Magnolin alleviated DSS-induced colitis by inhibiting ALOX5-mediated ferroptosis.

Inflammatory bowel disease (IBD) is a chronic and incurable disorder associated with higher cancer risk and currently faces unsatisfactory treatment outcomes. Ferroptotic cells secrete damage-associated molecular patterns (DAMPs) that recruit and activate immune cells, particularly macrophages. Magnolin has excellent antioxidant and anti-inflammatory properties, but its effect on IBD has not yet been clearly understood. This study aimed to investigate the therapeutic effects and mechanism of magnolin in IBD. For this purpose, in vivo and in vitro colitis models were established using dextran sulfate sodium (DSS), followed by optimization of magnolin concentration 2.5 µg/mL in vitro and 5 mg/kg in vivo. Bioinformatics analysis identified potential magnolin target sites and evaluated ferroptosis-associated gene expressions. Body weight, food intake, disease activity index (DAI), pathological changes, and inflammation levels were assessed. The effect of magnolin on ferroptosis and macrophages was evaluated using quantitative real time-polymerase chain reaction (qRT-PCR), immunofluorescent staining, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and western blotting. Results indicated that magnolin at a lower dose (5 mg/kg) alleviated DSS-induced colitis symptoms and reduced inflammation in mice. The bioinformatics analysis showed arachidonate 5-lipoxygenase (ALOX5) as a potential magnolin target. Furthermore, magnolin inhibited the expression of ALOX5 with no effect on GPX4. Moreover, magnolin regulated macrophage differentiation into the M2 phenotype and suppressed pro-inflammatory factors, that is, interleukin-6 and tumor necrosis factor-α (IL-6 and TNFα). These results suggested that magnolin possesses significant therapeutic potential in treating IBD by suppressing ALOX5-mediated ferroptosis, inhibiting M1 while promoting M2 macrophages, which is envisaged to provide novel strategies for treating IBD.

A double-blind vehicle-controlled study of R 68 151 in psoriasis: a topical 5-lipoxygenase inhibitor.

Recently the pharmacologic role of leukotrienes (LTs), especially that of LTB4, has been intensively investigated in psoriasis. In vitro, R 68 151 is a potent 5-lipoxygenase inhibitor and consequently reduces LTB4 formation. Therefore the role of an in vitro 5-lipoxygenase inhibitor and its clinical use in psoriasis were evaluated with topical R 68 151 in a double-blind vehicle-controlled study. Eighty-eight patients with localized psoriatic lesions were treated twice daily with R 68 151 2% ointment (n = 44) or vehicle ointment (n = 44) during 4 weeks. Most patients (n = 73) had psoriasis vulgaris (n = 37, R 68 151; n = 36, vehicle). In 27% of the R 68 151-treated patients with psoriasis vulgaris, the lesions disappeared or showed marked improvement, compared with 8% in the vehicle group (X2, p = 0.06). The scores in global evaluation, however, were significantly different between both treatment groups (p less than 0.05, Mann-Whitney U test). The improvement of the mean symptom score with R 68 151 was 46% for scaling and 34% for erythema at the end of the study compared with an improvement of 6% and a deterioration of 3%, respectively, in the control group (p less than 0.05, p less than 0.01; Mann-Whitney U test). The global evaluation in the total group of patients with psoriasis (all different subtypes) was consistent with the response rate in the group of patients with psoriasis vulgaris: 30% in the test group versus 11% in the control group (X2, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)