Genetic background modifies amyloidosis in a mouse model of ATTR neuropathy

Panayiotou, Elena; Papacharalambous, Revekka; Antoniou, Antonis C.; Christophides, George K.; Papageorgiou, Loula; Fella, Eleni; Malas, Stavros; Kyriakides, T.

doi:10.1016/j.bbrep.2016.08.005

Cited by 3 publications

(4 citation statements)

References 28 publications

(36 reference statements)

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“…TTR amyloidosis is a rare life-threatening disease with complex phenotype–genotype correlations characterized by strong variability in penetrance, age of onset, and clinical symptoms [35,36]. Several studies have been conducted to understand the mechanisms determining the phenotypic variability observed among the carriers of TTR amyloidogenic mutations [37,38,39,40]. However, although Val30Met and Val122Ile are the most frequent TTR mutations, there is an evident disparity in the ongoing research efforts to understand the molecular mechanisms associated with these disease-causing variants.…”

Section: Discussionmentioning

confidence: 99%

Increased Risk of Multiple Outpatient Surgeries in African-American Carriers of Transthyretin Val122Ile Mutation Is Modulated by Non-Coding Variants

Polimanti

Nuñez

2019

JCM

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Background: African-Americans (AAs) have a 3.5% carrier prevalence of Transthyretin (TTR) Val122Ile mutation (rs76992529), which is the genetic cause of a hereditary form of amyloidosis. Methods: We investigated the medical history of Val122Ile carriers and assessed the role of a non-coding variation in 4361 unrelated AAs. Results: We observed that the Ile122 allele was associated with a 6.8-fold increase in the odds of having 10 or more outpatient surgeries (p = 7.81 × 10−5). Stratifying the analysis by sex, the Ile122 allele was associated with a 15.2-fold increase in the odds of having 10 or more outpatient surgeries in men (p = 6.49 × 10−7). A similar sex difference was observed with respect to the association of Val122Ile with musculoskeletal and connective-tissue disorders in an independent cohort of British subjects (n = 361,194, p = 2.47 × 10−13; nmale = 167,020, pmale = 4.02 × 10−24). In Val122Ile African-American carriers, we observed that haplotypes in the upstream region regulating TTR hepatic expression are associated with having 10 or more outpatient surgeries (p = 2.56 × 10−9). Conclusions: TTR Val122Ile showed a large effect with respect to an extreme phenotype identified in medical history that may be related to osteoarthritis, an early sign of the disease. Additionally, the non-coding variation appears to accelerate the negative consequences associated with Val122Ile mutation via TTR expression regulation.

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Section: Discussionmentioning

confidence: 99%

Increased Risk of Multiple Outpatient Surgeries in African-American Carriers of Transthyretin Val122Ile Mutation Is Modulated by Non-Coding Variants

Polimanti

Nuñez

2019

JCM

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“…Quantitative RT-PCR was performed using ThunderBird® STBR® qPCR mix (TOYOBO). The primers used for q RT-PCR were as follows: SOD forward 5’-TGGGGACAATACACAAGGCTGT-3’ and reverse 5’-TTTCCACCTTTGCCCAAGTCA-3’; Catalase forward 5’-CCTCCTCGTTCAGGATGTGGTT-3’ and reverse 5’-CGAGGGTCACGAACTGTGTCAG-3’; GPx forward 5’-CCGGGACTACACCGAGATGAA-3’ and reverse 5’-CACCAGGTCGGACGTACTTGAG-3’; GAPDH, forward 5′-CGACTTCAA-CAGCAACTCCCACTCTTCC-3′ and reverse 5′-TGGGTGG-TCCAGGGTTTCTTACTCCTT-3′ [ 31 , 32 , 33 ].…”

Section: Methodsmentioning

confidence: 99%

“…GPx forward 5'-CCGGGACTACACCGAGATGAA-3' and reverse 5'-CACCAGGTCGGACGTACTTGAG-3'; GAPDH, forward 5 -CGACTTCAA-CAGCAACTCCCACTCTTCC-3 and reverse 5 -TGGGTGG-TCCAGGGTTTCTTACTCCTT-3 [31][32][33].…”

Section: Real-time Quantitative Pcrmentioning

confidence: 99%

Novel Therapeutic Application of Self-Assembly Peptides Targeting the Mitochondria in In Vitro and In Vivo Experimental Models of Gastric Cancer

Kim

Jeena

Kim

et al. 2020

IJMS

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Here, we provide the possibility of a novel chemotherapeutic agent against gastric cancer cells, comprising the combination of 5-fluorouracil (5-FU) and a mitochondria-targeting self-assembly peptide, which is a phenylalanine dipeptide with triphenyl phosphonium (Mito-FF). The anticancer effects and mechanisms of 5-FU and Mito-FF, individually or in combination, were compared through both in vitro and in vivo models of gastric cancer. Our experiments consistently demonstrated that the 5-FU and Mito-FF combination therapy was superior to monotherapy with either, as manifested by both higher reduction of proliferation as well as an induction of apoptotic cell death. Interestingly, we found that combining 5-FU with Mito-FF leads to a significant increase of reactive oxygen species (ROS) and reduction of antioxidant enzymes in gastric cancer cells. Moreover, the inhibition of ROS abrogated the pro-apoptotic effects of combination therapy, suggesting that enhanced oxidative stress could be the principal mechanism of the action of combination therapy. We conclude that the combination of 5-FU and Mito-FF exerts potent antineoplastic activity against gastric cancer cells, primarily by promoting ROS generation and suppressing the activities of antioxidant enzymes.

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“…As a proposed therapy for transthyretin (TTR) amyloidosis, a fatal disease caused by the extrahepatic accumulation of TTR fibrils (89), Finn et al described a lipid-based nanocarrier system that could deliver CRISPR/Cas9 to target the murine TTR gene (90). The CRISPR/Cas9 was delivered as a combination of Cas9 mRNA and chemically modified sgRNA targeting TTR .…”

Section: Crispr/cas9 Delivery Systems: Strategies and Barriersmentioning

confidence: 99%

Nanoparticle-Based Delivery of CRISPR/Cas9 Genome-Editing Therapeutics

Givens

Naguib

Geary

et al. 2018

AAPS J

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The recent progress in harnessing the efficient and precise method of DNA editing provided by CRISPR/Cas9 is one of the most promising major advances in the field of gene therapy. However, the development of safe and optimally efficient delivery systems for CRISPR/Cas9 elements capable of achieving specific targeting of gene therapy to the location of interest without off-target effects is a primary challenge for clinical therapeutics. Nanoparticles (NPs) provide a promising means to meet such challenges. In this review, we present the most recent advances in developing innovative NP-based delivery systems that efficiently deliver CRISPR-Cas9 constructs and maximize their effectiveness.

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Genetic background modifies amyloidosis in a mouse model of ATTR neuropathy

Cited by 3 publications

References 28 publications

Increased Risk of Multiple Outpatient Surgeries in African-American Carriers of Transthyretin Val122Ile Mutation Is Modulated by Non-Coding Variants

Increased Risk of Multiple Outpatient Surgeries in African-American Carriers of Transthyretin Val122Ile Mutation Is Modulated by Non-Coding Variants

Novel Therapeutic Application of Self-Assembly Peptides Targeting the Mitochondria in In Vitro and In Vivo Experimental Models of Gastric Cancer

Nanoparticle-Based Delivery of CRISPR/Cas9 Genome-Editing Therapeutics

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