Relationship Between TGF-? and Liver Regeneration Rate in Wistar Rats After Partial Hepatectomy Treated with Lactococcus lactis D4
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Liver regeneration following partial hepatectomy is regulated by coordinated proliferative and growth-termination signals. Transforming growth factor-beta (TGF-?) plays an important role in regulating hepatocyte proliferation and tissue remodeling, while Lactococcus lactis D4 has been reported to support hepatic repair in experimental models. This study aimed to investigate the relationship between hepatic TGF-? expression and the liver regeneration rate (LRR) in male Wistar rats following partial hepatectomy and treatment with L. lactis D4. A randomized, posttest-only experimental design was employed, comprising five groups: sham-operated, partial hepatectomy control, L. lactis D4 administration before hepatectomy (P1), administration after hepatectomy (P2), and administration both before and after hepatectomy (P3). Hepatic TGF-? expression was assessed using immunohistochemistry, while LRR was calculated based on liver and body weights. Differences among groups were analyzed using one-way analysis of variance (ANOVA), followed by post hoc testing, while the relationship between TGF-? expression and LRR was examined using Pearson's correlation analysis. Mean TGF-? values were 59.89 ± 6.38, 52.77 ± 5.03, 51.31 ± 1.27, 38.69 ± 0.52, and 47.53 ± 2.47 in the sham, control, P1, P2, and P3 groups, respectively (p < 0.001). The corresponding LRR values were 200.63 ± 66.03%, 207.50 ± 92.06%, 150.86 ± 71.79%, and 225.85 ± 95.42% in the control, P1, P2, and P3 groups, respectively, with no statistically significant differences among groups (p = 0.670). Pearson's correlation analysis revealed a moderate positive correlation between hepatic TGF-? expression and LRR (r = 0.470; p = 0.037). These findings indicated that L. lactis D4 administration was associated with variations in hepatic TGF-? expression, while TGF-? expression demonstrated a moderate positive correlation with liver regeneration at seven days after partial hepatectomy. However, L. lactis D4 treatment did not produce a statistically significant difference in LRR among the experimental groups.
Abshar, I., Irwan, & Rivai, M. I. (2025). The effect of Lactococcus lactis D4 on liver regeneration rate and hepatocyte proliferation index (Ki67) in Wistar rats after partial hepatectomy. International Journal of Surgery Science, 9(3), 5–7.
Amelia, R., Philip, K., Pratama, Y. E., & Purwati, E. (2021). Characterization and probiotic potential of lactic acid bacteria isolated from dadiah sampled in West Sumatra. Food Science and Technology, 41(Suppl. 2), 746–752. https://doi.org/10.1590/fst.30020
Cao, Y. N., Zhang, H. T., & Zhang, G. H. (2015). PTHrP/PTHR1 and TGF-? levels are inversely associated in liver regeneration. [Nama Jurnal Perlu Dikonfirmasi — Terbitan CSCanada], 2(1), 1–7.
Cao, Y. N., Zhang, H. T., Zhang, G. H., Liu, X. H., Ferraro, N., Jackson, L. N., Evers, B. M., Falzon, M., & Ko, T. C. (2015). PTHrP/PTHR1 and TGF-? levels are inversely associated in liver regeneration. Canadian Social Science, 2(1), 1–7. https://doi.org/10.3968/6175
Chan, A., Kow, A., Hibi, T., Di Benedetto, F., & Serrablo, A. (2020). Liver resection in cirrhotic liver: Are there any limits? International Journal of Surgery, 82(Suppl.), 109–114. https://doi.org/10.1016/j.ijsu.2020.06.050
Chari, R. S., Price, D. T., Sue, S. R., Meyers, W. C., & Jirtle, R. L. (1995a). Down-regulation of transforming growth factor beta receptor type I, II, and III during liver regeneration. The American Journal of Surgery, 169(1), 126–131. https://doi.org/10.1016/S0002-9610(99)80120-2
Chari, R. S., Price, D. T., Sue, S. R., Meyers, W. C., & Jirtle, R. L. (1995b). Down-regulation of transforming growth factor beta receptor type I, II, and III during liver regeneration. American Journal of Surgery, 169(1), 126–131. https://doi.org/10.1016/s0002-9610(99)80120-2
Collaborative, T. LiverGroup. org. (2023). Outcomes of elective liver surgery worldwide: A global, prospective, multicenter, cross-sectional study. International Journal of Surgery, 109(12), 3954–3966. https://doi.org/10.1097/JS9.0000000000000711
De Gasperi, A., Petrò, L., & Amici, O. (2024). Major liver resections, perioperative issues and posthepatectomy liver failure: A comprehensive update for the anesthesiologist. World Journal of Critical Care Medicine, 13(2), 92751. https://doi.org/10.5492/wjccm.v13.i2.92751
de Haan, L. R., van Golen, R. F., & Heger, M. (2024a). Molecular pathways governing the termination of liver regeneration. Pharmacological Reviews, 76(3), 500–558. https://doi.org/10.1124/pharmrev.123.000955
de Haan, L. R., van Golen, R. F., & Heger, M. (2024b). Molecular pathways governing the termination of liver regeneration. Pharmacological Reviews, 76(3), 500–558. https://doi.org/10.1124/pharmrev.123.000955
Deng, Z., Fan, T., & Xiao, C. (2024a). TGF-? signaling in health, disease and therapeutics. Signal Transduction and Targeted Therapy, 9, 61. https://doi.org/10.1038/s41392-024-01764-w
Deng, Z., Fan, T., & Xiao, C. (2024b). TGF-? signaling in health, disease and therapeutics. Signal Transduction and Targeted Therapy, 9, 61. https://doi.org/10.1038/s41392-024-01764-w
Dooley, S., & ten Dijke, P. (2012a). TGF-? in progression of liver disease. Cell and Tissue Research, 347(1), 245–256. https://doi.org/10.1007/s00441-011-1246-y
Dooley, S., & ten Dijke, P. (2012b). TGF-? in progression of liver disease. Cell and Tissue Research, 347(1), 245–256. https://doi.org/10.1007/s00441-011-1246-y
Hoffmann, K., Nagel, A. J., & Tanabe, K. (2020). Markers of liver regeneration—The role of growth factors and cytokines: A systematic review. BMC Surgery, 20(1), 31. https://doi.org/10.1186/s12893-019-0664-8
Hoffmann, K., Nagel, A. J., Tanabe, K., Fuchs, J., Dehlke, K., Ghamarnejad, O., Lemekhova, A., & Mehrabi, A. (2020). Markers of liver regeneration—the role of growth factors and cytokines: A systematic review. BMC Surgery, 20(1), 31. https://doi.org/10.1186/s12893-019-0664-8
Kahn, J., Pregartner, G., & Schemmer, P. (2020a). Effects of both pro- and synbiotics in liver surgery and transplantation with special focus on the gut-liver axis—A systematic review and meta-analysis. Nutrients, 12(8), 2461. https://doi.org/10.3390/nu12082461
Kahn, J., Pregartner, G., & Schemmer, P. (2020b). Effects of both pro- and synbiotics in liver surgery and transplantation with special focus on the gut-liver axis—a systematic review and meta-analysis. Nutrients, 12(8), 2461. https://doi.org/10.3390/nu12082461
Karkampouna, S., ten Dijke, P., & Dooley, S. (2012). TGF? signaling in liver regeneration. Current Pharmaceutical Design, 18(27), 4103–4113. https://doi.org/10.2174/138161212802430521
Karkampouna, S., Ten Dijke, P., Dooley, S., & Julio, M. K. (2012). TGF? signaling in liver regeneration. Current Pharmaceutical Design, 18(27), 4103–4113. https://doi.org/10.2174/138161212802430521
Kisseleva, T., & Brenner, D. (2021a). Molecular and cellular mechanisms of liver fibrosis and its regression. Nature Reviews Gastroenterology & Hepatology, 18(3), 151–166. https://doi.org/10.1038/s41575-020-00372-7
Kisseleva, T., & Brenner, D. (2021b). Molecular and cellular mechanisms of liver fibrosis and its regression. Nature Reviews Gastroenterology & Hepatology, 18, 151–166. https://doi.org/10.1038/s41575-020-00372-7
Korchilava, B., Khachidze, T., Megrelishvili, N., Svanadze, L., Kakabadze, M., & Tsomaia, K. (2025). Liver regeneration after partial hepatectomy: Triggers and mechanisms. World Journal of Hepatology, 17(7), 107378. https://doi.org/10.4254/wjh.v17.i7.107378
Korchilava, B., Khachidze, T., Megrelishvili, N., Svanadze, L., Kakabadze, M., Tsomaia, K., Jintcharadze, M., & Kordzaia, D. (2025). Liver regeneration after partial hepatectomy: Triggers and mechanisms. World Journal of Hepatology, 17(7), 107378. https://doi.org/10.4254/wjh.v17.i7.107378
Liu, Q., Wang, S., & Fu, J. (2024a). Liver regeneration after injury: Mechanisms, cellular interactions and therapeutic innovations. Clinical and Translational Medicine, 14(8), e1812. https://doi.org/10.1002/ctm2.1812
Liu, Q., Wang, S., & Fu, J. (2024b). Liver regeneration after injury: Mechanisms, cellular interactions and therapeutic innovations. Clinical and Translational Medicine, 14(8), e1812. https://doi.org/10.1002/ctm2.1812
Meier, M., Andersen, K. J., & Knudsen, A. R. (2016). Liver regeneration is dependent on the extent of hepatectomy. Journal of Surgical Research, 205(1), 76–84. https://doi.org/10.1016/j.jss.2016.06.021
Meier, M., Andersen, K. J., Knudsen, A. R., Nyengaard, J. R., Hamilton-Dutoit, S., & Mortensen, F. V. (2016). Liver regeneration is dependent on the extent of hepatectomy. Journal of Surgical Research, 205(1), 76–84. https://doi.org/10.1016/j.jss.2016.06.020
Michalopoulos, G. K., & Bhushan, B. (2021a). Liver regeneration: Biological and pathological mechanisms and implications. Nature Reviews Gastroenterology & Hepatology, 18(1), 40–55. https://doi.org/10.1038/s41575-020-0342-4
Michalopoulos, G. K., & Bhushan, B. (2021b). Liver regeneration: Biological and pathological mechanisms and implications. Nature Reviews Gastroenterology & Hepatology, 18(1), 40–55. https://doi.org/10.1038/s41575-020-0342-4
Orcutt, S. T., & Anaya, D. A. (2018). Liver resection and surgical strategies for management of primary liver cancer. Cancer Control, 25(1), 1073274817744621. https://doi.org/10.1177/1073274817744621
Romero-Gallo, J., Sozmen, E. G., & Chytil, A. (2005). Inactivation of TGF-beta signaling in hepatocytes results in an increased proliferative response after partial hepatectomy. Oncogene, 24(18), 3028–3041. https://doi.org/10.1038/sj.onc.1208475
Sowa, J. P., Best, J., & Benko, T. (2008). Extent of liver resection modulates the activation of transcription factors and the production of cytokines involved in liver regeneration. World Journal of Gastroenterology, 14(46), 7093–7100. https://doi.org/10.3748/wjg.14.7093
Sowa, J. P., Best, J., Benko, T., Bockhorn, M., Gu, Y., & Niehues, E. M. (2008). Extent of liver resection modulates the activation of transcription factors and the production of cytokines involved in liver regeneration. World Journal of Gastroenterology, 14(46), 7093–7100.
Sukma, A., Toh, H., Nguyen, T. T. T., Fitria, N., Mimura, I., Kaneko, R., Arakawa, K., & Morita, H. (2018). Microbiota community structure in traditional fermented milk dadiah in Indonesia: Insights from high-throughput 16S rRNA gene sequencing. Milk Science International, 71(1–3).
Utami, R. P., Suchitra, A., Irwan, Rivai, M. I., & Sukma, A. (2025). The effect of Lactococcus lactis D4 on the expression of Ki-67 and liver fibrosis in a rat model of obstructive jaundice. Annals of Hepato-Biliary-Pancreatic Surgery, 29, 396–404.
Utami, R. P., Suchitra, A., Irwan, Rivai, M. I., Suswita, R., & Sukma, A. (2025). The effect of Lactococcus lactis D4 on the expression of Ki-67 and liver fibrosis in a rat model of obstructive jaundice. Annals of Hepato-Biliary-Pancreatic Surgery, 29(4), 396–404. https://doi.org/10.14701/ahbps.25-104
Xie, C., Zhang, Z., & Yang, M. (2022). Lactiplantibacillus plantarum AR113 exhibit accelerated liver regeneration by regulating gut microbiota and plasma glycerophospholipid. Frontiers in Microbiology, 12, 800470. https://doi.org/10.3389/fmicb.2021.800470
Xie, C., Zhang, Z., Yang, M., Cao, C., Zhou, Y., Zhu, Z., Gong, W., Xu, C., Yan, L., Hu, Z., Ai, L., & Peng, Y. (2022). Lactiplantibacillus plantarum AR113 exhibit accelerated liver regeneration by regulating gut microbiota and plasma glycerophospholipid. Frontiers in Microbiology, 12, 800470. https://doi.org/10.3389/fmicb.2021.800470
Xu, Z., Jiang, N., & Xiao, Y. (2022). The role of gut microbiota in liver regeneration. Frontiers in Immunology, 13, 1003376. https://doi.org/10.3389/fimmu.2022.1003376
Xu, Z., Jiang, N., Xiao, Y., Yuan, K., & Wang, Z. (2022). The role of gut microbiota in liver regeneration. Frontiers in Immunology, 13, 1003376. https://doi.org/10.3389/fimmu.2022.1003376
Yagi, S., Hirata, M., & Miyachi, Y. (2020). Liver regeneration after hepatectomy and partial liver transplantation. International Journal of Molecular Sciences, 21(21), 8414. https://doi.org/10.3390/ijms21218414
Yagi, S., Hirata, M., Miyachi, Y., & Uemoto, S. (2020). Liver regeneration after hepatectomy and partial liver transplantation. International Journal of Molecular Sciences, 21(21), 8414. https://doi.org/10.3390/ijms21218414
Yuan, S., Dong, M., Zhang, H., Xu, H., Wang, Q., & Yan, C. (2021). Oral delivery of a Lactococcus lactis expressing extracellular TGF?R2 alleviates hepatic fibrosis. Applied Microbiology and Biotechnology, 105(14–15), 6007–6018. https://doi.org/10.1007/s00253-021-11485-7
Yuan, S., Dong, M., Zhang, H., Xu, H., Wang, Q., Yan, C., Ye, R., Jiang, X., Zhou, H., Chen, L., Cheng, J., Xie, W., & Jin, W. (2021). Oral delivery of a Lactococcus lactis expressing extracellular TGF?R2 alleviates hepatic fibrosis. Applied Microbiology and Biotechnology, 105(14), 6007–6018. https://doi.org/10.1007/s00253-021-11485-7
Zhang, C., Sun, C., & Zhao, Y. (2024). Signaling pathways of liver regeneration: Biological mechanisms and implications. IScience, 27(1), 108683. https://doi.org/10.1016/j.isci.2023.108683
Zhang, C., Sun, C., Zhao, Y., Ye, B., & Yu, G. (2023). Signaling pathways of liver regeneration: Biological mechanisms and implications. IScience, 27(1), 108683. https://doi.org/10.1016/j.isci.2023.108683
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