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Journal ArticleDOI: 10.1016/J.BRAINRES.2021.147399

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

02 Mar 2021-Brain Research (Elsevier)-Vol. 1761, pp 147399-147399
Abstract: The cerebral ischemic reperfusion injury may leads to morbidity and mortality in patients. phosphatidylinositol 3-kinase (PI3K) signaling pathway has been believed to work in association with its downstream targets, other receptors, and pathways that may offer antioxidant, anti-inflammatory, anti-apoptotic effects, neuroprotective role in neuronal excitotoxicity. This review elaborates the mechanistic interventions of the PI3K pathway in cerebral ischemic injury in context to nuclear factor erythroid 2-related factor 2 (Nrf2) regulation, Hypoxia-inducible factor 1 signaling (HIF-1), growth factors, Endothelial NOS (eNOS) proinflammatory cytokines, Erythropoietin (EPO), Phosphatase and tensin homologous protein of chromosome 10 gene (PTEN) signaling, NF-κB/Notch signaling, c-Jun N-terminal kinase (JNK) and Glycogen synthase kinase-3β (GSK-3β) signaling pathway. Evidences showing the activation of PI3K inhibits apoptotic pathway, which results in its neuroprotective effect in ischemic injury. Despite discussing the therapeutic role of the PI3K pathway in treating cerebral ischemic injury, the review also enlighten the selective modulation of PI3K pathway with activators and inhibitors which may provide promising results in clinical and preclinical settings.

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Topics: PI3K/AKT/mTOR pathway (58%), Notch signaling pathway (55%), Neuroprotection (55%) ... show more
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5 results found


Open accessJournal ArticleDOI: 10.1016/J.BIOPHA.2021.111729
Abstract: Neurodegenerative diseases (NDDs) are the primary cause of disabilities in the elderly people. Growing evidence indicates that oxidative stress, mitochondrial dysfunction, neuroinflammation and apoptosis are associated with aging and the basis of most neurodegenerative disorders. Quercetin is a flavonoid with significant pharmacological effects and promising therapeutic potential. It is widely distributed among plants and typically found in daily diets mainly in fruits and vegetables. It shows a number of biological properties connected to its antioxidant activity. Neuroprotection by quercetin has been reported in many in vitro as well as in in vivo studies. However, the exact mechanism of action is still mystery and similarly there are a number of hypothesis exploring the mechanism of neuroprotection. Quercetin enhances neuronal longevity and neurogenesis by modulating and inhibiting wide number of pathways. This review assesses the food sources of quercetin, its pharmacokinetic profile, structure activity relationship and its pathophysiological role in various NDDs and it also provides a synopsis of the literature exploring the relationship between quercetin and various downstream signalling pathways modulated by quercetin for neuroprotection for eg. nuclear factor erythroid 2-related factor 2 (Nrf2), Paraoxonase-2 (PON2), c-Jun N-terminal kinase (JNK), Tumour Necrosis Factor alpha (TNF-α), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α), Sirtuins, Mitogen-activated protein kinases (MAPKs) signalling cascades, CREB (Cyclic AMP response element binding protein) and Phosphoinositide 3- kinase(PI3K/Akt). Therefore, the aim of the present review was to elaborate on the cellular and molecular mechanisms of the quercetin involved in the protection against NDDs.

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11 Citations


Journal ArticleDOI: 10.1007/S11064-021-03418-7
Abstract: Apoptosis is an intrinsic biochemical, cellular process that regulates cell death and is crucial for cell survival, cellular homeostasis, and maintaining the optimum functional status. Apoptosis in a predetermined and programmed manner regulates several molecular events, including cell turnover, embryonic development, and immune system functions but may be the exclusive contributor to several disorders, including neurodegenerative manifestations, when it functions in an aberrant and disorganized manner. Alzheimer's disease (AD) is a fatal, chronic neurodegenerative disorder where apoptosis has a compelling and divergent role. The well-characterized pathological features of AD, including extracellular plaques of amyloid-beta, intracellular hyperphosphorylated tangles of tau protein (NFTs), inflammation, mitochondrial dysfunction, oxidative stress, and excitotoxic cell death, also instigate an abnormal apoptotic cascade in susceptible brain regions (cerebral cortex, hippocampus). The apoptotic players in these regions affect cellular organelles (mitochondria and endoplasmic reticulum), interact with trophic factors, and several pathways, including PI3K/AKT, JNK, MAPK, mTOR signalling. This dysregulated apoptotic cascade end with an abnormal neuronal loss which is a primary event that may precede the other events of AD progression and correlates well with the degree of dementia. The present review provides insight into the diverse and versatile apoptotic mechanisms that are indispensable for neuronal survival and constitute an integral part of the pathological progression of AD. Identification of potential targets (restoring apoptotic and antiapoptotic balance, caspases, TRADD, RIPK1, FADD, TNFα, etc.) may be valuable and advantageous to decide the fate of neurons and to develop potential therapeutics for treatment of AD.

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Topics: TRADD (56%), Cellular homeostasis (55%), FADD (54%) ... show more

2 Citations


Open accessJournal ArticleDOI: 10.3390/IJMS222111971
Abstract: The ubiquitin-proteasome pathway (UPP) is involved in regulating several biological functions, including cell cycle control, apoptosis, DNA damage response, and apoptosis. It is widely known for its role in degrading abnormal protein substrates and maintaining physiological body functions via ubiquitinating enzymes (E1, E2, E3) and the proteasome. Therefore, aberrant expression in these enzymes results in an altered biological process, including transduction signaling for cell death and survival, resulting in cancer. In this review, an overview of profuse enzymes involved as a pro-oncogenic or progressive growth factor in tumors with their downstream signaling pathways has been discussed. A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on modulation of ubiquitin-proteasome pathways in oncogenic signaling. Various in vitro, in vivo studies demonstrating the involvement of ubiquitin-proteasome systems in varied types of cancers and the downstream signaling pathways involved are also discussed in the current review. Several inhibitors of E1, E2, E3, deubiquitinase enzymes and proteasome have been applied for treating cancer. Some of these drugs have exhibited successful outcomes in in vivo studies on different cancer types, so clinical trials are going on for these inhibitors. This review mainly focuses on certain ubiquitin-proteasome enzymes involved in developing cancers and certain enzymes that can be targeted to treat cancer.

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Topics: Ubiquitin (52%), Proteasome (52%), Deubiquitinating enzyme (51%)

1 Citations


Open accessJournal ArticleDOI: 10.1016/J.LFS.2021.120186
Priyanka Saklani1, Heena Khan1, Saurabh Gupta1, Amarjot Kaur1  +1 moreInstitutions (1)
28 Nov 2021-Life Sciences
Abstract: Aim Ischemic damage to the brain is linked to an increased rate of morbidity and mortality worldwide. In certain parts of the world, it remains a leading cause of mortality and the primary cause of long-term impairment. Ischemic injury is exacerbated when particular neuropeptides are removed, or their function in the brain is blocked, whereas supplying such neuropeptides lowers ischemic harm. Here, we have discussed the role of neuropeptides in ischemic injury. Materials & methods Numerous neuropeptides had their overexpression following cerebral ischemia. Neuropeptides such as NPY, CGRP, CART, SP, BK, PACAP, oxytocin, nociception, neurotensin and opioid peptides act as transmitters, documented in several “in vivo” and “in vitro” studies. Neuropeptides provide neuroprotection by activating the survival pathways or inhibiting the death pathways, i.e., MAPK, BDNF, Nitric Oxide, PI3k/Akt and NF-κB. Key findings Neuropeptides have numerous beneficial effects in ischemic models, including antiapoptotic, anti-inflammatory, and antioxidant actions that provide a powerful protective impact in neurons when combined. These innovative therapeutic substances have the potential to treat ischemia injury due to their pleiotropic modes of action. Significance This review emphasizes the neuroprotective role of neuropeptides in ischemic injury via modulation of various signalling pathways i.e., MAPK, BDNF, Nitric Oxide, PI3k/Akt and NF-κB.

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Topics: Neuroprotection (54%), Ischemia (51%), Neuropeptide (51%) ... show more

Open accessJournal ArticleDOI: 10.3390/MOLECULES26185675
Yulin Ren1, Sijin Wu1, Sijie Chen1, Joanna E. Burdette2  +2 moreInstitutions (2)
18 Sep 2021-Molecules
Abstract: 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.

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Topics: Na+/K+-ATPase (56%), Cardiac glycoside (55%), Aglycone (54%) ... show more
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189 results found


Journal ArticleDOI: 10.1038/NRG1879
Abstract: Phosphatidylinositol 3-kinases (PI3Ks) evolved from a single enzyme that regulates vesicle trafficking in unicellular eukaryotes into a family of enzymes that regulate cellular metabolism and growth in multicellular organisms. In this review, we examine how the PI3K pathway has evolved to control these fundamental processes, and how this pathway is in turn regulated by intricate feedback and crosstalk mechanisms. In light of the recent advances in our understanding of the function of PI3Ks in the pathogenesis of diabetes and cancer, we discuss the exciting therapeutic opportunities for targeting this pathway to treat these diseases.

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2,671 Citations


Open accessJournal ArticleDOI: 10.1038/SREP21230
23 Feb 2016-Scientific Reports
Abstract: Scientific Reports 5: Article number: 10942; published online: 01 June 2015; updated: 23 February 2016 This Article contains typographical errors in Table 2 where ‘Week 2 (N = 32)’ was incorrectly given as ‘Week (N = 2)’.

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Topics: Typographical error (50%)

2,328 Citations


Open accessJournal ArticleDOI: 10.1016/S0092-8674(00)81883-8
21 Feb 1997-Cell
Abstract: Exciting insights into the function of Akt/PKB have been revealed by studies investigating its function in PI3K-dependent pathways that are involved in the regulation of cell survival. Previous studies have demonstrated that PI3K is involved in serum-dependent survival of PC12 cells (reviewed byCarpenter and Cantley 1996xCarpenter, C.L. and Cantley, L.C. Curr. Opin. Cell Biol. 1996; 8: 153–158CrossRef | PubMed | Scopus (542)See all ReferencesCarpenter and Cantley 1996). Recent results indicate that PI3K also mediates type 1 insulin-like growth factor (IGF-1)-dependent survival of Rat-1 and COS-7 cells (Kulik et al. 1997xKulik, G., Klippel, A., and Weber, M.J. Mol. Cell. Biol., in press. 1997; See all ReferencesKulik et al. 1997) and granule neurons (D'Mello et al. 1997xD'Mello, S.R., Borodezt, K., and Soltoff, S. J. Neurosci., in press. 1997; See all ReferencesD'Mello et al. 1997).A role for Akt/PKB in IGF-1-mediated cell survival has been indicated (Dudek et al. 1997xDudek, H., Datta, S.R., Franke, T.F., Birnbaum, M.J., Yao, R., Cooper, G.M., Segal, R.A., Kaplan, D.R., and Greenberg, M.E. Science. 1997; 275: 661–665CrossRef | PubMed | Scopus (1900)See all ReferencesDudek et al. 1997): overexpression of Akt/PKB prevents apoptosis in primary cultures of cerebellar neurons that are induced by survival factor withdrawal or inhibition of PI3K. The expression of dominant-negative forms of Akt/PKB interferes with growth factor-mediated survival in these cells, indicating that Akt/PKB is necessary and sufficient for neuronal survival. Studies from Weber and colleagues have shown that overexpression of constitutively activated Akt/PKB also blocks UV-induced apoptosis in Rat-1 and COS-7 cells (Kulik et al. 1997xKulik, G., Klippel, A., and Weber, M.J. Mol. Cell. Biol., in press. 1997; See all ReferencesKulik et al. 1997). A different approach taken by Downward and colleagues indicated that activated Akt/PKB prevents apoptosis that is induced by detachment of MDCK cells from their extracellular matrix (anoikis; Khwaja et al. 1997xKhwaja, A., Rodriguez-Viciana, P., Wennstrom, S., Warne, P.H., and Downward, J. EMBO J., in press. 1997; See all ReferencesKhwaja et al. 1997).Finally, Evan and colleagues demonstrated that mutants of V12 Ras that selectively stimulate PI3K and Akt/PKB but not the Raf/MEK/MAPK pathway are able to prevent c-myc-induced cell death in Rat-1 cells (Kauffmann-Zeh et al. 1997xKauffmann-Zeh, A., Rodriguez-Viciana, P., Ulrich, E., Gilbert, C., Coffer, P., Downward, J., and Evan, G. Nature, in press. 1997; See all ReferencesKauffmann-Zeh et al. 1997). In this system, activated forms of PI3K and Akt/PKB are sufficient to prevent apoptosis that is induced by c-myc. p70S6kinase activity was not necessary for the prevention of apoptosis caused by deregulated c-myc (Kauffmann-Zeh et al. 1997xKauffmann-Zeh, A., Rodriguez-Viciana, P., Ulrich, E., Gilbert, C., Coffer, P., Downward, J., and Evan, G. Nature, in press. 1997; See all ReferencesKauffmann-Zeh et al. 1997), nor was it necessary for Akt/PKB-dependent neuronal survival in primary cerebellar neurons (Dudek et al. 1997xDudek, H., Datta, S.R., Franke, T.F., Birnbaum, M.J., Yao, R., Cooper, G.M., Segal, R.A., Kaplan, D.R., and Greenberg, M.E. Science. 1997; 275: 661–665CrossRef | PubMed | Scopus (1900)See all ReferencesDudek et al. 1997). Therefore, IGF-1 and certain other growth factors stimulate a cell survival pathway that involves Ras-dependent stimulation of PI3K, leading to activation of Akt/PKB. This pathway appears to be independent of MAPK and p70S6kinase and to prevent apoptosis induced by a variety of cellular challenges. Its importance in tissue culture systems as well as in primary neuronal cells suggests that this pathway may be of general significance. Further studies are needed to determine if Akt/PKB can be a suitable target for drug therapy directed at neurodegenerative and other degenerative human diseases.Many groups are currently extending these findings and contributing to the further understanding of Akt/PKB in survival in other cell systems. GSK3 has not been implicated in the regulation of survival (see references inKauffmann-Zeh et al. 1997xKauffmann-Zeh, A., Rodriguez-Viciana, P., Ulrich, E., Gilbert, C., Coffer, P., Downward, J., and Evan, G. Nature, in press. 1997; See all ReferencesKauffmann-Zeh et al. 1997), suggesting that Akt/PKB has more widespread roles in cell regulation and employs distinct subsets of substrates in different signaling systems. Additional direct downstream targets of Akt/PKB other than GSK3 must exist that have not been identified. Recent studies have provided some insight into the mechanism by which cell survival factors cause modifications to members of the Bcl-2 family of proteins (reviewed byGajewski and Thompson 1996xGajewski, T.F. and Thompson, C.B. Cell. 1996; 87: 589–592Abstract | Full Text | Full Text PDF | PubMed | Scopus (286)See all ReferencesGajewski and Thompson 1996). The exact mechanisms of prevention of apoptosis by Akt/PKB are undetermined; future studies will address whether Akt/PKB mediates survival by phosphorylation and inhibition of proteins that are involved in programmed cell death. The observation that PI3K and Akt/PKB are involved in cell survival certainly could explain why so many oncoproteins, growth factors, and survival factors have evolved mechanisms for activation of PI3K.

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Topics: PI3K/AKT/mTOR pathway (57%), Protein kinase B (55%)

1,656 Citations


Journal ArticleDOI: 10.1038/NRM2882
Abstract: Phosphoinositide 3-kinases (PI3Ks) function early in intracellular signal transduction pathways and affect many biological functions. A further level of complexity derives from the existence of eight PI3K isoforms, which are divided into class I, class II and class III PI3Ks. PI3K signalling has been implicated in metabolic control, immunity, angiogenesis and cardiovascular homeostasis, and is one of the most frequently deregulated pathways in cancer. PI3K inhibitors have recently entered clinical trials in oncology. A better understanding of how the different PI3K isoforms are regulated and control signalling could uncover their roles in pathology and reveal in which disease contexts their blockade could be most beneficial.

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1,324 Citations


Open accessJournal ArticleDOI: 10.1038/NCOMMS4289
Abstract: Nature Communications 4: Article number: 1828 (2013); Published: 7 May 2013; Updated: 11 February 2014. In this Article, the museum catalogue numbers for the paratype and referred specimens of Acrotholus audeti nov. gen. et. sp. were inadvertently exchanged. The paratype reference should have been ROM 2964 and the catalogue number for the referred specimen should have been ROM 2962.

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Topics: Paratype (59%)

987 Citations