Therapeutic modulation of the phosphatidylinositol 3-kinases (PI3K) pathway in cerebral ischemic injury

Khan, Heena; Singh, Anjali; Thapa, Komal; Garg, Nikhil; Grewal, Amarjot Kaur; Singh, Thakur Gurjeet

doi:10.1016/j.brainres.2021.147399

Cited by 37 publications

(10 citation statements)

References 151 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found the PI3K signaling pathway to be one of the main pathways of MSC-EV-mediated protection of hippocampal neuroglial cells under OGD conditions, and this pathway was identified among the top enriched categories in the MSC-EV proteome. The PI3K/AKT signaling pathway is essential for cell survival and neuroprotection 91 and its modulation by MSC-EV has been recently shown 92 - 94 . Moreover, MSC-conditioned medium protected primary cortical neurons from OGD-induced cell death 95 and inhibition of the PI3K/AKT pathway completely abolished this neuroprotective effect.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cell-derived extracellular vesicles afford neuroprotection by modulating PI3K/AKT pathway and calcium oscillations

Turovsky¹,

Golovicheva²,

Varlamova³

et al. 2022

Int. J. Biol. Sci.

View full text Add to dashboard Cite

Mesenchymal stromal cells (MSC) are widely recognized as potential effectors in neuroprotective therapy. The protective properties of MSC were considered to be associated with the secretion of extracellular vesicles (MSC-EV). We explored the effects of MSC-EV in vivo on models of traumatic and hypoxia-ischemia (HI) brain injury. Neuroprotective mechanisms triggered by MSC-EV were also studied in vitro using a primary neuroglial culture. Intranasal administration of MSC-EV reduced the volume of traumatic brain damage, correlating with a recovery of sensorimotor functions. Neonatal HI-induced brain damage was mitigated by the MSC-EV administration. This therapy also promoted the recovery of sensorimotor functions, implying enhanced neuroplasticity, and MSC-EV-induced growth of neurites in vitro supports this. In the in vitro ischemic model, MSC-EV prevented cell calcium (Ca 2+ ) overload and subsequent cell death. In mixed neuroglial culture, MSC-EV induced inositol trisphosphate (IP3) receptor-related Ca 2+ oscillations in astrocytes were associated with resistance to calcium overload not only in astrocytes but also in co-cultured neurons, demonstrating intercellular positive crosstalk between neural cells. This implies that phosphatidylinositol 3-Kinase/AKT signaling is one of the main pathways in MSC-EV-mediated protection of neural cells exposed to ischemic challenge. Components of this pathway were identified among the most enriched categories in the MSC-EV proteome.

show abstract

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cell-derived extracellular vesicles afford neuroprotection by modulating PI3K/AKT pathway and calcium oscillations

Turovsky¹,

Golovicheva²,

Varlamova³

et al. 2022

Int. J. Biol. Sci.

View full text Add to dashboard Cite

show abstract

“…It has been demonstrated that NF-κB, Nrf2, and PI3K all correlate with reactive oxygen species (ROS) [ 29 ]. A crosstalk between NF-κB and Nrf2 has been evidenced by their regulation of the response to oxidative stress [ 22 , 23 ], and Nrf2 has been demonstrated as a downstream target of PI3K [ 30 ], indicating some potential crosstalk among NF-κB, Nrf2, and PI3K. In addition, activation of PI3K was observed from inhibition of NKA by ouabain in LLC-PK1 porcine renal epithelial cells [ 31 ], and inhibition of the PI3K pathway can yield multifaceted cancer cell-extrinsic effects to support cancer treatment [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

Interaction of (+)-Strebloside and Its Derivatives with Na+/K+-ATPase and Other Targets

Ren

Chen

et al. 2021

Molecules

View full text Add to dashboard Cite

Docking profiles for (+)-strebloside, a cytotoxic cardiac glycoside identified from Streblus asper, and some of its derivatives and Na+/K+-ATPase have been investigated. In addition, binding between (+)-strebloside and its aglycone, strophanthidin, and several of their other molecular targets, including FIH-1, HDAC, KEAP1 and MDM2 (negative regulators of Nrf2 and p53, respectively), NF-κB, and PI3K and Akt1, have been inspected and compared with those for digoxin and its aglycone, digoxigenin. The results showed that (+)-strebloside, digoxin, and their aglycones bind to KEAP1 and MDM2, while (+)-strebloside, strophanthidin, and digoxigenin dock to the active pocket of PI3K, and (+)-strebloside and digoxin interact with FIH-1. Thus, these cardiac glycosides could directly target HIF-1, Nrf2, and p53 protein–protein interactions, Na+/K+-ATPase, and PI3K to mediate their antitumor activity. Overall, (+)-strebloside seems more promising than digoxin for the development of potential anticancer agents.

show abstract

“…PTEN is thought to exert its effects via negative regulation of phosphoinositide 3-kinase (PI3K). Deletion of PTEN firstly activates class I PI3K, then phosphorylates phosphatidylinositol 4,5-biphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3) and recruits signaling proteins, including AKT and downstream mammalian target of rapamycin (mTOR) activation ( Khan et al, 2021 ; Alcaraz et al, 2022 ).…”

Section: Downstream Molecules Of N6-methyladenosine Modification In C...mentioning

confidence: 99%

Crosstalk among N6-methyladenosine modification and RNAs in central nervous system injuries

Tian

Mao

Zhang

2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Central nervous system (CNS) injuries, including traumatic brain injury (TBI), intracerebral hemorrhage (ICH) and ischemic stroke, are the most common cause of death and disability around the world. As the most common modification on ribonucleic acids (RNAs), N6-methyladenosine (m6A) modification has recently attracted great attentions due to its functions in determining the fate of RNAs through changes in splicing, translation, degradation and stability. A large number of studies have suggested that m6A modification played an important role in brain development and involved in many neurological disorders, particularly in CNS injuries. It has been proposed that m6A modification could improve neurological impairment, inhibit apoptosis, suppress inflammation, reduce pyroptosis and attenuate ferroptosis in CNS injuries via different molecules including phosphatase and tensin homolog (PTEN), NLR family pyrin domain containing 3 (NLRP3), B-cell lymphoma 2 (Bcl-2), glutathione peroxidase 4 (GPX4), and long non-coding RNA (lncRNA). Therefore, m6A modification showed great promise as potential targets in CNS injuries. In this article, we present a review highlighting the role of m6A modification in CNS injuries. Hence, on the basis of these properties and effects, m6A modification may be developed as therapeutic agents for CNS injury patients.

show abstract

Therapeutic modulation of the phosphatidylinositol 3-kinases (PI3K) pathway in cerebral ischemic injury

Cited by 37 publications

References 151 publications

Mesenchymal stromal cell-derived extracellular vesicles afford neuroprotection by modulating PI3K/AKT pathway and calcium oscillations

Mesenchymal stromal cell-derived extracellular vesicles afford neuroprotection by modulating PI3K/AKT pathway and calcium oscillations

Interaction of (+)-Strebloside and Its Derivatives with Na+/K+-ATPase and Other Targets

Crosstalk among N6-methyladenosine modification and RNAs in central nervous system injuries

Contact Info

Product

Resources

About