Phloretin combined with sodium hyaluronate inhibits formation of postoperative abdominal adhesions in a rat model and its mechanism_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Zhixing ¹ , LONG Yanbin ² , SONG Bin ² , NIE Lingzhi ² , WU Yunhua ² ,  DU Qingguo ²

1. Yan’an University School of Medicine, Yan’an, Shaanxi 716000, P. R. China;
2. Department of General Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710061, P. R. China;

Corresponding author：

DU Qingguo, Email: dr_duqingguo@163.com

Keywords：

intra-abdominal adhesion; phloretin; oxidative stress response; Nrf2 pathway

DOI：

10.7507/1007-9424.202307023

Video：

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Objective To investigate the efficacy of phloretin combined with sodium hyaluronate in preventing postoperative abdominal adhesion formation in rats and its possible mechanisms. Methods Forty rats were randomly divided into five groups, the rats in the sham-operatinon group only underwent open and closed abdominal surgery, and the remaining rats of four groups underwent cecum scratch-and-rub method of modeling to receive different treatments: the rats in the control group and the phloretin group (PHL group) were closed abdominally after modeling, while the rats in the sodium hyaluronate group (HA group) and the phloretin combined with sodium hyaluronate group (PHL+HA group) were closed abdominally by using 2 mL of sodium hyaluronate gel coated with the damaged abdominal wall and the cecum; the postoperative groups treated with phloretin (the PHL and PHL+HA groups) were treated with 2 mL of40 mg/kg phloretin dissolved in 0.5% sodium carboxymethylcellulose by gavage daily, and the rest of the groups were treated with 2 mL of 0.5% sodium carboxymethylcellulose solution by gavage. After general anesthesia, the rats were executed on the 7th day after surgery, and the Nair’s score was used to evaluate the adhesion status of each group on the 7th day after surgery; the adhesive tissue or normal peritoneal tissue were collected (cecum and its opposite side of the peritoneal tissue was collected in the sham-operation group), and immunohistochemistry was performed to evaluate the degree of staining with Nrf2 antibody, HE staining was performed to evaluate the inflammation scores, and Sirius red staining was performed to evaluate the thickness of the collagen fibers, and levels of transforming growth factor β1 (TGF-β1), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. Results All rats successfully completed the experiment. Compared with the control group, Nair’s score, inflammation score, expression level of TGF-β1, thickness of collagen fibers in the adherent tissues, and MDA level were significantly lower in the PHL+HA group (P<0.05), but the SOD level and expression lever of Nrf2 were significantly higher in the PHL+HA group (P<0.05). Conclusion Phloretin combined with sodium hyaluronate can prevent the formation of postoperative abdominal adhesions in the rat model, which may be related to reducing inflammation, reducing collagen deposition, activating Nrf2 pathway and inhibiting oxidative stress.

Citation： ZHANG Zhixing, LONG Yanbin, SONG Bin, NIE Lingzhi, WU Yunhua, DU Qingguo. Phloretin combined with sodium hyaluronate inhibits formation of postoperative abdominal adhesions in a rat model and its mechanism. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(11): 1323-1328. doi: 10.7507/1007-9424.202307023 Copy

1.	Moris D, Chakedis J, Rahnemai-Azar AA, et al. Postoperative abdominal adhesions: clinical significance and advances in prevention and management. J Gastrointest Surg, 2017, 21(10): 1713-1722.
2.	Arjmand MH, Hashemzehi M, Soleimani A, et al. Therapeutic potential of active components of saffron in post-surgical adhesion band formation. J Tradit Complement Med, 2021, 11(4): 328-335.
3.	Soltany S. Postoperative peritoneal adhesion: an update on physiopathology and novel traditional herbal and modern medical therapeutics. Naunyn Schmiedebergs Arch Pharmacol, 2021, 394(2): 317-336.
4.	Gumán-Valdivia-Gómez G, Tena-Betancourt E, de Alva-Coria PM. Postoperative abdominal adhesions: pathogenesis and current preventive techniques. Cir Cir, 2019, 87(6): 698-703.
5.	Beyene RT, Kavalukas SL, Barbul A. Intra-abdominal adhesions: anatomy, physiology, pathophysiology, and treatment. Curr Probl Surg, 2015, 52(7): 271-319.
6.	de Oliveira MR. Phloretin-induced cytoprotective effects on mammalian cells: a mechanistic view and future directions. Biofactors, 2016, 42(1): 13-40.
7.	Aliomrani M, Sepand MR, Mirzaei HR, et al. Effects of phloretin on oxidative and inflammatory reaction in rat model of cecal ligation and puncture induced sepsis. Daru, 2016, 24(1): 15. doi: 10.1186/s40199-016-0154-9.
8.	Kim J, Durai P, Jeon D, et al. Phloretin as a potent natural TLR2/1 inhibitor suppresses TLR2-induced inflammation. Nutrients, 2018, 10(7): 868. doi: 10.3390/nu10070868.
9.	Wei G, Wu Y, Gao Q, et al. Effect of emodin on preventing postoperative intra-abdominal adhesion formation. Oxid Med Cell Longev, 2017, 2017: 1740317.
10.	Brüggmann D, Tchartchian G, Wallwiener M, et al. Intra-abdominal adhesions: definition, origin, significance in surgical practice, and treatment options. Dtsch Arztebl Int, 2010, 107(44): 769-775.
11.	Pouly JL, Darai E, Yazbeck C, et al. Postoperative abdominal adhesions and their prevention in gynaecological surgery: Ⅱ. How can they be prevented? Gynecol Obstet Fertil, 2012, 40(7-8): 419-428.
12.	Zhang Y, Li X, Zhang Q, et al. Berberine hydrochloride prevents postsurgery intestinal adhesion and inflammation in rats. J Pharmacol Exp Ther, 2014, 349(3): 417-426.
13.	de Oliveira PP, Bavaresco VP, Silveira-Filho LM, et al. Use of a novel polyvinyl alcohol membrane as a pericardial substitute reduces adhesion formation and inflammatory response after cardiac reoperation. J Thorac Cardiovasc Surg, 2014, 147(4): 1405-1410.
14.	Chegini N. TGF-beta system: the principal profibrotic mediator of peritoneal adhesion formation. Semin Reprod Med, 2008, 26(4): 298-312.
15.	Lim IJ, Phan TT, Bay BH, et al. Fibroblasts cocultured with keloid keratinocytes: normal fibroblasts secrete collagen in a keloidlike manner. Am J Physiol Cell Physiol, 2002, 283(1): C212-C222.
16.	Corona R, Verguts J, Schonman R, et al. Postoperative inflammation in the abdominal cavity increases adhesion formation in a laparoscopic mouse model. Fertil Steril, 2011, 95(4): 1224-1228.
17.	van Baal JO, Van de Vijver KK, Nieuwland R, et al. The histophysiology and pathophysiology of the peritoneum. Tissue Cell, 2017, 49(1): 95-105.
18.	Ersoy E, Ozturk V, Yazgan A, et al. Effect of polylactic acid film barrier on intra-abdominal adhesion formation. J Surg Res, 2008, 147(1): 148-152.
19.	Munireddy S, Kavalukas SL, Barbul A. Intra-abdominal healing: gastrointestinal tract and adhesions. Surg Clin North Am, 2010, 90(6): 1227-1236.
20.	Wei G, Zhou C, Wang G, et al. Keratinocyte growth factor combined with a sodium hyaluronate gel inhibits postoperative intra-abdominal adhesions. Int J Mol Sci, 2016, 17(10): 1611. doi: 10.3390/ijms17101611.
21.	Yan S, Yue Y, Zeng L, et al. Ligustrazine nanoparticles nano spray’s activation on Nrf2/ARE pathway in oxidative stress injury in rats with postoperative abdominal adhesion. Ann Transl Med, 2019, 7(16): 379. doi: 10.21037/atm.2019.07.72.
22.	Yung S, Chan TM. Mesothelial cells. Perit Dial Int, 2007, 27 Suppl 2: S110-S115.
23.	Wu Y, Li E, Wang Z, et al. TMIGD1 inhibited abdominal adhesion formation by alleviating oxidative stress in the mitochondria of peritoneal mesothelial cells. Oxid Med Cell Longev, 2021, 2021: 9993704.
24.	Wu Y, Wei G, Yu J, et al. Danhong injection alleviates postoperative intra-abdominal adhesion in a rat model. Oxid Med Cell Longev, 2019, 2019: 4591384.
25.	Dierckx T, Haidar M, Grajchen E, et al. Phloretin suppresses neuroinflammation by autophagy-mediated Nrf2 activation in macrophages. J Neuroinflammation, 2021, 18(1): 148. doi: 10.1186/s12974-021-02194-z.

1. Moris D, Chakedis J, Rahnemai-Azar AA, et al. Postoperative abdominal adhesions: clinical significance and advances in prevention and management. J Gastrointest Surg, 2017, 21(10): 1713-1722.
2. Arjmand MH, Hashemzehi M, Soleimani A, et al. Therapeutic potential of active components of saffron in post-surgical adhesion band formation. J Tradit Complement Med, 2021, 11(4): 328-335.
3. Soltany S. Postoperative peritoneal adhesion: an update on physiopathology and novel traditional herbal and modern medical therapeutics. Naunyn Schmiedebergs Arch Pharmacol, 2021, 394(2): 317-336.
4. Gumán-Valdivia-Gómez G, Tena-Betancourt E, de Alva-Coria PM. Postoperative abdominal adhesions: pathogenesis and current preventive techniques. Cir Cir, 2019, 87(6): 698-703.
5. Beyene RT, Kavalukas SL, Barbul A. Intra-abdominal adhesions: anatomy, physiology, pathophysiology, and treatment. Curr Probl Surg, 2015, 52(7): 271-319.
6. de Oliveira MR. Phloretin-induced cytoprotective effects on mammalian cells: a mechanistic view and future directions. Biofactors, 2016, 42(1): 13-40.
7. Aliomrani M, Sepand MR, Mirzaei HR, et al. Effects of phloretin on oxidative and inflammatory reaction in rat model of cecal ligation and puncture induced sepsis. Daru, 2016, 24(1): 15. doi: 10.1186/s40199-016-0154-9.
8. Kim J, Durai P, Jeon D, et al. Phloretin as a potent natural TLR2/1 inhibitor suppresses TLR2-induced inflammation. Nutrients, 2018, 10(7): 868. doi: 10.3390/nu10070868.
9. Wei G, Wu Y, Gao Q, et al. Effect of emodin on preventing postoperative intra-abdominal adhesion formation. Oxid Med Cell Longev, 2017, 2017: 1740317.
10. Brüggmann D, Tchartchian G, Wallwiener M, et al. Intra-abdominal adhesions: definition, origin, significance in surgical practice, and treatment options. Dtsch Arztebl Int, 2010, 107(44): 769-775.
11. Pouly JL, Darai E, Yazbeck C, et al. Postoperative abdominal adhesions and their prevention in gynaecological surgery: Ⅱ. How can they be prevented? Gynecol Obstet Fertil, 2012, 40(7-8): 419-428.
12. Zhang Y, Li X, Zhang Q, et al. Berberine hydrochloride prevents postsurgery intestinal adhesion and inflammation in rats. J Pharmacol Exp Ther, 2014, 349(3): 417-426.
13. de Oliveira PP, Bavaresco VP, Silveira-Filho LM, et al. Use of a novel polyvinyl alcohol membrane as a pericardial substitute reduces adhesion formation and inflammatory response after cardiac reoperation. J Thorac Cardiovasc Surg, 2014, 147(4): 1405-1410.
14. Chegini N. TGF-beta system: the principal profibrotic mediator of peritoneal adhesion formation. Semin Reprod Med, 2008, 26(4): 298-312.
15. Lim IJ, Phan TT, Bay BH, et al. Fibroblasts cocultured with keloid keratinocytes: normal fibroblasts secrete collagen in a keloidlike manner. Am J Physiol Cell Physiol, 2002, 283(1): C212-C222.
16. Corona R, Verguts J, Schonman R, et al. Postoperative inflammation in the abdominal cavity increases adhesion formation in a laparoscopic mouse model. Fertil Steril, 2011, 95(4): 1224-1228.
17. van Baal JO, Van de Vijver KK, Nieuwland R, et al. The histophysiology and pathophysiology of the peritoneum. Tissue Cell, 2017, 49(1): 95-105.
18. Ersoy E, Ozturk V, Yazgan A, et al. Effect of polylactic acid film barrier on intra-abdominal adhesion formation. J Surg Res, 2008, 147(1): 148-152.
19. Munireddy S, Kavalukas SL, Barbul A. Intra-abdominal healing: gastrointestinal tract and adhesions. Surg Clin North Am, 2010, 90(6): 1227-1236.
20. Wei G, Zhou C, Wang G, et al. Keratinocyte growth factor combined with a sodium hyaluronate gel inhibits postoperative intra-abdominal adhesions. Int J Mol Sci, 2016, 17(10): 1611. doi: 10.3390/ijms17101611.
21. Yan S, Yue Y, Zeng L, et al. Ligustrazine nanoparticles nano spray’s activation on Nrf2/ARE pathway in oxidative stress injury in rats with postoperative abdominal adhesion. Ann Transl Med, 2019, 7(16): 379. doi: 10.21037/atm.2019.07.72.
22. Yung S, Chan TM. Mesothelial cells. Perit Dial Int, 2007, 27 Suppl 2: S110-S115.
23. Wu Y, Li E, Wang Z, et al. TMIGD1 inhibited abdominal adhesion formation by alleviating oxidative stress in the mitochondria of peritoneal mesothelial cells. Oxid Med Cell Longev, 2021, 2021: 9993704.
24. Wu Y, Wei G, Yu J, et al. Danhong injection alleviates postoperative intra-abdominal adhesion in a rat model. Oxid Med Cell Longev, 2019, 2019: 4591384.
25. Dierckx T, Haidar M, Grajchen E, et al. Phloretin suppresses neuroinflammation by autophagy-mediated Nrf2 activation in macrophages. J Neuroinflammation, 2021, 18(1): 148. doi: 10.1186/s12974-021-02194-z.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Phloretin combined with sodium hyaluronate inhibits formation of postoperative abdominal adhesions in a rat model and its mechanism

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