Pub Date : 2026-01-22DOI: 10.1016/j.phymed.2026.157782
Jia-Hua Zou , Mei-Ling Tai , Bao-Ying Li , Jian-Jun Liu , Zhi-Meng Zhang , Han Wang , Dong-Li Zhang , Zhuang Zhou , Shan-Shan Feng , Man-Mei Li , Zhong Liu
Background
Chronic UVA exposure accelerates photoaging by inducing oxidative stress and mitochondrial dysfunction. Autophagy maintains dermal homeostasis, but its decline promotes aging. Afzelin, a flavonoid with antioxidant activity, has not been fully studied for its autophagy-related photoprotective effects.
Purpose
To determine whether afzelin protects against UVA-induced photoaging through autophagy and mitophagy activation, and to assess its synergy with ganoderic acid A (GAA), a triterpenoid possessing established anti-aging activity.
Methods
UVA-irradiated and D-galactose–induced senescence models of human dermal fibroblasts were examined by Western blotting, immunofluorescence, and flow cytometry. A 20-day UVA mouse model evaluated topical efficacy. Synergy was calculated using the Bliss model.
Results
Afzelin restored UVA-impaired cell viability and reduced β-galactosidase, p53, and p21 while recovering Lamin B1. It lowered ROS levels and restored mitochondrial membrane potential (2.8-fold) via AMPK–AKT/mTOR–ULK1 and PINK1–Parkin activation. Combined with GAA (50 mM), afzelin showed strong synergy (Bliss = 67.6 ± 5.1). In vivo, co-treatment reduced epidermal thickness (∼37.3 %), restored collagen I and elastin, and suppressed p53/p21 expression.
Conclusion
Afzelin alleviates UVA-induced photodamage by activating autophagy and mitophagy. Together with the anti-aging triterpenoid GAA, it exerts synergistic anti-photoaging effects, supporting its potential as a natural autophagy-targeting agent for skin rejuvenation.
{"title":"Afzelin resists UVA damage through autophagy and synergizes with ganoderic acid A to skin photoaging","authors":"Jia-Hua Zou , Mei-Ling Tai , Bao-Ying Li , Jian-Jun Liu , Zhi-Meng Zhang , Han Wang , Dong-Li Zhang , Zhuang Zhou , Shan-Shan Feng , Man-Mei Li , Zhong Liu","doi":"10.1016/j.phymed.2026.157782","DOIUrl":"10.1016/j.phymed.2026.157782","url":null,"abstract":"<div><h3>Background</h3><div>Chronic UVA exposure accelerates photoaging by inducing oxidative stress and mitochondrial dysfunction. Autophagy maintains dermal homeostasis, but its decline promotes aging. Afzelin, a flavonoid with antioxidant activity, has not been fully studied for its autophagy-related photoprotective effects.</div></div><div><h3>Purpose</h3><div>To determine whether afzelin protects against UVA-induced photoaging through autophagy and mitophagy activation, and to assess its synergy with ganoderic acid A (GAA), a triterpenoid possessing established anti-aging activity.</div></div><div><h3>Methods</h3><div>UVA-irradiated and D-galactose–induced senescence models of human dermal fibroblasts were examined by Western blotting, immunofluorescence, and flow cytometry. A 20-day UVA mouse model evaluated topical efficacy. Synergy was calculated using the Bliss model.</div></div><div><h3>Results</h3><div>Afzelin restored UVA-impaired cell viability and reduced β-galactosidase, p53, and p21 while recovering Lamin B1. It lowered ROS levels and restored mitochondrial membrane potential (2.8-fold) via AMPK–AKT/mTOR–ULK1 and PINK1–Parkin activation. Combined with GAA (50 mM), afzelin showed strong synergy (Bliss = 67.6 ± 5.1). <em>In vivo</em>, co-treatment reduced epidermal thickness (∼37.3 %), restored collagen I and elastin, and suppressed p53/p21 expression.</div></div><div><h3>Conclusion</h3><div>Afzelin alleviates UVA-induced photodamage by activating autophagy and mitophagy. Together with the anti-aging triterpenoid GAA, it exerts synergistic anti-photoaging effects, supporting its potential as a natural autophagy-targeting agent for skin rejuvenation.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157782"},"PeriodicalIF":8.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158098","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}
Pub Date : 2026-01-22DOI: 10.1016/j.phymed.2026.157872
Xiangjun Zhou , Guangli Yang , Weifu Tan , Hongyan Ding , Wujuan Zheng , Yong Liu , Liyi Zou , Xiaohua Su , Linzhong Yu , Wei Li , Liling Yang
Background
Sepsis, driven by dysregulated host inflammation, remains a leading cause of global mortality and lacks sufficiently effective therapies. Phillyrin (PHN), a lignan glycoside from Forsythia suspensa (Thunb.) Vahl (Oleaceae), exhibits anti-inflammatory and antimicrobial properties. However, its molecular mechanism in sepsis remains poorly understood.
Objective
To delineate the molecular pathways by which PHN mitigates sepsis.
Methods
Reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, cytotoxicity assessments, and calcein acetoxymethyl ester/propidium iodide staining were employed to evaluate the protective effects of PHN against lipopolysaccharide (LPS)-mediated pyroptosis in human pulmonary microvascular endothelial cells (HPMECs). Network pharmacology and integrative bioinformatics were used to identify candidate regulatory axes. Findings were then validated across multiple models: HPMEC-differentiated human promyelocytic acute leukemia cell co-cultures systems, Tg(mpx:GFP) zebrafish, and BALB/c mice. Validation techniques comprised luciferase reporters, pharmacological modulators, and morpholino knockdown.
Results
PHN significantly attenuated LPS-induced inflammatory pyroptosis in HPMECs. Evidence included reduced proinflammatory cytokine production, decreased lactate dehydrogenase leakage, and fewer pyroptotic cells. Computational analyses identified the microRNA (miR)-203a-caspase-4 (CASP4) axis as a primary mediator of PHN's anti-septic activity. In co-culture systems, PHN suppressed cytoplasmic LPS-triggered pyroptosis through miR-203a-dependent CASP4 downregulation, thereby reducing inflammatory cytokine secretion and neutrophil recruitment. In LPS-challenged zebrafish, PHN upregulated miR-203a to suppress caspase-B (CASPB), diminishing cytokine expression and neutrophil migration while improving survival. In murine sepsis models induced by LPS or cecal ligation and puncture, PHN modulated the miR-203a-caspase-11 (CASP11) axis to confer multiple therapeutic benefits. These included improved survival rates, stabilized body temperature, reduced bronchoalveolar lavage protein levels and neutrophil infiltration, attenuated multi-organ injury, and decreased systemic cytokine levels.
Conclusion
These data identify the miR-203a-CASP4/11/B axis as a critical mediator of endothelial pyroptosis in sepsis. PHN attenuates sepsis by upregulating miR-203a to inhibit CASP4/11/B-dependent pyroptosis. Therefore, PHN warrants further investigation as a potential therapeutic agent for sepsis.
{"title":"Phillyrin ameliorates sepsis via targeting microRNA-203a-mediated caspase-4/caspase-11/caspase-B downregulation to suppress endothelial pyroptosis","authors":"Xiangjun Zhou , Guangli Yang , Weifu Tan , Hongyan Ding , Wujuan Zheng , Yong Liu , Liyi Zou , Xiaohua Su , Linzhong Yu , Wei Li , Liling Yang","doi":"10.1016/j.phymed.2026.157872","DOIUrl":"10.1016/j.phymed.2026.157872","url":null,"abstract":"<div><h3>Background</h3><div>Sepsis, driven by dysregulated host inflammation, remains a leading cause of global mortality and lacks sufficiently effective therapies. Phillyrin (PHN), a lignan glycoside from <em>Forsythia suspensa</em> (Thunb.) Vahl (Oleaceae), exhibits anti-inflammatory and antimicrobial properties. However, its molecular mechanism in sepsis remains poorly understood.</div></div><div><h3>Objective</h3><div>To delineate the molecular pathways by which PHN mitigates sepsis.</div></div><div><h3>Methods</h3><div>Reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, cytotoxicity assessments, and calcein acetoxymethyl ester/propidium iodide staining were employed to evaluate the protective effects of PHN against lipopolysaccharide (LPS)-mediated pyroptosis in human pulmonary microvascular endothelial cells (HPMECs). Network pharmacology and integrative bioinformatics were used to identify candidate regulatory axes. Findings were then validated across multiple models: HPMEC-differentiated human promyelocytic acute leukemia cell co-cultures systems, <em>Tg(mpx:GFP)</em> zebrafish, and BALB/c mice. Validation techniques comprised luciferase reporters, pharmacological modulators, and morpholino knockdown.</div></div><div><h3>Results</h3><div>PHN significantly attenuated LPS-induced inflammatory pyroptosis in HPMECs. Evidence included reduced proinflammatory cytokine production, decreased lactate dehydrogenase leakage, and fewer pyroptotic cells. Computational analyses identified the microRNA (miR)-203a-caspase-4 (CASP4) axis as a primary mediator of PHN's anti-septic activity. In co-culture systems, PHN suppressed cytoplasmic LPS-triggered pyroptosis through miR-203a-dependent CASP4 downregulation, thereby reducing inflammatory cytokine secretion and neutrophil recruitment. In LPS-challenged zebrafish, PHN upregulated miR-203a to suppress caspase-B (CASPB), diminishing cytokine expression and neutrophil migration while improving survival. In murine sepsis models induced by LPS or cecal ligation and puncture, PHN modulated the miR-203a-caspase-11 (CASP11) axis to confer multiple therapeutic benefits. These included improved survival rates, stabilized body temperature, reduced bronchoalveolar lavage protein levels and neutrophil infiltration, attenuated multi-organ injury, and decreased systemic cytokine levels.</div></div><div><h3>Conclusion</h3><div>These data identify the miR-203a-CASP4/11/B axis as a critical mediator of endothelial pyroptosis in sepsis. PHN attenuates sepsis by upregulating miR-203a to inhibit CASP4/11/B-dependent pyroptosis. Therefore, PHN warrants further investigation as a potential therapeutic agent for sepsis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"152 ","pages":"Article 157872"},"PeriodicalIF":8.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132953","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}
Pub Date : 2026-01-22DOI: 10.1016/j.phymed.2026.157878
Lin Zhou , Qi Qian , Yaqin Zhen , Hanyu Ma , Liying Niu , Xinguo Wang
Background
Semen Sojae Praeparatum (SSP) exhibits both preventive and therapeutic effects against drug-induced liver injury (DILI). Traditionally, SSP is used in combination with Gardeniae fructus to prevent its hepatotoxicity. Isoflavones, the primary components of SSP, can mitigate DILI induced by chemotherapeutic agents such as acetaminophen and cisplatin. However, the potential of SSP to alleviate the hepatotoxicity of triptolide (TP, a prototypical compound in DILI research) remains unexplored.
Purpose
This study aimed to explore the protective effects and potential mechanisms of SSP on TP-induced liver injury.
Methods
The phytochemical profile of the SSP extracts was characterized using UPLC-Q-TOF-MS. Hepatoprotective effects of SSP were assessed using a TP-induced liver injury mouse model. The mechanisms were predicted by metabolomic and proteomic analyses, and further elucidated by RT-qPCR, western blotting and transmission electron microscopy.
Results
Isoflavones were identified as the main components of the SSP extracts. SSP treatment alleviated TP-induced abnormalities in serum biochemical markers, liver index and pathological damage. Multi-omics analysis revealed SSP modulated bile acid (BA) metabolism and autophagy, with Keap1 serving as a core protein. Furthermore, SSP reduced intrahepatic BA accumulation by enhancing hepatic BA transport rather than inhibiting BA synthesis. Additionally, SSP reversed TP-induced abnormalities in Keap1 and p62 expression and nuclear translon cation of the Nrf2 transcription factor, and mitigated oxidative imbalance and autophagic cell death.
Conclusions
SSP ameliorated TP-induced liver injury by modulating bile acid homeostasis and the Keap1/Nrf2/p62 pathway, thereby alleviating oxidative stress and excessive autophagy.
{"title":"Semen Sojae Praeparatum ameliorates triptolide-induced liver injury by regulating bile acid homeostasis and the Keap1/Nrf2/p62 axis","authors":"Lin Zhou , Qi Qian , Yaqin Zhen , Hanyu Ma , Liying Niu , Xinguo Wang","doi":"10.1016/j.phymed.2026.157878","DOIUrl":"10.1016/j.phymed.2026.157878","url":null,"abstract":"<div><h3>Background</h3><div>Semen Sojae Praeparatum (SSP) exhibits both preventive and therapeutic effects against drug-induced liver injury (DILI). Traditionally, SSP is used in combination with <em>Gardeniae fructus</em> to prevent its hepatotoxicity. Isoflavones, the primary components of SSP, can mitigate DILI induced by chemotherapeutic agents such as acetaminophen and cisplatin. However, the potential of SSP to alleviate the hepatotoxicity of triptolide (TP, a prototypical compound in DILI research) remains unexplored.</div></div><div><h3>Purpose</h3><div>This study aimed to explore the protective effects and potential mechanisms of SSP on TP-induced liver injury.</div></div><div><h3>Methods</h3><div>The phytochemical profile of the SSP extracts was characterized using UPLC-Q-TOF-MS. Hepatoprotective effects of SSP were assessed using a TP-induced liver injury mouse model. The mechanisms were predicted by metabolomic and proteomic analyses, and further elucidated by RT-qPCR, western blotting and transmission electron microscopy.</div></div><div><h3>Results</h3><div>Isoflavones were identified as the main components of the SSP extracts. SSP treatment alleviated TP-induced abnormalities in serum biochemical markers, liver index and pathological damage. Multi-omics analysis revealed SSP modulated bile acid (BA) metabolism and autophagy, with Keap1 serving as a core protein. Furthermore, SSP reduced intrahepatic BA accumulation by enhancing hepatic BA transport rather than inhibiting BA synthesis. Additionally, SSP reversed TP-induced abnormalities in Keap1 and p62 expression and nuclear translon cation of the Nrf2 transcription factor, and mitigated oxidative imbalance and autophagic cell death.</div></div><div><h3>Conclusions</h3><div>SSP ameliorated TP-induced liver injury by modulating bile acid homeostasis and the Keap1/Nrf2/p62 pathway, thereby alleviating oxidative stress and excessive autophagy.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157878"},"PeriodicalIF":8.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192028","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}
Pub Date : 2026-01-22DOI: 10.1016/j.phymed.2026.157864
Mingyue Han, Zhuoxuan Su, Bingyao Yang, Xuebing Li, Dan Wang, Xin Zhang, Xin Du, Qiqi Fu, Chunxia Wang, Yongwei Li
Background: The Chinese herbal formula Guben Antai Decoction (GBAT) demonstrates efficacy in reducing pregnancy loss associated with recurrent spontaneous abortion (RSA). However, the molecular mechanisms underlying its impact on the physiological functions of the placental trophoblast cells remain unclear.
Purpose: The objectives were to assess GBAT's efficacy in both a trophoblast-cell oxidative-stress model and a pregnant mouse model of RSA and to elucidate the complex mechanisms underlying the prevention of pregnancy loss using comprehensive multi-omics analysis integrated with a network pharmacology framework.
Materials and methods: Network pharmacology and bioinformatics were used to screen key GBAT targets associated with regulating autophagy and improving RSA. We established an RSA pregnant mouse model (CBA/J x DBA/2) comprising normal, RSA, low-dose GBAT (L-GBAT), high-dose GBAT (H-GBAT), and Dydrogesterone (DYD) groups. The maternal-fetal interface was analyzed at the autophagy level by performing HE staining, immunohistochemistry, transmission electron microscopy, and western blotting. We treated HTR-8/Svneo cells with H₂O₂ (40 μM, 3 h) to establish a trophoblast cell oxidative damage model with the following groups: control, H₂O₂, H₂O₂+GBAT, H₂O₂+GBAT+RAPA (autophagy activator), and H₂O₂+GBAT+Gefitinib (EGFR inhibitor). We performed drug-containing serum interventions in these groups and examined GBAT's modulation of autophagic activity and EGFR/PI3K phosphorylation via western blotting, MDC assay, and immunofluorescence.
Results: Network pharmacology and bioinformatics analyses showed that the EGFR/PI3K signaling pathway was an important mediator of GBAT-induced RSA autophagy. In vivo, GBAT inhibited autophagy and downregulated EGFR/PI3K phosphorylation in the Placental tissue placental villi of the RSA mice, which improved pregnancy outcomes. In vitro, GBAT-containing serum inhibited autophagy in oxidatively stressed HTR-8/Svneo cells. This effect was partially reversed by RAPA or gefitinib treatment.
Conclusions: GBAT may effectively inhibit excessive autophagic activation in RSA. The EGFR/PI3K pathway plays an important role in its therapeutic efficacy. Thus, GBAT is a promising candidate for alleviating RSA-induced miscarriage.
背景：中药固本安泰汤（GBAT）具有减少复发性自然流产（RSA）导致的妊娠丢失的疗效。然而，其影响胎盘滋养细胞生理功能的分子机制尚不清楚。目的：目的是评估GBAT在滋养细胞氧化应激模型和RSA妊娠小鼠模型中的功效，并通过综合多组学分析和网络药理学框架阐明其预防妊娠丢失的复杂机制。材料和方法：利用网络药理学和生物信息学技术筛选与调节自噬和改善RSA相关的关键GBAT靶点。我们建立了RSA妊娠小鼠模型（CBA/J x DBA/2），包括正常组、RSA组、低剂量GBAT组（L-GBAT）、高剂量GBAT组（H-GBAT）和地屈孕酮组（DYD）。通过HE染色、免疫组织化学、透射电镜和western blotting分析自噬水平的母胎界面。我们将HTR-8/Svneo细胞用40 μM的H₂O₂（3 H）处理，建立滋养细胞氧化损伤模型，分为对照组、H₂O₂、H₂O₂+GBAT、H₂O₂+GBAT+RAPA（自噬激活剂）、H₂O₂+GBAT+吉非替尼（EGFR抑制剂）。我们对这些组进行了含药物的血清干预，并通过western blotting、MDC测定和免疫荧光检测了GBAT对自噬活性和EGFR/PI3K磷酸化的调节。结果：网络药理学和生物信息学分析表明，EGFR/PI3K信号通路是gbat诱导的RSA自噬的重要介质。在体内，GBAT抑制了RSA小鼠胎盘组织的自噬，下调了胎盘绒毛中EGFR/PI3K的磷酸化，从而改善了妊娠结局。在体外，含gbat的血清可抑制氧化应激HTR-8/Svneo细胞的自噬。RAPA或吉非替尼治疗可部分逆转这种效应。结论：GBAT可有效抑制RSA过度自噬激活。EGFR/PI3K通路在其治疗效果中起重要作用。因此，GBAT是缓解rsa诱导流产的有希望的候选药物。
{"title":"GuBen AnTai decoction ameliorates recurrent spontaneous abortion by suppressing excessive autophagy via EGFR/PI3K pathway modulation.","authors":"Mingyue Han, Zhuoxuan Su, Bingyao Yang, Xuebing Li, Dan Wang, Xin Zhang, Xin Du, Qiqi Fu, Chunxia Wang, Yongwei Li","doi":"10.1016/j.phymed.2026.157864","DOIUrl":"https://doi.org/10.1016/j.phymed.2026.157864","url":null,"abstract":"<p><strong>Background: </strong>The Chinese herbal formula Guben Antai Decoction (GBAT) demonstrates efficacy in reducing pregnancy loss associated with recurrent spontaneous abortion (RSA). However, the molecular mechanisms underlying its impact on the physiological functions of the placental trophoblast cells remain unclear.</p><p><strong>Purpose: </strong>The objectives were to assess GBAT's efficacy in both a trophoblast-cell oxidative-stress model and a pregnant mouse model of RSA and to elucidate the complex mechanisms underlying the prevention of pregnancy loss using comprehensive multi-omics analysis integrated with a network pharmacology framework.</p><p><strong>Materials and methods: </strong>Network pharmacology and bioinformatics were used to screen key GBAT targets associated with regulating autophagy and improving RSA. We established an RSA pregnant mouse model (CBA/J x DBA/2) comprising normal, RSA, low-dose GBAT (L-GBAT), high-dose GBAT (H-GBAT), and Dydrogesterone (DYD) groups. The maternal-fetal interface was analyzed at the autophagy level by performing HE staining, immunohistochemistry, transmission electron microscopy, and western blotting. We treated HTR-8/Svneo cells with H₂O₂ (40 μM, 3 h) to establish a trophoblast cell oxidative damage model with the following groups: control, H₂O₂, H₂O₂+GBAT, H₂O₂+GBAT+RAPA (autophagy activator), and H₂O₂+GBAT+Gefitinib (EGFR inhibitor). We performed drug-containing serum interventions in these groups and examined GBAT's modulation of autophagic activity and EGFR/PI3K phosphorylation via western blotting, MDC assay, and immunofluorescence.</p><p><strong>Results: </strong>Network pharmacology and bioinformatics analyses showed that the EGFR/PI3K signaling pathway was an important mediator of GBAT-induced RSA autophagy. In vivo, GBAT inhibited autophagy and downregulated EGFR/PI3K phosphorylation in the Placental tissue placental villi of the RSA mice, which improved pregnancy outcomes. In vitro, GBAT-containing serum inhibited autophagy in oxidatively stressed HTR-8/Svneo cells. This effect was partially reversed by RAPA or gefitinib treatment.</p><p><strong>Conclusions: </strong>GBAT may effectively inhibit excessive autophagic activation in RSA. The EGFR/PI3K pathway plays an important role in its therapeutic efficacy. Thus, GBAT is a promising candidate for alleviating RSA-induced miscarriage.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":" ","pages":"157864"},"PeriodicalIF":8.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143177","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}
Pub Date : 2026-01-21DOI: 10.1016/j.phymed.2026.157865
Xiaoyun Wu , Wan Peng , Qianyu Yong , Xinlu Zhan , Yunyun Xu , Lu Liu , Tingtao Chen , Buzhen Tan
Background
In our previous study, tripterygium glycosides (TG) demonstrated to combine with cisplatin (DDP) in reversing DDP resistance in A2780/DDP cells by exacerbating ferroptosis via downregulation of glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter (System Xc−) expression. However, the regulation of ferroptosis-related proteins alone is insufficient to explain the reversal of DDP resistance in epithelial ovarian cancer (EOC), suggesting the involvement of additional mechanisms.
Purpose
This study focused on the underlying mechanisms through which TG contributes to reversing DDP resistance in EOC.
Methods
In this study, using DDP-resistant A2780/DDP cells and a nude mouse xenograft model, we comprehensively investigated the underlying mechanisms by which TG reverses DDP resistance via ferroptosis regulation through combined animal and cellular research.
Results
The results demonstrated that TG can induce ferroptosis in A2780/DDP cells. Mechanistic studies confirmed that TG induces ferroptosis through a dual-pathway mechanism involving both Keap1/Nrf2/ARE and HIF-1α/ACSL4 signaling. Furthermore, TG combined with DDP co-regulates the p53/Bax/Bcl-2 pathway to enhance apoptosis, thereby strengthening the inhibitory effect of DDP on drug-resistant EOC. Animal studies confirmed that the combination of TG and DDP significantly suppressed tumor growth compared to DDP monotherapy, with no observed increase in toxicity, indicating favorable treatment safety.
Conclusion
In conclusion, our findings reveal for the first time that the TG combined with DDP reverses EOC drug resistance through the simultaneous induction of ferroptosis (HIF-1α/ACSL4 and Keap1/Nrf2/ARE) and apoptosis (p53/Bax/Bcl-2). These results provide experimental evidence supporting the clinical application of TG in overcoming DDP chemotherapy resistance in EOC.
{"title":"Tripterygium glycosides reverse cisplatin resistance in epithelial ovarian cancer by activating ferroptosis via two different pathways","authors":"Xiaoyun Wu , Wan Peng , Qianyu Yong , Xinlu Zhan , Yunyun Xu , Lu Liu , Tingtao Chen , Buzhen Tan","doi":"10.1016/j.phymed.2026.157865","DOIUrl":"10.1016/j.phymed.2026.157865","url":null,"abstract":"<div><h3>Background</h3><div>In our previous study, tripterygium glycosides (TG) demonstrated to combine with cisplatin (DDP) in reversing DDP resistance in A2780/DDP cells by exacerbating ferroptosis <em>via</em> downregulation of glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter (System Xc−) expression. However, the regulation of ferroptosis-related proteins alone is insufficient to explain the reversal of DDP resistance in epithelial ovarian cancer (EOC), suggesting the involvement of additional mechanisms.</div></div><div><h3>Purpose</h3><div>This study focused on the underlying mechanisms through which TG contributes to reversing DDP resistance in EOC.</div></div><div><h3>Methods</h3><div>In this study, using DDP-resistant A2780/DDP cells and a nude mouse xenograft model, we comprehensively investigated the underlying mechanisms by which TG reverses DDP resistance via ferroptosis regulation through combined animal and cellular research.</div></div><div><h3>Results</h3><div>The results demonstrated that TG can induce ferroptosis in A2780/DDP cells. Mechanistic studies confirmed that TG induces ferroptosis through a dual-pathway mechanism involving both Keap1/Nrf2/ARE and HIF-1α/ACSL4 signaling. Furthermore, TG combined with DDP co-regulates the p53/Bax/Bcl-2 pathway to enhance apoptosis, thereby strengthening the inhibitory effect of DDP on drug-resistant EOC. Animal studies confirmed that the combination of TG and DDP significantly suppressed tumor growth compared to DDP monotherapy, with no observed increase in toxicity, indicating favorable treatment safety.</div></div><div><h3>Conclusion</h3><div>In conclusion, our findings reveal for the first time that the TG combined with DDP reverses EOC drug resistance through the simultaneous induction of ferroptosis (HIF-1α/ACSL4 and Keap1/Nrf2/ARE) and apoptosis (p53/Bax/Bcl-2). These results provide experimental evidence supporting the clinical application of TG in overcoming DDP chemotherapy resistance in EOC.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"152 ","pages":"Article 157865"},"PeriodicalIF":8.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080633","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}
Pub Date : 2026-01-21DOI: 10.1016/j.phymed.2026.157866
Zhen-Ling Liu , Yu Wang , Feng-Xian Hu , Huai-Qian Bo , Tao Xu , Zong-Yan Yin , Kai-Xin Zhang , Yi-Ran Wang , Heng-Ye Zhao , Xiang-Qing Xu , Xiang-Dong Xu , Wen-Qiang Cui
Background
Post-stroke depression (PSD) is a common and debilitating complication of stroke, characterized by persistent abnormalities in neuronal excitability and synaptic plasticity. The lateral habenula (LHb) has emerged as a key regulatory hub in the pathophysiology of PSD. Tongmai Yishen Formula (TMYSF) has demonstrated clinical efficacy in alleviating PSD symptoms, yet its mechanism in restoring the excitability–plasticity balance remains unclear.
Purpose
We aimed to determine whether TMYSF alleviates PSD by modulating the inositol-trisphosphate 3-kinase A (ITPKA)–mediated beta isoform of calcium/calmodulin-dependent protein kinase II/extracellular signal-regulated kinase/cyclic adenosine monophosphate response element-binding protein (βCaMKII/ERK/CREB) signaling pathway and restoring neuronal homeostasis within the LHb.
Methods
A PSD rat model was established using middle cerebral artery occlusion/reperfusion (MCAO/R) combined with chronic unpredictable mild stress (CUMS). Behavioral assessments, electrophysiological recordings, molecular analyses, and gene interference techniques were employed to evaluate changes in neuronal excitability, synaptic plasticity, and the therapeutic effects of TMYSF.
Results
TMYSF treatment significantly alleviated depressive-like behaviors, reduced neuronal hyperexcitability, and restored synaptic ultrastructure. Mechanistically, TMYSF suppressed the ITPKA-dependent βCaMKII/ERK/CREB signaling cascade, thereby normalizing neuronal excitability and synaptic plasticity. Conversely, overexpression of ITPKA or βCaMKII abolished the antidepressant effects of TMYSF by maintaining pathway activation and disrupting neuronal homeostasis.
Conclusion
Dual dysregulation of neuronal excitability and synaptic plasticity in the LHb represents a core pathological feature of PSD. TMYSF exerts potent neuroprotective and antidepressant effects by targeting the ITPKA–βCaMKII/ERK/CREB signaling axis.
{"title":"Tongmai Yishen Formula alleviates post-stroke depression by restoring neuronal homeostasis in the lateral habenula via the ITPKA signaling pathway","authors":"Zhen-Ling Liu , Yu Wang , Feng-Xian Hu , Huai-Qian Bo , Tao Xu , Zong-Yan Yin , Kai-Xin Zhang , Yi-Ran Wang , Heng-Ye Zhao , Xiang-Qing Xu , Xiang-Dong Xu , Wen-Qiang Cui","doi":"10.1016/j.phymed.2026.157866","DOIUrl":"10.1016/j.phymed.2026.157866","url":null,"abstract":"<div><h3>Background</h3><div>Post-stroke depression (PSD) is a common and debilitating complication of stroke, characterized by persistent abnormalities in neuronal excitability and synaptic plasticity. The lateral habenula (LHb) has emerged as a key regulatory hub in the pathophysiology of PSD. Tongmai Yishen Formula (TMYSF) has demonstrated clinical efficacy in alleviating PSD symptoms, yet its mechanism in restoring the excitability–plasticity balance remains unclear.</div></div><div><h3>Purpose</h3><div>We aimed to determine whether TMYSF alleviates PSD by modulating the inositol-trisphosphate 3-kinase A (ITPKA)–mediated beta isoform of calcium/calmodulin-dependent protein kinase II/extracellular signal-regulated kinase/cyclic adenosine monophosphate response element-binding protein (βCaMKII/ERK/CREB) signaling pathway and restoring neuronal homeostasis within the LHb.</div></div><div><h3>Methods</h3><div>A PSD rat model was established using middle cerebral artery occlusion/reperfusion (MCAO/R) combined with chronic unpredictable mild stress (CUMS). Behavioral assessments, electrophysiological recordings, molecular analyses, and gene interference techniques were employed to evaluate changes in neuronal excitability, synaptic plasticity, and the therapeutic effects of TMYSF.</div></div><div><h3>Results</h3><div>TMYSF treatment significantly alleviated depressive-like behaviors, reduced neuronal hyperexcitability, and restored synaptic ultrastructure. Mechanistically, TMYSF suppressed the ITPKA-dependent βCaMKII/ERK/CREB signaling cascade, thereby normalizing neuronal excitability and synaptic plasticity. Conversely, overexpression of ITPKA or βCaMKII abolished the antidepressant effects of TMYSF by maintaining pathway activation and disrupting neuronal homeostasis.</div></div><div><h3>Conclusion</h3><div>Dual dysregulation of neuronal excitability and synaptic plasticity in the LHb represents a core pathological feature of PSD. TMYSF exerts potent neuroprotective and antidepressant effects by targeting the ITPKA–βCaMKII/ERK/CREB signaling axis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157866"},"PeriodicalIF":8.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143344","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}
Pub Date : 2026-01-21DOI: 10.1016/j.phymed.2026.157869
Chunyang Zhu , Fengyan Zhang , Xueni Li , Daijun Xing , Houhao Cai , Xinran Wang , Honglin Qu , Lisha Li , Xin Zheng
Background
Non-small cell lung cancer (NSCLC), which constitutes approximately 85% of all lung cancer cases, is a leading cause of cancer mortality worldwide. Isoginkgetin (ISO), a biflavonoid isolated from Ginkgo biloba leaves, has demonstrated anticancer effects against various malignancies. However, its anti-NSCLC effects are unclear.
Objective
To explore the therapeutic potential of ISO and its mechanism of suppressing NSCLC proliferation. To provide experimental evidence for the translational potential of ISO as a candidate clinical drug.
Methods
Cell cytotoxicity and proliferation were assessed by cell viability, propidium iodide staining, colony formation, and cell cycle detection assays. Cell migration was evaluated by wound healing and transwell assays. Reactive oxygen species and the mitochondrial membrane potential were detected by fluorescent staining. Malondialdehyde and glutathione content were quantified by commercial assay kits. Transcriptome analysis for exploring the mechanism of ISO inhibition in NSCLC. The relationships between ISO and the tribbles pseudokinase 3 (TRIB3)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway were investigated through Western blot, siRNA-mediated TRIB3 knockdown, and overexpression of TRIB3. Cellular thermal shift assay and surface plasmon resonance were explored to investigate the binding and direct interaction between ISO and TRIB3. A non-contact co-culture model of NSCLC cells and macrophages was used to assess macrophage polarization. The anti-NSCLC effect of ISO in vivo was evaluated in a BALB/c nude mouse subcutaneous tumor model.
Results
ISO suppressed the cell viability, proliferation, and migration of NSCLC cells. ISO induces oxidative stress in NSCLC cells, characterized by an increase in reactive oxygen species and malondialdehyde and a decrease in mitochondrial membrane potential and glutathione. ISO has a strong binding affinity and direct interaction for the TRIB3 protein. Furthermore, ISO inhibited the antioxidant Nrf2 pathway by suppressing TRIB3 expression. Mechanistically, TRIB3 knockdown or overexpression significantly regulated the levels of oxidative stress and the Nrf2 pathway. ISO also promoted M1 macrophage polarization. Furthermore, ISO suppressed tumor growth in vivo.
Conclusion
ISO inhibits NSCLC through direct targeting and downregulation of TRIB3, thereby inducing oxidative stress and suppressing the antioxidant Nrf2 pathway. Furthermore, ISO regulates the tumor microenvironment by promoting M1 macrophage polarization. These findings may contribute to improved prognosis for NSCLC patients and provide insights into the mechanism of ISO as an antitumor drug, thereby supporting its potential for clinical translation.
{"title":"Isoginkgetin inhibits non-small cell lung cancer by inducing oxidative stress and regulating M1 macrophage polarization","authors":"Chunyang Zhu , Fengyan Zhang , Xueni Li , Daijun Xing , Houhao Cai , Xinran Wang , Honglin Qu , Lisha Li , Xin Zheng","doi":"10.1016/j.phymed.2026.157869","DOIUrl":"10.1016/j.phymed.2026.157869","url":null,"abstract":"<div><h3>Background</h3><div>Non-small cell lung cancer (NSCLC), which constitutes approximately 85% of all lung cancer cases, is a leading cause of cancer mortality worldwide. Isoginkgetin (ISO), a biflavonoid isolated from <em>Ginkgo biloba</em> leaves, has demonstrated anticancer effects against various malignancies. However, its anti-NSCLC effects are unclear.</div></div><div><h3>Objective</h3><div>To explore the therapeutic potential of ISO and its mechanism of suppressing NSCLC proliferation. To provide experimental evidence for the translational potential of ISO as a candidate clinical drug.</div></div><div><h3>Methods</h3><div>Cell cytotoxicity and proliferation were assessed by cell viability, propidium iodide staining, colony formation, and cell cycle detection assays. Cell migration was evaluated by wound healing and transwell assays. Reactive oxygen species and the mitochondrial membrane potential were detected by fluorescent staining. Malondialdehyde and glutathione content were quantified by commercial assay kits. Transcriptome analysis for exploring the mechanism of ISO inhibition in NSCLC. The relationships between ISO and the tribbles pseudokinase 3 (TRIB3)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway were investigated through Western blot, siRNA-mediated TRIB3 knockdown, and overexpression of TRIB3. Cellular thermal shift assay and surface plasmon resonance were explored to investigate the binding and direct interaction between ISO and TRIB3. A non-contact co-culture model of NSCLC cells and macrophages was used to assess macrophage polarization. The anti-NSCLC effect of ISO <em>in vivo</em> was evaluated in a BALB/c nude mouse subcutaneous tumor model.</div></div><div><h3>Results</h3><div>ISO suppressed the cell viability, proliferation, and migration of NSCLC cells. ISO induces oxidative stress in NSCLC cells, characterized by an increase in reactive oxygen species and malondialdehyde and a decrease in mitochondrial membrane potential and glutathione. ISO has a strong binding affinity and direct interaction for the TRIB3 protein. Furthermore, ISO inhibited the antioxidant Nrf2 pathway by suppressing TRIB3 expression. Mechanistically, TRIB3 knockdown or overexpression significantly regulated the levels of oxidative stress and the Nrf2 pathway. ISO also promoted M1 macrophage polarization. Furthermore, ISO suppressed tumor growth <em>in vivo</em>.</div></div><div><h3>Conclusion</h3><div>ISO inhibits NSCLC through direct targeting and downregulation of TRIB3, thereby inducing oxidative stress and suppressing the antioxidant Nrf2 pathway. Furthermore, ISO regulates the tumor microenvironment by promoting M1 macrophage polarization. These findings may contribute to improved prognosis for NSCLC patients and provide insights into the mechanism of ISO as an antitumor drug, thereby supporting its potential for clinical translation.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"152 ","pages":"Article 157869"},"PeriodicalIF":8.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080565","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}
Moringa oleifera Lam. (Family: Moringaceae) possesses diverse pharmacological properties, including anti-inflammatory, antioxidant, anticancer, antidiabetic, neuroprotective, and cardioprotective effects. Despite growing evidence of its cardiovascular benefits, a comprehensive synthesis of the molecular mechanisms involved in cardiovascular diseases (CVDs) is lacking.
Purpose
This review aims to consolidate existing evidence on the molecular mechanisms underlying the cardioprotective effects of Moringa oleifera Lam. and its nanoformulations, thereby providing a framework for future investigations in CVD therapy.
Methods
Relevant literature published between 2015 and 2025 on the cardioprotective activities of Moringa oleifera Lam. was systematically retrieved from major scientific databases, including ScienceDirect, PubMed, Springer, Taylor & Francis, and Web of Science.
Results
A comprehensive review of literature from 2015 to 2025 identified 89 in vivo, 24 in vitro, 8 clinical, and 6 nanoformulation studies, addressing major cardiovascular conditions. Leaves were the most studied plant part (78%), mainly as aqueous and ethanolic extracts. Key bioactives included flavonoids (quercetin, kaempferol), glucosinolates, and isothiocyanates. Cardioprotection was mediated through modulation of multiple pathways, NF-κB, Nrf2/Keap1, PI3K/Akt, PPAR, AMPK, and MAPK. Nanoformulation-based delivery systems demonstrated superior bioavailability and enhanced cardioprotective efficacy at lower doses compared to crude extracts. Clinical trials reported significant improvements in blood pressure, lipid profiles, and oxidative stress markers, although the rigour and sample sizes varied considerably.
Conclusion
Moringa oleifera Lam. exhibits strong cardioprotective potential, and nanoformulation-based delivery systems further augment its therapeutic efficacy. While preclinical evidence is encouraging, rigorously designed clinical studies are urgently required to validate its safety, effectiveness, and translational value in CVD management.
背景：辣木。（家族：辣木科）具有多种药理作用，包括抗炎、抗氧化、抗癌、抗糖尿病、神经保护和心脏保护作用。尽管越来越多的证据表明其对心血管有益，但缺乏对心血管疾病（cvd）相关分子机制的全面综合。目的：综述辣木对心脏保护作用的分子机制。及其纳米制剂，从而为心血管疾病治疗的未来研究提供了一个框架。方法：查阅2015 ~ 2025年发表的辣木对心脏保护作用的相关文献。系统地检索了主要的科学数据库，包括ScienceDirect、PubMed、b施普林格、Taylor & Francis和Web of Science。结果：对2015年至2025年的文献进行了全面回顾，确定了89项体内研究、24项体外研究、8项临床研究和6项纳米制剂研究，涉及主要心血管疾病。研究最多的植物部位是叶片（78%），主要是水提物和醇提物。主要生物活性成分包括黄酮类化合物（槲皮素、山奈酚）、硫代葡萄糖苷和异硫氰酸酯。心脏保护是通过多种途径介导的，包括NF-κB、Nrf2/Keap1、PI3K/Akt、PPAR、AMPK和MAPK。与粗提取物相比，以纳米配方为基础的给药系统在较低剂量下表现出优越的生物利用度和增强的心脏保护功效。临床试验报告了血压、血脂和氧化应激指标的显著改善，尽管严格程度和样本量差异很大。结论：辣木；显示出强大的心脏保护潜力，基于纳米配方的给药系统进一步增强了其治疗效果。虽然临床前证据令人鼓舞，但迫切需要严格设计的临床研究来验证其在心血管疾病治疗中的安全性、有效性和转化价值。
{"title":"A molecular perspective on cardioprotective potential of Moringa oleifera Lam. and its nano-formulations","authors":"Punniyakoti Veeraveedu Thanikachalam , Poojitha Mallapu , Vidhya Varshini Dhalapathy , Mohamed Ishaq Hydar , Karthika Ramesh , Srinivasan Ramamurthy , Pavithra Bharathy","doi":"10.1016/j.phymed.2026.157867","DOIUrl":"10.1016/j.phymed.2026.157867","url":null,"abstract":"<div><h3>Background</h3><div><em>Moringa oleifera</em> Lam. (Family: Moringaceae) possesses diverse pharmacological properties, including anti-inflammatory, antioxidant, anticancer, antidiabetic, neuroprotective, and cardioprotective effects. Despite growing evidence of its cardiovascular benefits, a comprehensive synthesis of the molecular mechanisms involved in cardiovascular diseases (CVDs) is lacking.</div></div><div><h3>Purpose</h3><div>This review aims to consolidate existing evidence on the molecular mechanisms underlying the cardioprotective effects of <em>Moringa oleifera</em> Lam. and its nanoformulations, thereby providing a framework for future investigations in CVD therapy.</div></div><div><h3>Methods</h3><div>Relevant literature published between 2015 and 2025 on the cardioprotective activities of <em>Moringa oleifera</em> Lam. was systematically retrieved from major scientific databases, including ScienceDirect, PubMed, Springer, Taylor & Francis, and Web of Science.</div></div><div><h3>Results</h3><div>A comprehensive review of literature from 2015 to 2025 identified 89 <em>in vivo</em>, 24 <em>in vitro</em>, 8 clinical, and 6 nanoformulation studies, addressing major cardiovascular conditions. Leaves were the most studied plant part (78%), mainly as aqueous and ethanolic extracts. Key bioactives included flavonoids (quercetin, kaempferol), glucosinolates, and isothiocyanates. Cardioprotection was mediated through modulation of multiple pathways, NF-κB, Nrf2/Keap1, PI3K/Akt, PPAR, AMPK, and MAPK. Nanoformulation-based delivery systems demonstrated superior bioavailability and enhanced cardioprotective efficacy at lower doses compared to crude extracts. Clinical trials reported significant improvements in blood pressure, lipid profiles, and oxidative stress markers, although the rigour and sample sizes varied considerably.</div></div><div><h3>Conclusion</h3><div><em>Moringa oleifera</em> Lam. exhibits strong cardioprotective potential, and nanoformulation-based delivery systems further augment its therapeutic efficacy. While preclinical evidence is encouraging, rigorously designed clinical studies are urgently required to validate its safety, effectiveness, and translational value in CVD management.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157867"},"PeriodicalIF":8.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181903","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}
Pub Date : 2026-01-20DOI: 10.1016/j.phymed.2026.157855
Jianlu Lyu Lv , Danyang Zhu , Ze Wang , Jianqiao Fang , Yuanji Zhao , Lin Ma , Yun Tang , Jiaying Wang , Xu Shen
Background
Women face a heightened risk of Alzheimer’s disease (AD), partly attributed to post-menopausal estrogen loss. Given that ERβ activation avoids the oncogenic risks of ERα and GPR40 plays a pivotal role in neuronal function, the ERβ/GPR40 axis show a promising therapeutic target for anti-AD drug discovery. To inspect the role of this axis, we employed Vincamine (Vin), a monoterpenoid indole alkaloid from Madagascar periwinkle that we previously identified as a GPR40 agonist.
Purpose
To elucidate the role of ERβ/GPR40 axis in AD pathogenesis and to investigate the therapeutic potential of Vin in ameliorating AD-related deficits.
Methods
We combined analyses of clinical data from female AD patients (GSE33000) with the research in 3×Tg-AD mice to examine the differences in ERβ/GPR40 expression. The binding of ERβ and GPR40 was detected by CUT&Tag assay, protein-DNA docking simulation and molecular dynamics simulation assays. Vin was used to evaluate the therapeutic potential of ERβ/GPR40 axis activation for AD. The underlying mechanisms were investigated by assay against the adeno-associated virus (AAV)-CMV-PHP.eB-KD-GPR40 injected 3×Tg-AD female mice.
Results
ERβ and GPR40 are both downregulated in brains of female AD patients and 3×Tg-AD mice, and ERβ directly binds to GPR40 promoter. Brain-specific GPR40 knockdown caused cognitive impairment in female wild type (WT) mice. Vin as a GPR40 agonist but not an ERβ ligand ameliorated AD-like pathology in 3×Tg-AD female mice. Specifically, Vin suppressed neuroinflammation via GPR40/NF-κB/NLRP3 pathway, inhibited neuronal tau hyperphosphorylation via GPR40/GSK3β/CaMKII pathway, while promoted synaptic plasticity via GPR40/PKA/CREB/BDNF pathway.
Conclusion
To our knowledge, our study provides the first identification of the specific ERβ-binding regions and key residues within the GPR40 promoter, offering novel mechanistic insight into their transcriptional regulation. Furthermore, our work establishes ERβ/GPR40 axis as a potentially therapeutic strategy for female AD and highlight the medication interest of Vin in treating this disease.
{"title":"Vincamine as a GPR40 agonist shows potential in treating female Alzheimer’s disease","authors":"Jianlu Lyu Lv , Danyang Zhu , Ze Wang , Jianqiao Fang , Yuanji Zhao , Lin Ma , Yun Tang , Jiaying Wang , Xu Shen","doi":"10.1016/j.phymed.2026.157855","DOIUrl":"10.1016/j.phymed.2026.157855","url":null,"abstract":"<div><h3>Background</h3><div>Women face a heightened risk of Alzheimer’s disease (AD), partly attributed to post-menopausal estrogen loss. Given that ERβ activation avoids the oncogenic risks of ERα and GPR40 plays a pivotal role in neuronal function, the ERβ/GPR40 axis show a promising therapeutic target for anti-AD drug discovery. To inspect the role of this axis, we employed Vincamine (Vin), a monoterpenoid indole alkaloid from <em>Madagascar periwinkle</em> that we previously identified as a GPR40 agonist.</div></div><div><h3>Purpose</h3><div>To elucidate the role of ERβ/GPR40 axis in AD pathogenesis and to investigate the therapeutic potential of Vin in ameliorating AD-related deficits.</div></div><div><h3>Methods</h3><div>We combined analyses of clinical data from female AD patients (GSE33000) with the research in 3×Tg-AD mice to examine the differences in ERβ/GPR40 expression. The binding of ERβ and GPR40 was detected by CUT&Tag assay, protein-DNA docking simulation and molecular dynamics simulation assays. Vin was used to evaluate the therapeutic potential of ERβ/GPR40 axis activation for AD. The underlying mechanisms were investigated by assay against the adeno-associated virus (AAV)-CMV-PHP.eB-KD-GPR40 injected 3×Tg-AD female mice.</div></div><div><h3>Results</h3><div>ERβ and GPR40 are both downregulated in brains of female AD patients and 3×Tg-AD mice, and ERβ directly binds to GPR40 promoter. Brain-specific GPR40 knockdown caused cognitive impairment in female wild type (WT) mice. Vin as a GPR40 agonist but not an ERβ ligand ameliorated AD-like pathology in 3×Tg-AD female mice. Specifically, Vin suppressed neuroinflammation via GPR40/NF-κB/NLRP3 pathway, inhibited neuronal tau hyperphosphorylation via GPR40/GSK3β/CaMKII pathway, while promoted synaptic plasticity via GPR40/PKA/CREB/BDNF pathway.</div></div><div><h3>Conclusion</h3><div>To our knowledge, our study provides the first identification of the specific ERβ-binding regions and key residues within the GPR40 promoter, offering novel mechanistic insight into their transcriptional regulation. Furthermore, our work establishes ERβ/GPR40 axis as a potentially therapeutic strategy for female AD and highlight the medication interest of Vin in treating this disease.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"152 ","pages":"Article 157855"},"PeriodicalIF":8.3,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080057","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}
Pub Date : 2026-01-20DOI: 10.1016/j.phymed.2026.157863
Jiawei Ling , Ziwei Han , Junjie Qiu , Boyu Li , Dan Chen , Yongbo Wang , Jie Liu , Renhu Li , Dongchen Xu , Xuesong Liu , Yong Chen , Jinghui Zhang , Tengfei Xu
Background
Alcohol-associated liver disease (ALD) is a major global health burden with incompletely understood molecular mechanisms. Endoplasmic reticulum stress (ERS) and sphingolipid dysregulation contribute to ALD, but their mechanistic link remains unclear.
Purpose
This study aimed to elucidate how Dendrobium polysaccharides (DPs) protect against ALD through modulation of the ERS-sphingolipid axis.
Methods
A Gao-binge mouse model of ALD was established. Polysaccharides from Dendrobium loddigesii Rolfe (DLP) and Dendrobium officinale Kimura et Migo (DOP) were administered. Integrated liver transcriptomics, metabolomics, and lipidomics were conducted, with validation by qRT-PCR and Western blot. Hepatocyte assays were performed to assess oxidative stress and inflammation.
Results
DPs markedly alleviated alcohol-induced hepatic and intestinal injury, evidenced by improved biochemical markers, histology, and reduced oxidative stress. Unbiased multi-omics analysis subsequently identified a pathogenic “ERS-sphingolipid axis” as the core responsive mechanism, where alcohol-induced ERS drives the accumulation of toxic ceramides. Targeted validation confirmed that DLP, which exhibited superior efficacy to DOP, potently suppressed key ERS sensors (PERK, IRE1α, ATF6), thereby normalizing ceramide levels and restoring sphingolipid homeostasis.
Conclusion
Dendrobium polysaccharides protect against ALD by disrupting the ERS-sphingolipid axis, alleviating lipotoxicity and inflammation. This study identifies the axis as a central pathogenic hub and provides mechanistic insight into Dendrobium polysaccharides as promising candidates for therapeutic development for for ALD.
{"title":"Dendrobium polysaccharides ameliorate alcohol-induced liver injury by inhibiting the pathogenic ER stress-sphingolipid axis","authors":"Jiawei Ling , Ziwei Han , Junjie Qiu , Boyu Li , Dan Chen , Yongbo Wang , Jie Liu , Renhu Li , Dongchen Xu , Xuesong Liu , Yong Chen , Jinghui Zhang , Tengfei Xu","doi":"10.1016/j.phymed.2026.157863","DOIUrl":"10.1016/j.phymed.2026.157863","url":null,"abstract":"<div><h3>Background</h3><div>Alcohol-associated liver disease (ALD) is a major global health burden with incompletely understood molecular mechanisms. Endoplasmic reticulum stress (ERS) and sphingolipid dysregulation contribute to ALD, but their mechanistic link remains unclear.</div></div><div><h3>Purpose</h3><div>This study aimed to elucidate how Dendrobium polysaccharides (DPs) protect against ALD through modulation of the ERS-sphingolipid axis.</div></div><div><h3>Methods</h3><div>A Gao-binge mouse model of ALD was established. Polysaccharides from <em>Dendrobium loddigesii</em> Rolfe (DLP) and <em>Dendrobium officinale</em> Kimura et Migo (DOP) were administered. Integrated liver transcriptomics, metabolomics, and lipidomics were conducted, with validation by qRT-PCR and Western blot. Hepatocyte assays were performed to assess oxidative stress and inflammation.</div></div><div><h3>Results</h3><div>DPs markedly alleviated alcohol-induced hepatic and intestinal injury, evidenced by improved biochemical markers, histology, and reduced oxidative stress. Unbiased multi-omics analysis subsequently identified a pathogenic “ERS-sphingolipid axis” as the core responsive mechanism, where alcohol-induced ERS drives the accumulation of toxic ceramides. Targeted validation confirmed that DLP, which exhibited superior efficacy to DOP, potently suppressed key ERS sensors (PERK, IRE1α, ATF6), thereby normalizing ceramide levels and restoring sphingolipid homeostasis.</div></div><div><h3>Conclusion</h3><div>Dendrobium polysaccharides protect against ALD by disrupting the ERS-sphingolipid axis, alleviating lipotoxicity and inflammation. This study identifies the axis as a central pathogenic hub and provides mechanistic insight into Dendrobium polysaccharides as promising candidates for therapeutic development for for ALD.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"152 ","pages":"Article 157863"},"PeriodicalIF":8.3,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047137","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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