Novel siRNA delivery strategy: a new “strand” in CNS translational medicine?

Gherardini, Lisa; Bardi, Giuseppe; Gennaro, Mariangela; Pizzorusso, Tommaso

doi:10.1007/s00018-013-1310-8

Cited by 19 publications

(13 citation statements)

References 191 publications

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“…The reduction or absence of the C-terminal domain has been previously observed in other dinoflagellates [ 68 ]. Evolutionarily, dinoflagellate KatGs belong to the minor KatG clades, which are intermediate between bifunctional KatGs and uni-functional peroxidases like APX (including hybrid APX-CcP) and cytochrome c peroxidases [ 69 ]. The observed SymKatG Inserts 1 and 3 are essentially an extension of the characteristic first and second KatG loop [ 70 ], while SymKatG Insert 2 is a unique feature only shared by Prorocentrum minutum .…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic characterization of the enzymatic antioxidants FeSOD, MnSOD, APX and KatG in the dinoflagellate genus Symbiodinium

et al. 2015

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BackgroundThe diversity of the symbiotic dinoflagellate Symbiodinium sp., as assessed by genetic markers, is well established. To what extent this diversity is reflected on the amino acid level of functional genes such as enzymatic antioxidants that play an important role in thermal stress tolerance of the coral-Symbiodinium symbiosis is, however, unknown. Here we present a predicted structural analysis and phylogenetic characterization of the enzymatic antioxidant repertoire of the genus Symbiodinium. We also report gene expression and enzymatic activity under short-term thermal stress in Symbiodinium of the B1 genotype.ResultsBased on eight different ITS2 types, covering six clades, multiple protein isoforms for three of the four investigated antioxidants (ascorbate peroxidase [APX], catalase peroxidase [KatG], manganese superoxide dismutase [MnSOD]) are present in the genus Symbiodinium. Amino acid sequences of both SOD metalloforms (Fe/Mn), as well as KatG, exhibited a number of prokaryotic characteristics that were also supported by the protein phylogeny. In contrast to the bacterial form, KatG in Symbiodinium is characterized by extended functionally important loops and a shortened C-terminal domain. Intercladal sequence variations were found to be much higher in both peroxidases, compared to SODs. For APX, these variable residues involve binding sites for substrates and cofactors, and might therefore differentially affect the catalytic properties of this enzyme between clades. While expression of antioxidant genes was successfully measured in Symbiodinium B1, it was not possible to assess the link between gene expression and protein activity due to high variability in expression between replicates, and little response in their enzymatic activity over the three-day experimental period.ConclusionsThe genus Symbiodinium has a diverse enzymatic antioxidant repertoire that has similarities to prokaryotes, potentially as a result of horizontal gene transfer or events of secondary endosymbiosis. Different degrees of sequence evolution between SODs and peroxidases might be the result of potential selective pressure on the conserved molecular function of SODs as the first line of defence. In contrast, genetic redundancy of hydrogen peroxide scavenging enzymes might permit the observed variations in peroxidase sequences. Our data and successful measurement of antioxidant gene expression in Symbiodinium will serve as basis for further studies of coral health.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-015-0326-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic characterization of the enzymatic antioxidants FeSOD, MnSOD, APX and KatG in the dinoflagellate genus Symbiodinium

et al. 2015

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“…However, this potential treatment for impaired learning also faces the major hurdle of attaining effective delivery to the CNS, which could provide a specific means to knock down the expression of targets involved in CNS diseases (24,25). Several reports showed that nanoparticle-linked siRNA can be delivered into the brain by intranasal administration to knock down target proteins (26,27).…”

Section: Introductionmentioning

confidence: 99%

Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice

Pardo¹,

Cheng²,

Velmeshev³

et al. 2017

JCI Insight

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“…Recently, the gene therapy toolbox was enriched by virally delivered shRNAs and microRNAs to knockdown disease‐associated proteins (Deng et al ., ; Gurevich et al ., ). Non‐viral methods of delivery of therapeutic siRNAs and microRNAs are actively being developed (Yuan et al ., ; Gherardini et al ., ). Despite multiple challenges (off‐target effects, immune response, delivery problems), siRNAs are considered very attractive for treatment of such deadly diseases as cancer (Petrocca and Lieberman, ) and HIV/AIDS (Zeller and Kumar, ), with several clinical trials already underway (Castanotto and Rossi, ; Burnett et al ., ; Petrocca and Lieberman, ).…”

Section: Gene Therapy and Genome Editingmentioning

confidence: 97%

Beyond traditional pharmacology: new tools and approaches

Gurevich

2015

British J Pharmacology

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Traditional pharmacology is defined as the science that deals with drugs and their actions. While small molecule drugs have clear advantages, there are many cases where they have proved to be ineffective, prone to unacceptable side effects, or where due to a particular disease aetiology they cannot possibly be effective. A dominant feature of the small molecule drugs is their single mindedness: they provide either continuous inhibition or continuous activation of the target. Because of that, these drugs tend to engage compensatory mechanisms leading to drug tolerance, drug resistance or, in some cases, sensitization and consequent loss of therapeutic efficacy over time and/or unwanted side effects. Here we discuss new and emerging therapeutic tools and approaches that have potential for treating the majority of disorders for which small molecules are either failing or cannot be developed. These new tools include biologics, such as recombinant hormones and antibodies, as well as approaches involving gene transfer (gene therapy and genome editing) and the introduction of specially designed self‐replicating cells. It is clear that no single method is going to be a ‘silver bullet’, but collectively, these novel approaches hold promise for curing practically every disorder. Linked Articles This article is part of a themed section on 5th BPS Focused Meeting on Cell Signalling. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-13

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Novel siRNA delivery strategy: a new “strand” in CNS translational medicine?

Cited by 19 publications

References 191 publications

Transcriptomic characterization of the enzymatic antioxidants FeSOD, MnSOD, APX and KatG in the dinoflagellate genus Symbiodinium

Transcriptomic characterization of the enzymatic antioxidants FeSOD, MnSOD, APX and KatG in the dinoflagellate genus Symbiodinium

Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice

Beyond traditional pharmacology: new tools and approaches

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