Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. In Vivo Evaluation of the Anti-Fibrogenic Potential of CM414, a Dual HDAC-PDE5 Inhibitor
2.2. Mechanisms of CM414 Anti-Fibrogenic and Anti-Inflammatory Effects
3. Discussion
4. Materials and Methods
4.1. CM414
4.2. Animal Studies
4.3. Immunohistochemistry and Tissue Staining
4.4. Cell Culture and Treatments
4.5. Immunoblotting
4.6. RNA Isolation and Quantitative Real-Time RT-PCR
4.7. Histone Extraction
4.8. Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
Gene | Fw Sequence 5′-3′ | Rev Sequence 5′-3′ |
---|---|---|
Ck19 (mouse) | CTCGGATTGAGGAGCTGAAC | TCACGCTCTGGATCTGTGAC |
ColIα1 (mouse) | CAGATTGAGAACATCCGCAG | GAATCCATCGGTCATGCTCTC |
H3f3a (mouse) | AAAGCCGCTCGCAAGAGTGCG | ACTTGCCTCCTGCAAAGCAC |
Hdac1 (mouse) | CTACTACGACGGGGATGTTGG | GAATCTCTGCATCTGCTTGCT |
Hdac2 (mouse) | GAGGGATATTGGTGCTGGAA | AAGGGCAACTGCAGTCTCAT |
Hdac3 (mouse) | GAGAGTCAGCCCCACCAATA | GACCCGGTCAGTGAGGTAGA |
Hdac6 (mouse) | GCTGACTACATTGCTGCTTTCCT | ACTCCAGCATGGGGCAAG |
Il-1β (mouse) | CATTGTGGCTGTGGAGAAGC | CCTTGTACAAAGCTCATGGAG |
Il-10 (mouse) | CTGCACCCACTTCCCAG | AGAAATCGATGACAGCG |
iNos (mouse) | GTGAGGATCAAAAACTGG | TTTGCCTCTTTGAAGGAGC |
Lox (mouse) | TAGGGCGGATGTCAGAGACT | CCAGGACTCAATCCCTGTGT |
Mcp1 (mouse) | CCACTCACCTGCTGCTACTC | TTCACATTCAAAGGTGCTGAAG |
Mmp13 (mouse) | CCTGATGTGGGTGAATACAATG | GGTTTCATCATCATCAAAATGG |
Pde5 (mouse) | GAAGGGGACCAGTGCTCAAG | CCACAATGCCTTTGTTCCA |
Tenascin C (mouse) | GGATTGGTGTTTCTGCTGTCAA | TTTCAGACACCCGTAAGTCCTT |
Tgfβ2 (mouse) | CAGATCCTGAGCAAGCTGAA | CTGAAGTAGGGTCTGTAGAAAGTGG |
Timp1 (mouse) | AGACCACCTTATACCAGCG | AACAGGGAAACACTGTGCA |
Tnfα (mouse) | GAGTGACAAGCCTGTAGCCC | CCCTTCTCCAGCTGGAAGAC |
Wnt-5a (mouse) | GTCCTTTGAGATGGGTGGTATC | ACCTCTGGGTTAGGGAGTGTCT |
α-SMA (human) | CCAGGGCTGTTTTCCCATCC | GTCATTTTCTCCCGGTTGGCC |
BAMBI (human) | TGGATCGCCACTCCAGCTA | TGTCTTCATGACAGCATTCCA |
c-MYC (human) | CTCAACGACAGCAGCTCGCC | CTTGAGGACCAGTGGGCTGTG |
COLIα1 (human) | CAGATTGAGAACATCCGCAG | GAATCCATCGGTCATGCTCTC |
DKK1 (human) | CAAAAATGTATCACACCAAAGG | TGGCTTGATGGTGATCTTTC |
DKK2 (human) | TGCCACAGTCCCCACCAA | TACAGACTTCCCCCTGATGG |
sGCβ1 (human) | GCAAGCATGCATCTGGAGAA | CCAGCAATTTCCATCATGTC |
GFAP (human) | GAGATGATGGAGCTCAATGAC | TCCAGCCTCAGGTTGGTTTC |
H3F3A (human) | AAAGCCGCTCGCAAGAGTGCG | ACTTGCCTCCTGCAAAGCAC |
IL-6 (human) | CCTTCCAAAGATGGCTGAAA | AAAGCTGCGCAGAATGAGAT |
MCP1 (human) | TCTGCCGCCCTTCTGTGCCTG | CTTCTTTGGGACACTTGCTGC |
PDGFRβ (human) | GTGATGTGGGAACAGATGTCC | GAGGAAGCCCATGGTGGGATC |
PGC-1α (human) | GCTGACAGATGGAGACGTGA | GTGTGAGGAGGGTCATCGTT |
PI3K (human) | ATTGAACCAGTAGGCAACCG | GAAACTATTACCCAGATCACCAC |
PKG (human) | CGCCAACCTGAAGCTGTCT | CCTTTGGAATGCAGATAGGC |
PTEN (human) | GACTTAGACTTGACCTATATTTATCC | ACTCCCTTTTTGTCTCTGGTCC |
TGFβ2 (human) | CAGATCCTGAGCAAGCTGAA | CTGAAGTAGGGTCTGTAGAAAGTGG |
WNT-5A (human) | GGGTGGGAACCAAGAAAAAT | TGGAACCTACCCATCCCATA |
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Claveria-Cabello, A.; Colyn, L.; Uriarte, I.; Latasa, M.U.; Arechederra, M.; Herranz, J.M.; Alvarez, L.; Urman, J.M.; Martinez-Chantar, M.L.; Banales, J.M.; et al. Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis. Cancers 2020, 12, 3748. https://doi.org/10.3390/cancers12123748
Claveria-Cabello A, Colyn L, Uriarte I, Latasa MU, Arechederra M, Herranz JM, Alvarez L, Urman JM, Martinez-Chantar ML, Banales JM, et al. Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis. Cancers. 2020; 12(12):3748. https://doi.org/10.3390/cancers12123748
Chicago/Turabian StyleClaveria-Cabello, Alex, Leticia Colyn, Iker Uriarte, Maria Ujue Latasa, Maria Arechederra, Jose M. Herranz, Laura Alvarez, Jesus M. Urman, Maria L. Martinez-Chantar, Jesus M. Banales, and et al. 2020. "Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis" Cancers 12, no. 12: 3748. https://doi.org/10.3390/cancers12123748