In this study, we pharmacologically characterized gambierol, a marine polycyclic ether toxin which is produced by the dinoflagellate Gambierdiscus toxicus.
Among the scorpion venom components whose function are poorly known or even show contrasting pharmacological results are those called "orphan peptides". The most widely distributed are named beta-KTx or scorpine-like peptides. They contain three disulfide bridges with two recognizable domains: a freely moving N-terminal amino acid sequence and a tightly folded C-terminal region with a cysteine-stabilized alpha/beta (CS-alphabeta) motif. Four such peptides and three cloned genes are reported here. They were assayed for their cytolytic, antimicrobial and K (+) channel-blocking activities. Two main characteristics were found: the existence of an unusual structural and functional diversity, whereby the full-length peptide can lyse cells or kill microorganisms, and a C-terminal domain containing the CS-alphabeta motif that can block K (+) channels. Furthermore, sequence analyses and phylogenetic reconstructions are used to discuss the evolution of this type of peptide and to highlight the versatility of the CS-alphabeta structures.
Alzheimer's disease (AD) is characterized by a robust inflammatory response elicited by the accumulation and deposition of amyloid-β (Aβ) within the brain. Aβ induces detrimental inflammatory responses through toll-like receptors (TLRs) signaling pathway. Thymoquinone (TQ), the main active constituent of Nigella sativa oil, has been reported by several previous studies for its potent anti-inflammatory effect. The aim of this study is to elucidate the effect of TQ in improving learning and memory, using a rat model of AD induced by a combination of aluminum chloride (AlCl) and d-galactose (d-Gal). TQ was administered orally at doses of 10, 20, and 40 mg/kg/day for 14 days after AD induction. Memory functions were assessed using the step through passive avoidance test. Amyloid plaques were shown to be present using hematoxylin and eosin staining. Tumor necrosis factor-alpha (TNF-α) and Interleukin-1beta (IL-1β) levels in brain were assessed via ELISA and profiling TLR-2, TLR-4, myeloid differential factor 88, toll-interleukin-1 receptor domain-containing adapter-inducing interferon-β, interferon regulatory factor 3 (IRF-3), and nuclear factor-κB (NF-κB) expressions via real-time polymerase chain reaction. TQ improved AD rat cognitive decline, decreased Aβ formation and accumulation, significantly decreased TNF-α and IL-1β at all levels of doses and significantly downregulated the expression of TLRs pathway components as well as their downstream effectors NF-κB and IRF-3 mRNAs at all levels of doses ( p < 0.05). We concluded that TQ reduced the inflammation induced by d-Gal/AlCl combination. It is therefore reasonable to assign the anti-inflammatory responses to the modulation of TLRs pathway.
Given their medical importance, most attention has been paid towards the venom composition of scorpions of the Buthidae family. Nevertheless, research has shown that the venom of scorpions of other families is also a remarkable source of unique peptidyl toxins. The κ-KTX family of voltage-gated potassium channel (VGPC) scorpion toxins is hereof an example. From the telson of the scorpion Heterometrus laoticus (Scorpionidae), a peptide, Hl15-1-1, with unique primary sequence was purified through HPLC and sequenced by Edman degradation. Based on the amino acid sequence, the peptide could be cloned and the cDNA sequence revealed. Hl15-1-1 was chemically synthesized and functionally characterized on VGPCs of the Shaker-related, Shaw-related and Shal-related subfamilies. Furthermore, the toxin was also tested on small- and intermediate conductance Ca2+-activated K+ channels. From the channels studied, Kv1.1 and Kv1.6 were found to be the most sensitive (Kv1.1 EC50 = 9.9 ± 1.6 μM). The toxin did not alter the activation of the channels. Competition experiments with TEA showed that the toxin is a pore blocker. Mutational studies showed that the residues E353 and Y379 in the pore of Kv1.1 act as major interaction points for binding of the toxin. Given the amino acid sequence, the predicted secondary structure and the biological activity on VGPCs, Hl15-1-1 should be included in the κ-KTX family. Based on a phylogenetic study we rearranged this family of VGPC toxins into five subfamilies and suggest that HI15-1-1 is the first member of the new KTX5 subfamily.
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