A novel single‐chain enzyme complex with chain reaction properties rapidly producing thromboxane A₂ and exhibiting powerful anti‐bleeding functions

Abstract

Uncontrollable bleeding is still a worldwide killer. In this study, we aimed to investigate a novel approach to exhibit effective haemostatic properties, which could possibly save lives in various bleeding emergencies. According to the structure‐based enzymatic design, we have engineered a novel single‐chain hybrid enzyme complex (SCHEC), COX‐1‐10aa‐TXAS. We linked the C‐terminus of cyclooxygenase‐1 (COX‐1) to the N‐terminus of the thromboxane A2 (TXA2) synthase (TXAS), through a 10‐amino acid residue linker. This recombinant COX‐1‐10aa‐TXAS can effectively pass COX‐1–derived intermediate prostaglandin (PG) H2 (PGH2) to the active site of TXAS, resulting in an effective chain reaction property to produce the haemostatic prostanoid, TXA2, rapidly. Advantageously, COX‐1‐10aa‐TXAS constrains the production of other pro‐bleeding prostanoids, such as prostacyclin (PGI2) and prostaglandin E2 (PGE2), through reducing the common substrate, PGH2 being passed to synthases which produce aforementioned prostanoids. Therefore, based on these multiple properties, this novel COX‐1‐10aa‐TXAS indicated a powerful anti‐bleeding ability, which could be used to treat a variety of bleeding situations and could even be useful for bleeding prone situations, including nonsteroidal anti‐inflammatory drugs (NSAIDs)‐resulted TXA2‐deficient and PGI2‐mediated bleeding disorders. This novel SCHEC has a great potential to be developed into a biological haemostatic agent to treat severe haemorrhage emergencies, which will prevent the complications of blood loss and save lives.

Janus kinase inhibitors modify the fatty acid profile of extracellular vesicles and modulate the immune response

“…In fact, at low concentrations (2 μg/mL), arachidonate can induce platelet activation and phosphatidylserine exposure and promote a procoagulant state [ 92 ]. In addition, cyclooxygenase-1 can convert arachidonate into thromboxane A2 (TxA2) [ 93 , 94 ], thus amplifying the vesicular arachidonate effects [ [95] , [96] , [97] ].…”

Parsing the Q-Markers of Baoyin Jian to Treat Abnormal Uterine Bleeding by High-Throughput Chinmedomics Strategy

“…TXA 2 and PGI 2 are vasoactive substances, which are endogenous metabolites closely related to the formation mechanism of AUB and regulate hemodynamics in the endothelium. TXA 2 has a strong vasoconstrictive effect and promotes platelet aggregation and release [ 17 ], while PGI 2 is synthesized by the endothelial cells of blood vessels and has vasodilatory and platelet-inhibiting effects. Under normal conditions, TXA 2 and PGI 2 are in a dynamic balance, jointly regulating vasoconstriction and dilation and participating in the regulation of blood clotting [ 18 ].…”

Dissecting the mechanism of Yuzhi Zhixue granule on ovulatory dysfunctional uterine bleeding by network pharmacology and molecular docking

“…Animal experimental studies have shown that total flavonoids of Limonium bicolor, Sedum auriculatum, and purple pearl can significantly reduce bleeding and clotting time in mice. The mechanism of action may be through regulating the imbalance of TXA2 and PGI2, enhancing the contraction of small blood vessels in the endometrium to achieve hemostasis [ 58 ]. Therefore, we speculate that isorhamnetin, catechins and other flavonoids in YZG also regulate the expression of the PTGS gene to strengthen endometrial vasoconstriction and platelet aggregation, thereby achieving a hemostatic effect.…”