Joshi Vikram, Umashankara M, Ramakrishnan Chandrasekaran, Nanjaraj Urs Ankanahalli N, Suvilesh Kanve Nagaraj, Velmurugan Devadasan, Rangappa Kanchugarakoppal S, Vishwanath Bannikuppe Sannanaik
Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, India.
Department of Chemistry, Karnataka State Open University, Mukthagangotri, Mysuru, Karnataka, India.
Arch Biochem Biophys. 2016 May 15;598:28-39. doi: 10.1016/j.abb.2016.04.003. Epub 2016 Apr 6.
Overproduction of arachidonic acid (AA) mediated by secretory phospholipase A2 group IIA (sPLA2IIA) is a hallmark of many inflammatory disorders. AA is subsequently converted into pro-inflammatory eicosanoids through 5-lipoxygenase (5-LOX) and cyclooxygenase-1/2 (COX-1/2) activities. Hence, inhibition of sPLA2IIA, 5-LOX and COX-1/2 activities is critical in regulating inflammation. We have previously reported unconjugated bilirubin (UCB), an endogenous antioxidant, as sPLA2IIA inhibitor. However, lipophilic UCB gets conjugated in liver with glucuronic acid into hydrophilic conjugated bilirubin (CB). Since hydrophobicity is pre-requisite for sPLA2IIA inhibition, conjugation reduces the efficacy of UCB. In this regard, UCB was chemically modified and derivatives were evaluated for sPLA2IIA, 5-LOX and COX-1/2 inhibition. Among the derivatives, BD1 (dimethyl ester of bilirubin) exhibited ∼ 3 fold greater inhibitory potency towards sPLA2IIA compared to UCB. Both UCB and BD1 inhibited human 5-LOX and COX-2 activities; however only BD1 inhibited AA induced platelet aggregation. Molecular docking studies demonstrated BD1 as better inhibitor of aforesaid enzymes than UCB and other endogenous antioxidants. These data suggest that BD1 exhibits strong anti-inflammatory activity through inhibition of AA cascade enzymes which is of great therapeutic importance.
由分泌型磷脂酶A2 IIA组（sPLA2IIA）介导的花生四烯酸（AA）过量产生是许多炎症性疾病的一个标志。随后，AA通过5-脂氧合酶（5-LOX）和环氧化酶-1/2（COX-1/2）的活性转化为促炎性类花生酸。因此，抑制sPLA2IIA、5-LOX和COX-1/2的活性对于调节炎症至关重要。我们之前报道过，内源性抗氧化剂未结合胆红素（UCB）是一种sPLA2IIA抑制剂。然而，亲脂性的UCB在肝脏中与葡萄糖醛酸结合形成亲水性的结合胆红素（CB）。由于疏水性是抑制sPLA2IIA的先决条件，结合作用会降低UCB的功效。在这方面，我们对UCB进行了化学修饰，并评估了其衍生物对sPLA2IIA、5-LOX和COX-1/2的抑制作用。在这些衍生物中，BD1（胆红素二甲酯）对sPLA2IIA的抑制效力比UCB高约3倍。UCB和BD1都能抑制人5-LOX和COX-2的活性；然而，只有BD1能抑制AA诱导的血小板聚集。分子对接研究表明，BD1比UCB和其他内源性抗氧化剂更能有效抑制上述酶。这些数据表明，BD1通过抑制AA级联酶表现出强大的抗炎活性，具有重要的治疗意义。
