scholarly journals Activation of the phosphoinositide 3‐kinase pathway promotes axon regeneration of the optic nerve in vivo

2018 ◽  
Vol 96 (S261) ◽  
pp. 37-38
Keyword(s):  
Optic Nerve ◽  
Axon Regeneration ◽  
Phosphoinositide 3 Kinase ◽  
Kinase Pathway

scholarly journals Exosome-Mediated Delivery of the Neuroprotective Peptide PACAP38 Promotes Retinal Ganglion Cell Survival and Axon Regeneration in Rats With Traumatic Optic Neuropathy

2021 ◽  
Vol 9 ◽  
Author(s):  
Tian Wang ◽  
Yiming Li ◽  
Miao Guo ◽  
Xue Dong ◽  
Mengyu Liao ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Optic Neuropathy ◽  
Axon Regeneration ◽  
Retinal Ganglion ◽  
Traumatic Optic Neuropathy ◽  
Fiber Layer

Traumatic optic neuropathy (TON) refers to optic nerve damage caused by trauma, leading to partial or complete loss of vision. The primary treatment options, such as hormonal therapy and surgery, have limited efficacy. Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38), a functional endogenous neuroprotective peptide, has emerged as a promising therapeutic agent. In this study, we used rat retinal ganglion cell (RGC) exosomes as nanosized vesicles for the delivery of PACAP38 loaded via the exosomal anchor peptide CP05 (EXOPACAP38). EXOPACAP38 showed greater uptake efficiency in vitro and in vivo than PACAP38. The results showed that EXOPACAP38 significantly enhanced the RGC survival rate and retinal nerve fiber layer thickness in a rat TON model. Moreover, EXOPACAP38 significantly promoted axon regeneration and optic nerve function after injury. These findings indicate that EXOPACAP38 can be used as a treatment option and may have therapeutic implications for patients with TON.

scholarly journals B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

2014 ◽  
Vol 211 (5) ◽  
pp. 801-814 ◽  
Author(s):  
Kevin J. O’Donovan ◽  
Kaijie Ma ◽  
Hengchang Guo ◽  
Chen Wang ◽  
Fang Sun ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Loss Of Function ◽  
Pten Loss ◽  
Raf Kinase ◽  
Central Nervous Systems ◽  
Neurotrophin Signaling ◽  
Peripheral Sensory

Activation of intrinsic growth programs that promote developmental axon growth may also facilitate axon regeneration in injured adult neurons. Here, we demonstrate that conditional activation of B-RAF kinase alone in mouse embryonic neurons is sufficient to drive the growth of long-range peripheral sensory axon projections in vivo in the absence of upstream neurotrophin signaling. We further show that activated B-RAF signaling enables robust regenerative growth of sensory axons into the spinal cord after a dorsal root crush as well as substantial axon regrowth in the crush-lesioned optic nerve. Finally, the combination of B-RAF gain-of-function and PTEN loss-of-function promotes optic nerve axon extension beyond what would be predicted for a simple additive effect. We conclude that cell-intrinsic RAF signaling is a crucial pathway promoting developmental and regenerative axon growth in the peripheral and central nervous systems.

scholarly journals Upregulation of reggie-1/flotillin-2 promotes axon regeneration in the rat optic nerve in vivo and neurite growth in vitro

2013 ◽  
Vol 51 ◽  
pp. 168-176 ◽  
Author(s):  
Jan C. Koch ◽  
Gonzalo P. Solis ◽  
Vsevolod Bodrikov ◽  
Uwe Michel ◽  
Deana Haralampieva ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Axon Regeneration ◽  
Neurite Growth

scholarly journals Novel role of Lin28 signaling in regulation of mammalian PNS and CNS axon regeneration

2018 ◽  
Author(s):  
Xue-Wei Wang ◽  
Chang-Mei Liu ◽  
Philip A. Hall ◽  
Jing-Jing Jiang ◽  
Christopher D. Katchis ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Nerve Regeneration ◽  
Axon Regeneration ◽  
Ganglion Cells ◽  
Cellular Reprogramming ◽  
Optic Nerve Regeneration ◽  
Reprogramming Factors ◽  
Necessary And Sufficient

SummarySeveral signaling molecules involved in cellular reprogramming have been shown to regulate mammalian axon regeneration. We hypothesized that reprogramming factors are key regulators of axon regeneration. Here we investigated the role of Lin28, an important reprogramming factor, in the regulation of axon regeneration. We found that Lin28a and Lin28b and their regulatory partners, let-7 microRNAs (miRNAs), were both necessary and sufficient in regulating mature sensory axon regeneration in vivo. More importantly, overexpression of either Lin28a or Lin28b in mature retinal ganglion cells (RGCs) promoted robust and sustained optic nerve regeneration. Additionally, combined overexpression of Lin28a and downregulation of PTEN in RGCs acted additively to promote optic nerve regeneration by reducing the backward turning of regenerating RGC axons. Our findings not only identified a novel molecule promoting optic nerve regeneration but also suggested that reprogramming factors may play vital roles in regulating axon regeneration in mammals.

scholarly journals Overexpression of Reticulon 3 enhances CNS axon regeneration and functional recovery after injury

2021 ◽  
Author(s):  
Zubair Ahmed ◽  
Sharif Alhajlah ◽  
Adam Thompson
Keyword(s):  
Spinal Cord ◽  
Optic Nerve ◽  
Neurite Outgrowth ◽  
Functional Recovery ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Dorsal Root Ganglion Neurons ◽  
Ganglion Neurons

CNS neurons are generally incapable of regenerating their axons after injury due to several intrinsic and extrinsic factors, including the presence of axon growth inhibitory molecules. One such potent inhibitor of CNS axon regeneration is Reticulon (RTN) 4 or Nogo-66. Here, we focused on RTN3 as its contribution in CNS axon regeneration is currently unknown. We found that RTN3 expression correlated with an axon regenerative phenotype in dorsal root ganglion neurons (DRGN) after injury to the dorsal columns, a model of spinal cord injury. Overexpression of RTN3 promoted disinhibited DRGN neurite outgrowth in vitro and dorsal column axon regeneration/sprouting and electrophysiological, sensory and locomotor functional recovery after injury in vivo. Knockdown of protrudin however, ablated RTN3-enhanced neurite outgrowth/axon regeneration in vitro and in vivo. Moreover, overexpression of RTN3 in a second model of CNS injury, the optic nerve crush injury model, enhanced retinal ganglion cell (RGC) survival, disinhibited neurite outgrowth in vitro and survival and axon regeneration in vivo, an effect that was also dependent on protrudin. These results demonstrate that RTN3 enhances neurite outgrowth/axon regeneration in a protrudin-dependent manner after both spinal cord and optic nerve injury.

scholarly journals Inhibition of MAP/ERK kinase prevents IGF-I-induced hypertrophy in rat muscles

2004 ◽  
Vol 96 (1) ◽  
pp. 203-210 ◽  
Author(s):  
Fadia Haddad ◽  
Gregory R. Adams
Keyword(s):  
Cell Proliferation ◽  
Muscle Protein ◽  
In Vitro Studies ◽  
Ras Pathway ◽  
Igf I ◽  
Phosphoinositide 3 Kinase ◽  
Kinase Pathway ◽  
Erk Kinase

Insulin-like growth factor-I (IGF-I) has been shown to stimulate a hypertrophy response in skeletal muscles in vivo. In vitro studies have delineated two primary intracellular pathways that appear to mediate the effects of IGF-I in skeletal muscle: the Ras-ERK pathway and the phosphoinositide-3 kinase pathway. In vitro, the Ras pathway appears to regulate the mitogenic effects of IGF-I signaling, whereas the phosphoinositide-3 kinase pathway is associated with cellular differentiation. On the basis of the results from in vitro studies, we hypothesized that the coinfusion of both IGF-I and an inhibitor of the Ras pathway would result in some increase in muscle protein but an inhibition of cell proliferation. Our results show that 14 days of coinfusion of MAPK/ERK kinase inhibitor PD-098059 (PD) limited the phosphorylation of ERK and prevented IGF-I induced increases in protein (18%, P < 0.05 vs. 7%, not significant) or myofibrillar protein (23%, P < 0.01 vs. 5%, not significant). However, there were similar increases in indicators of cell proliferation (e.g., total DNA, 50 and 52%, P < 0.001) in both the IGF- and IGF+PD-infused muscles. The most notable impact on IGF-I signaling was a significant blunting of IGF-I induced increase in S6K1 phosphorylation by PD-98059 coinfusion (∼5-fold, P < 0.001 vs. 3-fold, P < 0.01). These results suggest that there are interactions between the various pathways down stream of the IGF-I receptor that may behave differently in vivo than in myogenic cell lines in vitro.

scholarly journals Overexpression of Reticulon 3 Enhances CNS Axon Regeneration and Functional Recovery after Traumatic Injury

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2015
Author(s):  
Sharif Alhajlah ◽  
Adam M Thompson ◽  
Zubair Ahmed
Keyword(s):  
Spinal Cord ◽  
Optic Nerve ◽  
Neurite Outgrowth ◽  
Functional Recovery ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Dorsal Root Ganglion Neurons ◽  
Ganglion Neurons

CNS neurons are generally incapable of regenerating their axons after injury due to several intrinsic and extrinsic factors, including the presence of axon growth inhibitory molecules. One such potent inhibitor of CNS axon regeneration is Reticulon (RTN) 4 or Nogo-A. Here, we focused on RTN3 as its contribution to CNS axon regeneration is currently unknown. We found that RTN3 expression correlated with an axon regenerative phenotype in dorsal root ganglion neurons (DRGN) after injury to the dorsal columns, a well-characterised model of spinal cord injury. Overexpression of RTN3 promoted disinhibited DRGN neurite outgrowth in vitro and dorsal column axon regeneration/sprouting and electrophysiological, sensory and locomotor functional recovery after injury in vivo. Knockdown of protrudin, however, ablated RTN3-enhanced neurite outgrowth/axon regeneration in vitro and in vivo. Moreover, overexpression of RTN3 in a second model of CNS injury, the optic nerve crush injury model, enhanced retinal ganglion cell (RGC) survival, disinhibited neurite outgrowth in vitro and survival and axon regeneration in vivo, an effect that was also dependent on protrudin. These results demonstrate that RTN3 enhances neurite outgrowth/axon regeneration in a protrudin-dependent manner after both spinal cord and optic nerve injury.

Inhibiting the phosphoinositide 3-kinase pathway for cancer treatment

2004 ◽  
Vol 32 (2) ◽  
pp. 393-396 ◽  
Author(s):  
P. Workman
Keyword(s):  
Cancer Treatment ◽  
Gene Knockout ◽  
Genomic Analysis ◽  
Gene Knockout Mouse ◽  
Show Evidence ◽  
In Vivo Animal Models ◽  
Phosphoinositide 3 Kinase ◽  
Kinase Pathway

There is extensive evidence from the molecular and genomic analysis of human cancers that the PI 3-kinase (phosphoinositide 3-kinase)–Akt/PKB (protein kinase B) pathway is deregulated in malignant progression. Furthermore, the causal involvement of PI 3-kinase is supported by gene-knockout mouse models. Prototype inhibitors show evidence of anticancer activity in vitro and in vivo animal models. The recent development of isoform-selective inhibitors shows considerable promise for cancer treatment.

Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 1942-1949 ◽  
Author(s):  
Christopher J. Ong ◽  
Andrew Ming-Lum ◽  
Matt Nodwell ◽  
Ali Ghanipour ◽  
Lu Yang ◽  
...  
Keyword(s):  
Small Molecule ◽  
Hematopoietic Cells ◽  
Pi3k Pathway ◽  
Cellular Activation ◽  
Phosphoinositide 3 Kinase ◽  
Identification And Characterization ◽  
Kinase Pathway

Abstract Because phosphoinositide 3-kinase (PI3K) plays a central role in cellular activation, proliferation, and survival, pharmacologic inhibitors targeting components of the PI3K pathway are actively being developed as therapeutics for the treatment of inflammatory disorders and cancer. These targeted drugs inhibit the activity of either PI3K itself or downstream protein kinases. However, a previously unexplored, alternate strategy is to activate the negative regulatory phosphatases in this pathway. The SH2-containing inositol-5′-phosphatase SHIP1 is a normal physiologic counter-regulator of PI3K in immune/hematopoietic cells that hydrolyzes the PI3K product phosphatidylinositiol-3,4,5-trisphosphate (PIP3). We now describe the identification and characterization of potent and specific small-molecule activators of SHIP1. These compounds represent the first small-molecule activators of a phosphatase, and are able to activate recombinant SHIP1 enzyme in vitro and stimulate SHIP1 activity in intact macrophage and mast cells. Mechanism of activation studies with these compounds suggest that they bind a previously undescribed, allosteric activation domain within SHIP1. Furthermore, in vivo administration of these compounds was protective in mouse models of endotoxemia and acute cutaneous anaphylaxis, suggesting that SHIP1 agonists could be used therapeutically to inhibit the PI3K pathway.

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