RETRACTED: Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases

Hasan Turkez; Ozlem Altay; Serkan Yildirim; Xiangyu Li; Hong Yang; Cemil Bayram; Ismail Bolat; Sena Oner; Ozlem Ozdemir Tozlu; Mehmet Enes Arslan; Muhammad Arif; Burak Yulug; Lutfu Hanoglu; Seyda Cankaya; Simon Lam; Halil Aziz Velioglu; Ebru Coskun; Ezgi Idil; Rahim Nogaylar; Ahmet Ozsimsek; Ahmet Hacimuftuoglu; Saeed Shoaie; Cheng Zhang; Jens Nielsen; Jan Borén; Mathias Uhlén; Adil Mardinoglu

doi:10.1016/j.lfs.2022.121325

RETRACTED: Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases

Hasan Turkez, Ozlem Altay, Serkan Yildirim, Xiangyu Li, Hong Yang, Cemil Bayram, Ismail Bolat, Sena Oner, Ozlem Ozdemir Tozlu, Mehmet Enes Arslan, Muhammad Arif, Burak Yulug, Lutfu Hanoglu, Seyda Cankaya, Simon Lam, Halil Aziz Velioglu, Ebru Coskun, Ezgi Idil, Rahim Nogaylar, Ahmet OzsimsekAhmet Hacimuftuoglu, Saeed Shoaie, Cheng Zhang, Jens Nielsen, Jan Borén, Mathias Uhlén^*, Adil Mardinoglu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

Abstract

Background: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism. Methods: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation. Findings: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats. Interpretation: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.

Original language	English
Article number	121325
Journal	Life Sciences
Volume	314
DOIs	https://doi.org/10.1016/j.lfs.2022.121325
Publication status	Published - 1 Feb 2023

Keywords

Animal model
Combined metabolic activators
Genome-scale metabolic model
Neurodegenerative diseases

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Turkez, H., Altay, O., Yildirim, S., Li, X., Yang, H., Bayram, C., Bolat, I., Oner, S., Tozlu, O. O., Arslan, M. E., Arif, M., Yulug, B., Hanoglu, L., Cankaya, S., Lam, S., Velioglu, H. A., Coskun, E., Idil, E., Nogaylar, R., ... Mardinoglu, A. (2023). RETRACTED: Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases. Life Sciences, 314, Article 121325. https://doi.org/10.1016/j.lfs.2022.121325

@article{e440a1f089dd4b178962e78ebdfd621c,

title = "RETRACTED: Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases",

abstract = "Background: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism. Methods: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation. Findings: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats. Interpretation: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.",

keywords = "Animal model, Combined metabolic activators, Genome-scale metabolic model, Neurodegenerative diseases",

author = "Hasan Turkez and Ozlem Altay and Serkan Yildirim and Xiangyu Li and Hong Yang and Cemil Bayram and Ismail Bolat and Sena Oner and Tozlu, {Ozlem Ozdemir} and Arslan, {Mehmet Enes} and Muhammad Arif and Burak Yulug and Lutfu Hanoglu and Seyda Cankaya and Simon Lam and Velioglu, {Halil Aziz} and Ebru Coskun and Ezgi Idil and Rahim Nogaylar and Ahmet Ozsimsek and Ahmet Hacimuftuoglu and Saeed Shoaie and Cheng Zhang and Jens Nielsen and Jan Bor{\'e}n and Mathias Uhl{\'e}n and Adil Mardinoglu",

note = "Publisher Copyright: {\textcopyright} 2022",

year = "2023",

month = feb,

day = "1",

doi = "10.1016/j.lfs.2022.121325",

language = "English",

volume = "314",

journal = "Life Sciences",

issn = "0024-3205",

publisher = "Elsevier Inc.",

}

Turkez, H, Altay, O, Yildirim, S, Li, X, Yang, H, Bayram, C, Bolat, I, Oner, S, Tozlu, OO, Arslan, ME, Arif, M, Yulug, B, Hanoglu, L, Cankaya, S, Lam, S, Velioglu, HA, Coskun, E, Idil, E, Nogaylar, R, Ozsimsek, A, Hacimuftuoglu, A, Shoaie, S , Zhang, C, Nielsen, J, Borén, J, Uhlén, M & Mardinoglu, A 2023, 'RETRACTED: Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases', Life Sciences, vol. 314, 121325. https://doi.org/10.1016/j.lfs.2022.121325

TY - JOUR

T1 - RETRACTED

T2 - Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases

AU - Turkez, Hasan

AU - Altay, Ozlem

AU - Yildirim, Serkan

AU - Li, Xiangyu

AU - Yang, Hong

AU - Bayram, Cemil

AU - Bolat, Ismail

AU - Oner, Sena

AU - Tozlu, Ozlem Ozdemir

AU - Arslan, Mehmet Enes

AU - Arif, Muhammad

AU - Yulug, Burak

AU - Hanoglu, Lutfu

AU - Cankaya, Seyda

AU - Lam, Simon

AU - Velioglu, Halil Aziz

AU - Coskun, Ebru

AU - Idil, Ezgi

AU - Nogaylar, Rahim

AU - Ozsimsek, Ahmet

AU - Hacimuftuoglu, Ahmet

AU - Shoaie, Saeed

AU - Zhang, Cheng

AU - Nielsen, Jens

AU - Borén, Jan

AU - Uhlén, Mathias

AU - Mardinoglu, Adil

PY - 2023/2/1

Y1 - 2023/2/1

N2 - Background: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism. Methods: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation. Findings: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats. Interpretation: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.

AB - Background: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism. Methods: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation. Findings: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats. Interpretation: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.

KW - Animal model

KW - Combined metabolic activators

KW - Genome-scale metabolic model

KW - Neurodegenerative diseases

UR - http://www.scopus.com/inward/record.url?scp=85145161292&partnerID=8YFLogxK

U2 - 10.1016/j.lfs.2022.121325

DO - 10.1016/j.lfs.2022.121325

M3 - Article

C2 - 36581096

AN - SCOPUS:85145161292

SN - 0024-3205

VL - 314

JO - Life Sciences

JF - Life Sciences

M1 - 121325

ER -

RETRACTED: Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases

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