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. 2022 May 13;15(5):600.
doi: 10.3390/ph15050600.

Perindopril/Ambrosin Combination Mitigates Dextran Sulfate Sodium-Induced Colitis in Mice: Crosstalk between Toll-Like Receptor 4, the Pro-Inflammatory Pathways, and SIRT1/PPAR-γ Signaling

Ahmed M Kabel  1 , Aliaa Atef  2 , Hany M Borg  3 , Azza A K El-Sheikh  4 , Hana J Al Khabbaz  5 , Hany H Arab  6 , Remon S Estfanous  7
Affiliations

Perindopril/Ambrosin Combination Mitigates Dextran Sulfate Sodium-Induced Colitis in Mice: Crosstalk between Toll-Like Receptor 4, the Pro-Inflammatory Pathways, and SIRT1/PPAR-γ Signaling

Ahmed M Kabel et al. Pharmaceuticals (Basel). .

V体育平台登录 - Abstract

Colitis is one of the inflammatory states that affect the intestinal wall and may even predispose to malignancy due to chronic irritation. Although the etiology of colitis is not yet fully explored, a combination of genetic and environmental factors is strongly incriminated. Perindopril is an angiotensin-converting enzyme inhibitor that is used for the management of a wide range of cardiovascular diseases. Ambrosin is a sesquiterpene lactone that was proven to have beneficial effects in disorders characterized by inflammatory nature. The objective of this study is to make a comparison between the effects of perindopril or ambrosin on dextran sulfate sodium (DSS)-induced colitis in mice and to explore the effect of their combination. The present findings indicate that each ambrosin or perindopril alone or in combination is able to ameliorate oxidative stress and suppress the proinflammatory pathways in the colonic tissues of DSS-treated mice via mechanisms related to toll-like receptor 4/nuclear factor kappa B signaling and modulation of peroxisome proliferator-activated receptor gamma/sirtuin-1 levels. In addition, each ambrosin or perindopril alone or in combination inhibits apoptosis and augments the mediators of autophagy in DSS-treated mice. These effects are reflected in the amelioration of the histopathological and electron microscopic changes in the colonic tissues. Interestingly, the most remarkable effects are those encountered with the perindopril/ambrosin combination compared to the groups treated with each of these agents alone. In conclusion, the perindopril/ambrosin combination might represent an effective modality for mitigation of the pathogenic events and the clinical sequelae of colitis VSports手机版. .

Keywords: ambrosin; colitis; dextran sulfate sodium; inflammation; mice; perindopril. V体育安卓版.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Perindopril with or without ambrosin mitigated the disease activity index (DAI) (A) and restored the colon length (B) in mice treated with dextran sulfate sodium (DSS) (Mean ± SD); where “a” denotes significant vs. the control group (p-value less than 0.05); “b” denotes significant vs. DSS group (p-value less than 0.05); “c” denotes significant vs. DSS + perindopril group (p-value less than 0.05); “d” denotes significant vs. DSS + ambrosin group (p-value less than 0.05).
Figure 2
Figure 2
Effect of perindopril with or without ambrosin on SIRT1/PPAR-γ signaling in the colonic tissues of DSS-treated mice (Mean ± SD); where “a” denotes significant vs. the control group (p-value less than 0.05); “b” denotes significant vs. DSS group (p-value less than 0.05); “c” denotes significant vs. DSS + perindopril group (p-value less than 0.05); “d” denotes significant vs. DSS + ambrosin group (p-value less than 0.05).
Figure 3
Figure 3
Effect of perindopril with or without ambrosin on beclin-1 and LC3-II levels in the colonic tissues of DSS-treated mice (Mean ± SD); where “a” denotes significant vs. the control group (p-value less than 0.05); “b” denotes significant vs. DSS group (p-value less than 0.05); “c” denotes significant vs. DSS + perindopril group (p-value less than 0.05); “d” denotes significant vs. DSS + ambrosin group (p-value less than 0.05).
Figure 4
Figure 4
Effect of perindopril with or without ambrosin on caspase-8 and Bcl-2 levels in the colonic tissues of DSS-treated mice (Mean ± SD); where “a” denotes significant vs. the control group (p-value less than 0.05); “b” denotes significant vs. DSS group (p-value less than 0.05); “c” denotes significant vs. DSS + perindopril group (p-value less than 0.05); “d” denotes significant vs. DSS + ambrosin group (p-value less than 0.05).
Figure 5
Figure 5
Hematoxylin and eosin stained sections of the colon of (a) The control untreated mice showing normal mucosa with intact mucosal glands, normal distribution of goblet cells and normal crypts (H and E ×100); (b) DSS mice showing surface ulceration of the colonic mucosa (Astrex) (×100); (c) DSS mice showing partial loss of the goblet cells (Thin arrow) with disruption of the crypts (Arrow head) (×200); (d) DSS mice showing massive inflammatory cellular infiltration mainly by lymphocytes (Thick arrow) (×400); (e) DSS mice treated with CMC showing disruption of the mucosal crypts (Arrow head) and inflammatory cellular infiltration mainly by lymphocytes (Arrow) (×200); (f) DSS mice treated with perindopril showing attenuated histological damage of the colonic tissues with minute ulcerations of the colonic mucosa and significant decrease in the inflammatory cellular infiltration (Arrow) (×200); (g) DSS mice treated with ambrosin showing significant amelioration of the histopathological damage of the colonic tissues with smaller ulcerations of the colonic mucosa and less dense inflammatory cellular infiltration (Arrows) (×200); (h) DSS mice treated with perindopril/ambrosin combination exhibiting restoration of the normal architecture of the colonic mucosa with absence of ulceration and mild inflammatory cellular infiltration (Arrow) (×200).
Figure 6
Figure 6
Effect of perindopril with or without ambrosin on the histological disease score in mice treated with DSS (Mean ± SD); where “a” denotes significant vs. the control group (p-value less than 0.05); “b” denotes significant vs. DSS group (p-value less than 0.05); “c” denotes significant vs. DSS + perindopril group (p-value less than 0.05); “d” denotes significant vs. DSS + ambrosin group (p-value less than 0.05).
Figure 7
Figure 7
Photomicrographs of sections of the colon of (A,B) The control untreated mice showing negative nuclear immunoreactivity to NF-κB (p65) (×200 and ×400, respectively); (C,D) DSS mice exhibiting strong positive nuclear immunoreactivity to NF-κB (p65) in the colonic glands epithelial cells (Arrows) (×200 and ×400, respectively); (E,F) DSS mice treated with CMC showing strong positive nuclear immunoreactivity to NF-κB (p65) in the colonic glands epithelial cells (Arrows) (×200 and ×400, respectively); (G,H) DSS mice treated with perindopril exhibiting decreased immunoreactivity to NF-κB(p65) (moderate immunostaining) (Arrows) (×100 and ×400, respectively); (I,J) DSS mice treated with ambrosin showing decreased immunoreactivity to NF-κB (p65) (moderate immunostaining) (Arrows) (×100 and ×400, respectively); (K,L) DSS mice treated with perindopril/ambrosin combination revealing marked decrease in the immunoreactivity to NF-κB (p65) (mild immunostaining) (Arrow) (×100 and ×400, respectively).
Figure 8
Figure 8
A transmission electron micrograph of a part of the colon of (A) The control untreated group showing absorptive columnar cells with apical microvilli (Asterisk), junctional complexes (Double arrows), mitochondria (Arrow), RER (Arrow head) and nuclei with prominent nucleoli (N) (×3000); (B) DSS mice exhibiting evident loss of the microvilli (Asterisk) and swollen mitochondria with destructed cristae (Arrow) (×3000); (C) DSS mice showing perinuclear cytoplasmic vacuolations (Arrow head) with hyperchromatic shrunken compressed nucleus (N) (×1500); (D) DSS mice exhibiting marked dilatation of RER (Arrow head) and marked cytoplasmic vacuolations (Arrow) (×3000); (E) DSS mice treated with CMC showing loss of the apical microvilli (Asterisk) and swollen mitochondria with destructed cristae (Arrow) (×2000); (F) DSS mice treated with CMC exhibiting perinuclear cytoplasmic vacuolations (Arrow head) and hyperchromatic shrunken compressed nucleus (N) (×3000); (G) DSS mice treated with perindopril showing partial loss of the apical microvilli (Asterisk), mild cytoplasmic vacuolation (Arrow head) and preserved normal mitochondria with scanty areas of mitochondrial swelling and destructed cristae (Arrow) (×2000); (H) DSS mice treated with ambrosin revealing nearly normal apical microvilli (Asterisk), cytoplasmic vacuolation (Arrow head) and preserved normal mitochondria (M) with scattered areas of mitochondrial swelling with destructed cristae (Arrow) (×2000); (I) DSS mice treated with perindopril/ambrosin combination showing apparently normal columnar cells with apical microvilli (Asterisk), RER (Arrow head), intercellular junctions (Double arrows), mitochondria (Arrow) and nucleus (N) (×2000).
Figure 9
Figure 9
A summative diagram showing the mechanisms, by which perindopril and/or ambrosin may combat DSS-induced colitis.
See this image and copyright information in PMC

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