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      Pure Total Flavonoids From Citrus Protect Against Nonsteroidal Anti-inflammatory Drug-Induced Small Intestine Injury by Promoting Autophagy in vivo and in vitro


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          Small intestine injury is an adverse effect of non-steroidal anti-inflammatory drugs (NSAIDs) that urgently needs to be addressed for their safe application. Although pure total flavonoids from citrus (PTFC) have been marketed for the treatment of digestive diseases, their effects on small intestine injury and the underlying mechanism of action remain unknown. This study aimed to investigate the potential role of autophagy in the mechanism of NSAID (diclofenac)-induced intestinal injury in vivo and in vitro and to demonstrate the protective effects of PTFC against NSAID-induced small intestine disease. The results of qRT-PCR, western blotting, and immunohistochemistry showed that the expression levels of autophagy-related 5 (Atg5), light chain 3 (LC3)-II, and tight junction (TJ) proteins ZO-1, claudin-1, and occludin were decreased in rats with NSAID-induced small intestine injury and diclofenac-treated IEC-6 cells compared with the control groups. In the PTFC group, Atg5 and LC3-II expression, TJ protein expression, and the LC3-II/LC3-I ratio increased. Furthermore, the mechanism by which PTFC promotes autophagy in vivo and in vitro was evaluated by western blotting. Expression levels of p-PI3K and p-Akt increased in the intestine disease-induced rat model group compared with the control, but decreased in the PTFC group. Autophagy of IEC-6 cells was upregulated after treatment with a PI3K inhibitor, and the upregulation was significantly more after PTFC treatment, suggesting PTFC promoted autophagy through the PI3K/Akt signaling pathway. In conclusion, PTFC protected intestinal barrier integrity by promoting autophagy, which demonstrates its potential as a therapeutic candidate for NSAID-induced small intestine injury.

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              Autophagy, a conserved catabolic process, plays an immensely significant role in a variety of diseases. However, whether it imparts a protective function in diseases remains debatable. During aging, autophagy gradually subsides, manifested by the reduced formation of autophagic vacuoles and improper fusion of these vacuoles with the lysosomes. Similarly, in neurodegenerative disorders, accumulation of tau and synuclein proteins has been attributed to the decline in the autophagic removal of proteins. Equivalently, lysosomal disorders show an impairment of the autophagic process leading to the accumulation of lipid molecules within lysosomes. On the other hand, activation of the autophagic pathway has also proved beneficial in evading various foreign pathogens, thereby contributing to the innate immunity. In the context of cancer, autophagy has shown to play a puzzling role where it serves as a tumor suppressor during initial stages but later protects the tumor cells from the immune system defense mechanisms. Similarly, muscular and heart disorders have been shown to be positively and negatively regulated by autophagy, respectively. In the present review, we, therefore, present a comprehensive review on the role of autophagy in various diseases and their corresponding outcomes.

                Author and article information

                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                19 April 2021
                : 12
                : 622744
                [ 1 ]First Affiliated Hospital, Zhejiang Chinese Medical University, Zhejiang, China
                [ 2 ]Department of Pharmacy, School of Medicine, Zhejiang University City College, Zhejiang, China
                [ 3 ]Zhejiang You-du Biotech Limited Company, Quzhou, China
                [ 4 ]Sir Run Run Shaw Hospital, Zhejiang, China
                Author notes

                Edited by: Peng Li, University of Macau, China

                Reviewed by: Jia Liu, China Academy of Chinese Medical Sciences, China

                Gianfranco Natale, University of Pisa, Italy

                *Correspondence: Shuo Zhang, zhangshuotcm@ 123456163.com

                These authors have contributed equally to these work

                This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology

                Copyright © 2021 Chen, Jiang, Chao, Hong, Cao and Zhang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 29 October 2020
                : 24 March 2021
                Original Research

                Pharmacology & Pharmaceutical medicine
                autophagy,pure total flavonoids from citrus,non-steroidal anti-inflammatory drugs,pi3k-akt pathway,small intestine injury


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