1,008 research outputs found
Targeting VEGF in eye neovascularization: What's new? A comprehensive review on current therapies and oligonucleotide-based interventions under development
No full textAbstractRoughly ten years ago the FDA approved most of the presently used anti-VEGF drugs for the treatment of neovascular AMD and other eye pathologies characterized by ocular neoangiogenesis. However, the recent findings on the physiologic activities of VEGF isoforms impose to reconsider the inhibitory effects of pan-VEGF antagonists and the concept that to face pathological alterations at ocular level is possible only through the full block of all VEGF isoforms. In fact, although pan-VEGF agents rapidly and effectively contrast ocular neovascularization, vascular leakage, and other pathological changes, in the long-term the inhibition of all VEGF isoforms likely may result in the loss of the physiologic effects exerted by VEGF121 and the anti-angiogenic VEGF165b. Notably, selective inhibitors of VEGF165a, such as pegaptanib, spare these targets. Moreover, preclinical and clinical evidence suggests that also systemic side effects, secondary to intraocular treatment with non-selective anti-VEGF drugs, may be reinterpreted in light of these recent findings, which may be useful to clinicians for the choice of the most appropriate anti-VEGF agent.Another aspect that should be considered is the involvement of VEGF-independent pathways in ocular neovascularization, therefore a combined therapy can represent a more effective pharmacological approach that might help also to counteract tachyphylaxis, an important issue in anti-VEGF treatment.This complex picture and the recent findings on current anti-VEGF drugs should be therefore taken into account to guide the development of novel agents targeting VEGF and/or other key factors involved in the pathogenesis of neovascular ocular diseases along the signaling pathways stimulated by the various isoforms. Accordingly, this review also reports on novel pharmacological molecules targeting VEGF at ocular level and currently under development, with a special attention to oligonucleotide-based interventions
CALCIUM ALTERATIONS IN ALZHEIMERS DISEASE: PATHOHYSIOLOGY, MODELS AND THERAPEUTIC OPPORTUNITIES
No full textThe complex world of post-transcriptional mechanisms: is their deregulation a common link for diseases? Focus on ELAV-like RNA-binding proteins
No full textPost-transcriptional mechanisms are key determinants
in the modulation of the expression of final gene
products. Within this context, fundamental players are
RNA-binding proteins (RBPs), and among them ELAV-like
proteins. RBPs are able to affect every aspect in the
processing of transcripts, from alternative splicing, polyadenylation,
and nuclear export to cytoplasmic localization,
stability, and translation. Of interest, more than one RBP can
bind simultaneously the same mRNA; therefore, since each
RBP is endowed with different properties, the balance of
these interactions dictates the ultimate fate of the transcript,
especially in terms of both stability and rate of translation.
Besides RBPs, microRNAs are also important contributors
to the post-transcriptional control of gene expression. Within
this general context, the present review focuses on ELAVlike
proteins describing their roles in the nucleus and in the
cytoplasm, also highlighting some examples of interactions
with other RBPs and with microRNAs. We also examine the
putative role and the observed changes of ELAV-like proteins
and of their interactions with other regulatory elements
in Alzheimer’s disease, cancer, and inflammation. The
changes in the expression of proteins involved in these
diseases are examples of how a derangement in the mRNA
stabilization process may be associated with disease development
and contribute to pathology. Overall, we hope that
the topics handled in the present manuscript provide a hint to
look at ELAV-like-mediated mRNA stabilization as a
mechanism relevant to disease as well as a novel putative
drug target
Protein Kinase C Signal Transduction Regulation in Physiological and Pathological Aging
No full textCalcium/phospholipid-regulated protein kinase C (PKC) signalling
is known to be involved in cellular functions relevant to brain health and disease, including ion channel modulation, receptor regulation, neurotransmitter
release, synaptic plasticity, and survival. Brain aging is characterized by altered neuronal molecular cascades and interneuronal communication in response to various stimuli. In the last few years we have provided evidence
that in rodents, despite no changes in PKC isoform levels (both calcium dependent and calcium independent), the activation/translocation process of the calcium-
dependent and -independent kinases and the content of the adaptor protein RACK1 (receptor for activated C kinase-1) are deficient in physiological brain aging. Moreover, human studies have shown that PKC and its adaptor protein RACK1 are also interdependent in pathological brain aging (e.g.,
Alzheimer’s disease); in fact, calcium-dependent PKC translocation and RACK1 levels are both deficient in an area-selective manner. These data point
to the notion that, in addition to a well-described lipid environment alteration, changes in protein–protein interactions may impair the mechanisms of PKC
activation in aging. It is interesting to note that interventions to counteract the age-related functional loss also restore PKC activation and the adaptor protein
machinery expression. A better insight into the factors controlling PKC activation may be important not only to elucidate the molecular basis of signal transmission,
but also to identify new strategies to correct or even to prevent agedependent alterations in cell-to-cell communication
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