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Gelsolin Amyloidogenesis Is Effectively Modulated by Curcumin and Emetine Conjugated PLGA Nanoparticles.

Srivastava A, Arya P, Goel S, Kundu B, Mishra P, Fnu A - PLoS ONE (2015)

Bottom Line: These two types of aggregates differed in their morphologies, surface hydrophobicity and secondary structural signatures, confirming that they followed distinct pathways.In spite of differences, both these aggregates displayed reduced toxicity against SH-SY5Y human neuroblastoma cells as compared to control gelsolin amyloids.We conclude that the cytotoxicity of gelsolin amyloids can be reduced by either stalling or accelerating its fibrillation process.

View Article: PubMed Central - PubMed

Affiliation: Kusuma School of Biological Sciences, IIT Delhi, New Delhi, India.

ABSTRACT
Small molecule based therapeutic intervention of amyloids has been limited by their low solubility and poor pharmacokinetic characteristics. We report here, the use of water soluble poly lactic-co-glycolic acid (PLGA)-encapsulated curcumin and emetine nanoparticles (Cm-NPs and Em-NPs, respectively), as potential modulators of gelsolin amyloidogenesis. Using the amyloid-specific dye Thioflavin T (ThT) as an indicator along with electron microscopic imaging we show that the presence of Cm-NPs augmented amyloid formation in gelsolin by skipping the pre-fibrillar assemblies, while Em-NPs induced non-fibrillar aggregates. These two types of aggregates differed in their morphologies, surface hydrophobicity and secondary structural signatures, confirming that they followed distinct pathways. In spite of differences, both these aggregates displayed reduced toxicity against SH-SY5Y human neuroblastoma cells as compared to control gelsolin amyloids. We conclude that the cytotoxicity of gelsolin amyloids can be reduced by either stalling or accelerating its fibrillation process. In addition, Cm-NPs increased the fibrillar bulk while Em-NPs defibrillated the pre-formed gelsolin amyloids. Moreover, amyloid modulation happened at a much lower concentration and at a faster rate by the PLGA encapsulated compounds as compared to their free forms. Thus, besides improving pharmacokinetic and biocompatible properties of curcumin and emetine, PLGA conjugation elevates the therapeutic potential of both small molecules against amyloid fibrillation and toxicity.

No MeSH data available.


Related in: MedlinePlus

Cytotoxicity profile of aggregates.Toxicity assessment of fAGel amyloids and aggregates formed at different concentrations of Cm-NPs or Em-NPs on SH-SY5Y cells, represented as percentage of untreated control. In each case the 24 h incubated aggregates were used.
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pone.0127011.g007: Cytotoxicity profile of aggregates.Toxicity assessment of fAGel amyloids and aggregates formed at different concentrations of Cm-NPs or Em-NPs on SH-SY5Y cells, represented as percentage of untreated control. In each case the 24 h incubated aggregates were used.

Mentions: The fibrillar and non-fibrillar aggregates formed in the presence of Cm-NPs and Em-NPs were tested for their toxic effects on the human neuroblastoma cells (SH-SY5Y). Since early proto- or pre-fibrillar aggregates are shown as the toxic amyloid species, we chose the 24 h incubated samples showing significant morphological differences [51]. The fAGel aggregates alone displayed high cellular toxicity reducing the cell viability to less than 40% after 24 h of incubation (Fig 7). Interestingly, while both the Cm- and Em-NP-induced aggregates displayed reduced cellular toxicity, the viability showed an upward trend in the case of Cm-NPs in a dose dependent manner. In the case of Em-NPs however, there was a loss of cell viability at higher concentrations which is probably due to the inhibitory effect of emetine on protein synthesis [52].


Gelsolin Amyloidogenesis Is Effectively Modulated by Curcumin and Emetine Conjugated PLGA Nanoparticles.

Srivastava A, Arya P, Goel S, Kundu B, Mishra P, Fnu A - PLoS ONE (2015)

Cytotoxicity profile of aggregates.Toxicity assessment of fAGel amyloids and aggregates formed at different concentrations of Cm-NPs or Em-NPs on SH-SY5Y cells, represented as percentage of untreated control. In each case the 24 h incubated aggregates were used.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440822&req=5

pone.0127011.g007: Cytotoxicity profile of aggregates.Toxicity assessment of fAGel amyloids and aggregates formed at different concentrations of Cm-NPs or Em-NPs on SH-SY5Y cells, represented as percentage of untreated control. In each case the 24 h incubated aggregates were used.
Mentions: The fibrillar and non-fibrillar aggregates formed in the presence of Cm-NPs and Em-NPs were tested for their toxic effects on the human neuroblastoma cells (SH-SY5Y). Since early proto- or pre-fibrillar aggregates are shown as the toxic amyloid species, we chose the 24 h incubated samples showing significant morphological differences [51]. The fAGel aggregates alone displayed high cellular toxicity reducing the cell viability to less than 40% after 24 h of incubation (Fig 7). Interestingly, while both the Cm- and Em-NP-induced aggregates displayed reduced cellular toxicity, the viability showed an upward trend in the case of Cm-NPs in a dose dependent manner. In the case of Em-NPs however, there was a loss of cell viability at higher concentrations which is probably due to the inhibitory effect of emetine on protein synthesis [52].

Bottom Line: These two types of aggregates differed in their morphologies, surface hydrophobicity and secondary structural signatures, confirming that they followed distinct pathways.In spite of differences, both these aggregates displayed reduced toxicity against SH-SY5Y human neuroblastoma cells as compared to control gelsolin amyloids.We conclude that the cytotoxicity of gelsolin amyloids can be reduced by either stalling or accelerating its fibrillation process.

View Article: PubMed Central - PubMed

Affiliation: Kusuma School of Biological Sciences, IIT Delhi, New Delhi, India.

ABSTRACT
Small molecule based therapeutic intervention of amyloids has been limited by their low solubility and poor pharmacokinetic characteristics. We report here, the use of water soluble poly lactic-co-glycolic acid (PLGA)-encapsulated curcumin and emetine nanoparticles (Cm-NPs and Em-NPs, respectively), as potential modulators of gelsolin amyloidogenesis. Using the amyloid-specific dye Thioflavin T (ThT) as an indicator along with electron microscopic imaging we show that the presence of Cm-NPs augmented amyloid formation in gelsolin by skipping the pre-fibrillar assemblies, while Em-NPs induced non-fibrillar aggregates. These two types of aggregates differed in their morphologies, surface hydrophobicity and secondary structural signatures, confirming that they followed distinct pathways. In spite of differences, both these aggregates displayed reduced toxicity against SH-SY5Y human neuroblastoma cells as compared to control gelsolin amyloids. We conclude that the cytotoxicity of gelsolin amyloids can be reduced by either stalling or accelerating its fibrillation process. In addition, Cm-NPs increased the fibrillar bulk while Em-NPs defibrillated the pre-formed gelsolin amyloids. Moreover, amyloid modulation happened at a much lower concentration and at a faster rate by the PLGA encapsulated compounds as compared to their free forms. Thus, besides improving pharmacokinetic and biocompatible properties of curcumin and emetine, PLGA conjugation elevates the therapeutic potential of both small molecules against amyloid fibrillation and toxicity.

No MeSH data available.


Related in: MedlinePlus