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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

The crystal structure of human plasma gelsolin (PDB: 3FFN) showing the presence of 8 kDa amyloidogenic fragment (fAGel; highlighted in red).The amino acid sequence of fAGel is also shown.
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pone.0127011.g001: The crystal structure of human plasma gelsolin (PDB: 3FFN) showing the presence of 8 kDa amyloidogenic fragment (fAGel; highlighted in red).The amino acid sequence of fAGel is also shown.

Mentions: Gelsolin is an actin-binding protein that remodels the actin cytoskeleton as well as scavenges actin fibrils released from injured tissues [15]. However, a mutation (D187N/Y) in gelsolin causes Familial Amyloidosis of Finnish Type (FAF), a disease characterized by amyloid deposits of an 8 kDa protein fragment (fAGel, residues 173–243, Fig 1). FAF is a systemic amyloidosis disease characterized by cranial lattice dystrophy which progresses with age and is associated with severe neuropathy [16]. Previously, we reported curcumin and emetine as potent binders of amyloidogenic stretch in gelsolin and modulate its amyloidogenic pathway [17]. However, a major drawback in the applicability of both curcumin and emetine in physiological systems is their poor solubility, high hydrophobicity and instability [18].


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)

The crystal structure of human plasma gelsolin (PDB: 3FFN) showing the presence of 8 kDa amyloidogenic fragment (fAGel; highlighted in red).The amino acid sequence of fAGel is also shown.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0127011.g001: The crystal structure of human plasma gelsolin (PDB: 3FFN) showing the presence of 8 kDa amyloidogenic fragment (fAGel; highlighted in red).The amino acid sequence of fAGel is also shown.
Mentions: Gelsolin is an actin-binding protein that remodels the actin cytoskeleton as well as scavenges actin fibrils released from injured tissues [15]. However, a mutation (D187N/Y) in gelsolin causes Familial Amyloidosis of Finnish Type (FAF), a disease characterized by amyloid deposits of an 8 kDa protein fragment (fAGel, residues 173–243, Fig 1). FAF is a systemic amyloidosis disease characterized by cranial lattice dystrophy which progresses with age and is associated with severe neuropathy [16]. Previously, we reported curcumin and emetine as potent binders of amyloidogenic stretch in gelsolin and modulate its amyloidogenic pathway [17]. However, a major drawback in the applicability of both curcumin and emetine in physiological systems is their poor solubility, high hydrophobicity and instability [18].

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