TY - JOUR
T1 - Linagliptin, a DPP-4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver
T2 - Novel mechanistic insights
AU - Abdelhady, Rasha
AU - Mohammed, Osama A.
AU - Doghish, Ahmed S.
AU - Hamad, Rabab S.
AU - Abdel-Reheim, Mustafa Ahmed
AU - Alamri, Mohannad Mohammad S.
AU - Alharthi, Muffarah Hamid
AU - Alfaifi, Jaber
AU - Adam, Masoud I.E.
AU - Alhalafi, Abdullah Hassan
AU - Mohammed, Nahid A.
AU - Isa, Adamu Imam
AU - Abdel-Ghany, Sameh
AU - Attia, Mohammed A.
AU - Elmorsy, Elsayed A.
AU - AL-Noshokaty, Tohada M
AU - Nomier, Yousra
AU - El-Dakroury, Walaa A.
AU - Saber, Sameh
N1 - Publisher Copyright:
© 2024 Federation of American Societies for Experimental Biology.
PY - 2024/2/29
Y1 - 2024/2/29
N2 - Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.
AB - Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.
KW - AMPK
KW - diethylnitrosamine
KW - FOXO3a
KW - Linagliptin
KW - liver damage
KW - NFκB
KW - Anti-Inflammatory Agents
KW - Protease Inhibitors
KW - Rats
KW - Linagliptin/pharmacology
KW - Antiviral Agents
KW - AMP-Activated Protein Kinases
KW - Hypoglycemic Agents
KW - Animals
KW - Diethylnitrosamine/toxicity
KW - Carcinoma, Hepatocellular/chemically induced
KW - Dipeptidyl-Peptidase IV Inhibitors
KW - Liver Neoplasms/chemically induced
UR - http://www.scopus.com/inward/record.url?scp=85185220645&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85185220645&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/86b61265-c57c-33d2-a36e-d45df3a3a427/
U2 - 10.1096/fj.202302461rr
DO - 10.1096/fj.202302461rr
M3 - Article
C2 - 38354025
AN - SCOPUS:85185220645
SN - 0892-6638
VL - 38
JO - FASEB Journal
JF - FASEB Journal
IS - 4
M1 - e23480
ER -