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![PTUPB decreases DOX-induced sEH and
COX-2 expression in human endothelial cells. (A) Basal gene
expression levels of sEH and COX-2 in endothelial cells. EA.hy926
cells were treated with 0.5 µM, 1 µM and 2 µM DOX for 24H. Gene
expression levels of (B) sEH and (C) COX-2 in DOX-treated cells.
Viability of EA.hy926 cells treated with either (D) PTUPB alone or
(E) in combination with DOX. EA.hy926 cells were treated with 2 µM
DOX with or without 1 µM PTUPB for 24 h. Gene expression levels of
(F) sEH and (G) COX-2. (H) Activity level of sEH. One-way ANOVA
followed by Tukey's multiple comparison tests was performed.
+P<0.05 vs. control, *P<0.05 vs. DOX). sEH,
soluble epoxide hydrolase; COX-2, cyclooxygenase-2; DOX,
doxorubicin; PTUPB,
4-[5-phenyl-3-[3-[[[[4-(trifluoromethyl)phenyl]amino]carbonyl]amino]propyl]-1H-pyrazol-1-yl]-benzenesulfonamide;
DHET, dihydroxyeicosatrienoic acid; Con, control.](/article_images/mmr/33/3/mmr-33-03-13810-g00.jpg)
![Inhibition of soluble epoxide
hydrolase and cyclooxygenase-2 using PTUPB attenuates DOX-induced
endothelial-to-mesenchymal transition. EA.hy926 cells were treated
with 2 µM DOX with or without 1 µM PTUPB for 24 h. Gene expression
levels of mesenchymal markers (A) ASMA, (B) SMA22, (C) VIM, (D)
CDH2, (E) TGF-β, (F) SNAI1 and (G) SNAI2, and (H) endothelial
marker CD31. (I) Ratio of mesenchymal to endothelial cells in cells
treated with DOX with or without 1 µM PTUPB was measured based on
morphological images. (J) Representative morphological images of
EA.hy926 cells incubated with DOX with or without 1 µM PTUPB for 24
h at a magnification of ×10 (scale bar, 100 µm). The light red
arrow indicates mesenchymal cells (long, spindle-like cells). The
dark red arrow indicates endothelial cells (cobblestone
monolayer-like cells). One-way ANOVA followed by Tukey's multiple
comparison test was performed to determine the significant
differences between groups (+P<0.05 vs. control,
*P<0.05 vs. DOX). PTUPB,
4-[5-phenyl-3-[3-[[[[4-(trifluoromethyl)phenyl]amino]carbonyl]amino]propyl]-1H-pyrazol-1-yl]-benzenesulfonamide;
DOX, doxorubicin; ASMA, smooth muscle actin α2; SMA22, smooth
muscle protein 22α; VIM, vimentin; CDH2, cadherin-2; SNAI1, snail
family transcriptional repressor 1; SNAI2, snail family
transcriptional repressor 2.](/article_images/mmr/33/3/mmr-33-03-13810-g01.jpg)
![PTUPB prevents DOX-induced
endothelial and vascular dysfunction in zebrafish. (A) Schematic
representation of the treatment protocol in zebrafish. Zebrafish
embryos were treated at 24 hpf with 100 µM DOX with or without 1 µM
PTUPB for 48 h. (B) Representative images of velocity-time integral
graphs obtained from the MicroZebralab software for the DA and PCV
of zebrafish at 72 hpf. (C and F) Blood velocity, (D and G)
diameter and (E and H) shear stress of the (C-E) DA and (F-H) PCV.
Gene expression levels of (I) sna1, (J) col1a1, (K) vim, (L) tgf-β,
(M) acta2 and (N) vegfr. +P<0.05 vs. control,
*P<0.05 vs. DOX). DOX, doxorubicin; PTUPB,
4-[5-phenyl-3-[3-[[[[4-(trifluoromethyl)phenyl]amino]carbonyl]amino]propyl]-1H-pyrazol-1-yl]-benzenesulfonamide;
hpf, hours post-fertilization; RT-q, reverse
transcription-quantitative PCR; DA, dorsal aorta; PCV, posterior
cardinal vein; sna1, snail family zinc finger 1a; col1a1, collagen
1a1; vim, vimentin; acta2, smooth muscle actin α2.](/article_images/mmr/33/3/mmr-33-03-13810-g02.jpg)
![PTUPB prevents DOX-induced cardiac
dysfunction in zebrafish. (A) Representative images of cardiac
morphology in zebrafish larvae at 72 h post-fertilization. (B)
Cross-sectional area of cardiac edema in mm2. (C) Stroke
volume, (D) cardiac output and (E) arterial pulse in zebrafish
larvae treated with DOX and PTUPB. Gene expression levels of
zebrafish cardiac injury markers (F) myh6, (G) myh7, (H) myl7 and
(I) nppb. One-way ANOVA followed by Tukey's multiple comparison
test was performed to determine the significant differences between
groups (+P<0.05 vs. control, *P<0.05 vs. DOX).
DOX, doxorubicin; PTUPB,
4-[5-phenyl-3-[3-[[[[4-(trifluoromethyl)phenyl]amino]carbonyl]amino]propyl]-1H-pyrazol-1-yl]-benzenesulfonamide;
myh6, myosin heavy chain 6; myh7, myosin heavy chain 7; myl7,
myosin light chain 7; nppb, natriuretic peptide B.](/article_images/mmr/33/3/mmr-33-03-13810-g03.jpg)
![PTUPB reduces DOX-induced
inflammation, oxidative stress and apoptosis. Gene expression
levels of zebrafish inflammatory markers (A) il1b, (B) tnfα, (C)
nfκb and (D) il10, oxidative stress markers (E) gpx, (F) cat, (G)
hmox and (H) nqo1, and apoptosis markers (I) bax, (J) bcl2, (K)
cas-3 and (L) cas-7. One-way ANOVA followed by Tukey's multiple
comparison test was performed. +P<0.05 vs. control,
*P<0.05 vs. DOX). DOX, doxorubicin; PTUPB,
4-[5-phen-yl-3-[3-[[[[4-(trifluoromethyl)phenyl]amino]carbonyl]amino]propyl]-1H-pyrazol-1-yl]-benzenesulfonamide;
gpx, glutathione peroxidase; cat, catalase; hmox, heme oxygenase
1a; nqo1, NAD(P)H dehydrogenase quinone 1; cas-3, caspase 3; cas-7,
caspase 7.](/article_images/mmr/33/3/mmr-33-03-13810-g04.jpg)
![Impact of PTUPB on the proteomic
profile of zebrafish treated with DOX. Volcano comparison plot of
-log10 P-values vs. log2 fold change of
differentially expressed proteins for (A) DOX vs. control and (B)
DOX + PTUPB vs. DOX. (C) Heatmap of significant differential
expression of proteins for control larvae, and zebrafish larvae
treated with DOX alone or a combination of DOX and PTUPB. PTUPB,
4-[5-phenyl-3-[3-[[[[4-(trifluoromethyl)phenyl]amino]carbonyl]amino]propyl]-1H-pyrazol-1-yl]-benzenesulfonamide;
DOX, doxorubicin.](/article_images/mmr/33/3/mmr-33-03-13810-g05.jpg)
![PTUPB does not negate the anticancer
effect of DOX in human breast cancer cells. Viability of MDA-MB-231
cells treated with (A) PTUPB alone or (B) DOX with PTUPB.
MDA-MB-231 cells were treated with 2 µM DOX alone or in combination
with 1 µM PTUPB for 24 h. Gene expression levels of apoptotic
markers (C) CAS-3, (D) BAX, (E) BCL2 and (F) BCL-XL. One-way ANOVA
followed by Tukey's multiple comparison test was performed to
determine the significant difference between groups
(+P<0.05 vs. control, *P<0.05 vs. DOX). DOX,
doxorubicin; PTUPB,
4-[5-phenyl-3-[3-[[[[4-(trifluoromethyl)phenyl]amino]carbonyl]amino]propyl]-1H-pyrazol-1-yl]-benzenesulfonamide;
Cas-3, caspase-3.](/article_images/mmr/33/3/mmr-33-03-13810-g06.jpg)
![Binding modes of docked PTUPB within
the active sites of the h- and z-COX-2 isoforms. (A) h-COX-2-PTUPB
complex. (B) z-COX-2-PTUPB complex. In each panel, there is a 3D
surface representation of the binding site along with a 2D
interaction map. The surface is colored according to
hydrophobicity, and the interacting amino acids are colored
according to the type of intermolecular interaction they are
involved in. (C) Superimposition of PTUPB in each complex and
binding orientation of celecoxib. PTUPB,
4-[5-phenyl-3-[3-[[[[4-(trifluoromethyl)phenyl]amino]carbonyl]amino]propyl]-1H-pyrazol-1-yl]-benzenesulfonamide;
COX-2, cyclooxygenase-2; h-, human; z-, zebrafish.](/article_images/mmr/33/3/mmr-33-03-13810-g07.jpg)
![Binding modes of docked PTUPB within
the active sites of the h- and z-sEH isoforms. (A) h-sEH-PTUPB
complex. (B) z-sEH-PTUPB complex. (C) Superimposition of PTUPB in
(A and B). PTUPB,
4-[5-phenyl-3-[3-[[[[4-(trifluoromethyl)phenyl]amino]carbonyl]amino]propyl]-1H-pyrazol-1-yl]-benzenesulfonamide;
sEH, soluble epoxide hydrolase; h-, human; z-, zebrafish.](/article_images/mmr/33/3/mmr-33-03-13810-g08.jpg)
![t-AUCB prevents DOX-induced cardiac
and vascular dysfunction in zebrafish. (A) Schematic representation
of the treatment protocol. (B) Representative images of cardiac
morphology in zebrafish larvae at 72 hpf. (C) Cross-sectional area
of cardiac edema in mm2. (D) Stroke volume, (E) cardiac
output and (F) arterial pulse in zebrafish larvae treated with DOX
and t-AUCB at 72 hpf. (G and I) Blood velocity and (H and J)
diameter for the (G and H) DA and (I and J) PCV of zebrafish.
One-way ANOVA followed by Tukey's multiple comparison test was
performed to determine the significant differences between groups
(+P<0.05 vs. control, *P<0.05 vs. DOX). DOX,
doxorubicin; t-AUCB,
4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic
acid; hpf, hours post-fertilization; DA, dorsal aorta; PCV,
posterior cardinal vein.](/article_images/mmr/33/3/mmr-33-03-13810-g09.jpg)
![Inhibition of epoxyeicosatrienoic
acid formation using MSPPOH abolishes the protective effect of
PTUPB against DOX-induced cardiac and vascular dysfunction in
zebrafish. (A) Schematic representation of the treatment protocol.
(B) Representative images of cardiac morphology in zebrafish larvae
at 72 hpf. (C) Cross-sectional area of cardiac edema in
mm2. (D) Stroke volume, (E) cardiac output and (F)
arterial pulse in zebrafish larvae treated with DOX and PTUPB with
or without MSPPOH at 72 hpf. (G and I) Blood velocity and (H and J)
diameter for the (G and H) DA and (I and J) PCV of zebrafish.
One-way ANOVA followed by Tukey's multiple comparison test was
performed to determine the significant differences between groups
(+P<0.05 vs. control, *P<0.05 vs. DOX,
#P<0.05 vs. DOX + PTUPB). MSPPOH,
N-methylsulfonyl-6-(2-propargyloxyphenyl)-hexanamide; PTUPB,
4-[5-phenyl-3-[3-[[[[4-(trifluoromethyl)phenyl]amino]carbonyl]amino]propyl]-1H-pyrazol-1-yl]-benzenesulfonamide;
hpf, hours post-fertilization; DOX, doxorubicin; DA, dorsal aorta;
PCV, posterior cardinal vein.](/article_images/mmr/33/3/mmr-33-03-13810-g10.jpg)
![Schematic of the beneficial effect of
PTUPB on DOX-induced endothelial, vascular and cardiac toxicity.
DOX, doxorubicin; PTUPB,
4-[5-phenyl-3-[3-[[[[4-(trifluoromethyl)phenyl]amino]carbonyl]amino]propyl]-1H-pyrazol-1-yl]-benzenesulfonamide;
hpf, hours post-fertilization; DHET, dihydroxyeicosatrienoic acid;
sEH, soluble epoxide hydrolase; EET, epoxyeicosatrienoic acid;
CYP450, cytochrome P450; COX-2, cyclooxygenase-2; EHET,
poxyhydroxyeicosatrienoic acid; PGE2, prostaglandin
E2; ROS, reactive oxygen species.](/article_images/mmr/33/3/mmr-33-03-13810-g11.jpg)
