College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, 24341, Republic of Korea.
J Nat Med. 2021 Jan;75(1):56-65. doi: 10.1007/s11418-020-01444-3. Epub 2020 Aug 10.
Fourteen triterpenes, lup-20(29)-ene-3β,6β-diol (1), betulin (2), lupeol caffeate (3), 3β-caffeoyloxylup-20(29)-en-6α-ol (4), betulin-3β-yl-caffeate (5), 3β-trans-feruloylbetulin (6), betulinaldehyde 3-caffeate (7), 3-O-trans-caffeoylbetulinic acid (8), dammarenediol II 3-caffeate (9), 12-oleanene-3β,6α-diol (10), 11α-hydroxy-3β-amyrin (11), nivadiol (12), 29-hydroxyfriedelin (13), and celastrusin A (14) were isolated from Celastrus orbiculatus Thunb. and evaluated for their activity on receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs). Compounds betulin (2), betulin-3β-yl-caffeate (5), 3β-trans-feruloylbetulin (6), and 3-O-trans-caffeoylbetulinic acid (8) significantly inhibited osteoclast formation in a dose-dependent manner. Among these, betulin-3β-yl-caffeate (5) exhibited the most potent inhibitory activity. We demonstrated that betulin-3β-yl-caffeate (5) suppressed F-actin-ring formation and bone resorption activity. At the molecular level, betulin-3β-yl-caffeate (5) inhibited RANK-induced expression of c-Fos and the induction of nuclear factor of activated T cells 1 (NFATc1), a key transcription factor for osteoclast formation, and it also downregulated mRNA expression of osteogenesis-associated marker genes including tartrate-resistant acid phosphatase (TRAP), dendritic cell-specific transmembrane protein (DC-STAMP), and matrix metalloprotein (MMP). These results indicate that betulin-3β-yl-caffeate (5) may be a promising candidate for the treatment of osteoclast-related diseases such as osteoporosis.
从南蛇藤中分离得到了 14 种三萜类化合物，包括 lup-20(29)-ene-3β,6β-二醇（1）、桦木醇（2）、羽扇豆醇咖啡酸酯（3）、3β-咖啡酰氧基 lup-20(29)-烯-6α-醇（4）、桦木醇-3β-基咖啡酸酯（5）、3β-反式-阿魏酰基桦木醇（6）、betulinaldehyde 3-caffeate（7）、3-O-反式-阿魏酰基 betulinic 酸（8）、dammarenediol II 3-caffeate（9）、12-oleanene-3β,6α-二醇（10）、11α-羟基-3β-金雀花醇（11）、nivadiol（12）、29-羟基 Friedelin（13）和 celastrusin A（14）。并评估了它们在核因子κB 配体（RANKL）诱导的骨髓巨噬细胞（BMM）破骨细胞分化中的活性。桦木醇（2）、桦木醇-3β-基咖啡酸酯（5）、3β-反式-阿魏酰基桦木醇（6）和 3-O-反式-阿魏酰基 betulinic 酸（8）均能显著抑制破骨细胞形成，呈剂量依赖性。其中桦木醇-3β-基咖啡酸酯（5）抑制活性最强。我们证明了桦木醇-3β-基咖啡酸酯（5）可抑制 F-肌动蛋白环形成和骨吸收活性。在分子水平上，桦木醇-3β-基咖啡酸酯（5）抑制 RANK 诱导的 c-Fos 表达和核因子活化 T 细胞 1（NFATc1）的诱导，NFATc1 是破骨细胞形成的关键转录因子，同时也下调了与成骨相关的标记基因如抗酒石酸酸性磷酸酶（TRAP）、树突状细胞特异性跨膜蛋白（DC-STAMP）和基质金属蛋白酶（MMP）的 mRNA 表达。这些结果表明桦木醇-3β-基咖啡酸酯（5）可能是治疗与破骨细胞相关疾病如骨质疏松症的有前途的候选药物。
