INTIMP-D-21-00845_R2-1 (2).pdf (2.24 MB)
Metformin inhibits polyphosphate-induced hyper-permeability and inflammation
journal contribution
posted on 2023-06-10, 00:37 authored by Ferehteh Asgharzadeh, Farnaz Barneh, Maryam Fakhraie, Seyede Leile Adel barkhordar, Mohammad Shabani, Atena Soleimani, Farzad Rahmani, Fatemeh Ariakia, Saeedeh Mehraban, Amir Avan, Milad Hashemzehi, Mohammad-Hassan Arjmand, Reyhaneh Behnam-Rassouli, Najmeh Jaberi, Sayyed-Hadi Sayyed-Hosseinian, Gordon FernsGordon Ferns, Mikhail Ryzhikov, Mohieddin Jafari, Majid Khazaei, Seyed Mahdi HassanianCirculating inflammatory factor inorganic polyphosphate (polyP) released from activated platelets could enhance factor XII and bradykinin resulted in increased capillary leakage and vascular permeability. PolyP induce inflammatory responses through mTOR pathway in endothelial cells, which is being reported in several diseases including atherosclerosis, thrombosis, sepsis, and cancer. Systems and molecular biology approaches were used to explore the regulatory role of the AMPK activator, metformin, on polyP-induced hyper-permeability in different organs in three different models of polyP-induced hyper-permeability including local, systemic short- and systemic long-term approaches in murine models. Our results showed that polyP disrupts endothelial barrier integrity in skin, liver, kidney, brain, heart, and lung in all three study models and metformin abrogates the disruptive effect of polyP. We also showed that activation of AMPK signaling pathway, regulation of oxidant/anti-oxidant balance, as well as decrease in inflammatory cell infiltration constitute a set of molecular mechanisms through which metformin elicits it's protective responses against polyP-induced hyper-permeability. These results support the clinical values of AMPK activators including the FDA-approved metformin in attenuating vascular damage in polyP-associated inflammatory diseases.
History
Publication status
- Published
File Version
- Accepted version
Journal
International ImmunopharmacologyISSN
1567-5769Publisher
ElsevierExternal DOI
Volume
99Article number
a107937Department affiliated with
- Division of Medical Education Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-08-13First Open Access (FOA) Date
2021-08-13First Compliant Deposit (FCD) Date
2021-08-12Usage metrics
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