Diabetic nephropathy (DN) serves as the major etiological factor of end-stage renal disease (ESRD) in DM patients. Balanophora involucrata Hook.f. & Thomson (BI) is a traditional medicine of the Tujia ethnic group in China, with good therapeutic effects on kidney diseases. However, both its effectiveness in the context of DN and the regulatory mechanism remain to be further clarified.
Purpose
To elucidate the role of BI in DN mice, with a focus on exploring the intrinsic mechanism responsible for this process.
Methods
UPLC-MS/MS was employed to identify the main ingredients of BI. The DN model was established using C57BLKS/J db/db mice, which received BI treatment. Serum/urine parameters, renal histology, and ultrastructure were assessed. Intrinsic microbial composition and corresponding metabolites were analyzed via 16S rDNA gene sequencing and nontargeted metabolomics. HK-2 cells were treated with high glucose to simulate DN and then treated with BI-containing drug serum and ferrostatin-1 (fer-1). Cell viability was assessed by CCK-8 assay, and lipid peroxidation was evaluated using the Bodipy 581/591 C11 fluorescence assay. Commercial kits were used to detect MDA and other ferroptosis-related indicators. Protein levels were analyzed by Western blotting.
Results
Terpenoids and flavonoids were the main identified components of BI. Fasting blood glucose was reduced, and lipid metabolism disorders were corrected by BI in DN mice. It also ameliorated renal injury in these mice. Meanwhile, BI regulated serum metabolites, and remodeled gut microbiota in DN mice. Furthermore, Nrf2, GPX4, FPN1, FTH1, and SLC7A11 were activated by BI, whereas TFR1 and ACSL4 were suppressed.
Conclusions
BI ameliorates DN by regulating serum metabolites, remodeling the gut microbiota, and inhibiting ferroptosis.
{"title":"Balanophora involucrata alleviates diabetic nephropathy by inhibiting ferroptosis, modulating serum metabolites and gut microbiota","authors":"Chaoxi Tian , Yawen Chen , Jing Huang , Fangyu Zhao , Xiane Tang , Jianhong Gao , Xianbing Chen , Xiuxue Yuan","doi":"10.1016/j.phymed.2026.157773","DOIUrl":"10.1016/j.phymed.2026.157773","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic nephropathy (DN) serves as the major etiological factor of end-stage renal disease (ESRD) in DM patients. <em>Balanophora involucrata</em> Hook.f. & Thomson (BI) is a traditional medicine of the Tujia ethnic group in China, with good therapeutic effects on kidney diseases. However, both its effectiveness in the context of DN and the regulatory mechanism remain to be further clarified.</div></div><div><h3>Purpose</h3><div>To elucidate the role of BI in DN mice, with a focus on exploring the intrinsic mechanism responsible for this process.</div></div><div><h3>Methods</h3><div>UPLC-MS/MS was employed to identify the main ingredients of BI. The DN model was established using C57BLKS/J db/db mice, which received BI treatment. Serum/urine parameters, renal histology, and ultrastructure were assessed. Intrinsic microbial composition and corresponding metabolites were analyzed via 16S rDNA gene sequencing and nontargeted metabolomics. HK-2 cells were treated with high glucose to simulate DN and then treated with BI-containing drug serum and ferrostatin-1 (fer-1). Cell viability was assessed by CCK-8 assay, and lipid peroxidation was evaluated using the Bodipy 581/591 C11 fluorescence assay. Commercial kits were used to detect MDA and other ferroptosis-related indicators. Protein levels were analyzed by Western blotting.</div></div><div><h3>Results</h3><div>Terpenoids and flavonoids were the main identified components of BI. Fasting blood glucose was reduced, and lipid metabolism disorders were corrected by BI in DN mice. It also ameliorated renal injury in these mice. Meanwhile, BI regulated serum metabolites, and remodeled gut microbiota in DN mice. Furthermore, Nrf2, GPX4, FPN1, FTH1, and SLC7A11 were activated by BI, whereas TFR1 and ACSL4 were suppressed.</div></div><div><h3>Conclusions</h3><div>BI ameliorates DN by regulating serum metabolites, remodeling the gut microbiota, and inhibiting ferroptosis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157773"},"PeriodicalIF":8.3,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941422","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 : 2026-01-04DOI: 10.1016/j.phymed.2026.157775
Xuedan Zhang , Baoyu Shen , Enjiang Li , Fang Yun , Yu Feng , Zhenyan Wei , Junzi Niu , Yu Huang , Song Yu , Yingmin Kuang , Haoming Liu , Buqing Sai , Yuechun Zhu
Introduction
Melanoma represents one of the most aggressive forms of skin cancers, with advanced metastatic stages largely managed through chemotherapy. However, current therapeutic strategies remain limited by drug resistance and systemic toxicity. Cannabidiol (CBD), the primary nonpsychoactive constituent of Cannabis sativa, has recently attracted attention for its anticancer properties across multiple tumor types.
Objectives
This study aimed to explore the antitumor efficacy of CBD in melanoma and elucidate its underlying molecular mechanisms, with the goal of identifying novel therapeutic strategies to overcome resistance and reduce adverse effects associated with conventional treatments.
Methods
The antiproliferative and pro-apoptotic effects of CBD were assessed in vitro using MTS, EdU, Transwell invasion, and flow cytometry. In vivo efficacy was evaluated using a murine lung metastasis model. Potential CBD targets in melanoma were identified through network pharmacology and molecular docking, with a focus on peroxisome proliferator-activated receptor γ (PPARγ) and validation by western blotting and immunofluorescence. Integrated transcriptomic and genome-wide methylation analyses were performed to investigate epigenetic modifications induced by CBD. Co-immunoprecipitation and chromatin immunoprecipitation assays were employed to detect the interaction between PPARγ and ten-eleven translocation 1 (TET1), including their binding to promoter regions of downstream factors. Methylation-regulated target genes were further validated using qPCR and MeDIP.
Results
CBD significantly induced apoptosis and inhibited cell proliferation and invasion of melanoma cells in vitro, while reducing pulmonary metastasis in vivo. Pharmacological and molecular docking analyses, supported by protein-level validation, identified PPARγ as a critical mediator of CBD activity. Transcriptomic and methylation analyses revealed that CBD modulated global DNA methylation patterns, partly through the formation of a PPARγ-TET1 complex. This complex regulated the demethylation of leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1), a newly identified anticancer gene whose upregulation markedly enhanced melanoma cell apoptosis and suppressed proliferation.
Conclusions
CBD exhibited strong antitumor activity in melanoma by modulating the PPARγ–TET1 complex to induce demethylation of LRSAM1, thereby suppressing tumor progression. These findings identify CBD as a promising candidate for melanoma therapy.
{"title":"Cannabidiol inhibits melanoma progression by regulating PPARγ-TET1 complex-dependent LRSAM1 demethylation","authors":"Xuedan Zhang , Baoyu Shen , Enjiang Li , Fang Yun , Yu Feng , Zhenyan Wei , Junzi Niu , Yu Huang , Song Yu , Yingmin Kuang , Haoming Liu , Buqing Sai , Yuechun Zhu","doi":"10.1016/j.phymed.2026.157775","DOIUrl":"10.1016/j.phymed.2026.157775","url":null,"abstract":"<div><h3>Introduction</h3><div>Melanoma represents one of the most aggressive forms of skin cancers, with advanced metastatic stages largely managed through chemotherapy. However, current therapeutic strategies remain limited by drug resistance and systemic toxicity. Cannabidiol (CBD), the primary nonpsychoactive constituent of <em>Cannabis sativa</em>, has recently attracted attention for its anticancer properties across multiple tumor types.</div></div><div><h3>Objectives</h3><div>This study aimed to explore the antitumor efficacy of CBD in melanoma and elucidate its underlying molecular mechanisms, with the goal of identifying novel therapeutic strategies to overcome resistance and reduce adverse effects associated with conventional treatments.</div></div><div><h3>Methods</h3><div>The antiproliferative and pro-apoptotic effects of CBD were assessed <em>in vitro</em> using MTS, EdU, Transwell invasion, and flow cytometry. <em>In vivo</em> efficacy was evaluated using a murine lung metastasis model. Potential CBD targets in melanoma were identified through network pharmacology and molecular docking, with a focus on peroxisome proliferator-activated receptor γ (PPARγ) and validation by western blotting and immunofluorescence. Integrated transcriptomic and genome-wide methylation analyses were performed to investigate epigenetic modifications induced by CBD. Co-immunoprecipitation and chromatin immunoprecipitation assays were employed to detect the interaction between PPARγ and ten-eleven translocation 1 (TET1), including their binding to promoter regions of downstream factors. Methylation-regulated target genes were further validated using qPCR and MeDIP.</div></div><div><h3>Results</h3><div>CBD significantly induced apoptosis and inhibited cell proliferation and invasion of melanoma cells <em>in vitro</em>, while reducing pulmonary metastasis <em>in vivo</em>. Pharmacological and molecular docking analyses, supported by protein-level validation, identified PPARγ as a critical mediator of CBD activity. Transcriptomic and methylation analyses revealed that CBD modulated global DNA methylation patterns, partly through the formation of a PPARγ-TET1 complex. This complex regulated the demethylation of leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1), a newly identified anticancer gene whose upregulation markedly enhanced melanoma cell apoptosis and suppressed proliferation.</div></div><div><h3>Conclusions</h3><div>CBD exhibited strong antitumor activity in melanoma by modulating the PPARγ–TET1 complex to induce demethylation of LRSAM1, thereby suppressing tumor progression. These findings identify CBD as a promising candidate for melanoma therapy.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157775"},"PeriodicalIF":8.3,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145979725","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 : 2026-01-03DOI: 10.1016/j.phymed.2025.157762
Qingxiu Zhang , Xingyi Chen , Meijuan Liao , Xianqiong Lu , Qiyuan Luo , Shiliang Li , Tao Ran , Yao Fan , Di Pan , Xiong Pan , Yan He , Xueke Zhao , Jiyu Chen
Background
Nonalcoholic fatty liver disease (NAFLD) is a global health challenge lacking effective treatments. Gastrodin (GAS), a major phenolglucoside from Gastrodia elata Blume (Orchidaceae), exhibits multiple beneficial properties but its potential role in NAFLD through ferroptosis remains unclear.
Objective
To investigate the therapeutic effects of GAS on NAFLD and clarify the underlying molecular mechanisms.
Methods
We established NAFLD models using high-fat diet (HFD)-fed mice and HepG2 cells treated with palmitic acid (PA) and oleic acid (OA). Therapeutic effects were assessed via histopathological and biochemical analyses. Molecular mechanisms and drug targets were investigated using co-immunoprecipitation (Co-IP), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and dual-luciferase reporter assays.
Results
GAS treatment significantly reduced hepatic inflammation and lipid accumulation, leading to improved metabolic parameters. Additionally, GAS decreased iron overload and oxidative stress markers, restored antioxidant defenses, and preserved mitochondrial function. Mechanistically, interaction assays revealed that GAS directly binds to Keap1, disrupting the Keap1/Nrf2 complex, promoting Nrf2 nuclear translocation, and enhancing the expression of target genes FSP1 and GPX4.
Conclusion
GAS demonstrates significant promise as a therapeutic agent for NAFLD by inhibiting hepatic ferroptosis via direct targeting of the Keap1/Nrf2 signaling pathway.
{"title":"Gastrodin ameliorates nonalcoholic fatty liver disease via inhibiting hepatic ferroptosis by the Keap1/Nrf2 signaling pathway","authors":"Qingxiu Zhang , Xingyi Chen , Meijuan Liao , Xianqiong Lu , Qiyuan Luo , Shiliang Li , Tao Ran , Yao Fan , Di Pan , Xiong Pan , Yan He , Xueke Zhao , Jiyu Chen","doi":"10.1016/j.phymed.2025.157762","DOIUrl":"10.1016/j.phymed.2025.157762","url":null,"abstract":"<div><h3>Background</h3><div>Nonalcoholic fatty liver disease (NAFLD) is a global health challenge lacking effective treatments. Gastrodin (GAS), a major phenolglucoside from <em>Gastrodia elata</em> Blume (Orchidaceae), exhibits multiple beneficial properties but its potential role in NAFLD through ferroptosis remains unclear.</div></div><div><h3>Objective</h3><div>To investigate the therapeutic effects of GAS on NAFLD and clarify the underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>We established NAFLD models using high-fat diet (HFD)-fed mice and HepG2 cells treated with palmitic acid (PA) and oleic acid (OA). Therapeutic effects were assessed via histopathological and biochemical analyses. Molecular mechanisms and drug targets were investigated using co-immunoprecipitation (Co-IP), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and dual-luciferase reporter assays.</div></div><div><h3>Results</h3><div>GAS treatment significantly reduced hepatic inflammation and lipid accumulation, leading to improved metabolic parameters. Additionally, GAS decreased iron overload and oxidative stress markers, restored antioxidant defenses, and preserved mitochondrial function. Mechanistically, interaction assays revealed that GAS directly binds to Keap1, disrupting the Keap1/Nrf2 complex, promoting Nrf2 nuclear translocation, and enhancing the expression of target genes <em>FSP1</em> and <em>GPX4</em>.</div></div><div><h3>Conclusion</h3><div>GAS demonstrates significant promise as a therapeutic agent for NAFLD by inhibiting hepatic ferroptosis via direct targeting of the Keap1/Nrf2 signaling pathway.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157762"},"PeriodicalIF":8.3,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941421","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 : 2026-01-02DOI: 10.1016/j.phymed.2026.157767
Shining Xiao , Wansong Wang , Pei Shi , Kaiying He , Chao Peng , Yu Zhang , Shue Hong , Youqing Yang , Jun Feng , Haidi Bi , Lang Shuai , Jun Wang
Background
Inhibiting the polarization of microglia toward the M1 pro-inflammatory phenotype to alleviate neuroinflammation and improve neuronal survival is a critical strategy for promoting spinal cord injury (SCI) repair. PTEN, a core regulator of cellular inflammatory responses, exerts its function by negatively modulating the PI3K/AKT signaling pathway. Columbianadin (CBN), a coumarin derivative isolated from the roots of Angelica sinensis (Oliv.) Diels, possesses multiple biological activities, including potent anti-inflammatory effects.
Objective
This study aimed to evaluate the regulatory effect of CBN on microglial polarization post-SCI and elucidate its underlying molecular mechanisms.
Methods
A combination of experimental techniques, including Western blotting, quantitative real-time PCR (qPCR), immunofluorescence, ubiquitination assays, co-immunoprecipitation (Co-IP), live/dead staining, molecular docking, cellular thermal shift assay (CETSA), bioluminescence imaging (BLI), differential scanning fluorimetry (DSF), and network pharmacology analysis, was employed in this study. Additionally, a rat SCI model was established to evaluate the impact of CBN on motor function recovery.
Results
CBN inhibited microglial M1 polarization, mitigated neuroinflammation, and improved neuronal survival, thereby facilitating SCI repair. Mechanistically, CBN directly targeted PTEN, by suppressing the ubiquitin-mediated degradation of PTEN while spatially promoting the interaction between PTEN and the PI3K regulatory subunit p85α. These dual effects synergistically enhanced PTEN protein stability and biological activity, jointly inhibiting PI3K/AKT signaling pathway activation.
Conclusion
Our study identifies CBN as a potential candidate drug for SCI treatment, as it enhances PTEN stability to inhibit the PI3K/AKT pathway, thereby regulating microglial polarization and protecting neurons from neuroinflammatory damage.
{"title":"Columbianadin improves M1 polarization of microglia after spinal cord injury by stabilizing PTEN and inhibiting the PI3K/AKT pathway","authors":"Shining Xiao , Wansong Wang , Pei Shi , Kaiying He , Chao Peng , Yu Zhang , Shue Hong , Youqing Yang , Jun Feng , Haidi Bi , Lang Shuai , Jun Wang","doi":"10.1016/j.phymed.2026.157767","DOIUrl":"10.1016/j.phymed.2026.157767","url":null,"abstract":"<div><h3>Background</h3><div>Inhibiting the polarization of microglia toward the M1 pro-inflammatory phenotype to alleviate neuroinflammation and improve neuronal survival is a critical strategy for promoting spinal cord injury (SCI) repair. PTEN, a core regulator of cellular inflammatory responses, exerts its function by negatively modulating the PI3K/AKT signaling pathway. Columbianadin (CBN), a coumarin derivative isolated from the roots of <em>Angelica sinensis</em> (Oliv.) Diels, possesses multiple biological activities, including potent anti-inflammatory effects.</div></div><div><h3>Objective</h3><div>This study aimed to evaluate the regulatory effect of CBN on microglial polarization post-SCI and elucidate its underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>A combination of experimental techniques, including Western blotting, quantitative real-time PCR (qPCR), immunofluorescence, ubiquitination assays, co-immunoprecipitation (Co-IP), live/dead staining, molecular docking, cellular thermal shift assay (CETSA), bioluminescence imaging (BLI), differential scanning fluorimetry (DSF), and network pharmacology analysis, was employed in this study. Additionally, a rat SCI model was established to evaluate the impact of CBN on motor function recovery.</div></div><div><h3>Results</h3><div>CBN inhibited microglial M1 polarization, mitigated neuroinflammation, and improved neuronal survival, thereby facilitating SCI repair. Mechanistically, CBN directly targeted PTEN, by suppressing the ubiquitin-mediated degradation of PTEN while spatially promoting the interaction between PTEN and the PI3K regulatory subunit p85α. These dual effects synergistically enhanced PTEN protein stability and biological activity, jointly inhibiting PI3K/AKT signaling pathway activation.</div></div><div><h3>Conclusion</h3><div>Our study identifies CBN as a potential candidate drug for SCI treatment, as it enhances PTEN stability to inhibit the PI3K/AKT pathway, thereby regulating microglial polarization and protecting neurons from neuroinflammatory damage.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157767"},"PeriodicalIF":8.3,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980906","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 : 2026-01-02DOI: 10.1016/j.phymed.2026.157766
Mengfei Tian , Ke Wang , Diping Chen
Background
Reflux esophagitis (RE) significantly impairs quality of life. Xiangsha Liujunzi Decoction (XSLJZD) is used in traditional Chinese medicine for RE, but its efficacy and mechanisms remain to be systematically evaluated.
Purpose
This study integrated meta-analysis, network pharmacology, and molecular docking to evaluate the clinical efficacy of XSLJZD for RE and elucidate its mechanisms of action.
Methods
Randomized controlled trials (RCTs) on XSLJZD for RE were systematically searched. Methodological quality was assessed using the Cochrane Risk of Bias tool, and data were synthesized with RevMan 5.3. Network pharmacology utilizing TCMSP identified active components, targets, and pathways. Molecular docking validated core compound-target interactions.
Results
Eight RCTs (n = 646) showed that XSLJZD significantly improved clinical outcomes compared with controls, demonstrating superior overall efficacy and reduced recurrence. Network analysis identified luteolin, baicalin, and β-sitosterol as core components, with AKT1, IL6, and CASP3 as key targets, potentially regulating apoptosis, IL-17, and TNF signaling pathways. Molecular docking confirmed stable binding.
Conclusion
XSLJZD may improve RE symptoms as an adjunctive therapy, but the evidence is low in certainty. The proposed anti-inflammatory and apoptotic mechanisms are computationally derived. High-quality trials and experimental validation are needed to confirm efficacy and mechanisms of action.
{"title":"Efficacy and mechanisms of Xiangsha Liujunzi Decoction for gastroesophageal reflux disease: A study integrating meta-analysis, network pharmacology and molecular docking","authors":"Mengfei Tian , Ke Wang , Diping Chen","doi":"10.1016/j.phymed.2026.157766","DOIUrl":"10.1016/j.phymed.2026.157766","url":null,"abstract":"<div><h3>Background</h3><div>Reflux esophagitis (RE) significantly impairs quality of life. Xiangsha Liujunzi Decoction (XSLJZD) is used in traditional Chinese medicine for RE, but its efficacy and mechanisms remain to be systematically evaluated.</div></div><div><h3>Purpose</h3><div>This study integrated meta-analysis, network pharmacology, and molecular docking to evaluate the clinical efficacy of XSLJZD for RE and elucidate its mechanisms of action.</div></div><div><h3>Methods</h3><div>Randomized controlled trials (RCTs) on XSLJZD for RE were systematically searched. Methodological quality was assessed using the Cochrane Risk of Bias tool, and data were synthesized with RevMan 5.3. Network pharmacology utilizing TCMSP identified active components, targets, and pathways. Molecular docking validated core compound-target interactions.</div></div><div><h3>Results</h3><div>Eight RCTs (<em>n</em> = 646) showed that XSLJZD significantly improved clinical outcomes compared with controls, demonstrating superior overall efficacy and reduced recurrence. Network analysis identified luteolin, baicalin, and β-sitosterol as core components, with AKT1, IL6, and CASP3 as key targets, potentially regulating apoptosis, IL-17, and TNF signaling pathways. Molecular docking confirmed stable binding.</div></div><div><h3>Conclusion</h3><div>XSLJZD may improve RE symptoms as an adjunctive therapy, but the evidence is low in certainty. The proposed anti-inflammatory and apoptotic mechanisms are computationally derived. High-quality trials and experimental validation are needed to confirm efficacy and mechanisms of action.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157766"},"PeriodicalIF":8.3,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908769","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 : 2026-01-02DOI: 10.1016/j.phymed.2026.157764
Jian Liu , Yeqing Liu , Changtie Liu , Jing Wang , Yuanyi Zhang , Yuxing Yang , Si Peng , Rongrong Xu , Lingxiang Xu , Xingchen Wang , Wei Xiong , Yun Gao
Visceral pain is frequently accompanied by depression, a comorbidity involving central neuroinflammation and abnormal neuronal plasticity. The P2X7 receptor (P2X7R) plays a crucial role in neuroinflammation and pyroptosis, while Jujuboside A (JuA), a major saponin extracted from Ziziphus jujuba seeds, has been reported to exert significant antidepressant and analgesic effects. In this study, we systematically evaluated the regulatory effects of JuA on the P2X7R-brain-derived neurotrophic factor (BDNF) pathway and on pyroptosis and apoptosis using a rat model of colorectal distension (CRD) and primary neuron/astrocyte cultures. JuA markedly alleviated visceral hypersensitivity and depressive-like behaviors in CRD rats and reduced P2X7R expression in both the spinal cord (SC) and hippocampus (HPC). Further investigations in vitro revealed that JuA inhibited excessive P2X7R activation in SC astrocytes, thereby decreasing the expression of NLRP3, Caspase-1, GSDMD, IL-1β and TNF-α, indicating suppression of pyroptosis. Similarly, JuA exerted an anti-pyroptotic effect in HPC astrocytes and inhibited neuronal apoptosis by reducing Caspase-3 and Bax levels while increasing Bcl2 expression, leading to upregulation of HPC BDNF. Collectively, JuA targets P2X7R and suppresses downstream pyroptotic and apoptotic signaling in vitro, which may contribute to its neuroprotective effects. These findings provide experimental evidence supporting the potential of JuA as a therapeutic agent for comorbid visceral pain and depression.
{"title":"Jujuboside A alleviates visceral pain and depression comorbidity and modulates the P2X7R-BDNF signaling axis","authors":"Jian Liu , Yeqing Liu , Changtie Liu , Jing Wang , Yuanyi Zhang , Yuxing Yang , Si Peng , Rongrong Xu , Lingxiang Xu , Xingchen Wang , Wei Xiong , Yun Gao","doi":"10.1016/j.phymed.2026.157764","DOIUrl":"10.1016/j.phymed.2026.157764","url":null,"abstract":"<div><div>Visceral pain is frequently accompanied by depression, a comorbidity involving central neuroinflammation and abnormal neuronal plasticity. The P2X7 receptor (P2X7R) plays a crucial role in neuroinflammation and pyroptosis, while Jujuboside A (JuA), a major saponin extracted from Ziziphus jujuba seeds, has been reported to exert significant antidepressant and analgesic effects. In this study, we systematically evaluated the regulatory effects of JuA on the P2X7R-brain-derived neurotrophic factor (BDNF) pathway and on pyroptosis and apoptosis using a rat model of colorectal distension (CRD) and primary neuron/astrocyte cultures. JuA markedly alleviated visceral hypersensitivity and depressive-like behaviors in CRD rats and reduced P2X7R expression in both the spinal cord (SC) and hippocampus (HPC). Further investigations in vitro revealed that JuA inhibited excessive P2X7R activation in SC astrocytes, thereby decreasing the expression of NLRP3, Caspase-1, GSDMD, IL-1β and TNF-α, indicating suppression of pyroptosis. Similarly, JuA exerted an anti-pyroptotic effect in HPC astrocytes and inhibited neuronal apoptosis by reducing Caspase-3 and Bax levels while increasing Bcl2 expression, leading to upregulation of HPC BDNF. Collectively, JuA targets P2X7R and suppresses downstream pyroptotic and apoptotic signaling in vitro, which may contribute to its neuroprotective effects. These findings provide experimental evidence supporting the potential of JuA as a therapeutic agent for comorbid visceral pain and depression.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157764"},"PeriodicalIF":8.3,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980197","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 : 2026-01-01DOI: 10.1016/j.phymed.2025.157730
Shu-Chun Liu , Hung-Chuan Pan , Pei-Yi Chu , Ming-Chu Tsai , Liang-Ju Chen , Yu-Chin Lin , Ching-Wen Chang , Yi-Ching Tsai , Chia-Yun Tsai , Meei-Ling Sheu , De-Wei Lai
Background: Skin cutaneous melanoma (SKCM) is a highly aggressive malignancy with increasing global incidence and limited therapeutic options in advanced stages. Cellular senescence, characterized by irreversible growth arrest and tumor suppression, has emerged as a promising therapeutic approach.
Purpose: This study aimed to investigate the anti-tumor and senescence-inducing effects of paeoniflorin on SKCM and to elucidate its underlying molecular mechanisms.
Study design: Paeoniflorin was evaluated through in vitro, in vivo, and bioinformatic analyses to determine its impact on melanoma progression and to clarify the involvement of the endoplasmic reticulum (ER) stress/calpain1/ERK5 signaling pathway.
Methods: Publicly available SKCM datasets were analyzed to evaluate the correlation between senescence-associated genes (RRAS, CDKN1B, LAMA1, and CDC25A) and patient prognosis. The effects of paeoniflorin on melanoma cells were examined by immunofluorescence, β-galactosidase staining, western blotting, electron microscopy, and calpain activity assays. Chemical inhibitors and siRNA were applied to verify the functional role of calpain1. Positron emission tomography/computed tomography (PET/CT) imaging, histopathological analysis, and metastasis assays were performed to assess the in vivo efficacy of paeoniflorin.
Results: Bioinformatic analysis revealed that high expression of RRAS and CDKN1B was associated with favorable prognosis, whereas elevated LAMA1 and CDC25A indicated poor survival outcomes in SKCM. Paeoniflorin treatment induced DNA damage, G2/M phase arrest, and senescence in melanoma cells, accompanied by enhanced ER stress, increased calpain1 activity, and downregulated ERK5 expression. Inhibition or knockdown of calpain1 reversed these effects. In mouse models, paeoniflorin markedly reduced tumor growth and metastasis, effects that were abolished by calpain1 silencing. Mechanistically, paeoniflorin triggered calpain1-dependent ERK5 degradation and p27 upregulation, leading to cellular senescence and tumor suppression.
Conclusions: Paeoniflorin induces melanoma cell senescence through the ER stress/calpain1/ERK5/p27 signaling axis, suggesting its potential as a novel therapeutic strategy against SKCM.
{"title":"Paeoniflorin promotes therapeutic senescence in melanoma through endoplasmic reticulum stress and the calpain1/ERK5/p27 axis","authors":"Shu-Chun Liu , Hung-Chuan Pan , Pei-Yi Chu , Ming-Chu Tsai , Liang-Ju Chen , Yu-Chin Lin , Ching-Wen Chang , Yi-Ching Tsai , Chia-Yun Tsai , Meei-Ling Sheu , De-Wei Lai","doi":"10.1016/j.phymed.2025.157730","DOIUrl":"10.1016/j.phymed.2025.157730","url":null,"abstract":"<div><div>Background: Skin cutaneous melanoma (SKCM) is a highly aggressive malignancy with increasing global incidence and limited therapeutic options in advanced stages. Cellular senescence, characterized by irreversible growth arrest and tumor suppression, has emerged as a promising therapeutic approach.</div><div>Purpose: This study aimed to investigate the anti-tumor and senescence-inducing effects of paeoniflorin on SKCM and to elucidate its underlying molecular mechanisms.</div><div>Study design: Paeoniflorin was evaluated through <em>in vitro, in vivo</em>, and bioinformatic analyses to determine its impact on melanoma progression and to clarify the involvement of the endoplasmic reticulum (ER) stress/calpain1/ERK5 signaling pathway.</div><div>Methods: Publicly available SKCM datasets were analyzed to evaluate the correlation between senescence-associated genes (RRAS, CDKN1B, LAMA1, and CDC25A) and patient prognosis. The effects of paeoniflorin on melanoma cells were examined by immunofluorescence, β-galactosidase staining, western blotting, electron microscopy, and calpain activity assays. Chemical inhibitors and siRNA were applied to verify the functional role of calpain1. Positron emission tomography/computed tomography (PET/CT) imaging, histopathological analysis, and metastasis assays were performed to assess the <em>in vivo</em> efficacy of paeoniflorin.</div><div>Results: Bioinformatic analysis revealed that high expression of RRAS and CDKN1B was associated with favorable prognosis, whereas elevated LAMA1 and CDC25A indicated poor survival outcomes in SKCM. Paeoniflorin treatment induced DNA damage, G2/M phase arrest, and senescence in melanoma cells, accompanied by enhanced ER stress, increased calpain1 activity, and downregulated ERK5 expression. Inhibition or knockdown of calpain1 reversed these effects. In mouse models, paeoniflorin markedly reduced tumor growth and metastasis, effects that were abolished by calpain1 silencing. Mechanistically, paeoniflorin triggered calpain1-dependent ERK5 degradation and p27 upregulation, leading to cellular senescence and tumor suppression.</div><div>Conclusions: Paeoniflorin induces melanoma cell senescence through the ER stress/calpain1/ERK5/p27 signaling axis, suggesting its potential as a novel therapeutic strategy against SKCM.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"Article 157730"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850668","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 : 2026-01-01DOI: 10.1016/j.phymed.2025.157748
Ya-xin Shi , Cheng-yuan Zhang , Yu-ning Xie , Zhi-yong Liu , Xin Wang , Ling-di Wang , Zi-lu Wang , Hong-bo Yuan , Rui-hua Zhao , Wei Shi
<div><h3>Background</h3><div>Ferroptosis is a newly characterized iron-dependent form of regulated cell death. In adenomyosis (AM), ectopic endometrial lesions exhibit resistance to ferroptosis, which contributes to disease progression and recurrence. Tongmai Huazheng mixture (TMHZ) is a hospital-formulated traditional Chinese medicine (TCM) compound that has demonstrated clinical efficacy in the management of AM. However, the precise mechanisms by which TMHZ regulates ferroptosis in AM remain unclear.</div></div><div><h3>Purpose</h3><div>The aim of this study was to determine whether TMHZ exerts its anti-AM effects by inducing ferroptosis through inhibition of the JAK2/STAT3 signaling pathway.</div></div><div><h3>Methods</h3><div>A multiomics strategy integrating UPLC-MS/MS, network pharmacology, and RNA sequencing was employed to identify candidate targets and key regulatory pathways of TMHZ. <em>In vitro</em>, the effects of TMHZ-containing serum on proliferation, migration, and invasion of adenomyosis-derived cells (AMDCs) were evaluated using CCK-8, EdU, wound healing, and Transwell assays. Ferroptosis induction and oxidative stress levels were assessed using FerroOrange and CM-H<sub>2</sub>DCFDA fluorescent probes, glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) assay kits, and transmission electron microscopy. Immunofluorescence and western blotting (WB) were performed to investigate the regulatory effects of TMHZ on the JAK2/STAT3 pathway and ferroptosis-related proteins. The JAK2 inhibitor AG490 and agonist coumermycin A1 were used to validate the involvement of the pathway. <em>In vivo</em>, a tamoxifen-induced AM mouse model was established to assess the therapeutic efficacy and safety of TMHZ. Histopathological changes in the uterus were examined by hematoxylin–eosin (HE) staining, and serum levels of estradiol (E2) and progesterone (P4) were measured to verify model establishment. SOD and MDA levels and the results of immunohistochemical and WB analyses were used to further confirm the <em>in vivo</em> regulation of ferroptosis and JAK2/STAT3 signaling by TMHZ. Additionally, HE staining of major organs (liver, spleen, and kidney) was performed to evaluate systemic safety.</div></div><div><h3>Results</h3><div>Bioinformatics analysis suggested that the therapeutic effects of TMHZ were closely associated with the regulation of the JAK2/STAT3 pathway and ferroptosis. <em>In vitro</em>, TMHZ significantly inhibited the proliferation, migration, and invasion of AMDCs; increased intracellular Fe²⁺ and reactive oxygen species (ROS) levels; reduced GSH and SOD activity; elevated the MDA content, and induced typical mitochondrial damage. TMHZ also downregulated the expressions of p-JAK2, p-STAT3, SLC7A11, and GPX4. Further rescue experiments using JAK2 inhibitors and agonists confirmed the key role of the JAK2/STAT3 pathway in this process. <em>In vivo</em>, TMHZ suppressed JAK2/STAT3 signaling to promote ferroptosis,
{"title":"Tongmai Huazheng mixture attenuates adenomyosis by inducing ferroptosis through suppression of the JAK2/STAT3 signaling pathway","authors":"Ya-xin Shi , Cheng-yuan Zhang , Yu-ning Xie , Zhi-yong Liu , Xin Wang , Ling-di Wang , Zi-lu Wang , Hong-bo Yuan , Rui-hua Zhao , Wei Shi","doi":"10.1016/j.phymed.2025.157748","DOIUrl":"10.1016/j.phymed.2025.157748","url":null,"abstract":"<div><h3>Background</h3><div>Ferroptosis is a newly characterized iron-dependent form of regulated cell death. In adenomyosis (AM), ectopic endometrial lesions exhibit resistance to ferroptosis, which contributes to disease progression and recurrence. Tongmai Huazheng mixture (TMHZ) is a hospital-formulated traditional Chinese medicine (TCM) compound that has demonstrated clinical efficacy in the management of AM. However, the precise mechanisms by which TMHZ regulates ferroptosis in AM remain unclear.</div></div><div><h3>Purpose</h3><div>The aim of this study was to determine whether TMHZ exerts its anti-AM effects by inducing ferroptosis through inhibition of the JAK2/STAT3 signaling pathway.</div></div><div><h3>Methods</h3><div>A multiomics strategy integrating UPLC-MS/MS, network pharmacology, and RNA sequencing was employed to identify candidate targets and key regulatory pathways of TMHZ. <em>In vitro</em>, the effects of TMHZ-containing serum on proliferation, migration, and invasion of adenomyosis-derived cells (AMDCs) were evaluated using CCK-8, EdU, wound healing, and Transwell assays. Ferroptosis induction and oxidative stress levels were assessed using FerroOrange and CM-H<sub>2</sub>DCFDA fluorescent probes, glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) assay kits, and transmission electron microscopy. Immunofluorescence and western blotting (WB) were performed to investigate the regulatory effects of TMHZ on the JAK2/STAT3 pathway and ferroptosis-related proteins. The JAK2 inhibitor AG490 and agonist coumermycin A1 were used to validate the involvement of the pathway. <em>In vivo</em>, a tamoxifen-induced AM mouse model was established to assess the therapeutic efficacy and safety of TMHZ. Histopathological changes in the uterus were examined by hematoxylin–eosin (HE) staining, and serum levels of estradiol (E2) and progesterone (P4) were measured to verify model establishment. SOD and MDA levels and the results of immunohistochemical and WB analyses were used to further confirm the <em>in vivo</em> regulation of ferroptosis and JAK2/STAT3 signaling by TMHZ. Additionally, HE staining of major organs (liver, spleen, and kidney) was performed to evaluate systemic safety.</div></div><div><h3>Results</h3><div>Bioinformatics analysis suggested that the therapeutic effects of TMHZ were closely associated with the regulation of the JAK2/STAT3 pathway and ferroptosis. <em>In vitro</em>, TMHZ significantly inhibited the proliferation, migration, and invasion of AMDCs; increased intracellular Fe²⁺ and reactive oxygen species (ROS) levels; reduced GSH and SOD activity; elevated the MDA content, and induced typical mitochondrial damage. TMHZ also downregulated the expressions of p-JAK2, p-STAT3, SLC7A11, and GPX4. Further rescue experiments using JAK2 inhibitors and agonists confirmed the key role of the JAK2/STAT3 pathway in this process. <em>In vivo</em>, TMHZ suppressed JAK2/STAT3 signaling to promote ferroptosis, ","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"Article 157748"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884120","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 : 2026-01-01DOI: 10.1016/j.phymed.2025.157735
Mengxin Li , Jiaying Yang , Keyan Wang , Aonan Zhu , Haoyuan Yin , Zongjun Li , Haoran Zhao , Qi Wang , Dhan V. Kalvakolanu , Yuewen Hao , Bing Cui , Ling Zhang , Baofen Guo
Background
Glioblastoma (GBM) progresses aggressively and resists therapy largely due to glioma stem cells (GSCs), which drive recurrence and treatment failure. Inducing GSC differentiation into non-stem-like cells offers a promising therapeutic approach. Taxifolin (TAX), a natural flavonoid with anti-inflammatory and antioxidant properties, has demonstrated anti-stemness effects in cancer but its impact on GSCs remains unclear.
Purpose
The study aimed to explore TAX as a differentiation-inducing agent targeting GSCs to enhance therapeutic response in GBM.
Study Design
We assessed the effects and mechanism of TAX on GSC proliferation, self-renewal, and differentiation using in vitro and in vivo models, supported by transcriptomic and rescue experiments.
Methods
Using human (TS576) and murine (CSC2078) GSC lines, along with an orthotopic xenograft model, we examined the effects of TAX on proliferation, self-renewal, and differentiation, as well as its downstream pathway. Funcional assays including cell viability, colony formation, neurosphere formation, apoptosis, and differentiation marker analysis were conducted in vitro. Transcriptomic profiling and KEGG pathway enrichment identified CYP1B1 as a key downstream target, whose role was validated through overexpression-based rescue experiments and epithelial-mesenchymal transition (EMT) marker analysis. TAX efficacy and biosafety were evaluated using bioluminescence imaging, histopathology and immunohistochemistry in vivo, with temozolomide as a positive control.
Results
Purified TAX (92.47%) from Larix olgensis roots inhibited the proliferation, self-renewal of GSCs and induced apoptosis. TAX promoted GSCs differentiation toward neuronal lineages, supporting its potential as a differentiation-based adjuvant therapy. TAX suppressed tumor growth without observable toxicity and enhanced the therapeutic efficacy of temozolomide (TMZ) in vivo. Bioinformatic analysis identified CYP1B1 as a TAX-responsive target, with elevated expression in glioma tissues and strong association with malignancy and poor prognosis. Functional assays confirmed that CYP1B1 overexpression promotes EMT, while TAX downregulates CYP1B1 and inhibits EMT progression.
Conclusion
This study is the first to demonstrate that TAX promotes neuronal differentiation of GSCs by suppressing the CYP1B1-mediated EMT pathway. Our work uncovers a novel mechanism linking CYP1B1 down-regulation to GSC differentiation. These findings establish TAX as a differentiation-inducing agent and propose a new therapeutic strategy for GBM by targeting stemness and EMT concurrently.
{"title":"Taxifolin promotes glioma stem cell differentiation via CYP1B1-mediated EMT suppression","authors":"Mengxin Li , Jiaying Yang , Keyan Wang , Aonan Zhu , Haoyuan Yin , Zongjun Li , Haoran Zhao , Qi Wang , Dhan V. Kalvakolanu , Yuewen Hao , Bing Cui , Ling Zhang , Baofen Guo","doi":"10.1016/j.phymed.2025.157735","DOIUrl":"10.1016/j.phymed.2025.157735","url":null,"abstract":"<div><h3>Background</h3><div>Glioblastoma (GBM) progresses aggressively and resists therapy largely due to glioma stem cells (GSCs), which drive recurrence and treatment failure. Inducing GSC differentiation into non-stem-like cells offers a promising therapeutic approach. Taxifolin (TAX), a natural flavonoid with anti-inflammatory and antioxidant properties, has demonstrated anti-stemness effects in cancer but its impact on GSCs remains unclear.</div></div><div><h3>Purpose</h3><div>The study aimed to explore TAX as a differentiation-inducing agent targeting GSCs to enhance therapeutic response in GBM.</div></div><div><h3>Study Design</h3><div>We assessed the effects and mechanism of TAX on GSC proliferation, self-renewal, and differentiation using <em>in vitro</em> and <em>in vivo</em> models, supported by transcriptomic and rescue experiments.</div></div><div><h3>Methods</h3><div>Using human (TS576) and murine (CSC2078) GSC lines, along with an orthotopic xenograft model, we examined the effects of TAX on proliferation, self-renewal, and differentiation, as well as its downstream pathway. Funcional assays including cell viability, colony formation, neurosphere formation, apoptosis, and differentiation marker analysis were conducted <em>in vitro</em>. Transcriptomic profiling and KEGG pathway enrichment identified CYP1B1 as a key downstream target, whose role was validated through overexpression-based rescue experiments and epithelial-mesenchymal transition (EMT) marker analysis. TAX efficacy and biosafety were evaluated using bioluminescence imaging, histopathology and immunohistochemistry <em>in vivo</em>, with temozolomide as a positive control.</div></div><div><h3>Results</h3><div>Purified TAX (92.47%) from <em>Larix olgensis</em> roots inhibited the proliferation, self-renewal of GSCs and induced apoptosis. TAX promoted GSCs differentiation toward neuronal lineages, supporting its potential as a differentiation-based adjuvant therapy. TAX suppressed tumor growth without observable toxicity and enhanced the therapeutic efficacy of temozolomide (TMZ) <em>in vivo</em>. Bioinformatic analysis identified CYP1B1 as a TAX-responsive target, with elevated expression in glioma tissues and strong association with malignancy and poor prognosis. Functional assays confirmed that CYP1B1 overexpression promotes EMT, while TAX downregulates CYP1B1 and inhibits EMT progression.</div></div><div><h3>Conclusion</h3><div>This study is the first to demonstrate that TAX promotes neuronal differentiation of GSCs by suppressing the CYP1B1-mediated EMT pathway. Our work uncovers a novel mechanism linking CYP1B1 down-regulation to GSC differentiation. These findings establish TAX as a differentiation-inducing agent and propose a new therapeutic strategy for GBM by targeting stemness and EMT concurrently.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"Article 157735"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900180","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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