tDCS Regulates ASBT-3-OxoLCA-PLOD2-PTEN Signaling Pathway to Confer Neuroprotection Following Rat Cerebral Ischemia-Reperfusion Injury

Xiangyi Kong; Xujin Yao; Jinyang Ren; Jingchen Gao; Yu Cui; Jiangdong Sun; Xiangyu Xu; Wenjie Hu; Hui Wang; Huanting Li; Oleg Glebov; Fengyuan Che; Qi Wan

doi:10.1007/s12035-023-03504-7

tDCS Regulates ASBT-3-OxoLCA-PLOD2-PTEN Signaling Pathway to Confer Neuroprotection Following Rat Cerebral Ischemia-Reperfusion Injury

Xiangyi Kong, Xujin Yao, Jinyang Ren, Jingchen Gao, Yu Cui, Jiangdong Sun, Xiangyu Xu, Wenjie Hu, Hui Wang, Huanting Li, Oleg Glebov, Fengyuan Che^*, Qi Wan^*

^*Corresponding author for this work

Old Age Psychiatry

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

9 Citations (Scopus)

Abstract

Humans exhibit a rich intestinal microbiome that contain high levels of bacteria capable of producing 3-oxo-lithocholic acid (3-oxoLCA) and other secondary bile acids (BAs). The molecular mechanism mediating the role of 3-oxoLCA in cerebral ischemia-reperfusion (I/R) injury remains unclear. We investigated the role of 3-oxoLCA in a rat cerebral I/R injury model. We found that the concentrations of 3-oxoLCA within the cerebrospinal fluid were increased following I/R. In the in vitro oxygen-glucose deprivation (OGD) model, the levels of intraneuronal 3-oxoLCA was elevated following OGD insult. We showed that the increase of membrane ASBT (apical sodium-dependent bile acid transporter) contributed to OGD-induced elevation of intraneuronal 3-oxoLCA. Increasing intraneuronal 3-oxoLCA promoted ischemia-induced neuronal death, whereas reducing 3-oxoLCA levels were neuroprotective. Our results revealed that PLOD2 (procollagen-lysine, 2-oxoglutarate 5-dioxygenases 2) functioned upstream of PTEN (the phosphatase and tensin homolog deleted on chromosome 10) and downstream of 3-oxoLCA to promote OGD-induced neuronal injury. We further demonstrated that direct-current stimulation (DCS) decreased the levels of intraneuronal 3-oxoLCA and membrane ASBT in OGD-insulted neurons, while bilateral transcranial DCS (tDCS) reduced brain infarct volume following I/R by inhibiting ASBT. Together, these data suggest that increased expression of ASBT promotes neuronal death via 3-oxoLCA-PLOD2-PTEN signaling pathway. Importantly, bilateral tDCS suppresses ischemia-induced increase of ASBT, thereby conferring neuroprotection after cerebral I/R injury.

Original language	English
Pages (from-to)	6715-6730
Number of pages	16
Journal	Molecular Neurobiology
Volume	60
Issue number	11
DOIs	https://doi.org/10.1007/s12035-023-03504-7
Publication status	Published - 21 Jul 2023

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@article{b61689b6707c4fe089bf6056a40a2b74,

title = "tDCS Regulates ASBT-3-OxoLCA-PLOD2-PTEN Signaling Pathway to Confer Neuroprotection Following Rat Cerebral Ischemia-Reperfusion Injury",

abstract = "Humans exhibit a rich intestinal microbiome that contain high levels of bacteria capable of producing 3-oxo-lithocholic acid (3-oxoLCA) and other secondary bile acids (BAs). The molecular mechanism mediating the role of 3-oxoLCA in cerebral ischemia-reperfusion (I/R) injury remains unclear. We investigated the role of 3-oxoLCA in a rat cerebral I/R injury model. We found that the concentrations of 3-oxoLCA within the cerebrospinal fluid were increased following I/R. In the in vitro oxygen-glucose deprivation (OGD) model, the levels of intraneuronal 3-oxoLCA was elevated following OGD insult. We showed that the increase of membrane ASBT (apical sodium-dependent bile acid transporter) contributed to OGD-induced elevation of intraneuronal 3-oxoLCA. Increasing intraneuronal 3-oxoLCA promoted ischemia-induced neuronal death, whereas reducing 3-oxoLCA levels were neuroprotective. Our results revealed that PLOD2 (procollagen-lysine, 2-oxoglutarate 5-dioxygenases 2) functioned upstream of PTEN (the phosphatase and tensin homolog deleted on chromosome 10) and downstream of 3-oxoLCA to promote OGD-induced neuronal injury. We further demonstrated that direct-current stimulation (DCS) decreased the levels of intraneuronal 3-oxoLCA and membrane ASBT in OGD-insulted neurons, while bilateral transcranial DCS (tDCS) reduced brain infarct volume following I/R by inhibiting ASBT. Together, these data suggest that increased expression of ASBT promotes neuronal death via 3-oxoLCA-PLOD2-PTEN signaling pathway. Importantly, bilateral tDCS suppresses ischemia-induced increase of ASBT, thereby conferring neuroprotection after cerebral I/R injury.",

author = "Xiangyi Kong and Xujin Yao and Jinyang Ren and Jingchen Gao and Yu Cui and Jiangdong Sun and Xiangyu Xu and Wenjie Hu and Hui Wang and Huanting Li and Oleg Glebov and Fengyuan Che and Qi Wan",

note = "Funding Information: This work was supported by the National Key R&D Program of China (2019YFC0120000; 2018YFC1312300), the National Natural Science Foundation of China (NSFC: 82071385), the Key Research and Development Project of Shandong (2019JZZY021010), and the TaiShan Industrial Experts Programme (No. tscy20200412) to Q.W. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2023",

month = jul,

day = "21",

doi = "10.1007/s12035-023-03504-7",

language = "English",

volume = "60",

pages = "6715--6730",

journal = "Molecular Neurobiology",

issn = "0893-7648",

publisher = "Humana Press",

number = "11",

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TY - JOUR

T1 - tDCS Regulates ASBT-3-OxoLCA-PLOD2-PTEN Signaling Pathway to Confer Neuroprotection Following Rat Cerebral Ischemia-Reperfusion Injury

AU - Kong, Xiangyi

AU - Yao, Xujin

AU - Ren, Jinyang

AU - Gao, Jingchen

AU - Cui, Yu

AU - Sun, Jiangdong

AU - Xu, Xiangyu

AU - Hu, Wenjie

AU - Wang, Hui

AU - Li, Huanting

AU - Glebov, Oleg

AU - Che, Fengyuan

AU - Wan, Qi

N1 - Funding Information: This work was supported by the National Key R&D Program of China (2019YFC0120000; 2018YFC1312300), the National Natural Science Foundation of China (NSFC: 82071385), the Key Research and Development Project of Shandong (2019JZZY021010), and the TaiShan Industrial Experts Programme (No. tscy20200412) to Q.W. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2023/7/21

Y1 - 2023/7/21

N2 - Humans exhibit a rich intestinal microbiome that contain high levels of bacteria capable of producing 3-oxo-lithocholic acid (3-oxoLCA) and other secondary bile acids (BAs). The molecular mechanism mediating the role of 3-oxoLCA in cerebral ischemia-reperfusion (I/R) injury remains unclear. We investigated the role of 3-oxoLCA in a rat cerebral I/R injury model. We found that the concentrations of 3-oxoLCA within the cerebrospinal fluid were increased following I/R. In the in vitro oxygen-glucose deprivation (OGD) model, the levels of intraneuronal 3-oxoLCA was elevated following OGD insult. We showed that the increase of membrane ASBT (apical sodium-dependent bile acid transporter) contributed to OGD-induced elevation of intraneuronal 3-oxoLCA. Increasing intraneuronal 3-oxoLCA promoted ischemia-induced neuronal death, whereas reducing 3-oxoLCA levels were neuroprotective. Our results revealed that PLOD2 (procollagen-lysine, 2-oxoglutarate 5-dioxygenases 2) functioned upstream of PTEN (the phosphatase and tensin homolog deleted on chromosome 10) and downstream of 3-oxoLCA to promote OGD-induced neuronal injury. We further demonstrated that direct-current stimulation (DCS) decreased the levels of intraneuronal 3-oxoLCA and membrane ASBT in OGD-insulted neurons, while bilateral transcranial DCS (tDCS) reduced brain infarct volume following I/R by inhibiting ASBT. Together, these data suggest that increased expression of ASBT promotes neuronal death via 3-oxoLCA-PLOD2-PTEN signaling pathway. Importantly, bilateral tDCS suppresses ischemia-induced increase of ASBT, thereby conferring neuroprotection after cerebral I/R injury.

AB - Humans exhibit a rich intestinal microbiome that contain high levels of bacteria capable of producing 3-oxo-lithocholic acid (3-oxoLCA) and other secondary bile acids (BAs). The molecular mechanism mediating the role of 3-oxoLCA in cerebral ischemia-reperfusion (I/R) injury remains unclear. We investigated the role of 3-oxoLCA in a rat cerebral I/R injury model. We found that the concentrations of 3-oxoLCA within the cerebrospinal fluid were increased following I/R. In the in vitro oxygen-glucose deprivation (OGD) model, the levels of intraneuronal 3-oxoLCA was elevated following OGD insult. We showed that the increase of membrane ASBT (apical sodium-dependent bile acid transporter) contributed to OGD-induced elevation of intraneuronal 3-oxoLCA. Increasing intraneuronal 3-oxoLCA promoted ischemia-induced neuronal death, whereas reducing 3-oxoLCA levels were neuroprotective. Our results revealed that PLOD2 (procollagen-lysine, 2-oxoglutarate 5-dioxygenases 2) functioned upstream of PTEN (the phosphatase and tensin homolog deleted on chromosome 10) and downstream of 3-oxoLCA to promote OGD-induced neuronal injury. We further demonstrated that direct-current stimulation (DCS) decreased the levels of intraneuronal 3-oxoLCA and membrane ASBT in OGD-insulted neurons, while bilateral transcranial DCS (tDCS) reduced brain infarct volume following I/R by inhibiting ASBT. Together, these data suggest that increased expression of ASBT promotes neuronal death via 3-oxoLCA-PLOD2-PTEN signaling pathway. Importantly, bilateral tDCS suppresses ischemia-induced increase of ASBT, thereby conferring neuroprotection after cerebral I/R injury.

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U2 - 10.1007/s12035-023-03504-7

DO - 10.1007/s12035-023-03504-7

M3 - Article

SN - 0893-7648

VL - 60

SP - 6715

EP - 6730

JO - Molecular Neurobiology

JF - Molecular Neurobiology

IS - 11

ER -

tDCS Regulates ASBT-3-OxoLCA-PLOD2-PTEN Signaling Pathway to Confer Neuroprotection Following Rat Cerebral Ischemia-Reperfusion Injury

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