Mustafa Jawad Jalil Al-Asady

Toll-like receptor 4 (TLR4) is a pattern-recognition receptor that detects lipopolysaccharides (LPSs) from Gram-negative bacteria, triggering innate immune and inflammatory responses. Research into TLR4 antagonists and agonists is crucial for developing novel therapies to modulate immune responses in infectious, inflammatory, and autoimmune diseases. Accordingly, some authors of this study developed synthetic TLR4 antagonists, including FP7 and FP12, and demonstrated their efficacy in inhibiting TLR4-mediated effects. This study specifically assesses the safety profile of these two novel TLR4 antagonists in mice following intraperitoneal administration. Clinical signs, body weights, and biochemical and haematological parameters in mice were assessed over four weeks after intraperitoneal administration of these molecules. No mortality or adverse effects were observed after administration of FP molecules. Key circulating biomarkers were also unaffected by these molecules. Preliminary LC–MS analysis detected both compounds in mouse plasma one hour after administration. Overall, this study demonstrates that FP7 and FP12 were well tolerated in mice, with no significant toxicological effects at the tested dose. These findings are an initial step toward further preclinical and clinical development of these molecules.

The puff adder (Bitis arietans) is a clinically relevant viper species found throughout Africa, and it is responsible for a greater incidence of health-related envenomations than all other snake species on the continent combined. Unresolved skeletal muscle damage is a common consequence of B. arietans envenomation that can result in long-term morbidity and even death. Antivenom treatment can mitigate the systemic effects of the venom but offers little protection against local tissue damage. Identifying the mechanisms through which B. arietans venom induces tissue damage and impedes skeletal muscle regeneration could identify possible treatment alternatives that could help alleviate the long-term consequences of envenomation. Skeletal muscle has an innate ability to regenerate, but constituents within the venom can impede multiple stages of this regeneration process. In this study, we employed a combination of biochemical analyses, cell-based assays, and in vivo experiments to assess the toxicological implications of B. arietans envenomation and its impacts on key processes of regeneration. Our findings demonstrate that the pathological characteristics of permanent muscle damage resulting from B. arietans envenomation may be attributed to the venom’s effects on muscle stem cell precursors, the extracellular matrix (ECM), and the influence of blood-borne proteins that promote fibrosis.