PMID- 36439719 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20221129 IS - 2405-8440 (Print) IS - 2405-8440 (Electronic) IS - 2405-8440 (Linking) VI - 8 IP - 11 DP - 2022 Nov TI - Regulation of the apoptosis/autophagy switch by propionic acid in ventromedial hypothalamus of rats with type 2 diabetes mellitus. PG - e11529 LID - 10.1016/j.heliyon.2022.e11529 [doi] LID - e11529 AB - BACKGROUND: Hypothalamic dysregulation may cause abnormal glucose metabolism and type 2 diabetes mellitus (T2DM). The balance between autophagy and apoptosis is important for maintaining cellular/tissue homeostasis and may be disrupted in T2DM. OBJECTIVES: Since propionic acid (PA) exerts neuroprotective effects, the aim was to investigate its effects on apoptosis/autophagy switch in the ventromedial hypothalamus (VMH) of T2DM rats. MATERIALS AND METHODS: Male Wistar rats were divided: 1) control; 2) T2DM; groups that received (14 days, orally): 3) metformin (60 mg/kg); 4) sodium salt of PA (60 mg/kg); 5) PA + metformin. Western blotting (Bax, Bcl-xl, LC3, Beclin-1, caspase-3), RT-PCR (Bax, Bcl-xl, LC3, Beclin-1), transmission electron microscopy and immunohistochemical staining (Bax, Bcl-xl) were performed on the VMH samples. RESULTS: T2DM-induced apoptosis and mitoptosis, enlarged endoplasmic reticulum (ER) tubules/cisterns were observed in VMH, and accompanied by an imbalance of pro- and anti-apoptotic factors: elevation of pro-apoptotic markers Bax and caspase-3, decrease in autophagy protein LC3 and anti-apoptotic Bcl-xl. Metformin and PA administration partially improved VMH ultrastructural changes by reducing mitochondrial swelling and diminishing the number of apoptotic neurons. Metformin inhibited neuronal apoptosis, however, caused reactive astrogliosis and accumulation of lipofuscin granules. Elevated number of autophagosomes was associated with the LC3, Beclin-1 and Bcl-xl increase and decrease in Bax and caspase-3 vs. T2DM. PA switched cell fate from apoptosis to autophagy by elevating LC3 and Beclin-1 levels, increasing Bcl-xl content that altogether may represent adaptive response to T2DM-induced apoptosis. PA + metformin administration lowered relative area of ER membranes/cisterns vs. control, T2DM and metformin, and was optimal considering ratio between the pro-apoptotic, anti-apoptotic and autophagy markers. CONCLUSION: T2DM was associated with apoptosis activation leading to impairments in VMH. PA in combination with metformin may be effective against diabetes-induced cell death by switching apoptosis to autophagy in VMH. CI - (c) 2022 The Author(s). FAU - Natrus, Larysa AU - Natrus L AD - Department of Modern Technologies of Medical Diagnostics & Treatment, Bogomolets National Medical University, 34 Peremoha Avenue, Kyiv 03115, Ukraine. FAU - Osadchuk, Yuliia AU - Osadchuk Y AD - Department of Histology and Embryology, Bogomolets National Medical University, 34 Peremoha Avenue, Kyiv 03115, Ukraine. FAU - Lisakovska, Olha AU - Lisakovska O AD - Department of Biochemistry of Vitamins and Coenzymes, Palladin Institute of Biochemistry, 9 Leontovicha Str., Kyiv 01054, Ukraine. FAU - Roch, Toralf AU - Roch T AD - Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr University Bochum, Holkeskampring 40, 44625 Herne, Germany. AD - Charite - Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, Berlin Center for Advanced Therapies (BeCAT), Augustenburger Platz 1, 13353 Berlin, Germany. FAU - Babel, Nina AU - Babel N AD - Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr University Bochum, Holkeskampring 40, 44625 Herne, Germany. AD - Charite - Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, Berlin Center for Advanced Therapies (BeCAT), Augustenburger Platz 1, 13353 Berlin, Germany. FAU - Klys, Yuliia AU - Klys Y AD - Department of Modern Technologies of Medical Diagnostics & Treatment, Bogomolets National Medical University, 34 Peremoha Avenue, Kyiv 03115, Ukraine. FAU - Labudzynskyi, Dmytro AU - Labudzynskyi D AD - Department of Biochemistry of Vitamins and Coenzymes, Palladin Institute of Biochemistry, 9 Leontovicha Str., Kyiv 01054, Ukraine. FAU - Chaikovsky, Yuri AU - Chaikovsky Y AD - Department of Histology and Embryology, Bogomolets National Medical University, 34 Peremoha Avenue, Kyiv 03115, Ukraine. LA - eng PT - Journal Article DEP - 20221114 PL - England TA - Heliyon JT - Heliyon JID - 101672560 PMC - PMC9681650 OTO - NOTNLM OT - Apoptosis OT - Autophagy OT - Metformin OT - Propionic acid OT - Type 2 diabetes OT - Ventromedial hypothalamus COIS- The authors declare no conflict of interest. EDAT- 2022/11/29 06:00 MHDA- 2022/11/29 06:01 PMCR- 2022/11/14 CRDT- 2022/11/28 04:42 PHST- 2022/03/05 00:00 [received] PHST- 2022/06/07 00:00 [revised] PHST- 2022/11/04 00:00 [accepted] PHST- 2022/11/28 04:42 [entrez] PHST- 2022/11/29 06:00 [pubmed] PHST- 2022/11/29 06:01 [medline] PHST- 2022/11/14 00:00 [pmc-release] AID - S2405-8440(22)02817-1 [pii] AID - e11529 [pii] AID - 10.1016/j.heliyon.2022.e11529 [doi] PST - epublish SO - Heliyon. 2022 Nov 14;8(11):e11529. doi: 10.1016/j.heliyon.2022.e11529. eCollection 2022 Nov.