Exploration of Neuroscience

Table 2. Summary of key neurological and neurovascular studies linking BMAL1/circadian regulation to PI3K/AKT-mTOR signaling under ischemic and vascular stress.

Ref.	Model/Context	CLOCK/BMAL1 axis	PI3K/AKT node(s) emphasized	Principal finding
[84]	Mouse focal cerebral ischemia	Time-of-day (ZT) + BMAL1 rhythmicity	pAKT T308, ERK1/2 phosphorylation, survival signaling mediators (mTOR/S6; Bad/PRAS40 axis)	Ischemic damage is time-of-day dependent; higher BMAL1 phase associates with enhanced AKT activation and improved survival signaling.
[85]	OGD (± reoxygenation)	BMAL1-melatonin interaction	PDK1, mTOR, PTEN, GSK3α/β, p70S6K phosphorylation panel	BMAL1/melatonin context amplifies phosphorylation across PI3K/AKT cascade, consistent with stress resilience.
[86]	Mouse focal cerebral ischemia + proteomics	BMAL1 overexpression vs. knockdown/deletion	mTOR (Ser2448) + mitochondrial/metabolic modules (OXPHOS/TCA/ATP synthase proteins)	BMAL1 gain-of-function reduces infarct and neuronal injury and reprograms metabolic pathways consistent with pro-survival PI3K/AKT-mTOR tone.
[87]	PC12 OGD/R	BMAL1 overexpression	Indirect support of PI3K/AKT via redox: Nrf2/HO-1, Bcl-2/Bax	BMAL1 enhances antioxidant defense and anti-apoptotic balance under ischemic stress.
[88]	Endothelial/hematopoietic BMAL1 deletion (vascular injury)	Cell-type-specific BMAL1 loss	pAKT S473, mTORC2/RICTOR implication; eNOS/NO signaling	BMAL1 deletion reduces pAKT (S473) and worsens microvascular outcomes (nitrative stress, degeneration).
[89]	Disturbed flow/vascular regions	BMAL1/CLOCK regulation by hemodynamic context	eNOS and AKT phosphorylation dynamics	Disturbed flow is associated with BMAL1/CLOCK changes and endothelial signaling remodeling.
[90]	VSMC proliferation under growth factor	BMAL1 induction via ROS–ERK–EGR1	ERK modulation (PI3K/AKT adjacent crosstalk)	BMAL1 participates in growth-factor-driven vascular proliferation via MAPK/ERK coupling.

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BMAL1: basic helix-loop-helix ARNT-like protein 1; PI3K: phosphatidylinositol 3-kinase; CLOCK: circadian locomotor output cycles kaput; ZT: zeitgeber time; pAKT: phospho AKT; T308: threonine 308; Bad: Bcl-2-associated agonist of cell death; PRAS40: proline-rich AKT substrate of 40 kDa; OGD: oxygen-glucose deprivation; PDK1: 3-phosphoinositide-dependent kinase-1; PTEN: phosphatase and tensin homolog; GSK3: glycogen synthase kinase 3; p70S6K: p70 ribosomal protein S6 kinase; OXPHOS: oxidative phosphorylation; TCA: tricarboxylic acid; Nrf2: nuclear factor erythroid 2-related factor 2; HO-1: heme oxygenase-1; S473: serine 473; mTORC2: mechanistic target of rapamycin complex 2; RICTOR: rapamycin-insensitive companion of mTOR; eNOS: endothelial nitric oxide synthase; VSMC: vascular smooth muscle cell; ROS: reactive oxygen species; ERK: extracellular signal-regulated kinase; EGR1: early growth response protein 1; MAPK: mitogen-activated protein kinase.

Declarations

Author contributions

MCB: Conceptualization, Writing—original draft, Writing—review & editing. DMH: Conceptualization, Writing—review & editing. EK: Conceptualization, Writing—review & editing, Funding acquisition. All authors read and approved the final version of the manuscript.

Conflicts of interest

Dirk M. Hermann, who is the Editor-in-Chief and Guest Editor of Exploration of Neuroscience; Ertugrul Kilic, who is the Associate Editor of Exploration of Neuroscience, had no involvement in the decision-making or the review process of this manuscript. The other author declares no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by Turkish Academy of Sciences (TUBA; to EK). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

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