liver regeneration and halts fibrosis progression in CLD models, suggesting that blocking activin A signaling may represent a new approach to treating people with CLD. |
| first_indexed | 2024-04-24T10:47:44Z |
| format | Article |
| id | doaj.art-645a524c9cd2403da680adf786157b77 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-04-24T10:47:44Z |
| publishDate | 2024-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-645a524c9cd2403da680adf786157b772024-04-12T13:16:38ZengMDPI AGCells2073-44092024-04-0113764910.3390/cells13070649Antagonizing Activin A/p15<sup>INK4b</sup> Signaling as Therapeutic Strategy for Liver DiseaseSowmya Mekala0Ravi Rai1Samantha Loretta Reed2Bill Bowen3George K. Michalopoulos4Joseph Locker5Reben Raeman6Michael Oertel7Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USADepartment of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USADepartment of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USADepartment of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USADepartment of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USADepartment of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USADepartment of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USADepartment of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USABackground/Aim: Activin A is involved in the pathogenesis of human liver diseases, but its therapeutic targeting is not fully explored. Here, we tested the effect of novel, highly specific small-molecule-based activin A antagonists (NUCC-474/555) in improving liver regeneration following partial hepatectomy and halting fibrosis progression in models of chronic liver diseases (CLDs). Methods: Cell toxicity of antagonists was determined in rat hepatocytes and Huh-7 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Hepatocytes and hepatic stellate cells (HSCs) were treated with activin A and NUCC-555 and analyzed by reverse transcription–polymerase chain reaction and immunohistochemistry. Partial hepatectomized Fisher (F)344 rats were treated with NUCC-555, and bromodeoxyuridine (BrdU) incorporation was determined at 18/24/36/120/240 h. NUCC-555 was administered into thioacetamide- or carbon tetrachloride-treated F344 rats or C57BL/6 mice, and the fibrosis progression was studied. Results: NUCC-474 showed higher cytotoxicity in cultured hepatic cells; therefore, NUCC-555 was used in subsequent studies. Activin A-stimulated overexpression of cell cycle-/senescence-related genes (e.g., <i>p15<sup>INK4b</sup></i>, <i>DEC1</i>, <i>Glb1</i>) was near-completely reversed by NUCC-555 in hepatocytes. Activin A-mediated HSC activation was blocked by NUCC-555. In partial hepatectomized rats, antagonizing activin A signaling resulted in a 1.9-fold and 2.3-fold increase in BrdU<sup>+</sup> cells at 18 and 24 h, respectively. Administration of NUCC-555 in rats and mice with progressing fibrosis significantly reduced collagen accumulation (7.9-fold), HSC activation indicated by reduced alpha smooth muscle actin<sup>+</sup> and vimentin<sup>+</sup> cells, and serum aminotransferase activity. Conclusions: Our studies demonstrate that activin A antagonist NUCC-555 promotes liver regeneration and halts fibrosis progression in CLD models, suggesting that blocking activin A signaling may represent a new approach to treating people with CLD.https://www.mdpi.com/2073-4409/13/7/649liver regenerationcell cycle arrestsenescenceactivin antagonistliver fibrosis |
| spellingShingle | Sowmya Mekala Ravi Rai Samantha Loretta Reed Bill Bowen George K. Michalopoulos Joseph Locker Reben Raeman Michael Oertel Antagonizing Activin A/p15<sup>INK4b</sup> Signaling as Therapeutic Strategy for Liver Disease Cells liver regeneration cell cycle arrest senescence activin antagonist liver fibrosis |
| title | Antagonizing Activin A/p15<sup>INK4b</sup> Signaling as Therapeutic Strategy for Liver Disease |
| title_full | Antagonizing Activin A/p15<sup>INK4b</sup> Signaling as Therapeutic Strategy for Liver Disease |
| title_fullStr | Antagonizing Activin A/p15<sup>INK4b</sup> Signaling as Therapeutic Strategy for Liver Disease |
| title_full_unstemmed | Antagonizing Activin A/p15<sup>INK4b</sup> Signaling as Therapeutic Strategy for Liver Disease |
| title_short | Antagonizing Activin A/p15<sup>INK4b</sup> Signaling as Therapeutic Strategy for Liver Disease |
| title_sort | antagonizing activin a p15 sup ink4b sup signaling as therapeutic strategy for liver disease |
| topic | liver regeneration cell cycle arrest senescence activin antagonist liver fibrosis |
| url | https://www.mdpi.com/2073-4409/13/7/649 |
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