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Regulation of the apoptosis/autophagy switch by propionic acid in ventromedial hypothalamus of rats with type 2 diabetes mellitus

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 neuroprote...

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Autores principales: Natrus, Larysa, Osadchuk, Yuliia, Lisakovska, Olha, Roch, Toralf, Babel, Nina, Klys, Yuliia, Labudzynskyi, Dmytro, Chaikovsky, Yuri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9681650/
https://www.ncbi.nlm.nih.gov/pubmed/36439719
http://dx.doi.org/10.1016/j.heliyon.2022.e11529
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author Natrus, Larysa
Osadchuk, Yuliia
Lisakovska, Olha
Roch, Toralf
Babel, Nina
Klys, Yuliia
Labudzynskyi, Dmytro
Chaikovsky, Yuri
author_facet Natrus, Larysa
Osadchuk, Yuliia
Lisakovska, Olha
Roch, Toralf
Babel, Nina
Klys, Yuliia
Labudzynskyi, Dmytro
Chaikovsky, Yuri
author_sort Natrus, Larysa
collection PubMed
description 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.
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spelling pubmed-96816502022-11-24 Regulation of the apoptosis/autophagy switch by propionic acid in ventromedial hypothalamus of rats with type 2 diabetes mellitus Natrus, Larysa Osadchuk, Yuliia Lisakovska, Olha Roch, Toralf Babel, Nina Klys, Yuliia Labudzynskyi, Dmytro Chaikovsky, Yuri Heliyon Research Article 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. Elsevier 2022-11-14 /pmc/articles/PMC9681650/ /pubmed/36439719 http://dx.doi.org/10.1016/j.heliyon.2022.e11529 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Natrus, Larysa
Osadchuk, Yuliia
Lisakovska, Olha
Roch, Toralf
Babel, Nina
Klys, Yuliia
Labudzynskyi, Dmytro
Chaikovsky, Yuri
Regulation of the apoptosis/autophagy switch by propionic acid in ventromedial hypothalamus of rats with type 2 diabetes mellitus
title Regulation of the apoptosis/autophagy switch by propionic acid in ventromedial hypothalamus of rats with type 2 diabetes mellitus
title_full Regulation of the apoptosis/autophagy switch by propionic acid in ventromedial hypothalamus of rats with type 2 diabetes mellitus
title_fullStr Regulation of the apoptosis/autophagy switch by propionic acid in ventromedial hypothalamus of rats with type 2 diabetes mellitus
title_full_unstemmed Regulation of the apoptosis/autophagy switch by propionic acid in ventromedial hypothalamus of rats with type 2 diabetes mellitus
title_short Regulation of the apoptosis/autophagy switch by propionic acid in ventromedial hypothalamus of rats with type 2 diabetes mellitus
title_sort regulation of the apoptosis/autophagy switch by propionic acid in ventromedial hypothalamus of rats with type 2 diabetes mellitus
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9681650/
https://www.ncbi.nlm.nih.gov/pubmed/36439719
http://dx.doi.org/10.1016/j.heliyon.2022.e11529
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