02666     2200337   4500001002100000005001500021035002000036007000300056008003900059082001500098084002100113100002400134245015800158250003400316260008200350300001400432650002300446650003000469650003200499650002200531700002100553700002300574700002600597700002500623700002400648700001600672700002900688520156000717856003602277990001502313INLIS00000000001933920250310012932  a0010-0225000025ta250310                |          | |    aARTVET2512  aARTVET2512 SIT d0 aSiti Irma Rahmawati1 aDual anti-inflammatory activities of COX-2/5-LOX driven by kratom alkaloid extracts in lipopolysaccharide-induced RAW  264.7 cells /cSiti Irma Rahmawati  aScientific Reports, 2024, ? 1  aJawa Barat,Indonesia :bNational Research and Innovation Agency (BRIN),c2024  a13 :bill 4aMITRAGYNA SPECIOSA 4aCELLULAR OXIDATIVE STRESS 4aDUAL INHIBITION COX-2/5-LOX 4aANTI-INFLAMMATORY0 aMutia Hardhiyuna0 aDwi Wahyu Indriani0 aFebby Nurdiya Ningsih0 aA’liyatur Rosyidah0 aFirdayani Firdayani0 aPeni Ahmadi0 aMasteria Yunovilsa Putra  aCyclooxygenase (COX) and lipoxygenase (LOX) enzymes play a pivotal role in producing proinflammatory eicosanoids, including prostaglandins (PGs) and Leukotrienes (LTs), in the inflammation process. Mitragynine is a primary alkaloid contained in the kratom’s leaves and has been reported to show anti-inflammatory activity by suppressing COX-2 mRNA translation to lowering PGs synthesis. In this study, the Kratom’s alkaloid extract Containing ~46% mitragynine was found to exhibit dual inhibition activity towards COX-2/5-LOX enzymes at concentrations below 25 ppm in the LPS-induced RAW 264.7 macrophage cells. At these levels, no cell toxicity was observed while the cells became death (e.g., 10–46% viability at 50–100 ppm) and only COX-2 inhibition activity was observed after exposed with more than 25 ppm of alkaloid extract. In contrast, the methanolic-crude extract of Kratom’s leaf Containing ~ 5% mitragynine showed no inhibition toward COX-2/5-LOX enzymes and did not toxic onto the cells, even after treated at 100 ppm. The alkaloid extract suppressed Several antiinflammation parameters, including ROS (64% reduction at 25 ppm), NO (30% reduction at 25 ppm), TNF-? (~ 50% reduction at 25 ppm), and IL-6 production (60% reduction at 6.25 ppm). In silico molecular studies indicated strong binding affinity of Kratom alkaloids to COX-2 and 5-LOX active sites, supporting the Kratom’s alkaloids to have great potential dual inhibition activity towards COX2/5-LOX enzymes and to be developed as a safer NSAIDs with fewer side effects.  aDOI: 10.1038/s41598-024-79229-x  aARTVET2512