Obesity and its related diseases are increasing worldwide. One of the best therapeutic strategies for obesity management is through the inhibition of pancreatic lipase (PL) enzyme. So far orlistat is the only FDA approved PL inhibitor, but with unpleasant side effects. New efficacious anti-obesity drugs are needed to achieve a successful reduction in the incidence and prevalence of obesity. Many microbial metabolites have PL inhibitory activity. Screening soil inhabitants for PL inhibitors could help in increasing the available anti-obesity drugs. We aimed to isolate and identify alternative PL inhibitors from soil flora. We screened the crude mycelial methanolic extracts of 39 soil samples for PL inhibitory activity by the quantitative lipase colorimetric assay, using the substrate p-nitrophenyl palmitate and orlistat as positive control. AspsarO, a PL inhibitor producer, was isolated from an agricultural field soil in Giza, Egypt. It was identified as Aspergillus oryzae using colony morphology, microscopical characteristics, 18S rDNA sequencing, and molecular phylogeny. Increasing the PL inhibitor activity, in AspsarO cultures, from 25.9 ± 2% to 61.4 ± 1.8% was achieved by optimizing the fermentation process using a Placket–Burman design. The dried 100% methanolic fraction of the AspsarO culture had an IC50 of 7.48 μg/ml compared to 3.72 μg/ml for orlistat. It decreased the percent weight gain, significantly reduced the food intake and serum triglycerides levels in high-fat diet-fed Sprague–Dawley rats. Kojic acid, the active metabolite, was identified using several biological guided chromatographic and 1H and 13C NMR techniques and had an IC50 of 6.62 μg/ml. Docking pattern attributed this effect to the interaction of kojic acid with the key amino acids (Lys80, Trp252, and Asn84) in PL enzyme binding site. Combining the results of the induced obesity animal model, in silico molecular docking and the lipase inhibitory assay, suggests that kojic acid can be a new therapeutic option for obesity management. Besides, it can lower serum triglycerides in obese patients.

中文翻译：

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曲酸作为胰脂肪酶抑制剂的再利用及其从当地米曲霉土壤分离物的生产优化

肥胖及其相关疾病在世界范围内呈上升趋势。肥胖管理的最佳治疗策略之一是通过抑制胰脂肪酶 (PL) 酶。迄今为止，奥利司他是唯一获得 FDA 批准的 PL 抑制剂，但具有令人不快的副作用。需要新的有效抗肥胖药物来成功降低肥胖的发生率和流行率。许多微生物代谢物具有PL抑制活性。筛选土壤居民的 PL 抑制剂有助于增加可用的抗肥胖药物。我们旨在从土壤菌群中分离和鉴定替代的 PL 抑制剂。我们使用底物对硝基苯基棕榈酸酯和奥利司他作为阳性对照，通过定量脂肪酶比色法筛选了 39 个土壤样品的粗菌丝体甲醇提取物的 PL 抑制活性。AspsarO，PL 抑制剂生产者，是从埃及吉萨的农田土壤中分离出来的。使用菌落形态、显微特征、18S rDNA 测序和分子系统发育将其鉴定为米曲霉。通过使用 Plaket-Burman 设计优化发酵过程，将 AspsarO 培养物中的 PL 抑制剂活性从 25.9 ± 2% 提高到 61.4 ± 1.8%。AspsarO 培养物的干燥 100% 甲醇组分的 IC50 为 7.48 μg/ml，而奥利司他的 IC50 为 3.72 μg/ml。它降低了体重增加百分比，显着降低了高脂肪饮食喂养的 Sprague-Dawley 大鼠的食物摄入量和血清甘油三酯水平。曲酸是活性代谢物，使用几种生物引导色谱法以及 1H 和 13C NMR 技术进行鉴定，其 IC50 为 6.62 μg/ml。对接模式将这种效应归因于曲酸与 PL 酶结合位点中的关键氨基酸（Lys80、Trp252 和 Asn84）的相互作用。结合诱导肥胖动物模型、计算机分子对接和脂肪酶抑制试验的结果，表明曲酸可以成为肥胖管理的新治疗选择。此外，它还可以降低肥胖患者的血清甘油三酯。