Combined Treatment with Sodium-Glucose Cotransporter-2 Inhibitor (Canagliflozin) and Dipeptidyl Peptidase-4 Inhibitor (Teneligliptin) Alleviates NASH Progression in A Non-Diabetic Rat Model of Steatohepatitis.
Animals
Cadherins
/ genetics
Canagliflozin
/ pharmacology
Carcinogenesis
/ drug effects
Carcinoma, Hepatocellular
/ drug therapy
Cell Proliferation
/ drug effects
Collagen Type I
/ genetics
Collagen Type I, alpha 1 Chain
Cytokines
/ metabolism
DNA Damage
/ drug effects
Disease Progression
Drug Synergism
Hepatic Stellate Cells
/ drug effects
Human Umbilical Vein Endothelial Cells
Humans
Lipid Peroxidation
/ drug effects
Liver Cirrhosis
/ drug therapy
Liver Neoplasms
/ drug therapy
Male
Neovascularization, Pathologic
/ drug therapy
Non-alcoholic Fatty Liver Disease
/ drug therapy
Pyrazoles
/ pharmacology
Rats
Rats, Inbred Strains
Thiazolidines
/ pharmacology
Transforming Growth Factor beta
/ genetics
Vascular Endothelial Growth Factor A
/ genetics
canagliflozin
hepatic fibrogenesis
hepatocarcinogenesis
non-alcoholic steatohepatitis
teneligliptin
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
21 Mar 2020
21 Mar 2020
Historique:
received:
11
02
2020
revised:
19
03
2020
accepted:
19
03
2020
entrez:
5
4
2020
pubmed:
5
4
2020
medline:
14
1
2021
Statut:
epublish
Résumé
Hepatocellular carcinoma (HCC) is the strongest independent predictor of mortality in non-alcoholic steatohepatitis (NASH)-related cirrhosis. The effects and mechanisms of combination of sodium-dependent glucose cotransporter inhibitor and canagliflozin (CA) and dipeptidyl peptidase-4 inhibitor and teneligliptin (TE) on non-diabetic NASH progression were examined. CA and TE suppressed choline-deficient, L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. CA alone or with TE significantly decreased proinflammatory cytokine expression. CA and TE significantly attenuated hepatic lipid peroxidation. In vitro studies showed that TE alone or with CA inhibited cell proliferation and TGF-β1 and α1 (I)-procollagen mRNA expression in Ac-HSCs. CA+TE inhibited liver fibrogenesis by attenuating hepatic lipid peroxidation and inflammation and by inhibiting Ac-HSC proliferation with concomitant attenuation of hepatic lipid peroxidation. Moreover, CA+TE suppressed in vivo angiogenesis and oxidative DNA damage. CA or CA+TE inhibited HCC cells and human umbilical vein endothelial cell (HUVEC) proliferation. CA+TE suppressed vascular endothelial growth factor expression and promoted increased E-cadherin expression in HUVECs. CA+TE potentially exerts synergistic effects on hepatocarcinogenesis prevention by suppressing HCC cell proliferation and angiogenesis and concomitantly reducing oxidative stress and by inhibiting angiogenesis with attenuation of oxidative stress. CA+TE showed chemopreventive effects on NASH progression compared with single agent in non-diabetic rat model of NASH, concurrent with Ac-HSC and HCC cell proliferation, angiogenesis oxidative stress, and inflammation. Both agents are widely, safely used in clinical practice; combined treatment may represent a potential strategy against NASH.
Identifiants
pubmed: 32245205
pii: ijms21062164
doi: 10.3390/ijms21062164
pmc: PMC7139722
pii:
doi:
Substances chimiques
3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine
0
Cadherins
0
Collagen Type I
0
Collagen Type I, alpha 1 Chain
0
Cytokines
0
Pyrazoles
0
Thiazolidines
0
Transforming Growth Factor beta
0
Vascular Endothelial Growth Factor A
0
Canagliflozin
0SAC974Z85
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
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