PMID- 36139470 OWN - NLM STAT- MEDLINE DCOM- 20220926 LR - 20221128 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 11 IP - 18 DP - 2022 Sep 16 TI - Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain-Barre Syndrome. LID - 10.3390/cells11182897 [doi] LID - 2897 AB - AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolic and immune functions mainly through the inhibition of the mechanistic target of rapamycin (mTOR)-dependent anabolic pathways and the activation of catabolic processes such as autophagy. The AMPK/mTOR signaling pathway and autophagy markers were analyzed by immunoblotting in blood mononuclear cells of 20 healthy control subjects and 23 patients with an acute demyelinating form of Guillain-Barre syndrome (GBS). The activation of the liver kinase B1 (LKB1)/AMPK/Raptor signaling axis was significantly reduced in GBS compared to control subjects. In contrast, the phosphorylated forms of mTOR activator AKT and mTOR substrate 4EBP1, as well as the levels of autophagy markers LC3-II, beclin-1, ATG5, p62/sequestosome 1, and NBR1 were similar between the two groups. The downregulation of LKB1/AMPK signaling, but not the activation status of the AKT/mTOR/4EBP1 pathway or the levels of autophagy markers, correlated with higher clinical activity and worse outcomes of GBS. A retrospective study in a diabetic cohort of GBS patients demonstrated that treatment with AMPK activator metformin was associated with milder GBS compared to insulin/sulphonylurea therapy. In conclusion, the impairment of the LKB1/AMPK pathway might contribute to the development/progression of GBS, thus representing a potential therapeutic target in this immune-mediated peripheral polyneuropathy. FAU - Paunovic, Verica AU - Paunovic V AUID- ORCID: 0000-0002-4912-7761 AD - Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia. FAU - Peric, Stojan AU - Peric S AUID- ORCID: 0000-0002-2979-556X AD - Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, Serbia. FAU - Vukovic, Irena AU - Vukovic I AD - Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia. FAU - Stamenkovic, Marina AU - Stamenkovic M AD - Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia. FAU - Milosevic, Emina AU - Milosevic E AUID- ORCID: 0000-0002-8155-0658 AD - Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia. FAU - Stevanovic, Danijela AU - Stevanovic D AD - Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia. FAU - Mandic, Milos AU - Mandic M AD - Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia. FAU - Basta, Ivana AU - Basta I AD - Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, Serbia. FAU - Berisavac, Ivana AU - Berisavac I AD - Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, Serbia. FAU - Arsenijevic, Mirjana AU - Arsenijevic M AD - Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, Serbia. FAU - Bozovic, Ivo AU - Bozovic I AD - Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, Serbia. FAU - Nikolic, Marko AU - Nikolic M AD - Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, Serbia. FAU - Stevic, Zorica AU - Stevic Z AD - Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr. Subotica 6, 11000 Belgrade, Serbia. FAU - Trajkovic, Vladimir AU - Trajkovic V AUID- ORCID: 0000-0002-8061-2968 AD - Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220916 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (Beclin-1) RN - 0 (Insulins) RN - 9100L32L2N (Metformin) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - AMP-Activated Protein Kinases/metabolism MH - Beclin-1/metabolism MH - Down-Regulation MH - *Guillain-Barre Syndrome MH - Humans MH - *Insulins/metabolism MH - *Metformin MH - Proto-Oncogene Proteins c-akt/metabolism MH - Retrospective Studies MH - Signal Transduction MH - Sirolimus MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC9496801 OTO - NOTNLM OT - AMP-activated protein kinase OT - Guillain-Barre syndrome OT - autophagy OT - mTOR OT - metformin OT - peripheral blood mononuclear cells COIS- The authors declare no conflict of interest. The sponsors had no role in the design, execution, interpretation, or writing of the study. EDAT- 2022/09/24 06:00 MHDA- 2022/09/28 06:00 PMCR- 2022/09/16 CRDT- 2022/09/23 01:06 PHST- 2022/05/15 00:00 [received] PHST- 2022/09/06 00:00 [revised] PHST- 2022/09/07 00:00 [accepted] PHST- 2022/09/23 01:06 [entrez] PHST- 2022/09/24 06:00 [pubmed] PHST- 2022/09/28 06:00 [medline] PHST- 2022/09/16 00:00 [pmc-release] AID - cells11182897 [pii] AID - cells-11-02897 [pii] AID - 10.3390/cells11182897 [doi] PST - epublish SO - Cells. 2022 Sep 16;11(18):2897. doi: 10.3390/cells11182897.