Pub Date : 2025-09-01DOI: 10.1016/S1875-5364(25)60975-7
Bo Tao , Xiangli Zhao , Zhengyi Shi , Jie Li , Yulin Duan , Xiaosheng Tan , Gang Chen , Changxing Qi , Yonghui Zhang
Hepatic ischemia/reperfusion injury (IRI) remains a critical complication contributing to graft dysfunction following liver surgery. As part of an ongoing search for hepatoprotective natural products, five previously unreported homoadamantane-type polycyclic polyprenylated acylphloroglucinols (PPAPs), named hyperhomanoons A–E (1−5), and one known analog, hypersampsone O (6), were isolated from Hypericum patulum. Among these, compound 6 demonstrated potent protective effects against CoCl₂-induced hypoxic injury in hepatocytes. Furthermore, in a murine model of hepatic IRI induced by vascular occlusion, pretreatment with 6 markedly alleviated liver damage and reduced hepatocyte apoptosis. This study is the first to identify PPAPs as promising scaffolds for the development of therapeutic agents targeting hepatic IRI, underscoring their potential as lead compounds in drug discovery efforts for ischemic liver diseases.
{"title":"Discovery of bioactive polycyclic polyprenylated acylphloroglucinol from Hypericum patulum that protects against hepatic ischemia/reperfusion injury","authors":"Bo Tao , Xiangli Zhao , Zhengyi Shi , Jie Li , Yulin Duan , Xiaosheng Tan , Gang Chen , Changxing Qi , Yonghui Zhang","doi":"10.1016/S1875-5364(25)60975-7","DOIUrl":"10.1016/S1875-5364(25)60975-7","url":null,"abstract":"<div><div>Hepatic ischemia/reperfusion injury (IRI) remains a critical complication contributing to graft dysfunction following liver surgery. As part of an ongoing search for hepatoprotective natural products, five previously unreported homoadamantane-type polycyclic polyprenylated acylphloroglucinols (PPAPs), named hyperhomanoons A–E (<strong>1</strong>−<strong>5</strong>), and one known analog, hypersampsone O (<strong>6</strong>), were isolated from <em>Hypericum patulum</em>. Among these, compound <strong>6</strong> demonstrated potent protective effects against CoCl₂-induced hypoxic injury in hepatocytes. Furthermore, in a murine model of hepatic IRI induced by vascular occlusion, pretreatment with <strong>6</strong> markedly alleviated liver damage and reduced hepatocyte apoptosis. This study is the first to identify PPAPs as promising scaffolds for the development of therapeutic agents targeting hepatic IRI, underscoring their potential as lead compounds in drug discovery efforts for ischemic liver diseases.</div></div>","PeriodicalId":10002,"journal":{"name":"Chinese Journal of Natural Medicines","volume":"23 9","pages":"Pages 1104-1110"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/S1875-5364(25)60972-1
Shan Han , Chi Teng Vong , Jia He , Qinqin Wang , Qiumei Fan , Siyuan Li , Jilang Li , Min Liao , Shilin Yang , Renyikun Yuan , Hongwei Gao
Acute lung injury (ALI) is a severe disease caused by viral infection that triggers an uncontrolled inflammatory response. This study investigated the capacity of jasurolignoside (JO), a natural compound, to bind to Toll-like receptor 4 (TLR4) and treat ALI. The anti-inflammatory properties of JO were evaluated in vitro through Western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and co-immunoprecipitation. The investigation utilized a lipopolysaccharide (LPS)-induced ALI animal model to examine the therapeutic efficacy and mechanism of JO in vivo. JO attenuated inflammatory symptoms in infected cells and tissues by modulating the NOD-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome and the nuclear factor κB (NF-κB)/mitogen-activated protein kinase (MAPK) pathway. Molecular docking simulations revealed JO binding to TLR4 active sites, confirmed by cellular thermal shift assay. Surface plasmon resonance (SPR) demonstrated direct interaction between JO and TLR4 with a Kd value of 35.1 μmol·L–1. Moreover, JO inhibited tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6 secretion and reduced leukocyte, neutrophil, lymphocyte, and macrophage infiltration in ALI-affected mice. JO also enhanced lung function and reduced ALI-related mortality. Immunohistochemical staining demonstrated JO’s ability to suppress TLR4 expression in ALI-affected mouse lung tissue. This study establishes that JO can bind to TLR4 and effectively treat ALI, indicating its potential as a therapeutic agent for clinical applications.
{"title":"Jasurolignoside from Ilex pubescens exerts a therapeutic effect on acute lung injury in vitro and in vivo by binding to TLR4","authors":"Shan Han , Chi Teng Vong , Jia He , Qinqin Wang , Qiumei Fan , Siyuan Li , Jilang Li , Min Liao , Shilin Yang , Renyikun Yuan , Hongwei Gao","doi":"10.1016/S1875-5364(25)60972-1","DOIUrl":"10.1016/S1875-5364(25)60972-1","url":null,"abstract":"<div><div>Acute lung injury (ALI) is a severe disease caused by viral infection that triggers an uncontrolled inflammatory response. This study investigated the capacity of jasurolignoside (JO), a natural compound, to bind to Toll-like receptor 4 (TLR4) and treat ALI. The anti-inflammatory properties of JO were evaluated <em>in vitro</em> through Western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and co-immunoprecipitation. The investigation utilized a lipopolysaccharide (LPS)-induced ALI animal model to examine the therapeutic efficacy and mechanism of JO <em>in vivo</em>. JO attenuated inflammatory symptoms in infected cells and tissues by modulating the NOD-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome and the nuclear factor <em>κ</em>B (NF-<em>κ</em>B)/mitogen-activated protein kinase (MAPK) pathway. Molecular docking simulations revealed JO binding to TLR4 active sites, confirmed by cellular thermal shift assay. Surface plasmon resonance (SPR) demonstrated direct interaction between JO and TLR4 with a Kd value of 35.1 μmol·L<sup>–1</sup>. Moreover, JO inhibited tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6 secretion and reduced leukocyte, neutrophil, lymphocyte, and macrophage infiltration in ALI-affected mice. JO also enhanced lung function and reduced ALI-related mortality. Immunohistochemical staining demonstrated JO’s ability to suppress TLR4 expression in ALI-affected mouse lung tissue. This study establishes that JO can bind to TLR4 and effectively treat ALI, indicating its potential as a therapeutic agent for clinical applications.</div></div>","PeriodicalId":10002,"journal":{"name":"Chinese Journal of Natural Medicines","volume":"23 9","pages":"Pages 1058-1068"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/S1875-5364(25)60919-8
Ye Zhang , Shanshan Su , Xiaoyu Xu , Zhixian He , Yiyan Zhou , Xiangrong Lu , Aiqin Jiang
Triple-negative breast cancer (TNBC) represents an aggressive breast cancer subtype with poor prognosis and limited targeted treatment options. This investigation examined the anti-cancer potential of Caerulomycin A (Cae A), a natural compound derived from marine actinomycetes, against TNBC. Cae A demonstrated selective inhibition of viability and proliferation in TNBC cell lines, including 4T1, MDA-MB-231, and MDA-MB-468, through apoptosis induction. Mechanistic analyses revealed that the compound induced sustained endoplasmic reticulum (ER) stress and subsequent upregulation of C/EBP homologous protein (CHOP) expression, resulting in mitochondrial damage-mediated apoptosis. Inhibition of ER stress or CHOP expression knockdown reversed mitochondrial damage and apoptosis, highlighting the essential role of ER stress and CHOP in Cae A’s anti-tumor mechanism. Both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) decreased in TNBC cells following Cae A treatment, indicating reduced mitochondrial respiratory and glycolytic capacities. This diminished energy metabolism potentially triggers ER stress and subsequent apoptosis. Furthermore, Cae A exhibited significant anti-tumor effects in the 4T1 tumor model in vivo without apparent toxicity. The compound also effectively inhibited human TNBC organoid growth. These results indicate that Cae A may serve as a potential therapeutic agent for TNBC, with its efficacy likely mediated through the disruption of glucose metabolism and the induction of ER stress-associated apoptosis.
{"title":"Caerulomycin A disrupts glucose metabolism and triggers ER stress-induced apoptosis in triple-negative breast cancer cells","authors":"Ye Zhang , Shanshan Su , Xiaoyu Xu , Zhixian He , Yiyan Zhou , Xiangrong Lu , Aiqin Jiang","doi":"10.1016/S1875-5364(25)60919-8","DOIUrl":"10.1016/S1875-5364(25)60919-8","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) represents an aggressive breast cancer subtype with poor prognosis and limited targeted treatment options. This investigation examined the anti-cancer potential of Caerulomycin A (Cae A), a natural compound derived from marine actinomycetes, against TNBC. Cae A demonstrated selective inhibition of viability and proliferation in TNBC cell lines, including 4T1, MDA-MB-231, and MDA-MB-468, through apoptosis induction. Mechanistic analyses revealed that the compound induced sustained endoplasmic reticulum (ER) stress and subsequent upregulation of C/EBP homologous protein (CHOP) expression, resulting in mitochondrial damage-mediated apoptosis. Inhibition of ER stress or CHOP expression knockdown reversed mitochondrial damage and apoptosis, highlighting the essential role of ER stress and CHOP in Cae A’s anti-tumor mechanism. Both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) decreased in TNBC cells following Cae A treatment, indicating reduced mitochondrial respiratory and glycolytic capacities. This diminished energy metabolism potentially triggers ER stress and subsequent apoptosis. Furthermore, Cae A exhibited significant anti-tumor effects in the 4T1 tumor model <em>in vivo</em> without apparent toxicity. The compound also effectively inhibited human TNBC organoid growth. These results indicate that Cae A may serve as a potential therapeutic agent for TNBC, with its efficacy likely mediated through the disruption of glucose metabolism and the induction of ER stress-associated apoptosis.</div></div>","PeriodicalId":10002,"journal":{"name":"Chinese Journal of Natural Medicines","volume":"23 9","pages":"Pages 1080-1091"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/S1875-5364(25)60974-5
Miaoping Lin , Yanhui Tan , Humu Lu , Yuyao Feng , Min Li , Chenghai Gao , Yonghong Liu , Xiaowei Luo
This study identified six novel azaphilones, isochromophilones G−L (1−6), and three novel biosynthetically related congeners (7−9) from Diaporthe sp. SCSIO 41011. The structures and absolute configurations were elucidated through comprehensive spectroscopic analyses combined with experimental and calculated electronic circular dichroism (ECD) spectra. Significantly, three highly oxygenated azaphilones contain an acetyl group at the terminal chain (4) or linear conjugated polyenoid moieties (5 and 6), which occur infrequently in the azaphilone family. Additionally, several compounds demonstrated inhibition of lipopolysaccharide (LPS)-induced nuclear factor kappa-B (NF-κB) activation in RAW 264.7 macrophages at 20 μmol·L−1. The novel compound (1) effectively inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation without exhibiting cytotoxicity in bone marrow and RAW 264.7 macrophages, indicating its potential as a promising lead compound for osteolytic disease treatment. This research presents the first documented evidence of azaphilone derivatives as inhibitors of RANKL-induced osteoclastogenesis.
本研究从Diaporthe sp. SCSIO 41011中鉴定出6个新的氮化氮素，G−L（1−6）和3个新的生物合成相关同源物（7−9）。通过综合光谱分析，结合实验和计算的电子圆二色性（ECD）光谱，阐明了其结构和绝对构型。值得注意的是，三种高度氧化的氮唑啉类化合物在末端链(4)或线性共轭多烯基团（5和6）上含有乙酰基，这在氮唑啉类化合物家族中并不常见。此外，几种化合物在20 μmol·L−1时抑制脂多糖（LPS）诱导的RAW 264.7巨噬细胞核因子κ b （NF-κB）的激活。新化合物(1)有效抑制NF-κB配体受体激活剂（RANKL）诱导的破骨细胞分化，而在骨髓和RAW 264.7巨噬细胞中不表现细胞毒性，表明其有潜力成为治疗溶骨性疾病的有希望的先导化合物。本研究首次提出了azaphilone衍生物作为rankl诱导的破骨细胞发生抑制剂的文献证据。
{"title":"Azaphilone derivatives with RANKL-induced osteoclastogenesis inhibition from the mangrove endophytic fungus Diaporthe sp.","authors":"Miaoping Lin , Yanhui Tan , Humu Lu , Yuyao Feng , Min Li , Chenghai Gao , Yonghong Liu , Xiaowei Luo","doi":"10.1016/S1875-5364(25)60974-5","DOIUrl":"10.1016/S1875-5364(25)60974-5","url":null,"abstract":"<div><div>This study identified six novel azaphilones, isochromophilones G−L (<strong>1</strong>−<strong>6</strong>), and three novel biosynthetically related congeners (<strong>7</strong>−<strong>9</strong>) from <em>Diaporthe</em> sp. SCSIO 41011. The structures and absolute configurations were elucidated through comprehensive spectroscopic analyses combined with experimental and calculated electronic circular dichroism (ECD) spectra. Significantly, three highly oxygenated azaphilones contain an acetyl group at the terminal chain (<strong>4</strong>) or linear conjugated polyenoid moieties (<strong>5</strong> and <strong>6</strong>), which occur infrequently in the azaphilone family. Additionally, several compounds demonstrated inhibition of lipopolysaccharide (LPS)-induced nuclear factor kappa-B (NF-<em>κ</em>B) activation in RAW 264.7 macrophages at 20 μmol·L<sup>−1</sup>. The novel compound (<strong>1</strong>) effectively inhibited receptor activator of NF-<em>κ</em>B ligand (RANKL)-induced osteoclast differentiation without exhibiting cytotoxicity in bone marrow and RAW 264.7 macrophages, indicating its potential as a promising lead compound for osteolytic disease treatment. This research presents the first documented evidence of azaphilone derivatives as inhibitors of RANKL-induced osteoclastogenesis.</div></div>","PeriodicalId":10002,"journal":{"name":"Chinese Journal of Natural Medicines","volume":"23 9","pages":"Pages 1143-1152"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/S1875-5364(25)60973-3
Pan Yu , Jialiang Yao , Long Zhang , Yanhong Wang , Xinyi Lu , Jiajun Liu , Zujun Que , Yao Liu , Qian Ba , Jiwei Liu , Yan Wu , Jianhui Tian
Metastasis remains the primary cause of cancer-related mortality worldwide. Circulating tumor cells (CTCs) represent critical targets for metastasis prevention and treatment. Traditional Chinese medicine may prevent lung cancer metastasis through long-term intervention in CTC activity. Tiao-Shen-Zhi-Ai Formular (TSZAF) represents a Chinese medicine compound prescription utilized clinically for lung cancer treatment. This study combined three principal active ingredients from TSZAF into a novel TSZAF monomer combination (TSZAF mc) to investigate its anti-metastatic effects and mechanisms. TSZAF mc demonstrated significant inhibition of proliferation, migration, and invasion in CTC-TJH-01 and LLC cells, while inducing cellular apoptosis in vitro. Moreover, TSZAF mc substantially inhibited LLC cell growth and metastasis in vivo. Mechanistically, TAZSF mc significantly suppressed the Wnt/β-catenin signaling pathway and CXCL5 expression in lung cancer cells and tissues. Additionally, TAZSF mc notably reduced neutrophil infiltration in metastatic lesions. These findings indicate that TSZAF mc inhibits lung cancer growth and metastasis by suppressing the Wnt/β-catenin signaling pathway and reducing CXCL5 secretion, thereby decreasing neutrophil recruitment and infiltration. TSZAF mc demonstrates potential as an effective therapeutic agent for lung cancer metastasis.
{"title":"TSZAF monomer combination downregulates the Wnt/β-catenin signaling pathway and inhibits neutrophil recruitment to prevent lung cancer metastasis","authors":"Pan Yu , Jialiang Yao , Long Zhang , Yanhong Wang , Xinyi Lu , Jiajun Liu , Zujun Que , Yao Liu , Qian Ba , Jiwei Liu , Yan Wu , Jianhui Tian","doi":"10.1016/S1875-5364(25)60973-3","DOIUrl":"10.1016/S1875-5364(25)60973-3","url":null,"abstract":"<div><div>Metastasis remains the primary cause of cancer-related mortality worldwide. Circulating tumor cells (CTCs) represent critical targets for metastasis prevention and treatment. Traditional Chinese medicine may prevent lung cancer metastasis through long-term intervention in CTC activity. Tiao-Shen-Zhi-Ai Formular (TSZAF) represents a Chinese medicine compound prescription utilized clinically for lung cancer treatment. This study combined three principal active ingredients from TSZAF into a novel TSZAF monomer combination (TSZAF mc) to investigate its anti-metastatic effects and mechanisms. TSZAF mc demonstrated significant inhibition of proliferation, migration, and invasion in CTC-TJH-01 and LLC cells, while inducing cellular apoptosis <em>in vitro</em>. Moreover, TSZAF mc substantially inhibited LLC cell growth and metastasis <em>in vivo</em>. Mechanistically, TAZSF mc significantly suppressed the Wnt/<em>β</em>-catenin signaling pathway and CXCL5 expression in lung cancer cells and tissues. Additionally, TAZSF mc notably reduced neutrophil infiltration in metastatic lesions. These findings indicate that TSZAF mc inhibits lung cancer growth and metastasis by suppressing the Wnt/<em>β</em>-catenin signaling pathway and reducing CXCL5 secretion, thereby decreasing neutrophil recruitment and infiltration. TSZAF mc demonstrates potential as an effective therapeutic agent for lung cancer metastasis.</div></div>","PeriodicalId":10002,"journal":{"name":"Chinese Journal of Natural Medicines","volume":"23 9","pages":"Pages 1069-1079"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/S1875-5364(25)60956-3
Donghui Liu , Qian Wang , Ruixue Zhang , Ruixin Su , Jiaxin Zhang , Shanshan Liu , Huiying Li , Zhesheng Chen , Yan Zhang , Dexin Kong , Yuling Qiu
Cancer multidrug resistance (MDR) impairs the therapeutic efficacy of various chemotherapeutics. Novel approaches, particularly the development of MDR reversal agents, are critically needed to address this challenge. This study demonstrates that tenacissoside I (TI), a compound isolated from Marsdenia tenacissima (Roxb.) Wight et Arn, traditionally used in clinical practice as an ethnic medicine for cancer treatment, exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells. TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin (DOX) and paclitaxel (PAC) by downregulating ABCB1 expression and reducing ABCB1 drug transport function. Mechanistically, protein arginine methyltransferase 1 (PRMT1), whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues, was differentially expressed in TI-treated SW620/AD300 cells. SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine (aDMA) and enhanced PRMT1-EGFR interaction compared to their parental cells. Moreover, TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR, PRMT1-EGFR interaction, and EGFR downstream signaling in SW620/AD300 and KBV200 cells. These effects were significantly reversed by PRMT1 overexpression. Additionally, TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities. This study establishes TI’s MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR, suggesting TI’s potential as an MDR modulator for improving chemotherapy outcomes.
肿瘤多药耐药（MDR）损害了多种化疗药物的治疗效果。迫切需要新方法，特别是开发耐多药逆转剂来应对这一挑战。本研究表明，从马蹄草（Marsdenia tenacissima, Roxb.）中分离得到的一种化合物tenacisso苷I （TI）具有一定的活性。Wight et Arn，传统上作为民族药用于临床治疗癌症，在abcb1介导的MDR癌细胞中显示出显著的MDR逆转作用。TI通过下调ABCB1表达和降低ABCB1药物转运功能，逆转了SW620/AD300和KBV200细胞对阿霉素（DOX）和紫杉醇（PAC）的耐药。机制上，蛋白精氨酸甲基转移酶1 （PRMT1）在ti处理的SW620/AD300细胞中存在差异表达，其表达与预后不良相关，与肿瘤组织中ABCB1和EGFR表达均呈正相关。与亲本细胞相比，SW620/AD300和KBV200细胞表现出EGFR不对称二甲基精氨酸（aDMA）水平升高，PRMT1-EGFR相互作用增强。此外，ti诱导的PRMT1下调损害了SW620/AD300和KBV200细胞中PRMT1介导的EGFR aDMA、PRMT1-EGFR相互作用和EGFR下游信号。这些影响被PRMT1过表达显著逆转。此外，TI在异种移植模型中显示对PAC的抗性逆转，没有可检测到的毒性。本研究通过抑制prmt1介导的EGFR aDMA，确立了TI对abcb1介导的MDR人癌细胞的MDR逆转作用，提示TI作为MDR调节剂改善化疗结果的潜力。
{"title":"Multidrug resistance reversal effect of tenacissoside I through impeding EGFR methylation mediated by PRMT1 inhibition","authors":"Donghui Liu , Qian Wang , Ruixue Zhang , Ruixin Su , Jiaxin Zhang , Shanshan Liu , Huiying Li , Zhesheng Chen , Yan Zhang , Dexin Kong , Yuling Qiu","doi":"10.1016/S1875-5364(25)60956-3","DOIUrl":"10.1016/S1875-5364(25)60956-3","url":null,"abstract":"<div><div>Cancer multidrug resistance (MDR) impairs the therapeutic efficacy of various chemotherapeutics. Novel approaches, particularly the development of MDR reversal agents, are critically needed to address this challenge. This study demonstrates that tenacissoside I (TI), a compound isolated from <em>Marsdenia tenacissima</em> (Roxb.) Wight et Arn, traditionally used in clinical practice as an ethnic medicine for cancer treatment, exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells. TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin (DOX) and paclitaxel (PAC) by downregulating ABCB1 expression and reducing ABCB1 drug transport function. Mechanistically, protein arginine methyltransferase 1 (PRMT1), whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues, was differentially expressed in TI-treated SW620/AD300 cells. SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine (aDMA) and enhanced PRMT1-EGFR interaction compared to their parental cells. Moreover, TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR, PRMT1-EGFR interaction, and EGFR downstream signaling in SW620/AD300 and KBV200 cells. These effects were significantly reversed by PRMT1 overexpression. Additionally, TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities. This study establishes TI’s MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR, suggesting TI’s potential as an MDR modulator for improving chemotherapy outcomes.</div></div>","PeriodicalId":10002,"journal":{"name":"Chinese Journal of Natural Medicines","volume":"23 9","pages":"Pages 1092-1103"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-01DOI: 10.1016/S1875-5364(25)60929-0
Yuhang He , Kexin Li , Yufei Wu , Zexin Jin , Jinfeng Hu , Yicheng Mao , Juan Xiong
Lirispirolides A−L (1−12), twelve novel sesquiterpene-monoterpene heterodimers featuring distinctive carbon skeletons, were isolated from the branches and leaves of Chinese tulip tree [Liriodendron chinense (L. chinense)], a rare medicinal and ornamental plant endemic to China. The structural elucidation was accomplished through comprehensive spectroscopic analyses, quantum-chemical calculations, and X-ray crystallography. These heterodimers exhibit a characteristic 2-oxaspiro[4.5]decan-1-one structural motif, biosynthetically formed through intermolecular [4 + 2]-cycloaddition between a germacrane-type sesquiterpene and an ocimene-type monoterpene. The majority of the isolated compounds demonstrated significant anti-neuroinflammatory effects in lipopolysaccharide (LPS)-induced BV-2 microglial cells by reducing the production of pro-inflammatory mediators, specifically tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Further investigation revealed that the lirispirolides’ inhibition of NO release correlated with decreased messenger ribonucleic acid (mRNA) expression of inducible NO synthase (iNOS).
{"title":"Lirispirolides A−L, a new class of sesquiterpene-monoterpene heterodimers with anti-neuroinflammatory activity from the rare medicinal plant Liriodendron chinense","authors":"Yuhang He , Kexin Li , Yufei Wu , Zexin Jin , Jinfeng Hu , Yicheng Mao , Juan Xiong","doi":"10.1016/S1875-5364(25)60929-0","DOIUrl":"10.1016/S1875-5364(25)60929-0","url":null,"abstract":"<div><div>Lirispirolides A−L (<strong>1</strong>−<strong>12</strong>), twelve novel sesquiterpene-monoterpene heterodimers featuring distinctive carbon skeletons, were isolated from the branches and leaves of Chinese tulip tree [<em>Liriodendron chinense</em> (<em>L. chinense</em>)], a rare medicinal and ornamental plant endemic to China. The structural elucidation was accomplished through comprehensive spectroscopic analyses, quantum-chemical calculations, and X-ray crystallography. These heterodimers exhibit a characteristic 2-oxaspiro[4.5]decan-1-one structural motif, biosynthetically formed through intermolecular [4 + 2]-cycloaddition between a germacrane-type sesquiterpene and an ocimene-type monoterpene. The majority of the isolated compounds demonstrated significant anti-neuroinflammatory effects in lipopolysaccharide (LPS)-induced BV-2 microglial cells by reducing the production of pro-inflammatory mediators, specifically tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Further investigation revealed that the lirispirolides’ inhibition of NO release correlated with decreased messenger ribonucleic acid (mRNA) expression of inducible NO synthase (iNOS).</div></div>","PeriodicalId":10002,"journal":{"name":"Chinese Journal of Natural Medicines","volume":"23 8","pages":"Pages 938-950"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-01DOI: 10.1016/S1875-5364(25)60927-7
Wen Wen , Jie Chen , Junbao Xiang , Shiqi Zhang , Jingru Liu , Jie Wang , Ping Wang , Shijun Xu
Triggering receptor expressed on myeloid cells 2 (TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta (Aβ) clearance in Alzheimer’s disease (AD). Energy metabolic reprogramming (EMR) in microglia induced by TREM2 presents therapeutic targets for cognitive impairment in AD. Jiawei Xionggui Decoction (JWXG) has demonstrated effectiveness in enhancing energy supply, protecting microglia, and mitigating cognitive impairment in APP/PS1 mice. However, the mechanism by which JWXG enhances Aβ phagocytosis through TREM2-mediated EMR in microglia remains unclear. This study investigates how JWXG facilitates microglial phagocytosis and alleviates cognitive deficits in AD through TREM2-mediated EMR. Microglial phagocytosis was evaluated through immunofluorescence staining in vitro and in vivo. The EMR level of microglia was assessed using high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA) kits. The TREM2/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway was analyzed using Western blotting in BV2 cells. TREM2−/− BV2 cells were utilized for reverse validation experiments. The Aβ burden, neuropathological features, and cognitive ability in APP/PS1 mice were evaluated using ELISA kits, immunohistochemistry (IHC), and the Morris water maze (MWM) test. JWXG enhanced both the phagocytosis of EMR disorder-BV2 cells (EMRD-BV2) and increased EMR levels. Notably, these effects were significantly reversed in TREM2−/− BV2 cells. JWXG elevated TREM2 expression, adenosine triphosphate (ATP) levels, and microglial phagocytosis in APP/PS1 mice. Additionally, JWXG reduced Aβ-burden, neuropathological lesions, and cognitive deficits in APP/PS1 mice. In conclusion, JWXG promoted TREM2-induced EMR and enhanced microglial phagocytosis, thereby reducing Aβ deposition, improving neuropathological lesions, and alleviating cognitive deficits.
{"title":"Facilitating microglial phagocytosis by which Jiawei Xionggui Decoction alleviates cognitive impairment via TREM2-mediated energy metabolic reprogramming","authors":"Wen Wen , Jie Chen , Junbao Xiang , Shiqi Zhang , Jingru Liu , Jie Wang , Ping Wang , Shijun Xu","doi":"10.1016/S1875-5364(25)60927-7","DOIUrl":"10.1016/S1875-5364(25)60927-7","url":null,"abstract":"<div><div>Triggering receptor expressed on myeloid cells 2 (TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta (Aβ) clearance in Alzheimer’s disease (AD). Energy metabolic reprogramming (EMR) in microglia induced by TREM2 presents therapeutic targets for cognitive impairment in AD. Jiawei Xionggui Decoction (JWXG) has demonstrated effectiveness in enhancing energy supply, protecting microglia, and mitigating cognitive impairment in APP/PS1 mice. However, the mechanism by which JWXG enhances Aβ phagocytosis through TREM2-mediated EMR in microglia remains unclear. This study investigates how JWXG facilitates microglial phagocytosis and alleviates cognitive deficits in AD through TREM2-mediated EMR. Microglial phagocytosis was evaluated through immunofluorescence staining <em>in vitro</em> and <em>in vivo</em>. The EMR level of microglia was assessed using high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA) kits. The TREM2/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway was analyzed using Western blotting in BV<sub>2</sub> cells. TREM2<sup>−/−</sup> BV<sub>2</sub> cells were utilized for reverse validation experiments. The Aβ burden, neuropathological features, and cognitive ability in APP/PS1 mice were evaluated using ELISA kits, immunohistochemistry (IHC), and the Morris water maze (MWM) test. JWXG enhanced both the phagocytosis of EMR disorder-BV<sub>2</sub> cells (EMRD-BV<sub>2</sub>) and increased EMR levels. Notably, these effects were significantly reversed in TREM2<sup>−/−</sup> BV<sub>2</sub> cells. JWXG elevated TREM2 expression, adenosine triphosphate (ATP) levels, and microglial phagocytosis in APP/PS1 mice. Additionally, JWXG reduced Aβ-burden, neuropathological lesions, and cognitive deficits in APP/PS1 mice. In conclusion, JWXG promoted TREM2-induced EMR and enhanced microglial phagocytosis, thereby reducing Aβ deposition, improving neuropathological lesions, and alleviating cognitive deficits.</div></div>","PeriodicalId":10002,"journal":{"name":"Chinese Journal of Natural Medicines","volume":"23 8","pages":"Pages 909-919"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-01DOI: 10.1016/S1875-5364(25)60936-8
Yang Yu , Changliang Yao , Jianqing Zhang , Yong Huang , Shuai Yao , Hua Qu , Tong Zhang , Dean Guo
Aconiti Lateralis Radix Praeparata (Fuzi) represents a significant traditional Chinese medicine (TCM) that exhibits both notable pharmacological effects and toxicity. Various processing methods are implemented to reduce the toxicity of raw Fuzi by modifying its toxic and effective components, primarily diterpenoid alkaloids. To comprehensively analyze the chemical variations between different Fuzi products, ultra-high performance liquid chromatography-linear ion trap quadrupole Orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MS) was employed to systematically characterize Shengfuzi, Heishunpian and Baifupian. A total of 249 diterpenoid alkaloids present in Shengfuzi were identified, while only 111 and 61 in Heishunpian and Baifupian were detected respectively, indicating substantial differences among these products. An untargeted metabolomics approach combined with multivariate statistical analysis revealed 42 potential chemical markers. Through subsequent validation using 52 batches of commercial Heishunpian and Baifupian samples, 8 robust markers distinguishing these products were identified, including AC1-propanoic acid-3OH, HE-glucoside, HE-hydroxyvaleric acid-2OH, dihydrosphingosine, N-dodecoxycarbonylvaline and three unknown compounds. Additionally, the MS imaging (MSI) technique was utilized to visualize the spatial distribution of chemical constituents in raw Fuzi, revealing how different processing procedures affect the chemical variations between Heishunpian and Baifupian. The distribution patterns of different diterpenoid alkaloid subtypes partially explained the chemical differences among products. This research provides valuable insights into the material basis for future investigations of different Fuzi products.
{"title":"Profiling the chemical differences of diterpenoid alkaloids in different processed products of Aconiti Lateralis Radix Praeparata by UHPLC-LTQ-Orbitrap mass spectrometry combined with untargeted metabolomics and mass spectrometry imaging","authors":"Yang Yu , Changliang Yao , Jianqing Zhang , Yong Huang , Shuai Yao , Hua Qu , Tong Zhang , Dean Guo","doi":"10.1016/S1875-5364(25)60936-8","DOIUrl":"10.1016/S1875-5364(25)60936-8","url":null,"abstract":"<div><div>Aconiti Lateralis Radix Praeparata (Fuzi) represents a significant traditional Chinese medicine (TCM) that exhibits both notable pharmacological effects and toxicity. Various processing methods are implemented to reduce the toxicity of raw Fuzi by modifying its toxic and effective components, primarily diterpenoid alkaloids. To comprehensively analyze the chemical variations between different Fuzi products, ultra-high performance liquid chromatography-linear ion trap quadrupole Orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MS) was employed to systematically characterize Shengfuzi, Heishunpian and Baifupian. A total of 249 diterpenoid alkaloids present in Shengfuzi were identified, while only 111 and 61 in Heishunpian and Baifupian were detected respectively, indicating substantial differences among these products. An untargeted metabolomics approach combined with multivariate statistical analysis revealed 42 potential chemical markers. Through subsequent validation using 52 batches of commercial Heishunpian and Baifupian samples, 8 robust markers distinguishing these products were identified, including AC1-propanoic acid-3OH, HE-glucoside, HE-hydroxyvaleric acid-2OH, dihydrosphingosine, <em>N</em>-dodecoxycarbonylvaline and three unknown compounds. Additionally, the MS imaging (MSI) technique was utilized to visualize the spatial distribution of chemical constituents in raw Fuzi, revealing how different processing procedures affect the chemical variations between Heishunpian and Baifupian. The distribution patterns of different diterpenoid alkaloid subtypes partially explained the chemical differences among products. This research provides valuable insights into the material basis for future investigations of different Fuzi products.</div></div>","PeriodicalId":10002,"journal":{"name":"Chinese Journal of Natural Medicines","volume":"23 8","pages":"Pages 1009-1015"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Saponins associated with Panax notoginseng (P. notoginseng) demonstrate significant therapeutic efficacy across multiple diseases. However, certain high-yield saponins face limited clinical applications due to their reduced pharmacological efficacy. This study synthesized and evaluated 36 saponin-1,2,3-triazole derivatives of ginsenosides Rg1/Rb1 and notoginsenoside R1 for anti-adipogenesis activity in vitro. The research revealed that the ginsenosides Rg1-1,2,3-triazole derivative a17 demonstrates superior adipogenesis inhibitory effects. Structure-activity relationships (SARs) analysis indicates that incorporating an amidyl-substituted 1,2,3-triazole into the saponin side chain via Click reaction enhances anti-adipogenesis activity. Additionally, several other derivatives exhibit general adipogenesis inhibition. Compound a17 demonstrated enhanced potency compared to the parent ginsenoside Rg1. Mechanistic investigations revealed that a17 exhibits dose-dependent inhibition of adipogenesis in vitro, accompanied by decreased expression of preadipocytes. Peroxisome proliferator-activated receptor γ (PPARγ), fatty acid synthase (FAS), and fatty acid binding protein 4 (FABP4) adipogenesis regulators. These findings establish the ginsenoside Rg1-1,2,3-triazole derivative a17 as a promising adipocyte differentiation inhibitor and potential therapeutic agent for obesity and associated metabolic disorders. This research provides a foundation for developing effective therapeutic approaches for various metabolic syndromes.
{"title":"Design and synthesis of novel saponin-triazole derivatives in the regulation of adipogenesis","authors":"Yongsheng Fang , Zhiyun Zhu , Chun Xie, Dazhen Xia, Huimin Zhao, Zihui Wang, Qian Lu, Caimei Zhang, Wenyong Xiong, Xiaodong Yang","doi":"10.1016/S1875-5364(25)60830-2","DOIUrl":"10.1016/S1875-5364(25)60830-2","url":null,"abstract":"<div><div>Saponins associated with <em>Panax notoginseng</em> (<em>P. notoginseng</em>) demonstrate significant therapeutic efficacy across multiple diseases. However, certain high-yield saponins face limited clinical applications due to their reduced pharmacological efficacy. This study synthesized and evaluated 36 saponin-1,2,3-triazole derivatives of ginsenosides Rg1/Rb1 and notoginsenoside R1 for anti-adipogenesis activity <em>in vitro</em>. The research revealed that the ginsenosides Rg1-1,2,3-triazole derivative <strong>a17</strong> demonstrates superior adipogenesis inhibitory effects. Structure-activity relationships (SARs) analysis indicates that incorporating an amidyl-substituted 1,2,3-triazole into the saponin side chain <em>via</em> Click reaction enhances anti-adipogenesis activity. Additionally, several other derivatives exhibit general adipogenesis inhibition. Compound <strong>a17</strong> demonstrated enhanced potency compared to the parent ginsenoside Rg1. Mechanistic investigations revealed that <strong>a17</strong> exhibits dose-dependent inhibition of adipogenesis <em>in vitro</em>, accompanied by decreased expression of preadipocytes. Peroxisome proliferator-activated receptor γ (PPARγ), fatty acid synthase (FAS), and fatty acid binding protein 4 (FABP4) adipogenesis regulators. These findings establish the ginsenoside Rg1-1,2,3-triazole derivative <strong>a17</strong> as a promising adipocyte differentiation inhibitor and potential therapeutic agent for obesity and associated metabolic disorders. This research provides a foundation for developing effective therapeutic approaches for various metabolic syndromes.</div></div>","PeriodicalId":10002,"journal":{"name":"Chinese Journal of Natural Medicines","volume":"23 8","pages":"Pages 920-931"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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