Cargando…

Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157

AIM: Although Clopidogrel is safe in healthy volunteers, it can induce recurrence of gastric ulcers in high-risk patients. Here, we investigated the protective effect of the natural product, stable gastric pentadecapeptide 157 (BPC 157) on Clopidogrel-induced gastric injury. METHODS: We used acetic...

Descripción completa

Detalles Bibliográficos
Autores principales: Wu, Hailu, Wei, Ming, Li, Nan, Lu, Qin, Shrestha, Sachin Mulmi, Tan, Jiacheng, Zhang, Zhenyu, Wu, Guoqiu, Shi, Ruihua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763470/
https://www.ncbi.nlm.nih.gov/pubmed/33376304
http://dx.doi.org/10.2147/DDDT.S284163
_version_ 1783628026305576960
author Wu, Hailu
Wei, Ming
Li, Nan
Lu, Qin
Shrestha, Sachin Mulmi
Tan, Jiacheng
Zhang, Zhenyu
Wu, Guoqiu
Shi, Ruihua
author_facet Wu, Hailu
Wei, Ming
Li, Nan
Lu, Qin
Shrestha, Sachin Mulmi
Tan, Jiacheng
Zhang, Zhenyu
Wu, Guoqiu
Shi, Ruihua
author_sort Wu, Hailu
collection PubMed
description AIM: Although Clopidogrel is safe in healthy volunteers, it can induce recurrence of gastric ulcers in high-risk patients. Here, we investigated the protective effect of the natural product, stable gastric pentadecapeptide 157 (BPC 157) on Clopidogrel-induced gastric injury. METHODS: We used acetic acid to induce gastric ulcer in Sprague Dawley rats. Clopidogrel alone or in combination with BPC 157 or L-NAME (nitric oxide system blockade) were administered after healing of acetic acid-induced ulcer. One percent methylcellulose solution was used as control. Ulcer recurrence rate and the ulcer index were compared between these groups. Gastric mucosal apoptosis rate, microscopic inflammation activity and angiogenesis markers vascular endothelial growth factor A (VEGF-A) and CD34 were examined by TUNEL, histological evaluations (HE) and immunohistochemistry (IHC). Pathways involved, expressions of endoplasmic reticulum (ER) stress apoptosis marker CHOP, angiogenic markers VEGF-A and its receptor VEGFR1, and endothelial NO synthase (eNOS) were all analyzed by Western blot. RESULTS: This study indicated that Clopidogrel significantly induced the gastric ulcers recurrence, severe inflammation and ER stress related apoptosis of the gastric mucosa, suppressed the synthesis of angiogenic markers and eNOS. Furthermore, Clopidrogel intervention resulted in the activation of protein kinase B (AKT) and p38 mitogen-activated protein kinase (p38/MAPK). BPC 157 attenuated the gastric mucosal damage caused by Clopidogrel and reversed these molecular effects. However, NO blockade L-NAME weakened the protective effect and thus the molecular effects of BPC 157 on gastric mucosa. CONCLUSION: In conclusion, these results suggest that BPC 157 inhibited Clopidogrel-induced gastric mucosa injury partially by inhibition of gastric mucosa cell ER stress-mediated apoptosis and inflammation, and promoting gastric mucosa angiogenesis via VEGF-A/VEGFR1 mediated-AKT/p38/MAPK signaling pathways.
format Online
Article
Text
id pubmed-7763470
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Dove
record_format MEDLINE/PubMed
spelling pubmed-77634702020-12-28 Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157 Wu, Hailu Wei, Ming Li, Nan Lu, Qin Shrestha, Sachin Mulmi Tan, Jiacheng Zhang, Zhenyu Wu, Guoqiu Shi, Ruihua Drug Des Devel Ther Original Research AIM: Although Clopidogrel is safe in healthy volunteers, it can induce recurrence of gastric ulcers in high-risk patients. Here, we investigated the protective effect of the natural product, stable gastric pentadecapeptide 157 (BPC 157) on Clopidogrel-induced gastric injury. METHODS: We used acetic acid to induce gastric ulcer in Sprague Dawley rats. Clopidogrel alone or in combination with BPC 157 or L-NAME (nitric oxide system blockade) were administered after healing of acetic acid-induced ulcer. One percent methylcellulose solution was used as control. Ulcer recurrence rate and the ulcer index were compared between these groups. Gastric mucosal apoptosis rate, microscopic inflammation activity and angiogenesis markers vascular endothelial growth factor A (VEGF-A) and CD34 were examined by TUNEL, histological evaluations (HE) and immunohistochemistry (IHC). Pathways involved, expressions of endoplasmic reticulum (ER) stress apoptosis marker CHOP, angiogenic markers VEGF-A and its receptor VEGFR1, and endothelial NO synthase (eNOS) were all analyzed by Western blot. RESULTS: This study indicated that Clopidogrel significantly induced the gastric ulcers recurrence, severe inflammation and ER stress related apoptosis of the gastric mucosa, suppressed the synthesis of angiogenic markers and eNOS. Furthermore, Clopidrogel intervention resulted in the activation of protein kinase B (AKT) and p38 mitogen-activated protein kinase (p38/MAPK). BPC 157 attenuated the gastric mucosal damage caused by Clopidogrel and reversed these molecular effects. However, NO blockade L-NAME weakened the protective effect and thus the molecular effects of BPC 157 on gastric mucosa. CONCLUSION: In conclusion, these results suggest that BPC 157 inhibited Clopidogrel-induced gastric mucosa injury partially by inhibition of gastric mucosa cell ER stress-mediated apoptosis and inflammation, and promoting gastric mucosa angiogenesis via VEGF-A/VEGFR1 mediated-AKT/p38/MAPK signaling pathways. Dove 2020-12-21 /pmc/articles/PMC7763470/ /pubmed/33376304 http://dx.doi.org/10.2147/DDDT.S284163 Text en © 2020 Wu et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Wu, Hailu
Wei, Ming
Li, Nan
Lu, Qin
Shrestha, Sachin Mulmi
Tan, Jiacheng
Zhang, Zhenyu
Wu, Guoqiu
Shi, Ruihua
Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157
title Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157
title_full Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157
title_fullStr Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157
title_full_unstemmed Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157
title_short Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157
title_sort clopidogrel-induced gastric injury in rats is attenuated by stable gastric pentadecapeptide bpc 157
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763470/
https://www.ncbi.nlm.nih.gov/pubmed/33376304
http://dx.doi.org/10.2147/DDDT.S284163
work_keys_str_mv AT wuhailu clopidogrelinducedgastricinjuryinratsisattenuatedbystablegastricpentadecapeptidebpc157
AT weiming clopidogrelinducedgastricinjuryinratsisattenuatedbystablegastricpentadecapeptidebpc157
AT linan clopidogrelinducedgastricinjuryinratsisattenuatedbystablegastricpentadecapeptidebpc157
AT luqin clopidogrelinducedgastricinjuryinratsisattenuatedbystablegastricpentadecapeptidebpc157
AT shresthasachinmulmi clopidogrelinducedgastricinjuryinratsisattenuatedbystablegastricpentadecapeptidebpc157
AT tanjiacheng clopidogrelinducedgastricinjuryinratsisattenuatedbystablegastricpentadecapeptidebpc157
AT zhangzhenyu clopidogrelinducedgastricinjuryinratsisattenuatedbystablegastricpentadecapeptidebpc157
AT wuguoqiu clopidogrelinducedgastricinjuryinratsisattenuatedbystablegastricpentadecapeptidebpc157
AT shiruihua clopidogrelinducedgastricinjuryinratsisattenuatedbystablegastricpentadecapeptidebpc157