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16.10.2024 | Original Article

Betulin gel alleviates esophageal stricture following endoscopic submucosal dissection: an animal study

verfasst von: Dan Ma, Fan Yang, Qihong Yu, Xin Zhou, Zhaoshen Li, Yunfeng Wang, Jie Chen

Erschienen in: Esophagus | Ausgabe 1/2025

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Abstract

Background

Esophageal stenosis is a troublesome complication after circumferential ESD. This study examined the efficacy of betulin gel in preventing esophageal stenosis after ESD in a porcine model.

Methods

Twelve pigs were randomized to betulin group and control group evenly. At the distal esophagus, circumferential ESD was performed in all animals. In the betulin group, betulin gel was applied at days 1, 3, and 7. Endoscopy examination was performed at day 3, 1 week, 2 weeks, and 4 weeks post-ESD. Then pigs were killed for macroscopic and histologic esophageal evaluation.

Results

The rate of esophageal stricture was lower in the betulin group (53.3 ± 12.5% vs 88.3% ± 2.9, p = 0.02). Betulin-treated pigs had lower dysphagia score (2.0 ± 0 vs 3.3 ± 0.5, p < 0.001), less weight loss (11.78% ± 2.16 vs 15.85% ± 3.63, p = 0.04), and better passability of the open and closed biopsies forceps (83.33% vs. 0%, p = 0.015, and 100% vs. 0%, p = 0.002) 4 weeks post-ESD. Histologically, better re-epithelization (63.2 ± 10.7 mm vs 22.8 ± 10.1 mm, p < 0.001), slighter submucosal fibrosis (0.95 ± 0.17 mm vs 2.32 ± 0.48 mm, p = 0.002), lower muscularis propria damage score (1 vs 3, p < 0.001), and less inflammatory cells (307 vs 675 per high-power field, p = 0.002) were noted in the betulin group. The expression levels of TGF-β1, collagen i, collagen III, and α-SMA were significantly lower in the betulin group compared to the control group (p < 0.05).

Conclusions

Betulin gel shows promise in reducing fibrosis, enhancing repair, and preventing esophageal stricture after ESD, suggesting a potential new strategy for prevention.
Literatur
1.
Zurück zum Zitat Pech O, May A, Manner H, et al. Long-term efficacy and safety of endoscopic resection for patients with mucosal adenocarcinoma of the esophagus. Gastroenterology. 2014;146:652-660.e1.CrossRefPubMed Pech O, May A, Manner H, et al. Long-term efficacy and safety of endoscopic resection for patients with mucosal adenocarcinoma of the esophagus. Gastroenterology. 2014;146:652-660.e1.CrossRefPubMed
2.
Zurück zum Zitat Perrod G, Rahmi G, Pidial L, et al. Cell sheet transplantation for esophageal stricture prevention after endoscopic submucosal dissection in a porcine model. PLoS ONE. 2016;11: e0148249.CrossRefPubMedPubMedCentral Perrod G, Rahmi G, Pidial L, et al. Cell sheet transplantation for esophageal stricture prevention after endoscopic submucosal dissection in a porcine model. PLoS ONE. 2016;11: e0148249.CrossRefPubMedPubMedCentral
3.
Zurück zum Zitat Ratone JP, Bories E, Caillol F, et al. Oral steroid prophylaxis is effective in preventing esophageal strictures after large endoscopic resection. Ann Gastroenterol. 2017;30:62–6.PubMed Ratone JP, Bories E, Caillol F, et al. Oral steroid prophylaxis is effective in preventing esophageal strictures after large endoscopic resection. Ann Gastroenterol. 2017;30:62–6.PubMed
4.
Zurück zum Zitat Li L, Linghu E, Chai N. Using a novel self-help inflatable balloon to prevent esophageal stricture after complete circular endoscopic submucosal dissection. Dig Endosc. 2018;30:790.CrossRefPubMed Li L, Linghu E, Chai N. Using a novel self-help inflatable balloon to prevent esophageal stricture after complete circular endoscopic submucosal dissection. Dig Endosc. 2018;30:790.CrossRefPubMed
5.
Zurück zum Zitat Woelfle U, Laszczyk MN, Kraus M, et al. Triterpenes promote keratinocyte differentiation in vitro, ex vivo and in vivo: a role for the transient receptor potential canonical (subtype) 6. J Invest Dermatol. 2010;130:113–23.CrossRefPubMed Woelfle U, Laszczyk MN, Kraus M, et al. Triterpenes promote keratinocyte differentiation in vitro, ex vivo and in vivo: a role for the transient receptor potential canonical (subtype) 6. J Invest Dermatol. 2010;130:113–23.CrossRefPubMed
6.
Zurück zum Zitat Barret JP, Podmelle F, Lipovy B, et al. Accelerated re-epithelialization of partial-thickness skin wounds by a topical betulin gel: Results of a randomized phase III clinical trials program. Burns. 2017;43:1284–94.CrossRefPubMed Barret JP, Podmelle F, Lipovy B, et al. Accelerated re-epithelialization of partial-thickness skin wounds by a topical betulin gel: Results of a randomized phase III clinical trials program. Burns. 2017;43:1284–94.CrossRefPubMed
7.
Zurück zum Zitat Frew Q, Rennekampff HO, Dziewulski P, et al. Betulin wound gel accelerated healing of superficial partial thickness burns: Results of a randomized, intra-individually controlled, phase III trial with 12-months follow-up. Burns. 2019;45:876–90.CrossRefPubMed Frew Q, Rennekampff HO, Dziewulski P, et al. Betulin wound gel accelerated healing of superficial partial thickness burns: Results of a randomized, intra-individually controlled, phase III trial with 12-months follow-up. Burns. 2019;45:876–90.CrossRefPubMed
8.
Zurück zum Zitat Szuster-Ciesielska A, Plewka K, Daniluk J, et al. Betulin and betulinic acid attenuate ethanol-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS), cytokine (TNF-alpha, TGF-beta) production and by influencing intracellular signaling. Toxicology. 2011;280:152–63.CrossRefPubMed Szuster-Ciesielska A, Plewka K, Daniluk J, et al. Betulin and betulinic acid attenuate ethanol-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS), cytokine (TNF-alpha, TGF-beta) production and by influencing intracellular signaling. Toxicology. 2011;280:152–63.CrossRefPubMed
9.
Zurück zum Zitat Sharma A, Thakur R, Lingaraju MC, et al. Betulinic acid attenuates renal fibrosis in rat chronic kidney disease model. Biomed Pharmacother. 2017;89:796–804.CrossRefPubMed Sharma A, Thakur R, Lingaraju MC, et al. Betulinic acid attenuates renal fibrosis in rat chronic kidney disease model. Biomed Pharmacother. 2017;89:796–804.CrossRefPubMed
10.
Zurück zum Zitat Rastogi S, Pandey MM, Rawat KS, A. Medicinal plants of the genus Betula–traditional uses and a phytochemical-pharmacological review. J Ethnopharmacol. 2015;159:62–83.CrossRefPubMed Rastogi S, Pandey MM, Rawat KS, A. Medicinal plants of the genus Betula–traditional uses and a phytochemical-pharmacological review. J Ethnopharmacol. 2015;159:62–83.CrossRefPubMed
11.
Zurück zum Zitat Coffin E, Grangier A, Perrod G, et al. Extracellular vesicles from adipose stromal cells combined with a thermoresponsive hydrogel prevent esophageal stricture after extensive endoscopic submucosal dissection in a porcine model. Nanoscale. 2021;13:14866–78.CrossRefPubMed Coffin E, Grangier A, Perrod G, et al. Extracellular vesicles from adipose stromal cells combined with a thermoresponsive hydrogel prevent esophageal stricture after extensive endoscopic submucosal dissection in a porcine model. Nanoscale. 2021;13:14866–78.CrossRefPubMed
12.
Zurück zum Zitat Wang S, Yang Z, Xiong F, et al. Betulinic acid ameliorates experimental diabetic-induced renal inflammation and fibrosis via inhibiting the activation of NF-kappaB signaling pathway. Mol Cell Endocrinol. 2016;434:135–43.CrossRefPubMed Wang S, Yang Z, Xiong F, et al. Betulinic acid ameliorates experimental diabetic-induced renal inflammation and fibrosis via inhibiting the activation of NF-kappaB signaling pathway. Mol Cell Endocrinol. 2016;434:135–43.CrossRefPubMed
13.
Zurück zum Zitat Takahashi H, Arimura Y, Okahara S, et al. Risk of perforation during dilation for esophageal strictures after endoscopic resection in patients with early squamous cell carcinoma. Endoscopy. 2011;43:184–9.CrossRefPubMed Takahashi H, Arimura Y, Okahara S, et al. Risk of perforation during dilation for esophageal strictures after endoscopic resection in patients with early squamous cell carcinoma. Endoscopy. 2011;43:184–9.CrossRefPubMed
14.
Zurück zum Zitat Thomas T, Abrams KR, Subramanian V, et al. Esophageal stents for benign refractory strictures: a meta-analysis. Endoscopy. 2011;43:386–93.CrossRefPubMed Thomas T, Abrams KR, Subramanian V, et al. Esophageal stents for benign refractory strictures: a meta-analysis. Endoscopy. 2011;43:386–93.CrossRefPubMed
15.
Zurück zum Zitat Yamashina T, Uedo N, Fujii M, et al. Delayed perforation after intralesional triamcinolone injection for esophageal stricture following endoscopic submucosal dissection. Endoscopy. 2013;45(Suppl 2):E92.PubMed Yamashina T, Uedo N, Fujii M, et al. Delayed perforation after intralesional triamcinolone injection for esophageal stricture following endoscopic submucosal dissection. Endoscopy. 2013;45(Suppl 2):E92.PubMed
16.
Zurück zum Zitat Han Y, Guo J, Sun S, et al. Acellular dermal matrix for esophageal stricture prevention after endoscopic submucosal dissection in a porcine model. Gastrointest Endosc. 2017;86:1160–7.CrossRefPubMed Han Y, Guo J, Sun S, et al. Acellular dermal matrix for esophageal stricture prevention after endoscopic submucosal dissection in a porcine model. Gastrointest Endosc. 2017;86:1160–7.CrossRefPubMed
17.
Zurück zum Zitat Barret M, Bordacahar B, Beuvon F, et al. Self-assembling peptide matrix for the prevention of esophageal stricture after endoscopic resection: a randomized controlled trial in a porcine model. Dis Esophagus. 2017;30:1–7.CrossRefPubMed Barret M, Bordacahar B, Beuvon F, et al. Self-assembling peptide matrix for the prevention of esophageal stricture after endoscopic resection: a randomized controlled trial in a porcine model. Dis Esophagus. 2017;30:1–7.CrossRefPubMed
18.
Zurück zum Zitat Schwiebs A, Radeke HH. Immunopharmacological Activity of Betulin in Inflammation-associated Carcinogenesis. Anticancer Agents Med Chem. 2018;18:645–51.CrossRefPubMed Schwiebs A, Radeke HH. Immunopharmacological Activity of Betulin in Inflammation-associated Carcinogenesis. Anticancer Agents Med Chem. 2018;18:645–51.CrossRefPubMed
19.
Zurück zum Zitat Dehelean CA, Feflea S, Molnár J, et al. Betulin as an antitumor agent tested in vitro on A431, HeLa and MCF7, and as an angiogenic inhibitor in vivo in the CAM assay. Nat Prod Commun. 2012;7:981–5.PubMed Dehelean CA, Feflea S, Molnár J, et al. Betulin as an antitumor agent tested in vitro on A431, HeLa and MCF7, and as an angiogenic inhibitor in vivo in the CAM assay. Nat Prod Commun. 2012;7:981–5.PubMed
20.
Zurück zum Zitat Ebeling S, Naumann K, Pollok S, et al. From a traditional medicinal plant to a rational drug: understanding the clinically proven wound healing efficacy of birch bark extract. PLoS ONE. 2014;9: e86147.CrossRefPubMedPubMedCentral Ebeling S, Naumann K, Pollok S, et al. From a traditional medicinal plant to a rational drug: understanding the clinically proven wound healing efficacy of birch bark extract. PLoS ONE. 2014;9: e86147.CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Amiri S, Dastghaib S, Ahmadi M, et al. Betulin and its derivatives as novel compounds with different pharmacological effects. Biotechnol Adv. 2020;38: 107409.CrossRefPubMed Amiri S, Dastghaib S, Ahmadi M, et al. Betulin and its derivatives as novel compounds with different pharmacological effects. Biotechnol Adv. 2020;38: 107409.CrossRefPubMed
22.
Zurück zum Zitat Wu Q, Li H, Qiu J, et al. Betulin protects mice from bacterial pneumonia and acute lung injury. Microb Pathog. 2014;75:21–8.CrossRefPubMed Wu Q, Li H, Qiu J, et al. Betulin protects mice from bacterial pneumonia and acute lung injury. Microb Pathog. 2014;75:21–8.CrossRefPubMed
23.
Zurück zum Zitat Schwieger-Briel A, Ott H, Kiritsi D, et al. Mechanism of Oleogel-S10: A triterpene preparation for the treatment of epidermolysis bullosa. Dermatol Ther. 2019;32: e12983.PubMedPubMedCentral Schwieger-Briel A, Ott H, Kiritsi D, et al. Mechanism of Oleogel-S10: A triterpene preparation for the treatment of epidermolysis bullosa. Dermatol Ther. 2019;32: e12983.PubMedPubMedCentral
24.
Zurück zum Zitat Wardecki T, Werner P, Thomas M, et al. Influence of Birch Bark Triterpenes on Keratinocytes and Fibroblasts from Diabetic and Nondiabetic Donors. J Nat Prod. 2016;79:1112–23.CrossRefPubMed Wardecki T, Werner P, Thomas M, et al. Influence of Birch Bark Triterpenes on Keratinocytes and Fibroblasts from Diabetic and Nondiabetic Donors. J Nat Prod. 2016;79:1112–23.CrossRefPubMed
25.
Zurück zum Zitat Ci X, Zhou J, Lv H, et al. Betulin exhibits anti-inflammatory activity in LPS-stimulated macrophages and endotoxin-shocked mice through an AMPK/AKT/Nrf2-dependent mechanism. Cell Death Dis. 2017;8: e2798.CrossRefPubMedPubMedCentral Ci X, Zhou J, Lv H, et al. Betulin exhibits anti-inflammatory activity in LPS-stimulated macrophages and endotoxin-shocked mice through an AMPK/AKT/Nrf2-dependent mechanism. Cell Death Dis. 2017;8: e2798.CrossRefPubMedPubMedCentral
26.
Zurück zum Zitat Honda M, Nakamura T, Hori Y, et al. Process of healing of mucosal defects in the esophagus after endoscopic mucosal resection: histological evaluation in a dog model. Endoscopy. 2010;42:1092–5.CrossRefPubMed Honda M, Nakamura T, Hori Y, et al. Process of healing of mucosal defects in the esophagus after endoscopic mucosal resection: histological evaluation in a dog model. Endoscopy. 2010;42:1092–5.CrossRefPubMed
Metadaten
Titel
Betulin gel alleviates esophageal stricture following endoscopic submucosal dissection: an animal study
verfasst von
Dan Ma
Fan Yang
Qihong Yu
Xin Zhou
Zhaoshen Li
Yunfeng Wang
Jie Chen
Publikationsdatum
16.10.2024
Verlag
Springer Nature Singapore
Erschienen in
Esophagus / Ausgabe 1/2025
Print ISSN: 1612-9059
Elektronische ISSN: 1612-9067
DOI
https://doi.org/10.1007/s10388-024-01091-7

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