Mild exacerbation of obesity- and age-dependent liver disease
progression by senolytic cocktail dasatinib plus quercetin

J 2021

Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib plus quercetin

RAFFAELE, Marco, Kristína KOVAČOVICOVÁ, Jan FROHLICH, Oriana LO RE, Sebastiano GIALLONGO et. al.

Basic information

Original name

Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib plus quercetin

Authors

RAFFAELE, Marco (guarantor), Kristína KOVAČOVICOVÁ (703 Slovakia), Jan FROHLICH (203 Czech Republic), Oriana LO RE, Sebastiano GIALLONGO (380 Italy, belonging to the institution), J. A. OBEN, Martin FALDYNA (203 Czech Republic), Lenka LEVA (203 Czech Republic), Antonino Giulio GIANNONE, Daniela CABIBI and Manlio VINCIGUERRA

Edition

Cell Communication and Signaling, LONDON, BMC, 2021, 1478-811X

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10601 Cell biology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 7.525

RIV identification code

RIV/00216224:14110/21:00122130

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1186/s12964-021-00731-0

UT WoS

000639130700003

Keywords in English

Senolytics; Liver diseases; Inflammation; Cancer; Obesity

Abstract

V originále

Background Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. A minority of affected patients develops inflammation, subsequently fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCC is a leading cause of cancer-related death. An increased number of senescent cells correlate with age-related tissue degeneration during NAFLD-induced HCC. Senolytics are promising agents that target selectively senescent cells. Previous studies showed that whereas a combination of the senolytic drugs dasatinib and quercetin (D + Q) reduced NAFLD in mice, D + Q lacked efficacy in removing doxorubicin-induced beta-gal-positive senescent cells in human HCC xenografted mice. Whether D + Q has an effect on the age-associated spectrum of NAFLD-inflammation-HCC remains unknown. Methods Here, we utilized an established model of age- and obesity-associated HCC, the low dose diethylnitrosamine (DEN)/high fat diet (HFD), a regimen promoting liver inflammation and tumorigenesis over a long period of 9 months. Four groups of mice each were created: group 1 included control untreated mice; group 2 included mice treated with D + Q; group 3 included mice undergoing the DEN/HFD protocol; group 4 included mice undergoing the DEN/HFD protocol with the administration of D + Q. At the end of the chemical/dietary regimen, we analyzed liver damage and cell senescence by histopathology, qPCR and immunoblotting approaches. Results Unexpectedly, D + Q worsened liver disease progression in the DEN/HFD mouse model, slightly increasing histological damage and tumorigenesis, while having no effect on senescent cells removal. Conclusions In summary, using an animal model that fully recapitulates NAFLD, we demonstrate that these compounds are ineffective against age-associated NAFLD-induced HCC.

Links

MUNI/A/1325/2020, interní kód MU

Name: Biomedicínské vědy

Investor: Masaryk University

Citovat

RAFFAELE, Marco, Kristína KOVAČOVICOVÁ, Jan FROHLICH, Oriana LO RE, Sebastiano GIALLONGO, J. A. OBEN, Martin FALDYNA, Lenka LEVA, Antonino Giulio GIANNONE, Daniela CABIBI and Manlio VINCIGUERRA. Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib plus quercetin. Cell Communication and Signaling. LONDON: BMC, 2021, vol. 19, No 1, p. 1-9. ISSN 1478-811X. Available from: https://dx.doi.org/10.1186/s12964-021-00731-0.

@article{1786885,
   author = {Raffaele, Marco and Kovačovicová, Kristína and Frohlich, Jan and Lo Re, Oriana and Giallongo, Sebastiano and Oben, J. A. and Faldyna, Martin and Leva, Lenka and Giannone, Antonino Giulio and Cabibi, Daniela and Vinciguerra, Manlio},
   article_location = {LONDON},
   article_number = {1},
   doi = {http://dx.doi.org/10.1186/s12964-021-00731-0},
   keywords = {Senolytics; Liver diseases; Inflammation; Cancer; Obesity},
   language = {eng},
   issn = {1478-811X},
   journal = {Cell Communication and Signaling},
   title = {Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib plus quercetin},
   url = {https://biosignaling.biomedcentral.com/articles/10.1186/s12964-021-00731-0},
   volume = {19},
   year = {2021}
}

TY  - JOUR
ID  - 1786885
AU  - Raffaele, Marco - Kovačovicová, Kristína - Frohlich, Jan - Lo Re, Oriana - Giallongo, Sebastiano - Oben, J. A. - Faldyna, Martin - Leva, Lenka - Giannone, Antonino Giulio - Cabibi, Daniela - Vinciguerra, Manlio
PY  - 2021
TI  - Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib plus quercetin
JF  - Cell Communication and Signaling
VL  - 19
IS  - 1
SP  - 1-9
EP  - 1-9
PB  - BMC
SN  - 1478811X
KW  - Senolytics
KW  - Liver diseases
KW  - Inflammation
KW  - Cancer
KW  - Obesity
UR  - https://biosignaling.biomedcentral.com/articles/10.1186/s12964-021-00731-0
N2  - Background Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. A minority of affected patients develops inflammation, subsequently fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCC is a leading cause of cancer-related death. An increased number of senescent cells correlate with age-related tissue degeneration during NAFLD-induced HCC. Senolytics are promising agents that target selectively senescent cells. Previous studies showed that whereas a combination of the senolytic drugs dasatinib and quercetin (D + Q) reduced NAFLD in mice, D + Q lacked efficacy in removing doxorubicin-induced beta-gal-positive senescent cells in human HCC xenografted mice. Whether D + Q has an effect on the age-associated spectrum of NAFLD-inflammation-HCC remains unknown. Methods Here, we utilized an established model of age- and obesity-associated HCC, the low dose diethylnitrosamine (DEN)/high fat diet (HFD), a regimen promoting liver inflammation and tumorigenesis over a long period of 9 months. Four groups of mice each were created: group 1 included control untreated mice; group 2 included mice treated with D + Q; group 3 included mice undergoing the DEN/HFD protocol; group 4 included mice undergoing the DEN/HFD protocol with the administration of D + Q. At the end of the chemical/dietary regimen, we analyzed liver damage and cell senescence by histopathology, qPCR and immunoblotting approaches. Results Unexpectedly, D + Q worsened liver disease progression in the DEN/HFD mouse model, slightly increasing histological damage and tumorigenesis, while having no effect on senescent cells removal. Conclusions In summary, using an animal model that fully recapitulates NAFLD, we demonstrate that these compounds are ineffective against age-associated NAFLD-induced HCC.
ER  -

RAFFAELE, Marco, Kristína KOVAČOVICOVÁ, Jan FROHLICH, Oriana LO RE, Sebastiano GIALLONGO, J. A. OBEN, Martin FALDYNA, Lenka LEVA, Antonino Giulio GIANNONE, Daniela CABIBI and Manlio VINCIGUERRA. Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib plus quercetin. \textit{Cell Communication and Signaling}. LONDON: BMC, 2021, vol.~19, No~1, p.~1-9. ISSN~1478-811X. Available from: https://dx.doi.org/10.1186/s12964-021-00731-0.

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