Imaging mass spectrometry (IMS) was conducted for the first time using ustalic acid (UA) and the fruiting body of Tricholoma kakishimeji to localize mushroom toxins. The mushroom materials were systematically collected in Japan, and analysis of the cross sections of the materials at a resolution of 120 μm using matrix-assisted laser desorption/ionization mass spectrometry (MALDI–IMS) revealed the localization of UA and its biogenically related metabolites. MALDI–IMS confirmed that UA was predominantly located on the entire surface of the fruiting body and accumulated in higher amounts in younger fruiting bodies than in mature ones. UA is the first toxic secondary metabolite in the genus Tricholoma locally identified using IMS in mushrooms.
{"title":"Visualizing the spatial distribution of ustalic acid in the fruiting body of Tricholoma kakishimeji","authors":"Tetsuro Ito, Syu Taira, Wataru Aoki, Hiroyuki Nagai, Masashi Fukaya, Kaori Ryu, Akiyoshi Yamada","doi":"10.1007/s11418-024-01823-0","DOIUrl":"10.1007/s11418-024-01823-0","url":null,"abstract":"<div><p>Imaging mass spectrometry (IMS) was conducted for the first time using ustalic acid (UA) and the fruiting body of <i>Tricholoma kakishimeji</i> to localize mushroom toxins. The mushroom materials were systematically collected in Japan, and analysis of the cross sections of the materials at a resolution of 120 μm using matrix-assisted laser desorption/ionization mass spectrometry (MALDI–IMS) revealed the localization of UA and its biogenically related metabolites. MALDI–IMS confirmed that UA was predominantly located on the entire surface of the fruiting body and accumulated in higher amounts in younger fruiting bodies than in mature ones. UA is the first toxic secondary metabolite in the genus <i>Tricholoma</i> locally identified using IMS in mushrooms.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"78 4","pages":"838 - 843"},"PeriodicalIF":2.5,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-12DOI: 10.1007/s11418-024-01817-y
Xiaoli Wang, Zhenyu Zan, Jun Chi, An Huang, Danyang Zhang, Houli Jiang, Yi Li, Jun Luo
Two new lindenane-type sesquiterpenoid dimers, chlotrichenes C and D (1 and 2) together with five known lindenane-type sesquiterpenoid dimers (3–7) were isolated from the roots of Chloranthus holostegius var. trichoneurus, a famous natural medicine named as “Sikuaiwa” for subduing swellings and relieving pain. The structures including absolute configuration were elucidated by their 1D and 2D NMR, HRESIMS, and ECD data. Compounds 1 and 2 were classical [4 + 2] lindenane-type sesquiterpenoid dimers that differed from known analogs in oxidation profile, side chain profile, and double bond position. The new isolates and compound 3 exhibited significant inhibitory activity on IL-1β production (IC50: 1–15 μM) in LPS-induced THP-1 cells and other compounds exhibited inhibitory activity on NO production in LPS-induced RAW 264.7 cells (IC50: 24–33 μM).
{"title":"Anti-inflammatory lindenane sesquiterpenoid dimers from the roots of Chloranthus holostegius var. trichoneurus","authors":"Xiaoli Wang, Zhenyu Zan, Jun Chi, An Huang, Danyang Zhang, Houli Jiang, Yi Li, Jun Luo","doi":"10.1007/s11418-024-01817-y","DOIUrl":"10.1007/s11418-024-01817-y","url":null,"abstract":"<div><p>Two new lindenane-type sesquiterpenoid dimers, chlotrichenes C and D (<b>1</b> and<b> 2</b>) together with five known lindenane-type sesquiterpenoid dimers (<b>3</b>–<b>7</b>) were isolated from the roots of <i>Chloranthus holostegius</i> var. <i>trichoneurus</i>, a famous natural medicine named as “Sikuaiwa” for subduing swellings and relieving pain. The structures including absolute configuration were elucidated by their 1D and 2D NMR, HRESIMS, and ECD data. Compounds <b>1</b> and<b> 2</b> were classical [4 + 2] lindenane-type sesquiterpenoid dimers that differed from known analogs in oxidation profile, side chain profile, and double bond position. The new isolates and compound <b>3</b> exhibited significant inhibitory activity on IL-1<i>β</i> production (IC<sub>50</sub>: 1–15 μM) in LPS-induced THP-1 cells and other compounds exhibited inhibitory activity on NO production in LPS-induced RAW 264.7 cells (IC<sub>50</sub>: 24–33 μM).</p><h3>Graphical abstract</h3><div><figure><div><div><picture><img></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"78 4","pages":"995 - 1002"},"PeriodicalIF":2.5,"publicationDate":"2024-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11418-024-01817-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140911132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In this study, 14 abietene and pimarene diterpenoids were isolated from the woods of Agathis dammara. Among them, 4 new compounds, dammarone A-C and dammaric acid A (1–4), were firstly reported, respectively. The structure of the new compounds was determined by HR ESI–MS and 1D/2D NMR spectroscopy, and their absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. The hypoglycemic effect of all compounds was evaluated by transgenic zebrafish model, and the structure–activity relationship was discussed. Hinokione (7, HO) has low toxicity and significant hypoglycemic effects on zebrafish, the mechanism is mainly by promoting the differentiation of zebrafish pancreatic endocrine precursor cells (PEP cells) into β cells, thereby promoting the regeneration of pancreatic β cells.
{"title":"Hinokione: an abietene diterpene with pancreatic β cells regeneration and hypoglycemic activity, and other derivatives with novel structures from the woods of Agathis dammara","authors":"Zheng Wang, Zhe-Wei Yu, Yi Zhang, Wen-Hui Wang, Xin-Yi Wu, Shun-Zhi Liu, Yan-Lin Bin, Bang-Ping Cai, Shi-Yan Huang, Mei-Juan Fang, Rong Qi, Ming-Yu Li, Ying-Kun Qiu","doi":"10.1007/s11418-024-01816-z","DOIUrl":"10.1007/s11418-024-01816-z","url":null,"abstract":"<div><p>In this study, 14 abietene and pimarene diterpenoids were isolated from the woods of <i>Agathis dammara</i>. Among them, 4 new compounds, dammarone A-C and dammaric acid A (<b>1–4</b>), were firstly reported, respectively. The structure of the new compounds was determined by HR ESI–MS and 1D/2D NMR spectroscopy, and their absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. The hypoglycemic effect of all compounds was evaluated by transgenic zebrafish model, and the structure–activity relationship was discussed. Hinokione (<b>7</b>, HO) has low toxicity and significant hypoglycemic effects on zebrafish, the mechanism is mainly by promoting the differentiation of zebrafish pancreatic endocrine precursor cells (PEP cells) into β cells, thereby promoting the regeneration of pancreatic β cells.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"78 4","pages":"849 - 862"},"PeriodicalIF":2.5,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hepatocellular carcinoma (HCC) is a malignant tumor with extremely high mortality. The tumor microenvironment is the “soil” of its occurrence and development, and the inflammatory microenvironment is an important part of the “soil”. Bile acid is closely related to the occurrence of HCC. Bile acid metabolism disorder is not only directly involved in the occurrence and development of HCC but also affects the inflammatory microenvironment of HCC. Yinchenhao decoction, a traditional Chinese medicine formula, can regulate bile acid metabolism and may affect the inflammatory microenvironment of HCC. To determine the effect of Yinchenhao decoction on bile acid metabolism in mice with HCC and to explore the possible mechanism by which Yinchenhao decoction improves the inflammatory microenvironment of HCC by regulating bile acid metabolism, we established mice model of orthotopic transplantation of hepatocellular carcinoma. These mice were treated with three doses of Yinchenhao decoction, then liver samples were collected and tested. Yinchenhao decoction can regulate the disorder of bile acid metabolism in liver cancer mice. Besides, it can improve inflammatory reactions, reduce hepatocyte degeneration and necrosis, and even reduce liver weight and the liver index. Taurochenodeoxycholic acid, hyodeoxycholic acid, and taurohyodeoxycholic acid are important molecules in the regulation of the liver inflammatory microenvironment, laying a foundation for the regulation of the liver tumor inflammatory microenvironment based on bile acids. Yinchenhao decoction may improve the inflammatory microenvironment of mice with HCC by ameliorating hepatic bile acid metabolism.
{"title":"Regulatory effect of Yinchenhao decoction on bile acid metabolism to improve the inflammatory microenvironment of hepatocellular carcinoma in mice","authors":"Jian Shi, Lin Zhu, Bang-Yi Tang, Wan-Qing Yang, Sheng-Yan Xi, Chen-Long Zhang, Peng-Fei Li, Yu-Jie Wang, Kai-Hang Guo, Jing-Ru Huang, Chen-Rui Huang, Zhou-Xin Yu, Bao-Kang Yu, Chun-Fang Zhang, Yu-Mei Zhang","doi":"10.1007/s11418-024-01812-3","DOIUrl":"10.1007/s11418-024-01812-3","url":null,"abstract":"<div><p>Hepatocellular carcinoma (HCC) is a malignant tumor with extremely high mortality. The tumor microenvironment is the “soil” of its occurrence and development, and the inflammatory microenvironment is an important part of the “soil”. Bile acid is closely related to the occurrence of HCC. Bile acid metabolism disorder is not only directly involved in the occurrence and development of HCC but also affects the inflammatory microenvironment of HCC. Yinchenhao decoction, a traditional Chinese medicine formula, can regulate bile acid metabolism and may affect the inflammatory microenvironment of HCC. To determine the effect of Yinchenhao decoction on bile acid metabolism in mice with HCC and to explore the possible mechanism by which Yinchenhao decoction improves the inflammatory microenvironment of HCC by regulating bile acid metabolism, we established mice model of orthotopic transplantation of hepatocellular carcinoma. These mice were treated with three doses of Yinchenhao decoction, then liver samples were collected and tested. Yinchenhao decoction can regulate the disorder of bile acid metabolism in liver cancer mice. Besides, it can improve inflammatory reactions, reduce hepatocyte degeneration and necrosis, and even reduce liver weight and the liver index. Taurochenodeoxycholic acid, hyodeoxycholic acid, and taurohyodeoxycholic acid are important molecules in the regulation of the liver inflammatory microenvironment, laying a foundation for the regulation of the liver tumor inflammatory microenvironment based on bile acids. Yinchenhao decoction may improve the inflammatory microenvironment of mice with HCC by ameliorating hepatic bile acid metabolism.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"78 3","pages":"633 - 643"},"PeriodicalIF":2.5,"publicationDate":"2024-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11418-024-01812-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We previously demonstrated that ginsenoside Re (G-Re) has protective effects on acute kidney injury. However, the underlying mechanism is still unclear. In this study, we conducted a meta-analysis and pathway enrichment analysis of all published transcriptome data to identify differentially expressed genes (DEGs) and pathways of G-Re treatment. We then performed in vitro studies to measure the identified autophagy and fibrosis markers in HK2 cells. In vivo studies were conducted using ureteric obstruction (UUO) and aristolochic acid nephropathy (AAN) models to evaluate the effects of G-Re on autophagy and kidney fibrosis. Our informatics analysis identified autophagy-related pathways enriched for G-Re treatment. Treatment with G-Re in HK2 cells reduced autophagy and mRNA levels of profibrosis markers with TGF-β stimulation. In addition, induction of autophagy with PP242 neutralized the anti-fibrotic effects of G-Re. In murine models with UUO and AAN, treatment with G-Re significantly improved renal function and reduced the upregulation of autophagy and profibrotic markers. A combination of informatics analysis and biological experiments confirmed that ginsenoside Re could improve renal fibrosis and kidney function through the regulation of autophagy. These findings provide important insights into the mechanisms of G-Re’s protective effects in kidney injuries.
Graphic abstract
我们曾证实人参皂苷 Re（G-Re）对急性肾损伤有保护作用。然而，其潜在机制仍不清楚。在本研究中，我们对所有已发表的转录组数据进行了荟萃分析和通路富集分析，以确定 G-Re 治疗的差异表达基因（DEGs）和通路。然后，我们进行了体外研究，以测量 HK2 细胞中已识别的自噬和纤维化标记物。我们使用输尿管梗阻（UUO）和马兜铃酸肾病（AAN）模型进行了体内研究，以评估 G-Re 对自噬和肾脏纤维化的影响。我们的信息学分析确定了G-Re治疗富集的自噬相关通路。在TGF-β刺激下，用G-Re处理HK2细胞可降低自噬和肾脏纤维化标志物的mRNA水平。此外，用PP242诱导自噬可中和G-Re的抗纤维化作用。在UUO和AAN小鼠模型中，G-Re能显著改善肾功能，减少自噬和组织坏死标志物的上调。结合信息学分析和生物学实验证实，人参皂苷 Re 可通过调节自噬改善肾脏纤维化和肾功能。这些发现为了解人参皂苷Re在肾损伤中的保护作用机制提供了重要启示。
{"title":"Integrative informatics analysis identifies that ginsenoside Re improves renal fibrosis through regulation of autophagy","authors":"Yingying Liu, Lingyun Mou, Zhengzi Yi, Qisheng Lin, Khadija Banu, Chengguo Wei, Xiaoxia Yu","doi":"10.1007/s11418-024-01800-7","DOIUrl":"10.1007/s11418-024-01800-7","url":null,"abstract":"<div><p>We previously demonstrated that ginsenoside Re (G-Re) has protective effects on acute kidney injury. However, the underlying mechanism is still unclear. In this study, we conducted a meta-analysis and pathway enrichment analysis of all published transcriptome data to identify differentially expressed genes (DEGs) and pathways of G-Re treatment. We then performed in vitro studies to measure the identified autophagy and fibrosis markers in HK2 cells. In vivo studies were conducted using ureteric obstruction (UUO) and aristolochic acid nephropathy (AAN) models to evaluate the effects of G-Re on autophagy and kidney fibrosis. Our informatics analysis identified autophagy-related pathways enriched for G-Re treatment. Treatment with G-Re in HK2 cells reduced autophagy and mRNA levels of profibrosis markers with TGF-β stimulation. In addition, induction of autophagy with PP242 neutralized the anti-fibrotic effects of G-Re. In murine models with UUO and AAN, treatment with G-Re significantly improved renal function and reduced the upregulation of autophagy and profibrotic markers. A combination of informatics analysis and biological experiments confirmed that ginsenoside Re could improve renal fibrosis and kidney function through the regulation of autophagy. These findings provide important insights into the mechanisms of G-Re’s protective effects in kidney injuries.</p><h3>Graphic abstract</h3>\u0000<div><figure><div><div><picture><img></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"78 3","pages":"722 - 731"},"PeriodicalIF":2.5,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140809493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-26DOI: 10.1007/s11418-024-01815-0
Xin Wang, Wenjing Guo, Bo Zhang, Haixia Xu, Qingyun Yang, Jingyi Zhao, Yi Feng, Jian Yang, Jiquan Zhang
Rhododendri Mollis Flos (R. mole Flos), the dried flowers of Rhododendron mole G. Don, have the ability to relieve pain, dispel wind and dampness, and dissolve blood stasis, but they are highly poisonous. The significance of this study is to explore the analgesic application potential of R. mole Flos and its representative component. According to the selected processing methods recorded in ancient literature, the analgesic activities of wine- and vinegar-processed R. mole Flos, as well as the raw product, were evaluated in a writhing test with acetic acid and a formalin-induced pain test. Subsequently, the HPLC-TOP-MS technique was utilized to investigate the changes in active components before and after processing once the variations in activities were confirmed. Based on the results, rhodojaponin VI (RJ-Vl) was chosen for further study. After processing, especially in vinegar, R. mole Flos did not only maintain the anti-nociception but also showed reduced toxicity, and the chemical composition corresponding to these effects also changed significantly. Further investigation of its representative components revealed that RJ-VI has considerable anti-nociceptive activity, particularly in inflammatory pain (0.3 mg/kg) and peripheral neuropathic pain (0.6 mg/kg). Its toxicity was about three times lower than that of rhodojaponin III, which is another representative component of R. mole Flos. Additionally, RJ-VI mildly inhibits several subtypes of voltage-gated sodium channels (IC50 > 200 μM) that are associated with pain or cardiotoxicity. In conclusion, the chemical substances and biological effects of R. mole Flos changed significantly before and after processing, and the representative component RJ-VI has the potential to be developed into an effective analgesic.
Graphical abstract
杜鹃花（Rhododendri Mollis Flos，R. mole Flos）是杜鹃花科植物杜鹃花的干燥花，具有止痛、祛风除湿、化瘀等功效，但有剧毒。本研究的意义在于探索杜鹃花及其代表性成分的镇痛应用潜力。根据古文献中记载的加工方法，在醋酸捻转试验和福尔马林致痛试验中，对酒、醋加工的胭脂虫及其原产品的镇痛活性进行了评价。随后，在确认活性变化后，利用 HPLC-TOP-MS 技术研究了加工前后活性成分的变化。根据研究结果，选择了红豆皂苷 VI（RJ-Vl）进行进一步研究。经过加工，特别是在醋中加工后，胭脂虫痣皂苷 VI 不仅保持了抗痛觉作用，而且毒性也有所降低，与这些作用相对应的化学成分也发生了显著变化。对其代表性成分的进一步研究表明，RJ-VI 具有相当强的抗痛觉活性，尤其是在炎症性疼痛（0.3 毫克/千克）和周围神经性疼痛（0.6 毫克/千克）方面。其毒性比 R. mole Flos 的另一种代表性成分 rhodojaponin III 低约三倍。此外，RJ-VI 还能轻度抑制与疼痛或心脏毒性相关的几种电压门控钠通道亚型（IC50 > 200 μM）。总之，R. mole Flos 的化学物质和生物效应在加工前后发生了显著变化，其代表性成分 RJ-VI 具有开发成有效镇痛剂的潜力。
{"title":"Evaluation of Rhododendri Mollis Flos and its representative component as a potential analgesic","authors":"Xin Wang, Wenjing Guo, Bo Zhang, Haixia Xu, Qingyun Yang, Jingyi Zhao, Yi Feng, Jian Yang, Jiquan Zhang","doi":"10.1007/s11418-024-01815-0","DOIUrl":"10.1007/s11418-024-01815-0","url":null,"abstract":"<div><p>Rhododendri Mollis Flos (<i>R. mole</i> Flos), the dried flowers of <i>Rhododendron mole</i> G. Don, have the ability to relieve pain, dispel wind and dampness, and dissolve blood stasis, but they are highly poisonous. The significance of this study is to explore the analgesic application potential of <i>R. mole</i> Flos and its representative component. According to the selected processing methods recorded in ancient literature, the analgesic activities of wine- and vinegar-processed <i>R. mole</i> Flos, as well as the raw product, were evaluated in a writhing test with acetic acid and a formalin-induced pain test. Subsequently, the HPLC-TOP-MS technique was utilized to investigate the changes in active components before and after processing once the variations in activities were confirmed. Based on the results, rhodojaponin VI (RJ-Vl) was chosen for further study. After processing, especially in vinegar, <i>R. mole</i> Flos did not only maintain the anti-nociception but also showed reduced toxicity, and the chemical composition corresponding to these effects also changed significantly. Further investigation of its representative components revealed that RJ-VI has considerable anti-nociceptive activity, particularly in inflammatory pain (0.3 mg/kg) and peripheral neuropathic pain (0.6 mg/kg). Its toxicity was about three times lower than that of rhodojaponin III, which is another representative component of <i>R. mole</i> Flos. Additionally, RJ-VI mildly inhibits several subtypes of voltage-gated sodium channels (IC<sub>50</sub> > 200 μM) that are associated with pain or cardiotoxicity. In conclusion, the chemical substances and biological effects of <i>R. mole</i> Flos changed significantly before and after processing, and the representative component RJ-VI has the potential to be developed into an effective analgesic.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"78 3","pages":"753 - 767"},"PeriodicalIF":2.5,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140652758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-26DOI: 10.1007/s11418-024-01811-4
Xinyu Zhou, Duanna Zhang, Jieting Lei, Jixia Ren, Bo Yang, Zhixing Cao, Chuanjie Guo, Yuzhi Li
Acute myeloid leukemia (AML) is a malignant disease that is difficult to completely cure. Polyphyllin I (PPI), a steroidal saponin isolated from Paris polyphylla, has exhibited multiple biological activities. Here, we discovered the superior cytotoxicity of PPI on AML cells MOLM-13 with an IC50 values of 0.44 ± 0.09 μM. Mechanically, PPI could cause ferroptosis via the accumulation of intracellular iron concentration and triggering lipid peroxidation. Interestingly, PPI could induced stronger ferroptosis in a short time of about 6 h compared to erastin. Furthermore, we demonstrate that PPI-induced rapid ferroptosis is due to the simultaneous targeting PI3K/SREBP-1/SCD1 axis and triggering lipid peroxidation, and PI3K inhibitor Alpelisib can enhance the activity of erastin-induced ferroptosis. Molecular docking simulations and kinase inhibition assays demonstrated that PPI is a PI3K inhibitor. In addition, PPI significantly inhibited tumor progression and prolonged mouse survival at 4 mg/kg with well tolerance. In summary, our study highlights the therapeutic potential of PPI for AML and shows its unique dual mechanism.
Graphical abstract
急性髓性白血病（AML）是一种难以完全治愈的恶性疾病。多粘菌素 I（PPI）是从巴黎多粘菌素中分离出来的一种甾体皂甙，具有多种生物活性。在这里，我们发现了 PPI 对 AML 细胞 MOLM-13 的卓越细胞毒性，其 IC50 值为 0.44 ± 0.09 μM。从机理上讲，PPI 可通过细胞内铁浓度的积累和引发脂质过氧化而导致铁变态反应。有趣的是，与厄拉斯汀相比，PPI能在短时间内（约6小时）诱导更强的铁变态反应。此外，我们还证明了PPI诱导的快速铁中毒是由于同时靶向PI3K/SREBP-1/SCD1轴和引发脂质过氧化所致，而PI3K抑制剂Alpelisib能增强厄拉斯汀诱导铁中毒的活性。分子对接模拟和激酶抑制实验证明，PPI 是一种 PI3K 抑制剂。此外，PPI能明显抑制肿瘤进展，并延长小鼠的生存期，4 mg/kg的剂量具有良好的耐受性。总之，我们的研究突出了PPI治疗急性髓细胞白血病的潜力，并显示了其独特的双重机制。
{"title":"Polyphyllin I induces rapid ferroptosis in acute myeloid leukemia through simultaneous targeting PI3K/SREBP-1/SCD1 axis and triggering of lipid peroxidation","authors":"Xinyu Zhou, Duanna Zhang, Jieting Lei, Jixia Ren, Bo Yang, Zhixing Cao, Chuanjie Guo, Yuzhi Li","doi":"10.1007/s11418-024-01811-4","DOIUrl":"10.1007/s11418-024-01811-4","url":null,"abstract":"<div><p>Acute myeloid leukemia (AML) is a malignant disease that is difficult to completely cure. Polyphyllin I (PPI), a steroidal saponin isolated from <i>Paris polyphylla</i>, has exhibited multiple biological activities. Here, we discovered the superior cytotoxicity of PPI on AML cells MOLM-13 with an IC<sub>50</sub> values of 0.44 ± 0.09 μM. Mechanically, PPI could cause ferroptosis via the accumulation of intracellular iron concentration and triggering lipid peroxidation. Interestingly, PPI could induced stronger ferroptosis in a short time of about 6 h compared to erastin. Furthermore, we demonstrate that PPI-induced rapid ferroptosis is due to the simultaneous targeting PI3K/SREBP-1/SCD1 axis and triggering lipid peroxidation, and PI3K inhibitor Alpelisib can enhance the activity of erastin-induced ferroptosis. Molecular docking simulations and kinase inhibition assays demonstrated that PPI is a PI3K inhibitor. In addition, PPI significantly inhibited tumor progression and prolonged mouse survival at 4 mg/kg with well tolerance. In summary, our study highlights the therapeutic potential of PPI for AML and shows its unique dual mechanism.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"78 3","pages":"618 - 632"},"PeriodicalIF":2.5,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11418-024-01811-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140652057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Two new sesterterpenoids, atractylodes japonica terpenoid acid I (1) and atractylodes japonica terpenoid aldehyde I (2), were isolated from the rhizomes of Atractylodes japonica Koidz. ex Kitam together with ten known compounds (3–12). Their structures were elucidated on the basis of comprehensive spectroscopic analysis (1D/2D NMR, HRESIMS and IR). In addition, all of these isolated compounds were evaluated for their cytotoxic activities against human gastric cancer cell MGC-803 and human hepatocellular cancer cell HepG-2. Most of them exhibited moderate to weak inhibitory effects with IC50 values in the range of 25.15–88.85 μM except for 9–12.
{"title":"Two new sesterterpenoids from Atractylodes japonica Koidz. ex Kitam","authors":"Yuan-Yuan Zhou, Zhao Sun, Yan Liu, Zhen-Xing Fang, Hui-Rui Gao, Ning-Yu Liu, Xiao-Juan Zhang, Bing-You Yang, Hai-Xue Kuang","doi":"10.1007/s11418-024-01793-3","DOIUrl":"10.1007/s11418-024-01793-3","url":null,"abstract":"<div><p>Two new sesterterpenoids, atractylodes japonica terpenoid acid I (<b>1</b>) and atractylodes japonica terpenoid aldehyde I (<b>2</b>), were isolated from the rhizomes of <i>Atractylodes japonica</i> Koidz. ex Kitam together with ten known compounds (<b>3–12</b>). Their structures were elucidated on the basis of comprehensive spectroscopic analysis (1D/2D NMR, HRESIMS and IR). In addition, all of these isolated compounds were evaluated for their cytotoxic activities against human gastric cancer cell MGC-803 and human hepatocellular cancer cell HepG-2. Most of them exhibited moderate to weak inhibitory effects with IC<sub>50</sub> values in the range of 25.15–88.85 μM except for <b>9</b>–<b>12</b>.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"78 3","pages":"702 - 708"},"PeriodicalIF":2.5,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11418-024-01793-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140657165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-25DOI: 10.1007/s11418-024-01809-y
Shin-Ji Park, So-Young An, Yeon Jin An, Kyoung-Sook Kim, Hyunju Kim, Jong Hyun Cho, Young-Choon Lee
In this study, the effects of 3,5,7,3ʹ,4ʹ-pentamethoxyflavone (KP1), a major bioactive ingredient isolated from the Kaempferia parviflora rhizomes, on a neurite outgrowth in Neuro2a cells and its mechanism have been investigated. KP1 increased concentration-dependently the percentage of neurite-bearing cells. KP1 showed a remarkable capability to elicit neurite outgrowth in Neuro2a cells, as evidenced by morphological alterations and immunostaining using anti-class III β-tubulin and anti-NeuN antibodies. KP1 also displayed a higher neurogenic activity than retinoic acid (RA), a promoter of neurite outgrowth in Neuro2a cells. KP1 treatment caused significant elevation in phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK) and glycogen synthase kinase-3β (GSK-3β). However, KP1-triggered neurite outgrowth was markedly inhibited by treatment with the ERK inhibitor U0126, whereas p38 MAPK inhibitor SB203580 and GSK-3β inhibitor SB216763 did not influence KP1-induced neurite outgrowth. These results demonstrate that KP1 elicits neurite outgrowth and triggers cell differentiation of Neuro2a cells through ERK signal pathway.
{"title":"Promotion of neurite outgrowth by 3,5,7,3ʹ,4ʹ-pentamethoxyflavone is mediated through ERK signaling pathway in Neuro2a cells","authors":"Shin-Ji Park, So-Young An, Yeon Jin An, Kyoung-Sook Kim, Hyunju Kim, Jong Hyun Cho, Young-Choon Lee","doi":"10.1007/s11418-024-01809-y","DOIUrl":"10.1007/s11418-024-01809-y","url":null,"abstract":"<div><p>In this study, the effects of 3,5,7,3ʹ,4ʹ-pentamethoxyflavone (KP1), a major bioactive ingredient isolated from the <i>Kaempferia parviflora</i> rhizomes, on a neurite outgrowth in Neuro2a cells and its mechanism have been investigated. KP1 increased concentration-dependently the percentage of neurite-bearing cells. KP1 showed a remarkable capability to elicit neurite outgrowth in Neuro2a cells, as evidenced by morphological alterations and immunostaining using anti-class III β-tubulin and anti-NeuN antibodies. KP1 also displayed a higher neurogenic activity than retinoic acid (RA), a promoter of neurite outgrowth in Neuro2a cells. KP1 treatment caused significant elevation in phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK) and glycogen synthase kinase-3β (GSK-3β). However, KP1-triggered neurite outgrowth was markedly inhibited by treatment with the ERK inhibitor U0126, whereas p38 MAPK inhibitor SB203580 and GSK-3β inhibitor SB216763 did not influence KP1-induced neurite outgrowth. These results demonstrate that KP1 elicits neurite outgrowth and triggers cell differentiation of Neuro2a cells through ERK signal pathway.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"78 3","pages":"599 - 607"},"PeriodicalIF":2.5,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11418-024-01809-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140655687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aimed to compare fat accumulation in young and aged mice raised on a high-fat diet and to characterize the obesity-reducing effects of a Kampo medicine, bofutsushosan (BTS; fangfengtongshengsan in Chinese). Aged mice fed a high-fat diet containing 2% BTS extract for 28 days exhibited a significant reduction in weight gain and accumulation of visceral and subcutaneous fat, which were greater degree of reduction than those of the young mice. When the treatment period was extended to two months, the serum aspartate aminotransferase and alanine aminotransferase levels and the accumulation of fat droplets in the hepatocytes decreased. The mRNA expression of mitochondrial uncoupling protein 1 (UCP1) in the brown adipose tissue was significantly reduced in the aged mice compared to the young mice but increased by 2% in the BTS-treated aged mice. Additionally, the effect of BTS extract on oleic acid–albumin-induced triglyceride accumulation in hepatoblastoma-derived HepG2 cells was significantly inhibited in a concentration-dependent manner. Evaluation of the single crude drug extracts revealed that Forsythia Fruit, Schizonepeta Spike, and Rhubarb were the active components in BTS extract. These results suggest that BTS extract is effective against visceral, subcutaneous, and ectopic fats in the liver, which tend to accumulate with aging. Thus, BTS extract is useful in preventing and ameliorating the development of obesity and metabolic syndrome.
{"title":"Ameliorative effect of bofutsushosan (Fangfengtongshengsan) extract on the progression of aging-induced obesity","authors":"Takafumi Saeki, Saya Yamamoto, Junji Akaki, Takahiro Tanaka, Misaki Nakasone, Hidemasa Ikeda, Wei Wang, Makoto Inoue, Yoshiaki Manse, Kiyofumi Ninomiya, Toshio Morikawa","doi":"10.1007/s11418-024-01803-4","DOIUrl":"10.1007/s11418-024-01803-4","url":null,"abstract":"<div><p>This study aimed to compare fat accumulation in young and aged mice raised on a high-fat diet and to characterize the obesity-reducing effects of a Kampo medicine, bofutsushosan (BTS; fangfengtongshengsan in Chinese). Aged mice fed a high-fat diet containing 2% BTS extract for 28 days exhibited a significant reduction in weight gain and accumulation of visceral and subcutaneous fat, which were greater degree of reduction than those of the young mice. When the treatment period was extended to two months, the serum aspartate aminotransferase and alanine aminotransferase levels and the accumulation of fat droplets in the hepatocytes decreased. The mRNA expression of mitochondrial uncoupling protein 1 (UCP1) in the brown adipose tissue was significantly reduced in the aged mice compared to the young mice but increased by 2% in the BTS-treated aged mice. Additionally, the effect of BTS extract on oleic acid–albumin-induced triglyceride accumulation in hepatoblastoma-derived HepG2 cells was significantly inhibited in a concentration-dependent manner. Evaluation of the single crude drug extracts revealed that Forsythia Fruit, Schizonepeta Spike, and Rhubarb were the active components in BTS extract. These results suggest that BTS extract is effective against visceral, subcutaneous, and ectopic fats in the liver, which tend to accumulate with aging. Thus, BTS extract is useful in preventing and ameliorating the development of obesity and metabolic syndrome.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"78 3","pages":"576 - 589"},"PeriodicalIF":2.5,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140657619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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