Differential coagulotoxic and neurotoxic venom activity from species of the arboreal viperid snake genus Bothriechis (palm-pitvipers).

The viperid snake genus Bothriechis consists of eleven species distributed among Central and South America, living across low and high-altitude habitats. Despite Bothriechis envenomations being prominent across the Central and South American region, the functional effects of Bothriechis venoms are poorly understood. Thus, the aim of this study was to investigate the coagulotoxic and neurotoxic activities of Bothriechis venoms to fill this knowledge gap. Coagulotoxic investigations revealed Bothriechis nigroviridis and B. schlegelii to have pseudo-procoagulant venom activity, forming weak clots that rapidly break down, thereby depleting fibrinogen levels and thus contributing to a net anticoagulant state. While one sample of B. lateralis also showed weaker pseudo-procoagulant activity, directly clotting fibrinogen, two samples of B. lateralis venom were anticoagulant through the inhibition of thrombin and factor Xa activity. Differential efficacy of PoliVal-ICP antivenom was also observed, with the pseudo-procoagulant effect of B. nigroviridis venom poorly neutralised, despite this same activity in the venom of B. schlegelii being effectively neutralised. Significant specificity of these fibrinogen cleaving toxins was also observed, with no activity upon model amphibian, avian, lizard or rodent plasma observed. However, upon avian plasma the venom of B. nigroviridis exerted a complete anticoagulant effect, in contrast to the pseudo-procoagulant effect seen on human plasma. Neurotoxic investigations revealed B. schlegelii to be unique among the genus in having potent binding to the orthosteric site of the alpha-1 postsynaptic nicotinic acetylcholine receptor (with B. lateralis having a weaker but still discernible effect). This represents the first identification of postsynaptic nAChR neurotoxic activity for Bothriechis. In conclusion this study identifies notable differential activity within the coagulotoxic and postsynaptic neurotoxic activity of Bothriechis venoms, supporting previous research, and highlights the need for further studies with respect to antivenom efficacy as well as coagulotoxin specificity for Bothriechis venoms.

7,7″-Dimethoxyagastisflavone Inhibits Proinflammatory Cytokine Release and Inflammatory Cell Recruitment through Modulating ERα Signaling.

Acute systemic inflammatory diseases, including sepsis, usually result in cytokine disorder and multiple-organ failure. 7,7″-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from the needles of Taxus x media var. Hicksii, has previously been evaluated for its antiproliferative and antineoplastic effects in cancer cells. In this study, the effects of DMGF on the cytokine production and cell migration of inflammatory macrophages were investigated. The inhibition of cytokine and chemokine production by DMGF in LPS-treated macrophages was analyzed by a multiplex cytokine assay. Then, the integrin molecules used for cell adhesion and regulators of actin polymerization were observed by RT-PCR and recorded using confocal imaging. The DMGF interaction with estrogen receptor α (ERα) was modeled structurally by molecular docking and validated by an ERα reporter assay. DMGF inhibited TNF-α, IL-1ß, and IL-6 production in LPS-induced macrophages. DMGF also inhibited inflammatory macrophage migration by downregulating the gene and protein expression of adhesion molecules (LFA-1 and VLA4) and regulators of actin assembly (Cdc42-Rac1 pathway). DMGF might interact with the ligand-binding domain of ERα and downregulate its transcriptional activity. These results indicated that DMGF effectively inhibited the production of proinflammatory cytokines and the recruitment of inflammatory cells through downregulating ERα signaling.