scholarly journals Formulation of Liver-Specific PLGA-DY-635 Nanoparticles Loaded with the Protein Kinase C Inhibitor Bisindolylmaleimide I

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1110
Author(s):  
Blerina Shkodra ◽  
Adrian T. Press ◽  
Antje Vollrath ◽  
Ivo Nischang ◽  
Stephanie Schubert ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Targeted Delivery ◽  
Near Infrared ◽  
Water Solubility ◽  
Analytical Ultracentrifugation ◽  
Therapeutic Potential ◽  
Kinase C ◽  
Protein Kinase C Inhibitor

Bisindolylmaleimide I (BIM-I) is a competitive pan protein kinase C inhibitor with anti-inflammatory and anti-metastatic properties, suggested to treat inflammatory diseases and various cancer entities. However, despite its therapeutic potential, BIM-I has two major drawbacks, i.e., it has a poor water solubility, and it binds the human ether-à-go-go-related gene (hERG) ion channels, potentially causing deadly arrhythmias. In this case, a targeted delivery of BIM-I is imperative to minimize peripheral side effects. To circumvent these drawbacks BIM-I was encapsulated into nanoparticles prepared from poly(lactic-co-glycolic acid) (PLGA) functionalized by the near-infrared dye DY-635. DY-635 served as an active targeting moiety since it selectively binds the OATP1B1 and OATP1B3 transporters that are highly expressed in liver and cancer cells. PLGA-DY-635 (BIM-I) nanoparticles were produced by nanoprecipitation and characterized using dynamic light scattering, analytical ultracentrifugation, and cryogenic transmission electron microscopy. Particle sizes were found to be in the range of 20 to 70 nm, while a difference in sizes between the drug-loaded and unloaded particles was observed by all analytical techniques. In vitro studies demonstrated that PLGA-DY-635 (BIM-I) NPs prevent the PKC activation efficiently, proving the efficacy of the inhibitor after its encapsulation, and suggesting that BIM-I is released from the PLGA-NPs. Ultimately, our results present a feasible formulation strategy that improved the cytotoxicity profile of BIM-I and showed a high cellular uptake in the liver as demonstrated in vivo by intravital microscopy investigations.

scholarly journals Evidence that interleukin-1 and phorbol esters activate NF-kappa B by different pathways: role of protein kinase C.

1991 ◽  
Vol 2 (4) ◽  
pp. 329-335 ◽  
Author(s):  
K Bomsztyk ◽  
J W Rooney ◽  
T Iwasaki ◽  
N A Rachie ◽  
S K Dower ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Line ◽  
Phorbol Esters ◽  
Interleukin 1 ◽  
Interleukin 2 ◽  
Nf Kappa B ◽  
Kinase C ◽  
Protein Kinase C Inhibitor

Nuclear factor kappa B (NF-kappa B) is a ubiquitous transcription factor that affects expression of many genes, including immunoglobulin kappa (kappa), the interleukin-2 receptor alpha chain, and two genes in HIV-1. NF-kappa B can be activated by a number of stimuli, including pharmacological stimulation of protein kinase C by phorbol 12-myristate 13-acetate (PMA) and treatment in vitro with either protein kinase C or protein kinase A. This has lead to the proposal that these kinases are key enzymes in the physiological activation of NF-kappa B as well. We have used a murine B cell line, 70Z/3, and T cell line, EL-4 6.1 C10, to study the activation of NF-kappa B by two physiological activators, interleukin-1 alpha (IL-1) and lipopolysaccharide (LPS). There are four reasons to propose that these agents activate pathways that do not include protein kinase C as a major component in these cell lines. First, the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) strongly inhibited PMA-induced activation of NF-kappa B in 70Z/3 cells but had no effect on NF-kappa B activated by IL-1 or LPS. Second, depletion of protein kinase C by prolonged growth of 70Z/3 in PMA abrogated the capacity of the cells to activate NF-kappa B in response to further PMA treatment. However, these same cells activated NF-kappa B normally after either IL-1 or LPS treatment. Third, IL-1 effectively activated NF-kappa B in EL-4 6.1 C10 cells, but PMA did not. Fourth, interferon-gamma is a potent activator of protein kinase C in 70Z/3 cells, but is completely inactive in the mobilization of NF-kappa B. These results suggest that the physiological inducers IL-1 and LPS activate NF-kappa B by pathways independent of protein kinase C in both 70Z/3 and EL-4 6.1 C10 cells.

scholarly journals Therapeutic Potential for Protein Kinase C Inhibitor in Vascular Restenosis

2010 ◽  
Vol 16 (2) ◽  
pp. 160-167 ◽  
Author(s):  
Richard Qinxue Ding ◽  
Jerry Tsao ◽  
Hong Chai ◽  
Daria Mochly-Rosen ◽  
Wei Zhou
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Therapeutic Potential ◽  
Kinase C ◽  
Protein Kinase C Inhibitor ◽  
Vascular Restenosis

scholarly journals Contrasting effects of the protein kinase C inhibitor, staurosporine, on cytokine and phorbol ester stimulation of fructose 2,6-bisphosphate and prostaglandin E production by fibroblasts in vitro. Comparative studies using interleukin-1α, tumour necrosis factor α, transforming growth factor β, interferon-γ and 12-O-tetradecanoylphorbol 13-acetate

1990 ◽  
Vol 269 (3) ◽  
pp. 573-577 ◽  
Author(s):  
D J Taylor ◽  
J M Evanson ◽  
D E Woolley
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Dermal Fibroblasts ◽  
Tnf Alpha ◽  
Prostaglandin E ◽  
Kinase C ◽  
Protein Kinase C Inhibitor ◽  
Necrosis Factor

It is known that both interleukin-1 alpha (IL-1 alpha) and 12-O-tetradecanoylphorbol 13-acetate (TPA) promote increases in intracellular levels of the glycolytic regulatory metabolite fructose 2,6-bisphosphate [Fru(2,6)P2] and in the production of prostaglandin E (PGE) by subcultured rheumatoid synovial cells (RSC) and human dermal fibroblasts in vitro. We report here that the protein kinase C inhibitor staurosporine enhanced the IL-1 alpha-induced increase in [Fru(2,6)P2] and PGE production by RSC, whereas in similar concentrations (3-30 nM) this inhibitor decreased the TPA-induced stimulation of these parameters. Staurosporine produced a similar enhancement of the response to IL-1 alpha by normal human dermal fibroblasts. The increased PGE production provoked by tumour necrosis factor alpha (TNF alpha) in RSC was also augmented by staurosporine, but, in contrast, the increases in cellular [Fru(2,6)P2] induced by transforming growth factor beta (TGF beta) and interferon-gamma (IFN-gamma) were diminished. Thus the protein kinase C inhibitor staurosporine discriminates not only between the effects produced by IL-1 alpha and TPA, but also between those of IL-1 alpha and two other cytokines (but not between IL-1 alpha and TNF alpha). These findings suggest that IL-1 alpha and probably TNF alpha act via an intracellular mechanism different from that mediating the action of TPA, TGF-beta and IFN-gamma, and provide evidence that staurosporine is capable of amplifying the IL-1 signal.

scholarly journals Inhibition of Neutrophil Apoptosis by Verotoxin 2 Derived from Escherichia coli O157:H7

1999 ◽  
Vol 67 (11) ◽  
pp. 6203-6205 ◽  
Author(s):  
Jiajia Liu ◽  
Tohru Akahoshi ◽  
Takeshi Sasahana ◽  
Hidero Kitasato ◽  
Rie Namai ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Neutrophil Apoptosis ◽  
Escherichia Coli O157 ◽  
Significant Delay ◽  
Kinase C ◽  
Protein Kinase C Inhibitor

ABSTRACT In order to evaluate the pathological role of verotoxin 2 (VT2), we investigated the effects of VT2 on neutrophil apoptosis in vitro. The results showed that VT2 caused a significant delay in spontaneous neutrophil apoptosis and that the effect was abrogated by a protein kinase C inhibitor. These data indicate that longer survival of neutrophils may aggravate neutrophil-mediated tissue damage in VT2-associated diseases.

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