Protection against ischemic brain injury by protein therapeutics

Asoh, Sadamitsu; Ohsawa, Ikuroh; Mori, Takashi; Katsura, Ken‐ichiro; Hiraide, Tomoharu; Katayama, Yasuo; Kimura, Megumi; Ozaki, Daiya; Yamagata, Kumi; Ohta, Shigeo

doi:10.1073/pnas.262460299

Cited by 195 publications

(151 citation statements)

References 36 publications

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“…1 It is noted that mitochondria play an important role in necrosis as well as apoptosis. 1,47 As PTD-FNK was shown to localize in the mitochondria, 17,18 further studies on the function of PTD-FNK would provide insight into the correlation between apoptosis and necrosis. Since FNK exhibited clearer results than Bcl-x L , FNK will be useful for investigating this issue in future.…”

Section: Discussionmentioning

confidence: 99%

“…59 PTD-FNK likely inhibits the disruption of Ca 2 þ homeostasis induced by CCl 4 because PTD-FNK affects the cytosolic movement of Ca 2 þ and protects neuronal cells from glutamate excitotoxicity. 18 PTD-FNK injected into mice was successfully delivered to the liver and prevented the acute and chronic death of hepatocytes caused by CCl 4 . On post-injection of PTD-FNK, an injection of Z-VAD-FMK significantly reduced the acute liver injury, as expected from the in vitro studies, indicating that the therapeutic window for combined injections extends after the administration of CCl 4 .…”

Section: Discussionmentioning

confidence: 99%

“…18 A pleiotropic cytokine, TNFa, has been shown to induce apoptosis and be involved in acute CCl 4 -induced hepatic injury. [41][42][43] We investigated whether PTD-FNK prevents HepG2 from TNFa/CHX-induced apoptosis.…”

Section: Necrosis In Hepg2 Induced By CCLmentioning

confidence: 99%

“…17,18 We examined the levels of intracellular ATP and the mitochondrial membrane potential to reveal the role of PTD-FNK on mitochondrial functions during the protection against necrosis. Exposure against CCl 4 decreased the intracellular ATP and PTD-FNK slightly but significantly suppressed the decrease (Figure 4a).…”

Section: Ptd-fnk Retains the Mitochondrial Membrane Potential And Intmentioning

confidence: 99%

“…16 In addition, PTD-FNK, a fusion protein of the PTD and FNK, penetrates the dense matrix of cartilage to reach chondrocytes. 17 In a previous study, PTD-FNK was demonstrated to reduce ischemic injury to hippocampal CA1 neurons after a transient forebrain ischemia, 18 which involves slow progressive neuronal degeneration, and an apoptotic pathway is suggested to contribute to the ischemic degeneration, to some extent. 19 The enhanced cytoprotective activity of FNK against oxidative stress and a calcium ionophore give rise to the possibility that FNK effectively protects cells from necrosis as well as apoptosis, because oxidative stress [20][21][22] and a disruption of calcium homeostasis [23][24][25] are known to induce necrosis.…”

Section: Introductionmentioning

confidence: 98%

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Zonal necrosis prevented by transduction of the artificial anti-death FNK protein

et al. 2005

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Protection of cells from necrosis would be important for many medical applications. Here, we show protein transduction domain (PTD)-FNK therapeutics based on protein transduction to prevent necrosis and acute hepatic injury with zonal death induced by carbon tetrachloride (CCl 4 ). PTD-FNK is a fusion protein comprising the HIV/Tat PTD and FNK, a gain-offunction mutant of anti-apoptotic Bcl-x L . PTD-FNK protected hepatoma HepG2 from necrotic death induced by CCl 4 , and additionally, increased the apoptotic population among cells treated with CCl 4 . A concomitant treatment with a pancaspase inhibitor Z-VAD-FMK (N-benzyloxycarbonyl-Val-AlaAsp-fluoromethylketone), which alone could not prevent the necrosis, protected these cells from the apoptosis. When preinjected intraperitoneally, PTD-FNK markedly reduced zonal liver necrosis caused by CCl 4 . Moreover, injection of PTD-FNK accompanied by Z-VAD-FMK suppressed necrotic injury even after CCl 4 administration. These results suggest that PTD-FNK has great potential for clinical applications to prevent cell death, whether from apoptosis or necrosis, and organ failure.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Necrosis In Hepg2 Induced By CCLmentioning

confidence: 99%

Section: Ptd-fnk Retains the Mitochondrial Membrane Potential And Intmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Zonal necrosis prevented by transduction of the artificial anti-death FNK protein

et al. 2005

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Intracellular Delivery of Proteins and Peptides

Sarısözen

Torchilin

2016

Drug Delivery

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Transduction Methods for Cytosolic Delivery of Proteins and Bioconjugates into Living Cells

Chiper

Niederreither

Zuber

2017

Adv Healthcare Materials

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The human organism and its constituting cells rely on interplay between multiple proteins exerting specific functions. Progress in molecular biotechnologies has facilitated the production of recombinant proteins. When administrated to patients, recombinant proteins can provide important healthcare benefits. To date, most therapeutic proteins must act from the extracellular environment, with their targets being secreted modulators or extracellular receptors. This is because proteins cannot passively diffuse across the plasma membrane into the cytosol. To expand the scope of action of proteins for cytosolic targets (representing more than 40% of the genome) effective methods assisting protein cytosolic entry are being developed. To date, direct protein delivery is extremely tedious and inefficient in cultured cells, even more so in animal models of pathology. Novel techniques are changing this limitation, as recently developed in vitro methods can robustly convey large amount of proteins into cell cultures. Moreover, advances in protein formulation or protein conjugates are slowly, but surely demonstrating efficiency for targeted cytosolic entry of functional protein in vivo in tumor xenograft models. In this review, various methods and recently developed techniques for protein transport into cells are summarized. They are put into perspective to address the challenges encountered during delivery.

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Protection against ischemic brain injury by protein therapeutics

Cited by 195 publications

References 36 publications

Zonal necrosis prevented by transduction of the artificial anti-death FNK protein

Zonal necrosis prevented by transduction of the artificial anti-death FNK protein

Intracellular Delivery of Proteins and Peptides

Transduction Methods for Cytosolic Delivery of Proteins and Bioconjugates into Living Cells

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