Phytomedicine最新文献

{"title":"Novel AMPK/ORP8-lipophagy axis: A therapeutic target for asiaticoside-mediated cardioprotection against ischemia-reperfusion injury in hyperlipidemia","authors":"Fenlan Bian ,&nbsp;Jun Wang ,&nbsp;Shiyao Ni ,&nbsp;Maonanxing Qi ,&nbsp;Peng Zhao ,&nbsp;Jinjun Liu ,&nbsp;Pinfang Kang","doi":"10.1016/j.phymed.2025.157317","DOIUrl":"10.1016/j.phymed.2025.157317","url":null,"abstract":"<div><h3>Background</h3><div>Hyperlipidemia significantly exacerbates myocardial ischemia-reperfusion (I/R) injurfy through lipid metabolic dysfunction and lipotoxicity. Current evidence suggests that lipid droplet accumulation and impaired lipophagy represent critical pathological mechanisms underlying cardiac dysfunction in hyperlipidemic conditions. This study investigated the cardioprotective effects of asiaticoside (AS) against myocardial I/R injury in hyperlipidemic mice and elucidated its underlying mechanisms, emphasizing the AMPK/ORP8-mediated lipophagy pathway.</div></div><div><h3>Methods</h3><div>Hyperlipidemic C57BL/6 mice were established using high-fat diet feeding and subjected to myocardial I/R injury. Mice received AS (12.5, 25, or 50 mg/kg) treatment for 4 weeks prior to surgery. <em>In vitro</em> experiments involved H9C2 cardiomyocytes treated with palmitic acid followed by hypoxia/reoxygenation. The role of AMPK/ORP8 signaling was evaluated using pharmacological modulators [AMPK activator (A-769662) and AMPK inhibitor (Compound C)] and genetic manipulation (ORP8 siRNA knockdown).</div></div><div><h3>Results</h3><div>AS dose-dependently improved cardiac function parameters, reduced myocardial infarct size (LVEF and LVFS) and decreased triglyceride and cardiac injury biomarkers (cTnI, LDH, CK-MB) in hyperlipidemic I/R mice. Treatment with AS significantly reduced cardiac lipid accumulation and triglyceride content while enhancing lipophagy markers (LC3B-II and Beclin-1) and reducing p62 levels. Mechanistically, AS activated AMPK phosphorylation and upregulated ORP8 expression, which was accompanied by enhanced lipophagy flux. In H9C2 cells, AS protected against palmitic acid-induced lipotoxicity and H/R injury through AMPK/ORP8-dependent lipophagy activation. AMPK inhibition (Compound C) or ORP8 knockdown significantly attenuated AS's protective effects, while AMPK activation (A-769,662) potentiated these benefits, which were reversed to some extent by ORP8 silencing.</div></div><div><h3>Conclusions</h3><div>This study demonstrates that AS mitigates myocardial I/R injury in hyperlipidemic conditions by promoting lipophagy through the AMPK/ORP8 signaling axis. The AMPK/ORP8-lipophagy pathway represents a novel therapeutic target for metabolic cardiovascular diseases, and AS emerges as a promising cardioprotective agent with significant translational potential.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157317"},"PeriodicalIF":8.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200703","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}

{"title":"Guipi Tang alleviates vascular dementia by regulating purine metabolism via gut microbiota-derived pantothenic acid","authors":"Yu Ren ,&nbsp;Yi Sun ,&nbsp;Qian Liu ,&nbsp;Jin-Ling Chen ,&nbsp;Yu-Han Chen ,&nbsp;Lan Sun ,&nbsp;Zhao Cui ,&nbsp;Shi-Yu Yan ,&nbsp;Ling Cheng ,&nbsp;Ning Li ,&nbsp;Shan-Shan Wang ,&nbsp;Gao-Bin Li ,&nbsp;Zhong-Shan Yang ,&nbsp;Jia-Li Yuan","doi":"10.1016/j.phymed.2025.157297","DOIUrl":"10.1016/j.phymed.2025.157297","url":null,"abstract":"<div><h3>Background</h3><div>Vascular dementia (VD) is the second-most common type of dementia. Chronic cerebral hypoperfusion (CCH) is a crucial trigger of VD. CCH can disrupt the gut microbiota (GM), thereby exacerbating VD. Guipi Tang (GPT) is a traditional Chinese medicine (TCM) formula for alleviating dementia. However, the mechanism by which GPT alleviates VD remains unclear.</div></div><div><h3>Purpose</h3><div>We employed multi-omics techniques to investigate the mechanism of action of GPT in mitigating VD through the metabolites of the GM.</div></div><div><h3>Methods</h3><div>We used a bilateral common carotid artery occlusion model and 16S rDNA sequencing, metabolomics, and RNA-sequencing (RNA-seq) analyses to explore the mitigating effects of GPT on VD. We also used antibiotic treatment, metabolite-backfilling, and other experiments to investigate the role of the GM and its metabolites.</div></div><div><h3>Results</h3><div>GPT repaired the damage to the hippocampal neurons, blood-brain barrier, and intestinal barrier in VD rats, significantly increased the abundance of <em>Faecalibaculum</em>, and promoted the production of the metabolite pantothenic acid (PA), which was introduced into the bloodstream and translocated in the brain. RNA-Seq and dual-luciferase reporter gene assays also showed that PA regulates purine metabolism and inhibits adenosine triphosphate (ATP) conversion by inhibiting the Vax1-AK8 pathway.</div></div><div><h3>Conclusion</h3><div>GPT regulates brain purine metabolism to alleviate VD by modulating the <em>Faecalibaculum</em>-PA-Vax1-AK8 pathway. This study provides new insights into the pathogenesis of VD and highlights the potential of GPT as an effective therapeutic and preventive agent.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157297"},"PeriodicalIF":8.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225955","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}

{"title":"Specnuezhenide attenuates rheumatoid arthritis bone destruction via dual regulation of osteoclast-osteoblast balance through KEAP1/NRF2 signaling","authors":"Huan Yao ,&nbsp;Qingman He ,&nbsp;Jiayue Yang ,&nbsp;Li Xiang ,&nbsp;Yuanyuan Luo ,&nbsp;Zhimin Chen ,&nbsp;Xueping Li","doi":"10.1016/j.phymed.2025.157293","DOIUrl":"10.1016/j.phymed.2025.157293","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA)-associated bone erosion is driven by osteoclast-osteoblast imbalance and oxidative stress. Specnuezhenide (SPN), a bioactive compound from <em>Ligustrum lucidum</em>, exhibits antioxidant properties, but its role in RA bone loss remains undefined.</div></div><div><h3>Purpose</h3><div>To explore the potential mechanisms and therapeutic targets of SPN in treating RA, with a focus on its regulation of bone remodeling and oxidative stress pathways.</div></div><div><h3>Study Design</h3><div>Collagen-induced arthritis (CIA) mice were treated with SPN (50/100/200 mg/kg) for 28 days. Joint inflammation, bone erosion, osteoclast/osteoblast markers, and oxidative stress pathways were evaluated. <em>In vitro</em>, SPN’s effects on osteoclastogenesis/osteoblastogenesis were assessed in inflammatory microenvironments. Molecular docking, dynamics simulations, and KEAP1 knockdown experiments were used to validate mechanisms.</div></div><div><h3>Methods</h3><div><em>In vivo</em>, CIA was induced in DBA/1 mice, followed by SPN treatment. Paw swelling, arthritis index (AI), micro-CT for bone erosion, H&amp;E and TRAP staining for histological analysis, Western blotting for marker proteins, and immunofluorescence for NRF2 localization were assessed. <em>In vitro</em>, osteoclast/osteoblast differentiation from bone marrow cells under inflammatory conditions (LPS/nigericin) was evaluated. Mechanistic investigations were performed via molecular docking, molecular dynamics simulations, cellular thermal shift assay, surface plasmon resonance, and adenovirus-mediated KEAP1 knockdown.</div></div><div><h3>Results</h3><div><em>In vivo</em>, SPN reduced paw swelling, AI, and bone erosion in CIA mice. It downregulated osteoclast markers (TRAP, NFATC1) and upregulated osteoblast markers (RUNX2, Col1), suppressed ROS, and activated NRF2/SOD1 pathways. <em>In vitro</em>, SPN inhibited osteoclastogenesis and promoted osteoblast mineralization in inflammatory microenvironments, with ROS scavenging dependent on NRF2 activation. Mechanistically, SPN bound to KEAP1, promoting NRF2 nuclear translocation.</div></div><div><h3>Conclusion</h3><div>SPN attenuates RA bone destruction by restoring osteoclast-osteoblast balance through precise targeting of the KEAP1, thereby modulating the KEAP1/NRF2/ROS axis. This mechanism-specific phytotherapeutic strategy provides a novel approach against RA-related osteolysis distinct from broad-spectrum antioxidants.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157293"},"PeriodicalIF":8.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226982","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}

{"title":"Astragali radix - Curcumae rhizoma herb pair enhances Sorafenib's efficacy by inducing ferroptosis and activates Th1 cell immune response synergistically against hepatocellular carcinoma","authors":"Chen Wang ,&nbsp;Hongtao Hu ,&nbsp;Hang Gao ,&nbsp;Zhihui Zhu ,&nbsp;Huajun Zhao","doi":"10.1016/j.phymed.2025.157326","DOIUrl":"10.1016/j.phymed.2025.157326","url":null,"abstract":"<div><h3>Background</h3><div>Sorafenib, as a first-line targeted drug for hepatocellular carcinoma (HCC), suffers from insufficient efficacy and dose-dependent toxic side effects, necessitating the development of combination therapy strategies. Clinical studies have shown that the Astragali radix - Curcumae rhizoma herb pair (ACHP) synergized with Sorafenib significantly enhanced the efficacy in advanced HCC patients, as well as improved immune function, but its synergistic mechanism remains unclear.</div></div><div><h3>Purpose</h3><div>This study aimed to reveal the mechanisms by which ACHP synergistically enhances Sorafenib's anti-HCC efficacy through a dual-mode of \"ferroptosis -immunomodulation\", and to provide a solid theoretical basis for its clinical application.</div></div><div><h3>Methods</h3><div>UPLC-Q-TOF-MS/MS was employed for the component characterization of ACHP extract. <em>In vivo</em> and <em>in vitro</em> HCC models were established to evaluate the efficacy and safety of ACHP synergized with Sorafenib against HCC. Transcriptome sequencing was utilized to screen potential molecular mechanisms, while molecular biology techniques, flow cytometry and inhibitors were applied to detect ferroptosis-related markers and Th1 cell-mediated immune response markers, aiming to reveal the underlying mechanisms.</div></div><div><h3>Results</h3><div>A total of 30 components were identified from ACHP extract. Pharmacodynamic evaluations showed that ACHP synergized with Sorafenib significantly suppressed tumor growth and cell proliferation of HCC, and exhibited favorable safety. Transcriptome sequencing suggested that the anti-HCC effect of ACHP synergized with Sorafenib might involve the induction of ferroptosis and modulation of Th1/Th2 cell differentiation. Further <em>in vivo</em> and <em>in vitro</em> experiments demonstrated that ACHP enhanced Sorafenib's efficacy by regulating the xCT/GPX4 and ACSL4/ALOX15 pathways to induce lipid peroxidation-related ferroptosis. Meanwhile, ACHP activated the IL-12/STAT4 signaling axis, promoted Th1 cell differentiation and up-regulated IFN-γ secretion, and further induced M1-type macrophages polarization and IL-12 secretion, thereby strengthening the IL-12-driven positive feedback immune loop.</div></div><div><h3>Conclusion</h3><div>ACHP enhances Sorafenib's efficacy by inducing lipid peroxidation-related ferroptosis and activates Th1-type anti-tumor immune responses, synergistically suppressing HCC. The study establishes a complete evidence chain of \"component characterization-mechanism verification\", providing novel therapeutic targets and strategic insights for the development of combination therapy for HCC.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157326"},"PeriodicalIF":8.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186683","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}

{"title":"Hesperidin mitigates deoxynivalenol-induced renal ferroptosis and necroptosis by regulating VDAC3","authors":"Xintong Zhou ,&nbsp;Yihan Wang ,&nbsp;Yongbao Ruan ,&nbsp;Cuicui Zhuang ,&nbsp;Hao Chen ,&nbsp;Jun Ma","doi":"10.1016/j.phymed.2025.157305","DOIUrl":"10.1016/j.phymed.2025.157305","url":null,"abstract":"<div><h3>Background</h3><div>Deoxynivalenol (DON), a secondary metabolite widespread in cereals and feeds generated by fungi, poses a major threat to the global economy and food safety. DON constituted a serious risk to the health of agricultural animals through biological chain enrichment. Hesperidin (HDN) is renowned for its broad spectrum of sources and exceptional antioxidant capability. Despite the fact that numerous pharmacological activities of HDN have been understood, the underlying ameliorative mechanisms of HDN in reducing kidney damage caused by DON exposure remain unclear.</div></div><div><h3>Purpose</h3><div>This study aimed to investigate mechanism of HDN against DON-induced nephrotoxicity.</div></div><div><h3>Methods</h3><div>We initially established an in vitro DON exposure model and administered two doses of HDN to TCMK-1. Proteomics, TEM, fluorescent probes, AFM, CETSA, and other techniques were employed to investigate whether HDN could mitigate DON-induced nephrotoxicity and specific mechanisms. Subsequently, in vivo validation was performed using C57BL/6 mice.</div></div><div><h3>Results</h3><div>We found that HDN could mitigate DON-induced TCMK-1 ferroptosis and necroptosis. Mechanistically, by targeting voltage-dependent anion channel 3 (VDAC3), HDN restored mitochondrial integrity and lowered mtROS buildup on TCMK-1 brought on by DON. In addition, DON-induced renal injury in mice was alleviated after HDN dosing intervention.</div></div><div><h3>Conclusions</h3><div>HDN, a VDAC3 target-like chemical, might reduce the vulnerability of the kidney to ferroptosis and necroptosis brought on by DON exposure. Our study offers an innovative therapeutic approach with regard to DON-induced kidney damage.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157305"},"PeriodicalIF":8.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213275","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}

{"title":"Theaflavins in black tea ameliorate high-fat diet-induced obesity and inflammation via gut microbiota, AMPK-mediated metabolism, and NF-κB pathway.","authors":"Wenwen Fang, Kuofei Wang, Shuai Wen, Fang Zhou, Jie Ouyang, Sheng Zhang, Hongzhe Zeng, Yukihiko Hara, Jian-An Huang, Zhonghua Liu","doi":"10.1016/j.phymed.2025.157314","DOIUrl":"https://doi.org/10.1016/j.phymed.2025.157314","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Obesity is typically identified by a high body mass index. Chronic inflammation is a central characteristic of obesity, contributing to many complications. The unrelenting rise in obesity and inflammation has been a global crisis. Due to the weight loss effects of black tea and anti-inflammatory effect of polyphenols, Theaflavins (TFs), the major bioactive polyphenols of black tea, may provide new strategies against obesity and inflammation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;This study aimed to investigate the potential regulatory roles and the underlying molecular mechanism of TFs on obesity and obesity-related inflammation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Study design: &lt;/strong&gt;Animal experiments were performed using high-fat diet induced obese SD rats. TFs were orally administered at doses of 25, 50, and 100 mg·kg⁻¹ for 8 consecutive weeks. The rats' weight and length were recorded. The blood, liver, epididymal fat pads, colon, interscapular adipose tissue, and feces were collected and stored.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;TFs' effects on obesity and inflammation were evaluated by body weight (daily observation) and inflammatory cytokines (ELISA). The lipid deposition and hepatic function was examined using biochemical assessment and histopathological analysis. AMPK-mediated metabolism assessed by Western blotting (WB), immunohistochemistry, and qRT-PCR. The intestinal barrier integrity was evaluated by biochemical assessment, histopathological analysis, WB, qRT-PCR, and immunofluorescence staining. Gut microbiota and fecal metabolites were using 16S rRNA sequencing and LC-MS/MS analysis, respectively.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;TFs exerted protective effects by mitigating body weight, lipid deposition, and immune response in the whole body, adipose tissues, and colon. The underlying mechanism was associated with the gut microbiota, AMPK-mediated metabolism, and NF-κB pathway. Specifically, TFs promoted the potential probiotics (Alistipes, Akkermansia, Coprococcus, NK4A214_group, Collinsella, and Rikenellaceae_RC9_gut_group) and regulated metabolic pathway (starch and sucrose metabolism, α-linolenic acid metabolism, and glycine‑serine-threonine metabolism), thereby inhibiting TRL4/MyD88/NF-κB pathway and protecting the intestinal barrier. Moreover, TFs activated the AMPK/SREBP-1 pathway and AMPK/SIRT1/PGC-1α/UCP1 pathway to mitigate the lipid metabolism and energy metabolism, respectively.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;We have innovatively demonstrated for the first time that TFs could alleviate the obesity and systemic inflammation via the modulation of gut microbiota and AMPK-mediated metabolism in HFD-fed rats. The impacts on white adipose tissue browning and thermogenic activity of brown adipose tissue of theaflavins firstly proposed a potential mechanism underlying the protection of theaflavins through the gut microbiota-liver/adipose tissue axis. These findings provide new sights on the bioactive ingredients throu","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"157314"},"PeriodicalIF":8.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252316","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}

{"title":"Dual targeting of lipogenesis and PUFAs homeostasis by compound kushen injection suppresses breast cancer bone metastasis","authors":"Chun-lan Dai ,&nbsp;Zi-yang Qiu ,&nbsp;Xin Guo ,&nbsp;Shen Yan ,&nbsp;An-qi Wang ,&nbsp;Jing Zhao ,&nbsp;Wan-qi Le ,&nbsp;Yi-xin Jiang ,&nbsp;Jia-yi Lin ,&nbsp;Li-jun Zhang ,&nbsp;Wei-dong Zhang ,&nbsp;Xin Luan","doi":"10.1016/j.phymed.2025.157323","DOIUrl":"10.1016/j.phymed.2025.157323","url":null,"abstract":"<div><h3>Background</h3><div>Bone metastasis is a major cause of mortality in patients with advanced breast cancer, yet effective therapies remain limited. Compound Kushen Injection (CKI), a standardized Traditional Chinese Medicine (TCM) formulation, has demonstrated clinical efficacy in relieving cancer-related pain and improving quality of life in patients with bone metastases. However, the effects of CKI on breast cancer bone metastasis and its action mechanisms remain to be elucidated.</div></div><div><h3>Purpose</h3><div>This study aims to determine the effect of CKI on breast cancer bone metastasis and explore its underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div><em>In vitro</em>, human breast cancer (MDA-MB-231) and bone-metastatic (MDA-BoM-1833) cell lines were used to assess the cytotoxic, anti-proliferative, and anti-migratory effects of CKI via MTT, colony formation, Transwell, wound healing, and flow cytometry. Two mouse models of breast cancer bone metastasis were established via left ventricular and tibial injection. Tumor progression was monitored by <em>in vivo</em> imaging, and therapeutic outcomes were evaluated using micro-CT, histopathology, and survival analysis. Multi-omics approaches—including metabolomics, transcriptomics, and proteomics—combined with network pharmacology, were used to identify CKI targets and pathways. Key findings were validated by qRT-PCR, Western blotting, lipid staining, ROS analysis, and mitochondrial function assays.</div></div><div><h3>Results</h3><div>CKI exhibits selective cytotoxicity against bone-tropic breast cancer cells and significantly reduces tumor burden in both intracardiac and intratibial metastatic mouse models, while maintaining a favorable safety profile. Metabolomics reveals that CKI treatment leads to the accumulation of polyunsaturated fatty acids (PUFAs). Multi-omics integration uncovers CKI-mediated inhibition of the HIF-1α/SREBP1 axis, suppressing de novo lipogenesis (DNL), and downregulation of the PPARα/SLC47A1 pathway, impairing fatty acid oxidation and lipid efflux. This dual blockade results in intracellular PUFAs accumulation and elevated lipid peroxidation, triggering mitochondrial dysfunction and oxidative stress-induced cell death.</div></div><div><h3>Conclusion</h3><div>CKI, a clinically approved traditional Chinese medicine, as a potent metabolic disruptor that impairs breast cancer bone metastasis through coordinated reprogramming of lipid metabolism and preservation of bone integrity.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157323"},"PeriodicalIF":8.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145227520","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}

{"title":"Psoraleae Fructus combined with Walnut kernels improves postmenopausal osteoporosis by inhibiting ferroptosis through the Nrf2/GPX4/SLC7A11 pathway","authors":"Letao Hu ,&nbsp;Meimei Luo ,&nbsp;Xingyu Zhu ,&nbsp;Zheng Wang ,&nbsp;Cuiping Yan ,&nbsp;Li Wu ,&nbsp;Hui Zhu ,&nbsp;Zijing Yang ,&nbsp;Yatong Xin ,&nbsp;Shuo Feng ,&nbsp;Yu Wu ,&nbsp;Weidong Li","doi":"10.1016/j.phymed.2025.157319","DOIUrl":"10.1016/j.phymed.2025.157319","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Postmenopausal osteoporosis (PMOP) is a bone metabolic disorder caused by estrogen (E2) deficiency. The traditional Chinese medicine Psoraleae Fructus (P) is often used in combination with walnut kernels (J, &lt;em&gt;Juglans regia&lt;/em&gt; L.) to treat osteoporosis. However, whether the combination of walnut kernels and Psoraleae Fructus (PJ) is more effective than Psoraleae Fructus alone remains unclear, and the material basis and mechanism of the synergistic effects of this combination are not fully understood.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;This study aimed to elucidate the synergistic mechanisms of PJ in the treatment of PMOP and to identify the active components and their targets.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The compounds in PJ were analyzed using UPLC-MS/MS. Bilateral ovariectomy (OVX) was performed to establish a rat model of PMOP. Femoral pathological changes were evaluated by serum ELISA, micro-CT, H&amp;E and TRAP staining. UPLC-MS/MS analysis was also performed to screen for active components in the serum, focusing on key monomers. Transcriptome sequencing was conducted to identify core pathways. An MC3T3-E1 ferroptosis model was established by erastin treatment. A combination index was used to evaluate the synergistic effects of the monomers. In addition to measuring cell viability, the effects of the key monomers on ferroptosis and osteoblastic differentiation were verified using cryogenic transmission electron microscopy, confocal laser scanning microscopy, and flow cytometry. Molecular docking, molecular dynamics (MD) simulations, microscale thermophoresis (MST), immunofluorescence, and western blotting were performed to validate the targets of this activity.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In vivo experimental results indicated that PJ significantly improved OVX-induced osteoporosis more prominently than P alone. The UPLC-MS/MS results showed that the serum concentrations of eight potentially active components increased significantly after compatibility with J. Transcriptome analysis revealed significant enrichment of ferroptosis in the OVX group, whereas in vivo experiments demonstrated that PJ inhibited ferroptosis by regulating the Nrf2/GPX4/SLC7A11 pathway. In vitro experiments identified norbakuchinic acid (NA) and α-linolenic acid (ALA) as the main pharmacodynamic components of PJ and confirmed that both components synergistically inhibited ferroptosis while promoting osteogenic mineralization. This effect was dependent on Nrf2/GPX4/SLC7A11 pathway activation. MST and MD simulations revealed that both NA and ALA were directly bind to Keap1, thereby promoting Nrf2 nuclear translocation and triggering downstream biological responses. Furthermore, when Nrf2 expression was inhibited in vitro by ML385, the inhibitory effects of NA and ALA on ferroptosis were suppressed.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;This study provided the first systematic evidence that walnut kernels can enhance ","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157319"},"PeriodicalIF":8.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186333","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}

{"title":"Enzyme-responsive liposomes target endoplasmic reticulum stress-mediated apoptosis for rheumatoid arthritis therapy","authors":"Chenglong Li ,&nbsp;Can Qian ,&nbsp;Jie Zhang ,&nbsp;Ya Huang ,&nbsp;Xiaolin Zhao ,&nbsp;Huaiyu Su ,&nbsp;Yingying Hou ,&nbsp;Chen Li","doi":"10.1016/j.phymed.2025.157299","DOIUrl":"10.1016/j.phymed.2025.157299","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and joint destruction. Insufficient apoptosis of fibroblast-like synoviocytes (FLSs) significantly contributes to the pathogenesis of RA by promoting hyperplasia and inflammatory cytokine secretion. Celastrol (CLT), a pentacyclic triterpene derived from <em>Tripterygium wilfordii</em>, has shown promise in inducing apoptosis via endoplasmic reticulum (ER) stress-mediated pathways. However, its clinical application is limited by poor solubility and off-target effects. Targeted delivery of CLT to FLSs and their ER could enhance therapeutic efficacy while minimizing toxicity.</div></div><div><h3>Methods</h3><div>We engineered CLT-loaded, enzyme-responsive liposomes (CLT-FELipos) functionalized with hyaluronic acid (HA), oligopeptide GPA (for FAP-α recognition on FLSs), an ER-targeting KDEL peptide, and cleavable PEG chains. <em>In vitro</em>, CLT-FELipos were evaluated for FLS-specific uptake (via FAP-α/GPA and CD44/HA interactions), ER accumulation, and apoptosis induction. <em>In vivo</em>, adjuvant-induced arthritis (AIA) rats were treated with various formulations. Joint distribution was assessed using near-infrared imaging, and therapeutic efficacy was evaluated through measurements of paw swelling, histological analysis, and micro-CT for bone erosion.</div></div><div><h3>Results</h3><div>CLT-FELipos demonstrated selective binding to FAP-α on FLSs, followed by PEG cleavage and CD44-mediated cellular uptake. Confocal microscopy confirmed specific accumulation within the ER. In AIA rats, CLT-FELipos showed joint-specific distribution and effectively reduced FLS numbers in arthritic joints. Treatment with CLT-FELipos brought about inflammatory remission, bone erosion repair, and minimal adverse effects. Notably, CLT-FELipos caused minimal systemic toxicity, as evidenced by stable body weight and normal liver and kidney function tests results.</div></div><div><h3>Conclusion</h3><div>CLT-FELipos represents a novel drug delivery system that specifically targets FLS and ER, which enhances CLT’s therapeutic index in RA by inducing apoptosis in hyperplastic FLSs. The dual-targeting strategy (FAP-α/CD44 for FLSs and KDEL for ER) ensures precise drug delivery while reducing inflammation and joint destruction with improved safety. This innovative approach holds potential for RA treatment and warrants further clinical investigation.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157299"},"PeriodicalIF":8.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145159296","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}

{"title":"Dihydroartemisinin inhibits histone lactylation through YAP1 to act as a ‘hot’ switch for ‘cold’ tumor in hepatocellular carcinoma","authors":"Yuting Gao ,&nbsp;Yi Gong ,&nbsp;Xiaoyong Song,&nbsp;Yajun Xiong,&nbsp;Junlan Lu,&nbsp;Yanguang Yang,&nbsp;Yanli Gong,&nbsp;Zhimin Du,&nbsp;Shanshan Wang,&nbsp;Ruilong Jia,&nbsp;Peng Gong,&nbsp;Xinli Shi","doi":"10.1016/j.phymed.2025.157307","DOIUrl":"10.1016/j.phymed.2025.157307","url":null,"abstract":"<div><h3>Background</h3><div>Hepatocellular carcinoma (HCC) is characterized by a ‘cold’ tumor microenvironment (TME), which limits the efficacy of immune checkpoint inhibitors (ICIs). In a previous study, we demonstrated that dihydroartemisinin (DHA) could disrupt the immunosuppressive TME and delay HCC progression.</div></div><div><h3>Purpose</h3><div>This study aimed to explore the precise mechanisms underlying the shift of the TME from an immunosuppressive to an immunostimulatory state.</div></div><div><h3>Methods</h3><div>We constructed HCC subcutaneous allograft mice model to investigate the in vivo antitumor effects of DHA. We further performed single-cell RNA sequencing (scRNA-seq) and multiplex immunohistochemistry (mIHC) to analyze the immune dynamics during DHA-induced TME transition in HCC. Using NCG mice (lacking T, B, and NK cells), BALB/c nude mice (lacking T cells), and CD8⁺ T cell-depleted mice, we assessed whether the antitumor effect of DHA in HCC depends on its immune functions and determined the key role of T cells in antitumor immunity. Additional downstream mechanisms were explored using YAP1 knockdown HCC cells and liver-specific Yap1 knockout mice through techniques such as Western blot, immunofluorescence (IF), metabolic flux analysis, co-immunoprecipitation (Co-IP), chemokine chip, and flow cytometry (FCM).</div></div><div><h3>Results</h3><div>We observed that DHA transforms the TME of HCC from an immune-cold to an immune-hot state by increasing the abundance and proportion of T cells, NK cells, M1-like TAMs, and DCs. Notably, DHA was found to enhance the proportion of IFN-γ⁺ CD8⁺ T cells within the TME of HCC-bearing mice, and its therapeutic effects were dependent on CD8⁺ T cells. Our results suggest that DHA could suppress histone lactylation (Kla) and acetylation (Kac) in HCC cells by inhibiting YAP1. Mechanistically, DHA reduces lactate transport, thereby decreasing lactate accumulation within the TME, lowering P300/CBP catalytic activity, and enhancing the deacetylation effect of HDAC1-3. This finding reveals a new mechanism by which DHA, through metabolic changes and epigenetic regulation, remodels the TME of HCC. Additionally, a combination strategy involving DHA and anti-PD-1 therapy demonstrated the potential to reshape the cold HCC TME via inhibition of the YAP1-lactylation positive feedback loop.</div></div><div><h3>Conclusion</h3><div>Our study confirms that DHA inhibits histone Kla in HCC cells through YAP1 inhibition, which shifts the TME from an immune-cold to immune-hot state. Moreover, DHA enhance the anti-HCC immune response dependent on CD8⁺ T cells, thereby sensitizing anti-PD-1 therapy. This novel finding positions DHA as a promising strategy for optimizing anti-PD-1 therapy in HCC, warranting further clinical application studies.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157307"},"PeriodicalIF":8.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186104","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}