Some arachnidan peptides with potential medical application

The search for new active drugs that can alleviate or cure different diseases is a constant challenge to researchers in the biological area and to the pharmaceutical industry. Historically, research has focused on the study of substances from plants. More recently, however, animal venoms have been attracting attention and studies have been successful in addressing treatment of accidents. Furthermore, venoms and their toxins have been considered good tools for prospecting for new active drugs or models for new therapeutic drugs. In this review, we discuss some possibilities of using different toxins, especially those from arachnid venoms, which have shown some potential application in diseases involving pain, hypertension, epilepsy and erectile dysfunction. A new generation of drugs is likely to emerge from peptides, including those found in animal venoms

mu-Theraphotoxin-An1a: primary structure determination and assessment of the pharmacological activity of a promiscuous anti-insect toxin from the venom of the tarantula Acanthoscurria natalensis (Mygalomorphae, Theraphosidae)

Tarantulas are included in the mygalomorph spider family Theraphosidae. Although the pharmacological diversity of theraphosid toxins (theraphotoxins) is broad, studies dedicated to the characterization of biologically active molecules from the theraphosid genus Acanthoscurria have been restricted to the investigation of antimicrobial peptides and polyamines produced by the hemocytes of Acanthoscurria gomesiana. The present study reports the purification, primary structure determination and electrophysiological effects of an anti-insect toxin, named mu-theraphotoxin-An1a (mu-TRTX-An1a), from the venom of Acanthoscurria natalensis - a tarantula species occurring in the Brazilian biomes caatinga and cerrado. The analysis of the primary structure of mu-TRTX-An1a revealed the similarity of this toxin to theraphosid toxins bearing a huwentoxin-II-like fold. Electrophysiological experiments showed that mu-TRTX-An1a (100 nM) induces membrane depolarization, increases the spontaneous firing frequency and reduces spike amplitude of cockroach dorsal unpaired median (DUM) neurons. In addition, under voltage-clamp conditions, mu-TRTX-An1a (100 nM) only partially blocks voltage-dependent sodium current amplitudes in DUM neurons without any effect on their voltage dependence. This effect correlates well with the reduction of the spontaneous action potential amplitudes. Altogether, these last results suggest that mu-TRTX-An1a affects insect neuronal voltage-dependent sodium channels, which are among possible channels targeted by this promiscuous toxin

Evaluation of post-surgical cognitive function and protein fingerprints in the cerebro-spinal fluid utilizing surface-enhanced laser desorption/ionization time-of-flight mass-spectrometry (SELDI-TOF MS) after coronary artery bypass grafting: Review of proteomic analytic tools and introducing a new syndrome

Cognitive dysfunction following surgery is a common complication, which increases the incidence of other co-morbid conditions, hospital and health-care costs. The reported rate of the occurrence of post-operative cognitive decline varies with different studies, depending on population profile, type of surgery, definition of cognitive disorder and detection methods, design of study, etc. It remains unclear whether these psychiatric signs and symptoms are direct results of the effects of surgery or general anesthesia. Nonetheless they are more frequent after cardiac surgery and are likely to be multi-factorial, but the patho-mechanisms are not yet fully characterized. This communication provides a synopsis of proteomics tools and delineates novel SELDI-TOF results to evaluate biomarkers in this regard. Presented for the first time is a classification of the clinically relevant forms of post-operative cognitive decline with the advent of a novel subclass. © 2011 Bentham Science Publishers Ltd

The renin-angiotensin system: going beyond the classical paradigms

Thirty years ago a novel axis of the renin-angiotensin system (RAS) was unveiled by the discovery of angiotensin (Ang)-(1-7) generation in-vivo. Later angiotensin-converting enzyme 2 (ACE2) was shown to be the main mediator of this reaction and Mas was found to be the receptor for the heptapeptide. The functional analysis of this novel axis of the RAS which followed its discovery revealed numerous protective actions in particular for cardiovascular diseases. In parallel, similar protective actions were also described for one of the two receptors of Ang II, AT2R, in contrast to the other, AT1R, which mediates deleterious actions of this peptide e.g. in the setting of cardiovascular disease. Very recently, another branch of the RAS was discovered, based on Ang peptides in which the aminoterminal aspartate is replaced by alanine, the alatensins. Ala-Ang-(1-7) or alamandine was shown to interact with the Mas-related receptor (MrgD) and first functional data indicate that this peptide also exerts protective effects in the cardiovascular system. This review summarizes the presentations given at the International Union of Physiological Sciences Congress in Rio de Janeiro, 2017, during the symposium "The renin-angiotensin system: going beyond the classical paradigms", in which the signaling and the physiological actions of Ang-(1-7), ACE2, AT2R and the alatensins were reported (with a focus on non-CNS tissues) and the therapeutic opportunities based on these findings were discussed

Tityus serrulatus Hypotensins: a new family of peptides from scorpion venom.

International audienceUsing a proteomic approach, a new structural family of peptides was put in evidence in the venom of the yellow scorpion Tityus serrulatus. Tityus serrulatus Hypotensins (TsHpt) are random-coiled linear peptides and have a similar bradykinin-potentiating peptide (BPP) amino acid signature. TsHpt-I (2.7kDa), the first member of this family, was able to potentiate the hypotensive effects of bradykinin (BK) in normotensive rats. Using the C-terminal of this peptide as a template, a synthetic analog peptide (TsHpt-I([17-25])) was designed to held the BK-potentiating effect. A relevant hypotensive effect, independent on BK, was also observed on both TsHpt (native and synthetic). To better evaluate this hypotensive effect, we examined the vasorelaxation of aortic rings from male Wistar rats and the peptides were able to induce endothelium-dependent vasorelaxation dependent on NO release. Both TsHpt could not inhibit ACE activity. These peptides appear to exert their anti-hypertensive effect through NO-dependent and ACE-independent mechanisms

Quantitative phosphoproteomics of the angiotensin AT(2)-receptor signaling network identifies HDAC1 (Histone-Deacetylase-1) and p53 as mediators of antiproliferation and apoptosis

BACKGROUND: Angiotensin AT(2)-receptor signaling is atypical for a G-protein coupled receptor and incompletely understood. To obtain novel insights into AT(2)-receptor signaling, we mapped changes in the phosphorylation status of the entire proteome of human aortic endothelial cells in response to AT(2)-receptor stimulation. METHODS: Phosphorylation status of human aortic endothelial cells after stimulation with C21 (1 µM; 0, 1, 3, 5, 20 minutes) was determined utilizing time-resolved quantitative phosphoproteomics. Specific changes in protein phosphorylation and acetylation were confirmed by Western Blotting. Functional tests included resazurin assay for cell proliferation, and caspase 3/7 luminescence assay or FACS analysis of annexin V expression for apoptosis. RESULTS: AT(2)-receptor stimulation significantly altered the phosphorylation status of 172 proteins (46% phosphorylations, 54% dephosphorylations). Bioinformatic analysis revealed a cluster of phospho-modified proteins involved in antiproliferation and apoptosis. Among these proteins, HDAC1 (histone-deacetylase-1) was dephosphorylated at serine (421/423)involving serine/threonine phosphatases. Resulting HDAC1 inhibition led to p53 acetylation and activation. AT(2)-receptor stimulation induced antiproliferation and apoptosis, which were absent when cells were co-incubated with the p53 inhibitor pifithrin-α, thus indicating p53-dependence of these AT(2)-receptor mediated functions. CONCLUSIONS: Contrary to the prevailing view that AT(2)-receptor signaling largely involves phosphatases, our study revealed significant involvement of kinases. HDAC1 inhibition and resulting p53 activation were identified as novel, AT(2)-receptor coupled signaling mechanisms. Furthermore, the study created an openly available dataset of AT(2)-receptor induced phospho-modified proteins, which has the potential to be the basis for further discoveries of currently unknown, AT(2)-receptor coupled signaling mechanisms