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Gentiopicroside attenuates lupus arthritis by targeting galectin-mediated macrophage activation Gentiopicroside通过靶向半凝集素介导的巨噬细胞激活来减轻狼疮关节炎。
IF 8.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-01-17 DOI: 10.1016/j.phymed.2026.157843
Yihong Gan , Shihui Zhou , Ke Lin , Yijing Bai , Jingqun Liu , Meng Jin , Shuo Huang , Qice Sun , Chao Sun , Yilin Zhang , Shengyu Chen , Xinchang Wang , Yongsheng Fan , Jie Bao , Li Xu

Background

Inflammatory arthritis represents a common and clinically challenging manifestation of systemic lupus erythematosus (SLE), with current therapeutic options often exhibiting limited efficacy.

Purpose

This study aimed to investigate the anti-arthritic effects and underlying mechanism of gentiopicroside (GPS), a key bioactive constituent of the Jiawei Baihu Jia Guizhi Decoction (JBH), with a specific focus on its interaction with galectin-9-mediated pathways in macrophage activation.

Study design

The anti-arthritic efficacy of GPS was investigated using a pristane-induced arthritis (PIA) mouse model, which recapitulates key features of SLE-associated arthritis. Integrated transcriptomic and network pharmacology approaches were employed for mechanistic exploration, followed by experimental validation in vitro and in vivo.

Methods

The PIA mouse model was treated with GPS to evaluate its effects on joint inflammation, synovial pathology, and bone remodeling. Transcriptomic profiling of joint tissues and network pharmacology analysis were conducted to identify potential targets. The interaction between GPS and Galectin-9 (Gal-9) was characterized using molecular docking and biophysical assays (determining a Kd of ∼350 nM). The functional impact of GPS on Gal-9-dependent NF-κB signaling, pro-inflammatory cytokine secretion, and macrophage activation was assessed in cellular models and PIA mice.

Results

GPS treatment significantly alleviated joint inflammation, synovial hyperplasia, and bone erosion in PIA mice, while also restoring the balance of bone remodeling. Integrative analyses pinpointed Gal-9 as a critical target, and GPS was confirmed to bind Gal-9 with high affinity. Functionally, GPS inhibited Gal-9-triggered NF-κB activation, suppressed the production of pro-inflammatory cytokines, and reduced macrophage infiltration and activation. Furthermore, GPS ameliorated systemic inflammation, lowered autoantibody levels, and improved joint integrity in PIA mice, demonstrating efficacy comparable to methotrexate.

Conclusion

Gentiopicroside, a key active constituent of the JBH, attenuates lupus arthritis by specifically targeting Galectin-9 and subsequently disrupting galectin-driven macrophage activation. These findings highlight GPS as a promising targeted therapeutic candidate for the management of SLE-related joint damage.
背景:炎性关节炎是系统性红斑狼疮(SLE)的一种常见且具有临床挑战性的表现,目前的治疗方案往往表现出有限的疗效。目的:研究加味白虎加桂枝汤关键活性成分龙胆苦苷(gentiopicroside, GPS)的抗关节炎作用及其机制,重点研究其与半乳糖凝集素-9介导的巨噬细胞激活途径的相互作用。研究设计:我们采用一种重现slea相关关节炎主要特征的前列腺素诱导关节炎(PIA)小鼠模型来研究GPS的抗关节炎功效。采用整合转录组学和网络药理学方法进行机制探索,然后进行体外和体内实验验证。方法:采用GPS治疗PIA小鼠模型,观察其对关节炎症、滑膜病理及骨重塑的影响。通过对关节组织的转录组学分析和网络药理学分析来确定潜在的靶点。GPS与半乳糖凝集素-9 (Gal-9)之间的相互作用通过分子对接和生物物理分析(确定Kd为~ 350 nM)进行了表征。在细胞模型和PIA小鼠中评估GPS对gal -9依赖性NF-κB信号传导、促炎细胞因子分泌和巨噬细胞活化的功能影响。结果:GPS治疗可显著缓解PIA小鼠关节炎症、滑膜增生、骨侵蚀,同时恢复骨重塑平衡。综合分析确定Gal-9为关键靶点,并证实GPS与Gal-9具有高亲和力。功能上,GPS可抑制gal -9触发的NF-κB活化,抑制促炎细胞因子的产生,减少巨噬细胞的浸润和活化。此外,GPS改善了PIA小鼠的全身炎症,降低了自身抗体水平,并改善了关节完整性,其疗效与甲氨蝶呤相当。结论:Gentiopicroside是JBH的关键活性成分,通过特异性靶向半乳糖凝集素-9并随后破坏半乳糖凝集素驱动的巨噬细胞激活来减轻狼疮关节炎。这些发现突出了GPS作为一种有希望的靶向治疗候选人来管理slel相关的关节损伤。
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引用次数: 0
Hemoglobin adduction and impaired oxygen transport define the etiology of pyrrolizidine alkaloid-induced pulmonary arterial hypertension. 血红蛋白内聚和氧运输受损是吡咯利西定生物碱引起肺动脉高压的病因。
IF 8.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-01-17 DOI: 10.1016/j.phymed.2026.157847
Caibin Zhang, Tianyang Huang, Xiaokai Guo, Yujian Fan, Zijing Song, Jiang Ma, Yisheng He

Background: Pyrrolizidine alkaloids (PAs), particularly monocrotaline (MCT), are common phytotoxins known to induce pulmonary arterial hypertension (PAH), a progressive and fatal cardiopulmonary disease. However, the specific mechanism initiating PAH and the basis for the differing toxic potencies among PAs, such as MCT and retrorsine (RTS), remain undefined.

Purpose: This study aimed to investigate the mechanistic basis for the marked difference in pulmonary toxicity between two representative PAs, MCT and RTS. We specifically tested the hypothesis that the severity of PA-induced lung injury is determined by the extent of hemoglobin adduction within red blood cells (RBCs) and the consequent impairment of oxygen transport.

Study design: We employed a comparative toxicological design using rat models, treating them with equimolar doses of MCT and RTS, to assess and compare their respective toxicological pathways and resulting pulmonary injury.

Methods: Rats were administered MCT or RTS. Dehydropyrrolizidine alkaloid (DHPA) adduct formation on RBC hemoglobin was profiled using proteomics. Pulmonary hemodynamics, pulmonary vascular remodeling, and systemic hypoxia levels were subsequently measured.

Results: DHPAs selectively and covalently bound to specific residues (D74, E91, H93, K133) on the hemoglobin β-1 chain, critically impairing the oxygen-carrying capacity of RBCs. MCT exposure resulted in significantly higher levels of pyrrole-hemoglobin adducts (approximately 95% binding) compared to RTS (approximately 70% binding). This higher adduction rate led to more severe systemic hypoxia, which was consistently associated with greater pulmonary arterial endothelial activation and more severe PAH in the MCT group.

Conclusion: The severity of PA-induced PAH is directly correlated with the degree of hemoglobin adduction and resulting hypoxia. Hemoglobin adduction and impaired oxygen transport are critical, upstream events that define the etiology of PA-induced pulmonary arterial hypertension.

背景:吡罗里西啶生物碱(PAs),特别是单罗塔碱(MCT),是一种常见的植物毒素,已知可诱发肺动脉高压(PAH),这是一种进行性和致命性的心肺疾病。然而,引发多环芳烃的具体机制以及不同PAs(如MCT和逆转录酶(RTS))毒性的基础仍未明确。目的:本研究旨在探讨MCT和RTS两种具有代表性的pa之间肺毒性显著差异的机制基础。我们特别验证了pa诱导的肺损伤的严重程度是由红细胞内合血红蛋白的程度和随后的氧运输损伤决定的假设。研究设计:我们采用比较毒理学设计,使用大鼠模型,用等摩尔剂量的MCT和RTS治疗它们,评估和比较它们各自的毒理学途径和导致的肺损伤。方法:给予大鼠MCT或RTS。用蛋白质组学分析了脱氢吡咯利西啶生物碱(DHPA)加合物在红细胞血红蛋白上的形成。随后测量肺血流动力学、肺血管重构和全身缺氧水平。结果:DHPAs选择性地与血红蛋白β-1链上的特定残基(D74, E91, H93, K133)共价结合,严重损害红细胞的载氧能力。与RTS(约70%结合)相比,MCT暴露导致吡罗-血红蛋白加合物水平显著升高(约95%结合)。较高的内收率导致更严重的全身性缺氧,这与MCT组更大的肺动脉内皮活化和更严重的PAH一致相关。结论:pa诱发PAH的严重程度与血红蛋白内收程度及由此引起的缺氧直接相关。血红蛋白内收和氧气运输受损是关键的上游事件,确定了pa诱导的肺动脉高压的病因。
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引用次数: 0
Dehydrocavidine alleviates lipopolysaccharide-induced acute liver injury by activating Nrf2 signaling pathway to inhibit hepatocyte ferroptosis. 脱氢卡维啶通过激活Nrf2信号通路抑制肝细胞铁凋亡,减轻脂多糖诱导的急性肝损伤。
IF 8.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-01-17 DOI: 10.1016/j.phymed.2026.157845
Hongbiao Liang, Guizimeng Hu, Dongmin Yang, Yuwei Song, Peng Zhang, Tianqi Chen, Xiangrui Zhu, Peiyi Li, Yuan Wang, Xinmei Huo, Xiaoyi Wang, Yi Zhang, Yujie Zhang, Jian Liu, Juan Feng

Background: Sepsis-induced acute liver injury (SALI) remains a major challenge with limited effective treatments. Although Corydalis saxicola Bunting (CSB) exhibits anti-inflammatory and hepatoprotective properties, its role in SALI remains poorly understood.

Purpose: To identify the active components and molecular mechanisms of CSB in protecting against SALI.

Methods: In vivo LPS-induced rat liver injury and in vitro cytokine-induced HepG2 injury models were established, treated with CSB extract or dehydrocavidine (DC). A series of advanced techniques including ferroptosis PCR array, super-resolution stimulated emission depletion (STED) microscopy, assay for transposase-accessible chromatin with sequencing (ATAC-seq), cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), molecular dynamics simulation, and site-directed mutation were employed to investigate the underlying mechanisms.

Results: DC significantly mitigated LPS-induced liver injury, microcirculatory disorder, and leukocyte adhesion. It also alleviated liver ferroptosis under LPS challenge. In vitro studies revealed that LPS-activated macrophages secreted tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), which triggered hepatocyte ferroptosis. DC countered this process by inhibiting the production of these cytokines and correcting cytokine-induced mitochondrial abnormalities in hepatocytes. Mechanistically, DC bound to Kelch-like ECH-associated protein 1 (Keap1) at arginine 415 (R415), disrupting the formation of the Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) complex. This enabled Nrf2 nuclear translocation and promoted antioxidant gene expression, thereby correcting LPS-induced redox imbalance in hepatocytes.

Conclusions: In addition to inhibiting LPS-induced macrophage activation, DC activates the Nrf2 signaling pathway in hepatocytes to alleviate inflammation-enhanced liver ferroptosis. It provides potential therapeutic strategies for sepsis and Gram-negative bacteria-associated liver injury.

背景:脓毒症引起的急性肝损伤(SALI)仍然是一个主要的挑战,有效的治疗方法有限。虽然紫连珠(CSB)具有抗炎和保护肝脏的特性,但其在SALI中的作用仍然知之甚少。目的:研究CSB抗SALI的活性成分及分子机制。方法:建立lps诱导的大鼠肝损伤模型和体外细胞因子诱导的HepG2损伤模型,分别给予CSB提取物或脱氢卡维啶(DC)处理。采用了一系列先进的技术,包括铁凋亡PCR阵列,超分辨率受激发射损耗(STED)显微镜,转座酶可及染色质测序(ATAC-seq),细胞热移测定(CETSA),表面等离子体共振(SPR),分子动力学模拟和位点定向突变来研究其潜在的机制。结果:DC显著减轻lps诱导的肝损伤、微循环障碍和白细胞粘附。它还能减轻LPS刺激下的肝脏铁下垂。体外研究发现,lps激活的巨噬细胞分泌肿瘤坏死因子-α (TNF-α)和干扰素-γ (IFN-γ),引发肝细胞铁下垂。DC通过抑制这些细胞因子的产生和纠正肝细胞中细胞因子诱导的线粒体异常来对抗这一过程。从机制上讲,DC在精氨酸415 (R415)处与kelch样ech相关蛋白1 (Keap1)结合,破坏Keap1/核因子红系2相关因子2 (Nrf2)复合物的形成。这使得Nrf2核易位,促进抗氧化基因表达,从而纠正脂多糖诱导的肝细胞氧化还原失衡。结论:DC除抑制lps诱导的巨噬细胞活化外,还激活肝细胞Nrf2信号通路,减轻炎症增强的肝铁下垂。它为败血症和革兰氏阴性菌相关肝损伤提供了潜在的治疗策略。
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引用次数: 0
Andrographolide ameliorates vascular injury in hypertension by suppressing EndMT via Sp1-Notch1 signaling. 穿心莲内酯通过抑制Sp1-Notch1信号通路抑制高血压血管损伤。
IF 8.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-01-17 DOI: 10.1016/j.phymed.2026.157846
Qiang Tu, Wenling Li, Yanxia Qiu, Yumin Qiu, Zhefu Liu, Meixin Zhang, Zhangchi Liu, Wenhao Xia, Bin Zhang, Zheng Cao, Jun Tao

Background: Endothelial-to-mesenchymal transition (EndMT) is a potential therapeutic target for hypertension-induced vascular injury. Andrographolide (AGP) is a bioactive labdane diterpenoid that confers cardiovascular protective effects. However, the role of AGP in regulating EndMT during hypertension-related vascular injury is not clear.

Purpose: In this study, we investigated the effect of AGP on EndMT in vascular injury and elucidated its underlying mechanism in hypertension.

Methods: Angiotensin II (Ang II)-induced hypertensive mice were used to evaluate the vascular protective effects of AGP. Mechanistic experiments were performed in Ang II-stimulated endothelial cells. We detected EndMT markers both in vitro and in vivo. We also conducted a small-scale clinical trial to assess the effects of AGP on vascular damage in patients with hypertension.

Results: In Ang II-induced hypertensive mice, AGP improved endothelial function, alleviated arterial stiffness, and decreased aortic remodeling while also lowering blood pressure. It also suppressed EndMT in hypertensive mice and Ang II-treated endothelial cells. Quantitative co-immunofluorescence staining of aortic sections revealed that the percentage of CD31/vimentin double-positive cells was significantly higher in Ang II-induced hypertensive mice, whereas AGP treatment considerably decreased this proportion. Endothelial Notch1 expression was upregulated during EndMT, whereas genetic or pharmacological inhibition of Notch1 blocked Ang II-induced EndMT. Ang II downregulated the expression of Sp1, whereas the overexpression of Sp1 mitigated Ang II-induced EndMT; moreover, knocking down Sp1 abrogated the protective effects of AGP. In mice, the overexpression of Sp1 via adeno-associated virus 9 or Notch1 inhibition attenuated vascular injury by suppressing EndMT. Moreover, AGP improved flow-mediated dilation and reduced brachial-ankle pulse wave velocity in hypertensive patients (ChiCTR2300071970).

Conclusions: We found that AGP ameliorates hypertension-induced vascular injury by inhibiting EndMT through the Sp1-Notch1 pathway. These findings suggest that AGP may serve as a promising therapeutic candidate for restoring vascular homeostasis in patients suffering from hypertension.

背景:内皮-间充质转化(EndMT)是高血压血管损伤的潜在治疗靶点。穿心莲内酯(AGP)是一种具有生物活性的双萜,具有心血管保护作用。然而,AGP在高血压相关血管损伤中调控EndMT的作用尚不清楚。目的:在本研究中,我们探讨了AGP对血管损伤中EndMT的影响,并阐明其在高血压中的潜在机制。方法:采用血管紧张素II (angii)诱导的高血压小鼠,评价AGP对血管的保护作用。在angii刺激的内皮细胞中进行了机制实验。我们在体外和体内检测了EndMT标记物。我们还进行了一项小规模临床试验,以评估AGP对高血压患者血管损伤的影响。结果:在angii诱导的高血压小鼠中,AGP改善内皮功能,减轻动脉僵硬,减少主动脉重塑,同时降低血压。它还能抑制高血压小鼠和angii处理的内皮细胞的EndMT。定量共免疫荧光染色显示,angii诱导的高血压小鼠中CD31/vimentin双阳性细胞比例显著升高,而AGP治疗显著降低了这一比例。内皮细胞Notch1的表达在EndMT过程中上调,而Notch1的遗传或药理学抑制可阻断Ang ii诱导的EndMT。Ang II下调Sp1的表达,而Sp1的过表达则减轻了Ang II诱导的EndMT;此外,敲除Sp1使AGP的保护作用失效。在小鼠中,Sp1通过腺相关病毒9或Notch1抑制过表达,通过抑制EndMT来减轻血管损伤。此外,AGP改善了高血压患者血流介导的舒张,降低了肱踝脉波速度(ChiCTR2300071970)。结论:我们发现AGP通过Sp1-Notch1通路抑制EndMT,从而改善高血压诱导的血管损伤。这些发现表明,AGP可能作为恢复高血压患者血管稳态的有希望的治疗候选者。
{"title":"Andrographolide ameliorates vascular injury in hypertension by suppressing EndMT via Sp1-Notch1 signaling.","authors":"Qiang Tu, Wenling Li, Yanxia Qiu, Yumin Qiu, Zhefu Liu, Meixin Zhang, Zhangchi Liu, Wenhao Xia, Bin Zhang, Zheng Cao, Jun Tao","doi":"10.1016/j.phymed.2026.157846","DOIUrl":"https://doi.org/10.1016/j.phymed.2026.157846","url":null,"abstract":"<p><strong>Background: </strong>Endothelial-to-mesenchymal transition (EndMT) is a potential therapeutic target for hypertension-induced vascular injury. Andrographolide (AGP) is a bioactive labdane diterpenoid that confers cardiovascular protective effects. However, the role of AGP in regulating EndMT during hypertension-related vascular injury is not clear.</p><p><strong>Purpose: </strong>In this study, we investigated the effect of AGP on EndMT in vascular injury and elucidated its underlying mechanism in hypertension.</p><p><strong>Methods: </strong>Angiotensin II (Ang II)-induced hypertensive mice were used to evaluate the vascular protective effects of AGP. Mechanistic experiments were performed in Ang II-stimulated endothelial cells. We detected EndMT markers both in vitro and in vivo. We also conducted a small-scale clinical trial to assess the effects of AGP on vascular damage in patients with hypertension.</p><p><strong>Results: </strong>In Ang II-induced hypertensive mice, AGP improved endothelial function, alleviated arterial stiffness, and decreased aortic remodeling while also lowering blood pressure. It also suppressed EndMT in hypertensive mice and Ang II-treated endothelial cells. Quantitative co-immunofluorescence staining of aortic sections revealed that the percentage of CD31/vimentin double-positive cells was significantly higher in Ang II-induced hypertensive mice, whereas AGP treatment considerably decreased this proportion. Endothelial Notch1 expression was upregulated during EndMT, whereas genetic or pharmacological inhibition of Notch1 blocked Ang II-induced EndMT. Ang II downregulated the expression of Sp1, whereas the overexpression of Sp1 mitigated Ang II-induced EndMT; moreover, knocking down Sp1 abrogated the protective effects of AGP. In mice, the overexpression of Sp1 via adeno-associated virus 9 or Notch1 inhibition attenuated vascular injury by suppressing EndMT. Moreover, AGP improved flow-mediated dilation and reduced brachial-ankle pulse wave velocity in hypertensive patients (ChiCTR2300071970).</p><p><strong>Conclusions: </strong>We found that AGP ameliorates hypertension-induced vascular injury by inhibiting EndMT through the Sp1-Notch1 pathway. These findings suggest that AGP may serve as a promising therapeutic candidate for restoring vascular homeostasis in patients suffering from hypertension.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"157846"},"PeriodicalIF":8.3,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Magnolia officinalis Rehder & E. Wilson extract and its main component honokiol alleviate asthma by reducing respiratory inflammation through the TRPV1/NFAT/TSLP pathway 厚朴提取物及其主要成分厚朴酚通过TRPV1/NFAT/TSLP通路减轻呼吸道炎症,缓解哮喘。
IF 8.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-01-16 DOI: 10.1016/j.phymed.2026.157840
Liming Tu , Xiaoying Zhu , Meihao Peng , Hongde Li , Yu Wang , Jiamin Liu , Xin Yang , Lang Chen , Yixi Yang , Rui Li , Di Gong , Qiuxia Lu , Qi Zhao
<div><h3>Background</h3><div>Asthma is a chronic respiratory disorder whose complexity presents significant challenges for effective treatment, necessitating ongoing innovation in therapeutic approaches. <em>Magnolia officinalis</em> Rehder & E. Wilson, a traditional Chinese medicine, possesses anti-inflammatory and antioxidant properties, along with diverse pharmacological activities. It is commonly included in traditional formulations such as Ping Wei San and Banxia Houpo Decoction. However, research investigating the mechanisms by which <em>Magnolia officinalis</em> Rehder & E. Wilson alleviates asthma remains limited.</div></div><div><h3>Purpose</h3><div>This study investigated the pharmacological activity of <em>Magnolia officinalis</em> Rehder & E. Wilson extract (MOE) and its main active compound, honokiol, in alleviating respiratory tract inflammation in asthmatic mice, and elucidated the underlying mechanisms.</div></div><div><h3>Methods</h3><div>An ovalbumin (OVA)-induced allergic asthma mouse model was established to evaluate the therapeutic efficacy of MOE by assessing pulmonary function, histopathological lung injury, and immune cell activation. Network pharmacology and molecular docking were then employed to predict the potential mechanisms of MOE. To validate these mechanisms, tumor necrosis factor (TNF)-α/interleukin-4 (IL-4)-induced BEAS-2B airway epithelial cell models were used to measure transient receptor potential vanilloid 1 (TRPV1) and thymic stromal lymphopoietin (TSLP) expression, intracellular calcium flux dynamics, and NFAT nuclear translocation. Finally, based on the identified mechanisms, the therapeutic effects of honokiol, the key bioactive compound derived from MOE, were further investigated using an in vivo model.</div></div><div><h3>Results</h3><div>MOE significantly restored tidal volume (TV) and Penh (enhanced pause) levels in asthmatic mice, while suppressing mucus hypersecretion, collagen deposition, and goblet cell hyperplasia. Additionally, MOE markedly attenuated OVA-induced airway inflammatory cell infiltration, as evidenced by reduced numbers of CD45<sup>+</sup>, CD4<sup>+</sup>, MHC II<sup>+</sup>, CD11c<sup>+</sup>, F4/80<sup>+</sup>, Arg1<sup>+</sup>, and CD206<sup>+</sup> cells in lung tissues, along with decreased production of IL-1β, IL-4, and TNF-α. These findings indicate that MOE exerts beneficial effects on airway hyperresponsiveness (AHR), airway remodeling, and airway inflammation. Network pharmacology and molecular docking identified TRPV1 as a pivotal target. KEGG enrichment analysis revealed the calcium signaling pathway among the top 20 enriched pathways. Further experimental validation demonstrated that MOE reduced TSLP production both in <em>vivo</em> and in <em>vitro</em> by modulating the TRPV1/NFAT pathway. Calcium flux assays showed that MOE inhibited inflammatory cytokine-mediated TRPV1-induced Ca²⁺ influx and blocked capsaicin (CAP)-triggered TRPV1 activation. Finally
背景:哮喘是一种慢性呼吸系统疾病,其复杂性对有效治疗提出了重大挑战,需要不断创新治疗方法。厚朴是一种中药,具有抗炎、抗氧化的作用,具有多种药理活性。它通常包含在传统的方剂中,如平胃散和半夏后坡汤。然而,关于厚朴缓解哮喘的机制的研究仍然有限。目的:研究厚朴提取物(MOE)及其主要活性物质厚朴酚(honokiol)对哮喘小鼠呼吸道炎症的缓解作用,并探讨其作用机制。方法:建立卵清蛋白(OVA)诱导的过敏性哮喘小鼠模型,通过肺功能、肺组织病理学损伤、免疫细胞活化等指标评价MOE的治疗效果。利用网络药理学和分子对接技术预测MOE的潜在作用机制。为了验证这些机制,使用肿瘤坏死因子(TNF)-α/白细胞介素-4 (IL-4)诱导的BEAS-2B气道上皮细胞模型来测量瞬时受体电位香草酸样蛋白1 (TRPV1)和胸腺基质淋巴生成素(TSLP)的表达、细胞内钙通量动力学和NFAT核易位。最后,在确定机制的基础上,利用体内模型进一步研究了从牡丹中提取的关键生物活性化合物厚朴酚的治疗作用。结果:MOE可显著恢复哮喘小鼠的潮气量(TV)和停顿量(Penh)水平,同时抑制粘液分泌过多、胶原沉积和杯状细胞增生。此外,MOE显著减弱ova诱导的气道炎症细胞浸润,肺组织中CD45+、CD4+、MHC II+、CD11c+、F4/80+、Arg1+和CD206+细胞数量减少,IL-1β、IL-4和TNF-α的产生减少。这些结果表明,MOE对气道高反应性(AHR)、气道重塑和气道炎症有有益的作用。网络药理学和分子对接发现TRPV1是关键靶点。KEGG富集分析显示,钙信号通路在富集前20位。进一步的实验验证表明,MOE通过调节TRPV1/NFAT通路,在体内和体外减少了TSLP的产生。钙通量测定显示,MOE抑制了炎症细胞因子介导的TRPV1诱导的ca2 +内流,阻断了辣椒素(CAP)触发的TRPV1激活。最后,厚朴酚通过调节TRPV1/TSLP轴减轻哮喘症状和炎症。结论:本研究首次证实MOE通过靶向TRPV1/NFAT/TSLP通路缓解呼吸道炎症和变应性哮喘,初步确定其关键生物活性成分为厚朴酚。这些发现阐明了MOE的药效学基础,并提出了一种新的植物源性哮喘治疗候选药物。
{"title":"Magnolia officinalis Rehder & E. Wilson extract and its main component honokiol alleviate asthma by reducing respiratory inflammation through the TRPV1/NFAT/TSLP pathway","authors":"Liming Tu ,&nbsp;Xiaoying Zhu ,&nbsp;Meihao Peng ,&nbsp;Hongde Li ,&nbsp;Yu Wang ,&nbsp;Jiamin Liu ,&nbsp;Xin Yang ,&nbsp;Lang Chen ,&nbsp;Yixi Yang ,&nbsp;Rui Li ,&nbsp;Di Gong ,&nbsp;Qiuxia Lu ,&nbsp;Qi Zhao","doi":"10.1016/j.phymed.2026.157840","DOIUrl":"10.1016/j.phymed.2026.157840","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Asthma is a chronic respiratory disorder whose complexity presents significant challenges for effective treatment, necessitating ongoing innovation in therapeutic approaches. &lt;em&gt;Magnolia officinalis&lt;/em&gt; Rehder &amp; E. Wilson, a traditional Chinese medicine, possesses anti-inflammatory and antioxidant properties, along with diverse pharmacological activities. It is commonly included in traditional formulations such as Ping Wei San and Banxia Houpo Decoction. However, research investigating the mechanisms by which &lt;em&gt;Magnolia officinalis&lt;/em&gt; Rehder &amp; E. Wilson alleviates asthma remains limited.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;This study investigated the pharmacological activity of &lt;em&gt;Magnolia officinalis&lt;/em&gt; Rehder &amp; E. Wilson extract (MOE) and its main active compound, honokiol, in alleviating respiratory tract inflammation in asthmatic mice, and elucidated the underlying mechanisms.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;An ovalbumin (OVA)-induced allergic asthma mouse model was established to evaluate the therapeutic efficacy of MOE by assessing pulmonary function, histopathological lung injury, and immune cell activation. Network pharmacology and molecular docking were then employed to predict the potential mechanisms of MOE. To validate these mechanisms, tumor necrosis factor (TNF)-α/interleukin-4 (IL-4)-induced BEAS-2B airway epithelial cell models were used to measure transient receptor potential vanilloid 1 (TRPV1) and thymic stromal lymphopoietin (TSLP) expression, intracellular calcium flux dynamics, and NFAT nuclear translocation. Finally, based on the identified mechanisms, the therapeutic effects of honokiol, the key bioactive compound derived from MOE, were further investigated using an in vivo model.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;MOE significantly restored tidal volume (TV) and Penh (enhanced pause) levels in asthmatic mice, while suppressing mucus hypersecretion, collagen deposition, and goblet cell hyperplasia. Additionally, MOE markedly attenuated OVA-induced airway inflammatory cell infiltration, as evidenced by reduced numbers of CD45&lt;sup&gt;+&lt;/sup&gt;, CD4&lt;sup&gt;+&lt;/sup&gt;, MHC II&lt;sup&gt;+&lt;/sup&gt;, CD11c&lt;sup&gt;+&lt;/sup&gt;, F4/80&lt;sup&gt;+&lt;/sup&gt;, Arg1&lt;sup&gt;+&lt;/sup&gt;, and CD206&lt;sup&gt;+&lt;/sup&gt; cells in lung tissues, along with decreased production of IL-1β, IL-4, and TNF-α. These findings indicate that MOE exerts beneficial effects on airway hyperresponsiveness (AHR), airway remodeling, and airway inflammation. Network pharmacology and molecular docking identified TRPV1 as a pivotal target. KEGG enrichment analysis revealed the calcium signaling pathway among the top 20 enriched pathways. Further experimental validation demonstrated that MOE reduced TSLP production both in &lt;em&gt;vivo&lt;/em&gt; and in &lt;em&gt;vitro&lt;/em&gt; by modulating the TRPV1/NFAT pathway. Calcium flux assays showed that MOE inhibited inflammatory cytokine-mediated TRPV1-induced Ca²⁺ influx and blocked capsaicin (CAP)-triggered TRPV1 activation. Finally","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"152 ","pages":"Article 157840"},"PeriodicalIF":8.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Phytochemical characterization and multi-target protective effects of Lycopodium serratum var. longipetiolatum against dysmenorrhea. 长叶松对痛经的植物化学特性及多靶点保护作用。
IF 8.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-01-16 DOI: 10.1016/j.phymed.2026.157838
Yi-Fen Chiang, Cheng-Pei Chung, Ko-Chieh Huang, Yi-PeI Li, Wei-Lun Hung, Nadia M Hamdy, Shih-Min Hsia

Background: Primary dysmenorrhea is associated with aberrant uterine contractility, inflammatory activation, and oxidative stress, resulting in nociceptive hypersensitivity and impaired quality of life. Lycopodium serratum Thunb. var. longipetiolatum Spring. (LS), a fern endemic to Taiwan, has been traditionally used to alleviate menstrual disorders; however, its mechanistic basis remains undefined.

Purpose: This study aimed to investigate the chemical constituents, uterine relaxant, and antinociceptive effects of LS extracts, and to elucidate their molecular mechanisms in dysmenorrhea.

Methods: Ethanolic extracts of LS and their solvent-partitioned fractions, ethyl acetate (LSE-EA), n-butanol (LSE-BuOH), and aqueous (LSE-H₂O) were characterized by LC-MS/MS for phenolic constituents. The relaxant and antinociceptive effects were assessed in ex vivo uterine contraction assays induced by prostaglandin F₂α (PGF₂α), oxytocin, acetylcholine, and carbachol, and in acetic acid- and oxytocin-induced pain models in ICR mice. Western blot, biochemical, and histopathological analyses were performed to delineate molecular and oxidative pathways.

Results: LSE-EA exhibited the strongest inhibition of uterine contraction and pain responses. LC-MS/MS identified ferulic acid, caffeic acid, and chlorogenic acid as major metabolites. Mechanistically, LSE-EA downregulated oxytocin receptor (OTR) and myosin light chain kinase (MLCK), suppressed TLR-4/NF-κB/COX-2 and ERK activation, reduced uterine IL-6 expression, and attenuated oxidative stress, as evidenced by decreased malondialdehyde levels and restoration of redox balance.

Conclusion: Lycopodium serratum extract confers protection against dysmenorrhea through concurrent suppression of Ca²⁺-dependent uterine contraction, inflammatory signaling, and oxidative stress. These findings identify LSE-EA as a novel bioactive fraction with therapeutic potential in redox-mediated uterine dysfunction.

背景:原发性痛经与子宫异常收缩、炎症激活和氧化应激有关,导致痛觉过敏和生活质量下降。石蒜。长柄扁桃一种台湾特有的蕨类植物,传统上被用来缓解月经紊乱;然而,其机制基础仍未明确。目的:研究紫苏提取物的化学成分、子宫松弛剂和抗痛经作用,并探讨其在痛经中的分子机制。方法:采用LC-MS/MS对紫苏醇提物及其溶剂分割部分、乙酸乙酯(LSE-EA)、正丁醇(LSE-BuOH)和水溶液(LSE-H₂O)的酚类成分进行表征。通过前列腺素F₂α (PGF₂α)、催产素、乙酰胆碱和乙醇诱导的体外子宫收缩实验,以及醋酸和催产素诱导的ICR小鼠疼痛模型,评估其松弛和抗痛觉作用。Western blot、生化和组织病理学分析描述了分子和氧化途径。结果:LSE-EA对子宫收缩和疼痛反应的抑制作用最强。LC-MS/MS鉴定阿魏酸、咖啡酸和绿原酸为主要代谢物。从机制上看,LSE-EA下调催产素受体(OTR)和肌球蛋白轻链激酶(MLCK),抑制TLR-4/NF-κB/COX-2和ERK活化,降低子宫IL-6表达,减轻氧化应激,其表现为丙二醛水平降低,氧化还原平衡恢复。结论:蛇藤石蒜提取物通过抑制ca2 +依赖性子宫收缩、炎症信号和氧化应激,对痛经有保护作用。这些发现表明LSE-EA是一种新的生物活性成分,具有治疗氧化还原介导的子宫功能障碍的潜力。
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引用次数: 0
Novel strategies for identification and prevention of idiosyncratic liver injury caused by TCM compatibility: Exemplification by Epimedii Folium and Psoraleae Fructus. 鉴别和预防中药配伍所致特异性肝损伤的新策略:以淫羊藿叶和补骨脂为例。
IF 8.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-01-16 DOI: 10.1016/j.phymed.2026.157841
Wei Shi, Hui Li, Tingting Liu, Ulpan Hlbiyat, Jianghua Yang, Zhiwei Liu, Yuan Gao, Zhaofang Bai, Xiaohe Xiao

Background: Traditional Chinese medicine (TCM) compatibility (TCMC) is an important form of clinical application of TCM, and proper compatibility are key to ensuring the safe use of TCM. However, reports of liver injury associated with the combination of Epimedii Folium (EF) and Psoraleae Fructus (PF), a commonly used pair of TCM in clinical, have gradually increased in recent years. The mechanism underlying this phenomenon remains unclear, which significantly hinders the development of risk prevention and control strategies for the EF and PF combination.

Methods: Bone marrow-derived macrophages (BMDMs) were employed to establish an in vitro inflammasome activation model for screening susceptibility factors of idiosyncratic liver injury exacerbated by the combination of EF and PF. Subsequently, a classical idiosyncratic liver injury evaluation model was utilized to objectively assess the susceptibility of the combined treatment in aggravating liver injury. Finally, mechanisms underlying the combined use of EF and PF in exacerbating idiosyncratic liver injury were systematically evaluated through RNA-seq, flow cytometry, immunofluorescence, and immunohistochemistry.

Results: The combined use of EF and PF significantly enhanced the activation of the inflammasome. Specifically, Icariside I, a main compound of EF, synergistically promoted the activation of the NLRP3 inflammasome induced by bavachinin, a main compound of PF, while bavachinin directly activated inflammasome components such as NLRP3, NLRC4, and AIM2, leading to enhanced inflammasome activation, increased inflammation, increased apoptosis, and exacerbated oxidative stress, ultimately exacerbating liver injury. In addition, RNA-seq and GSEA analyses further confirm the association between the exacerbation of liver injury and abnormal activation of inflammasomes. Therefore, inflammasome-promoting TCM, such as EF, and inflammasome-activating TCM, such as PF, should be avoided in combination with immune-activated populations, and co-administration with drugs that downregulate inflammasome activation can reduce toxicity.

Conclusion: In summary, this study proposes a precision toxicity control strategy represented by exacerbate idiosyncratic liver injury caused by the combination of EF and PF, offering new insights to ensure its clinical safety and thereby reduce the occurrence of TCM-related liver injury events.

背景:中药配伍是中医临床应用的重要形式,合理配伍是保证中药安全使用的关键。然而,近年来,临床常用的一对中药——淫羊藿叶(EF)和补骨脂(PF)联用引起肝损伤的报道逐渐增多。这一现象背后的机制尚不清楚,这极大地阻碍了EF和PF组合风险防控策略的发展。方法:采用骨髓源性巨噬细胞(bmdm)建立体外炎性小体激活模型,筛选EF与PF联合加重特异性肝损伤的易感因素,并建立经典特异性肝损伤评价模型,客观评价联合治疗加重肝损伤的易感性。最后,通过RNA-seq、流式细胞术、免疫荧光和免疫组织化学,系统地评估了EF和PF联合使用加剧特异性肝损伤的机制。结果:EF和PF联合使用可显著增强炎性体的活性。其中EF的主要化合物Icariside I协同促进PF的主要化合物bavachinin诱导的NLRP3炎性小体的活化,而bavachinin则直接激活NLRP3、NLRC4、AIM2等炎性小体成分,导致炎性小体活化增强,炎症增加,细胞凋亡增加,氧化应激加重,最终加重肝损伤。此外,RNA-seq和GSEA分析进一步证实了肝损伤加重与炎性小体异常活化之间的关联。因此,促炎中药(如EF)和促炎中药(如PF)应避免与免疫激活人群合用,并与下调炎性小体激活的药物合用可降低毒性。结论:综上所述,本研究提出了以EF与PF联用加重特异性肝损伤为代表的精准毒性控制策略,为确保其临床安全性,从而减少中医相关肝损伤事件的发生提供了新的见解。
{"title":"Novel strategies for identification and prevention of idiosyncratic liver injury caused by TCM compatibility: Exemplification by Epimedii Folium and Psoraleae Fructus.","authors":"Wei Shi, Hui Li, Tingting Liu, Ulpan Hlbiyat, Jianghua Yang, Zhiwei Liu, Yuan Gao, Zhaofang Bai, Xiaohe Xiao","doi":"10.1016/j.phymed.2026.157841","DOIUrl":"https://doi.org/10.1016/j.phymed.2026.157841","url":null,"abstract":"<p><strong>Background: </strong>Traditional Chinese medicine (TCM) compatibility (TCMC) is an important form of clinical application of TCM, and proper compatibility are key to ensuring the safe use of TCM. However, reports of liver injury associated with the combination of Epimedii Folium (EF) and Psoraleae Fructus (PF), a commonly used pair of TCM in clinical, have gradually increased in recent years. The mechanism underlying this phenomenon remains unclear, which significantly hinders the development of risk prevention and control strategies for the EF and PF combination.</p><p><strong>Methods: </strong>Bone marrow-derived macrophages (BMDMs) were employed to establish an in vitro inflammasome activation model for screening susceptibility factors of idiosyncratic liver injury exacerbated by the combination of EF and PF. Subsequently, a classical idiosyncratic liver injury evaluation model was utilized to objectively assess the susceptibility of the combined treatment in aggravating liver injury. Finally, mechanisms underlying the combined use of EF and PF in exacerbating idiosyncratic liver injury were systematically evaluated through RNA-seq, flow cytometry, immunofluorescence, and immunohistochemistry.</p><p><strong>Results: </strong>The combined use of EF and PF significantly enhanced the activation of the inflammasome. Specifically, Icariside I, a main compound of EF, synergistically promoted the activation of the NLRP3 inflammasome induced by bavachinin, a main compound of PF, while bavachinin directly activated inflammasome components such as NLRP3, NLRC4, and AIM2, leading to enhanced inflammasome activation, increased inflammation, increased apoptosis, and exacerbated oxidative stress, ultimately exacerbating liver injury. In addition, RNA-seq and GSEA analyses further confirm the association between the exacerbation of liver injury and abnormal activation of inflammasomes. Therefore, inflammasome-promoting TCM, such as EF, and inflammasome-activating TCM, such as PF, should be avoided in combination with immune-activated populations, and co-administration with drugs that downregulate inflammasome activation can reduce toxicity.</p><p><strong>Conclusion: </strong>In summary, this study proposes a precision toxicity control strategy represented by exacerbate idiosyncratic liver injury caused by the combination of EF and PF, offering new insights to ensure its clinical safety and thereby reduce the occurrence of TCM-related liver injury events.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"157841"},"PeriodicalIF":8.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Isodeoxyelephantopin mitigates DSS-induced ulcerative colitis by suppressing IL-1β-driven inflammation via the TXNIP/NLRP3 axis. 异脱氧象皮苷通过TXNIP/NLRP3轴抑制il -1β驱动的炎症,减轻dss诱导的溃疡性结肠炎。
IF 8.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-01-16 DOI: 10.1016/j.phymed.2026.157839
Li-Yuan Lin, Heng-Zhen Li, Xiang-Qian Liu, Si Xiong, Man-Mei Li, He-Yun Zhang, Chui-Wen Qian, Zhong Liu

Background: Isodeoxyelephantopin (IDET) is a sesquiterpene lactone isolated from traditional herb Elephantopus scaber, which is known for its anti-inflammatory activities. While our previous study demonstrated that IDET inhibits NLRP3 expression in an acute peritonitis model, its therapeutic potential in chronic inflammatory diseases such as ulcerative colitis (UC), as well as the underlying mechanisms involving inflammasome signaling, have not yet been fully elucidated.

Purpose: This research was designed to explain the protective capacity of IDET in UC and to clarify how IDET modulates IL-1β-mediated inflammatory responses through the TXNIP/NLRP3 signaling pathway, by integrating in vitro and in vivo experimental systems.

Results: IDET significantly reduced dextran sulfate sodium (DSS)-induced colitis in mice, improving disease scores, reducing inflammation, and preserving colon histology. Mechanistically, IDET exerted a multi-tiered suppression of the inflammasome pathway, which suppresses IL-1β-driven inflammation. Firstly, it disrupted the upstream priming signal by downregulating NLRP3 expression through NF-κB signaling pathway. Secondly, it inhibited inflammasome assembly, as evidenced by reduced ASC oligomerization and NLRP3-ASC interaction. Consequently, IDET reduced the cleavage of pro-caspase-1 and pro-IL-1β, resulting in an approximately 4-fold reduction in mature IL-1β secretion. A key finding was that IDET interfered with the activation signal by attenuating the TXNIP-NLRP3 interaction, according to immunoprecipitation and molecular docking results.

Conclusions: Extending our previous findings on its anti-acute inflammatory activity, this study demonstrates that IDET alleviates experimental ulcerative colitis by targeting multiple stages of NLRP3 inflammasome activation. The results highlight the translational potential of IDET, a natural compound, for treating chronic intestinal inflammation.

背景:异脱氧象皮素(IDET)是一种从传统草药象皮中分离得到的倍半萜内酯,具有抗炎活性。虽然我们之前的研究表明,IDET在急性腹膜炎模型中抑制NLRP3的表达,但其在溃疡性结肠炎(UC)等慢性炎症性疾病中的治疗潜力以及涉及炎性体信号传导的潜在机制尚未完全阐明。目的:本研究旨在通过体外和体内实验系统的整合,解释IDET在UC中的保护能力,阐明IDET如何通过TXNIP/NLRP3信号通路调节il -1β介导的炎症反应。结果:IDET显著减少小鼠葡聚糖硫酸钠(DSS)诱导的结肠炎,改善疾病评分,减轻炎症,并保留结肠组织学。从机制上讲,IDET对炎性小体通路进行多层抑制,从而抑制il -1β驱动的炎症。首先,通过NF-κB信号通路下调NLRP3表达,破坏上游启动信号。其次,它抑制了炎性小体的组装,这可以通过减少ASC寡聚化和NLRP3-ASC相互作用来证明。因此,IDET减少了前caspase-1和前IL-1β的裂解,导致成熟IL-1β分泌减少约4倍。根据免疫沉淀和分子对接结果,一个关键的发现是IDET通过减弱TXNIP-NLRP3相互作用来干扰激活信号。结论:延续我们之前关于其抗急性炎症活性的发现,本研究表明,IDET通过靶向NLRP3炎症小体激活的多个阶段来缓解实验性溃疡性结肠炎。这些结果强调了IDET(一种天然化合物)治疗慢性肠道炎症的转化潜力。
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引用次数: 0
Rewiring the regulated cell death network in diabetic retinopathy: natural products as system-level modulators. 糖尿病视网膜病变中受调节的细胞死亡网络的重新布线:作为系统级调节剂的天然产物。
IF 8.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-01-16 DOI: 10.1016/j.phymed.2026.157844
Qun Huang, Tingru Chen, Fang Wang, Jieying Wang, Biying Fan, Ruolan Wu, Jinlian Wang, Shunlin Peng, Yanlin Zheng

Background: Diabetic retinopathy (DR) pathogenesis is driven by the dysregulation of an interconnected network of regulated cell death (RCD) modalities, including apoptosis, autophagy-dependent cell death, pyroptosis, and ferroptosis. Current therapies often fail to address this upstream cellular damage. Natural products (NPs), with their inherent polypharmacology, offer a promising strategy to modulate this complex network.

Purpose: This review advances a framework conceptualizing DR as the collapse of a dynamic RCD network and positions NPs as "RCD network modulators". We delineate how these agents can restore homeostasis and overcome the limitations of existing mono-target therapies.

Methods: A systematic literature search was conducted using Web of Science and PubMed, integrating keywords related to "natural products", "diabetic retinopathy", and specific "regulated cell death" modalities. All animal experiments adhered to ethical guidelines and complied with both international and institutional ethical standards.

Results: NPs simultaneously engage the master regulatory nodes-mitochondrial dysfunction, hyperactivation of the inflammasome, and oxidative stress. By modulating the Bcl-2 rheostat, normalizing autophagic flux, suppressing NLRP3 assembly, and activating Nrf2/SIRT1 pathways, NPs orchestrate a "network rewiring" to halt DR progression. However, clinical translation is significantly constrained by pharmacokinetic challenges, including low oral bioavailability and poor ocular penetration.

Conclusion: DR pathology emerges from network-level RCD dysregulation. NPs, which function as modulators of the RCD network, represent a compelling therapeutic shift toward addressing the root drivers of retinal degeneration.

背景:糖尿病视网膜病变(DR)的发病机制是由一个相互关联的细胞死亡(RCD)模式网络的失调驱动的,包括细胞凋亡、自噬依赖性细胞死亡、焦亡和铁亡。目前的治疗方法往往不能解决这种上游细胞损伤。天然产物(NPs)以其固有的多药理学,为调节这一复杂网络提供了一种有前途的策略。目的:本文提出了一个框架,将DR概念化为动态RCD网络的崩溃,并将NPs定位为“RCD网络调制器”。我们描述了这些药物如何恢复体内平衡并克服现有单靶点治疗的局限性。方法:利用Web of Science和PubMed进行系统文献检索,整合“天然产物”、“糖尿病视网膜病变”和特定“调节细胞死亡”方式等相关关键词。所有动物实验均遵循伦理准则,符合国际和机构的伦理标准。结果:NPs同时参与主要调控节点——线粒体功能障碍、炎性体过度激活和氧化应激。通过调节Bcl-2变阻器,使自噬通量正常化,抑制NLRP3组装,激活Nrf2/SIRT1通路,NPs协调“网络重新布线”以阻止DR进展。然而,临床翻译明显受到药代动力学挑战的限制,包括口服生物利用度低和眼穿透性差。结论:网络水平的RCD失调导致了DR病理。NPs作为RCD网络的调节剂,代表了一个引人注目的治疗转变,以解决视网膜变性的根本驱动因素。
{"title":"Rewiring the regulated cell death network in diabetic retinopathy: natural products as system-level modulators.","authors":"Qun Huang, Tingru Chen, Fang Wang, Jieying Wang, Biying Fan, Ruolan Wu, Jinlian Wang, Shunlin Peng, Yanlin Zheng","doi":"10.1016/j.phymed.2026.157844","DOIUrl":"https://doi.org/10.1016/j.phymed.2026.157844","url":null,"abstract":"<p><strong>Background: </strong>Diabetic retinopathy (DR) pathogenesis is driven by the dysregulation of an interconnected network of regulated cell death (RCD) modalities, including apoptosis, autophagy-dependent cell death, pyroptosis, and ferroptosis. Current therapies often fail to address this upstream cellular damage. Natural products (NPs), with their inherent polypharmacology, offer a promising strategy to modulate this complex network.</p><p><strong>Purpose: </strong>This review advances a framework conceptualizing DR as the collapse of a dynamic RCD network and positions NPs as \"RCD network modulators\". We delineate how these agents can restore homeostasis and overcome the limitations of existing mono-target therapies.</p><p><strong>Methods: </strong>A systematic literature search was conducted using Web of Science and PubMed, integrating keywords related to \"natural products\", \"diabetic retinopathy\", and specific \"regulated cell death\" modalities. All animal experiments adhered to ethical guidelines and complied with both international and institutional ethical standards.</p><p><strong>Results: </strong>NPs simultaneously engage the master regulatory nodes-mitochondrial dysfunction, hyperactivation of the inflammasome, and oxidative stress. By modulating the Bcl-2 rheostat, normalizing autophagic flux, suppressing NLRP3 assembly, and activating Nrf2/SIRT1 pathways, NPs orchestrate a \"network rewiring\" to halt DR progression. However, clinical translation is significantly constrained by pharmacokinetic challenges, including low oral bioavailability and poor ocular penetration.</p><p><strong>Conclusion: </strong>DR pathology emerges from network-level RCD dysregulation. NPs, which function as modulators of the RCD network, represent a compelling therapeutic shift toward addressing the root drivers of retinal degeneration.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"157844"},"PeriodicalIF":8.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ginsenoside Rh2 and luteolin synergistically induce cellular senescence to suppress hepatocellular carcinoma progression through oxidative stress–mediated mechanisms 人参皂苷Rh2和木犀草素通过氧化应激介导的机制协同诱导细胞衰老,抑制肝癌进展
IF 8.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-01-15 DOI: 10.1016/j.phymed.2026.157825
Jieya Huang , Zhibing Wang , Ling Wu , Tianhao Tong , Jingting Zhang , Wenhui Gao , Mengzhou Xie , Renyi Yang , Puhua Zeng

Background

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, and effective therapeutic options are still limited. Inducing cellular senescence has emerged as a promising strategy to restrain tumor progression. Ginsenoside Rh2 (Rh2) and luteolin (Lut) each exhibits anticancer activity; however, their behavior in combination and underlying mechanisms in HCC remain largely unexplored.

Objective

To investigate the effects and molecular mechanisms of the Rh2/Lut combination in inducing cellular senescence in HCC.

Methods

Cell proliferation, migration, and invasion were assessed using cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), colony formation, wound-healing, and Transwell assays. Synergy was evaluated using SynergyFinder. Cellular senescence and mitochondrial dysfunction were examined through SA-β-Gal staining, senescence marker detection, ROS measurement, flow cytometry, and mitochondrial membrane potential (MMP) assays. Mechanistic studies were conducted via western blotting (WB), immunofluorescence (IF), and rescue experiments with the Nrf2 activator sulforaphane (SFN). γH2AX staining was performed to assess DNA damage. In vivo antitumor efficacy and biosafety were evaluated in a nude-mouse xenograft model, including histopathological examination of major organs (H&E staining).

Results

The Rh2/Lut (1:2) combination displayed strong inhibition of HCC cell proliferation, migration, and invasion. Mechanistically, the combination suppressed the Nrf2/HO-1 pathway while activating the p53/p21 signaling axis. Increased γH2AX expression indicated DNA damage–associated senescence. These effects were reversed by SFN treatment. In vivo, Rh2/Lut significantly inhibited tumor growth without inducing pathological abnormalities in major organs.

Conclusion

The Rh2/Lut combination triggers mitochondrial dysfunction–associated DNA damage and senescence through modulation of the Nrf2/HO-1–p53/p21 axis, exerting potent antitumor activity with favorable biosafety. These findings support Rh2/Lut as a promising therapeutic strategy for HCC.
背景:肝细胞癌(HCC)仍然是全球癌症相关死亡的主要原因之一,有效的治疗选择仍然有限。诱导细胞衰老已成为抑制肿瘤进展的一种有前途的策略。人参皂苷Rh2 (Rh2)和木犀草素(Lut)均表现出抗癌活性;然而,它们在HCC中的联合行为和潜在机制在很大程度上仍未被探索。目的探讨Rh2/Lut联合诱导肝癌细胞衰老的作用及其分子机制。方法采用细胞计数试剂盒-8 (CCK-8)、5-乙基-2′-脱氧尿苷(EdU)、菌落形成、创面愈合和Transwell试验评估细胞增殖、迁移和侵袭。使用SynergyFinder评估协同作用。通过SA-β-Gal染色、衰老标志物检测、ROS测定、流式细胞术和线粒体膜电位(MMP)检测细胞衰老和线粒体功能障碍。通过western blotting (WB)、免疫荧光(IF)和Nrf2激活剂萝卜硫素(SFN)的救援实验进行机制研究。用γ - h2ax染色评估DNA损伤。在裸鼠异种移植模型中评估体内抗肿瘤疗效和生物安全性,包括主要器官的组织病理学检查(H&;E染色)。结果Rh2/Lut(1:2)组合对肝癌细胞的增殖、迁移和侵袭具有较强的抑制作用。机制上,联合抑制Nrf2/HO-1通路,同时激活p53/p21信号轴。γ - h2ax表达增加提示DNA损伤相关衰老。这些效应被SFN治疗逆转。在体内,Rh2/Lut显著抑制肿瘤生长,但不引起主要器官的病理异常。结论Rh2/Lut通过调控Nrf2/ HO-1-p53 /p21轴引发线粒体功能障碍相关的DNA损伤和衰老,具有较强的抗肿瘤活性,且具有良好的生物安全性。这些发现支持Rh2/Lut作为一种有希望的HCC治疗策略。
{"title":"Ginsenoside Rh2 and luteolin synergistically induce cellular senescence to suppress hepatocellular carcinoma progression through oxidative stress–mediated mechanisms","authors":"Jieya Huang ,&nbsp;Zhibing Wang ,&nbsp;Ling Wu ,&nbsp;Tianhao Tong ,&nbsp;Jingting Zhang ,&nbsp;Wenhui Gao ,&nbsp;Mengzhou Xie ,&nbsp;Renyi Yang ,&nbsp;Puhua Zeng","doi":"10.1016/j.phymed.2026.157825","DOIUrl":"10.1016/j.phymed.2026.157825","url":null,"abstract":"<div><h3>Background</h3><div>Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, and effective therapeutic options are still limited. Inducing cellular senescence has emerged as a promising strategy to restrain tumor progression. Ginsenoside Rh2 (Rh2) and luteolin (Lut) each exhibits anticancer activity; however, their behavior in combination and underlying mechanisms in HCC remain largely unexplored.</div></div><div><h3>Objective</h3><div>To investigate the effects and molecular mechanisms of the Rh2/Lut combination in inducing cellular senescence in HCC.</div></div><div><h3>Methods</h3><div>Cell proliferation, migration, and invasion were assessed using cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), colony formation, wound-healing, and Transwell assays. Synergy was evaluated using SynergyFinder. Cellular senescence and mitochondrial dysfunction were examined through SA-β-Gal staining, senescence marker detection, ROS measurement, flow cytometry, and mitochondrial membrane potential (MMP) assays. Mechanistic studies were conducted via western blotting (WB), immunofluorescence (IF), and rescue experiments with the Nrf2 activator sulforaphane (SFN). γH2AX staining was performed to assess DNA damage. In vivo antitumor efficacy and biosafety were evaluated in a nude-mouse xenograft model, including histopathological examination of major organs (H&amp;E staining).</div></div><div><h3>Results</h3><div>The Rh2/Lut (1:2) combination displayed strong inhibition of HCC cell proliferation, migration, and invasion. Mechanistically, the combination suppressed the Nrf2/HO-1 pathway while activating the p53/p21 signaling axis. Increased γH2AX expression indicated DNA damage–associated senescence. These effects were reversed by SFN treatment. In vivo, Rh2/Lut significantly inhibited tumor growth without inducing pathological abnormalities in major organs.</div></div><div><h3>Conclusion</h3><div>The Rh2/Lut combination triggers mitochondrial dysfunction–associated DNA damage and senescence through modulation of the Nrf2/HO-1–p53/p21 axis, exerting potent antitumor activity with favorable biosafety. These findings support Rh2/Lut as a promising therapeutic strategy for HCC.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"152 ","pages":"Article 157825"},"PeriodicalIF":8.3,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145996163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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Phytomedicine
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