Phytomedicine [JOURNAL]
Sun
200 papers
Effect of isoginkgetin on targeting methylenetetrahydrofolate dehydrogenase 2 to induce ROS-mediated apoptosis in non-small cell lung cancer.
Ma C, Jin X, Sun A … +11 more , Wang Y, Hong X, Xu Y, Ye Y, Zhou Y, Zhou X, Zhao H, Cheng D, Chen J, Zhao C, Yang L
Phytomedicine · 2026 Jun · PMID 42361761 · Publisher ↗
BACKGROUND: Non-small cell lung cancer (NSCLC) remains a major cause of cancer mortality. Isoginkgetin, a natural biflavonoid, has shown pharmacological potential, yet its antitumor mechanisms in NSCLC are not well defin...
BACKGROUND: Non-small cell lung cancer (NSCLC) remains a major cause of cancer mortality. Isoginkgetin, a natural biflavonoid, has shown pharmacological potential, yet its antitumor mechanisms in NSCLC are not well defined. PURPOSE: This study investigated the antitumor activity of isoginkgetin in NSCLC and explored its molecular targets and underlying mechanisms. STUDY DESIGN: Cell-based assays and in vivo xenograft models combined with transcriptomic profiling, redox analyses, and in silico target identification/validation. METHODS: Cell-based assays were performed to evaluate the effects of isoginkgetin on NSCLC cell growth, migration, apoptosis, and epithelial-mesenchymal transition (EMT). Transcriptome profiling and redox analyses were conducted to assess mechanistic pathways. Target identification was conducted through in silico screening, followed by drug-target binding validation and functional characterization, including further validation through Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) overexpression and silencing. The antitumor efficacy of isoginkgetin was further examined in NSCLC xenograft models, and the safety was assessed through acute toxicity experiments. RESULTS: Isoginkgetin suppressed proliferation and migration, induced apoptosis, and blocked EMT in NSCLC cells. It disrupted redox homeostasis by enhancing oxidative stress, mediated by elevated reactive oxygen species (ROS) accumulation and activating endoplasmic reticulum (ER) stress and mitochondrial apoptosis. MTHFD2 was identified as a direct target of isoginkgetin, which binds to MTHFD2 and suppresses its functional role, ultimately leading to NADPH depletion and oxidative stress. Silencing MTHFD2 reproduced the effects of isoginkgetin, while overexpression of MTHFD2 partly attenuated these effects. In vivo, isoginkgetin markedly reduced tumor growth without systemic toxicity. CONCLUSION: Isoginkgetin exerts potent antitumor effects in NSCLC by targeting MTHFD2 and inducing redox imbalance, supporting its promise as a novel therapeutic candidate.
Pinocembrin inhibits melanoma progression via Ets1-mediated Smad3 transcription to enhance anti-PD-1 therapy.
Liao Y, Li YR, Wang YB … +4 more , Li JC, Tan RZ, Wang HL, Wang L
Phytomedicine · 2026 Jun · PMID 42361760 · Publisher ↗
BACKGROUND: The TGF-β/Smad3 signaling drives the malignant progression of melanoma, activates PD-L1 expression, and exerts immunosuppressive functions. Pinocembrin (PIN), a natural dihydroxyflavanone has been shown to ha...
BACKGROUND: The TGF-β/Smad3 signaling drives the malignant progression of melanoma, activates PD-L1 expression, and exerts immunosuppressive functions. Pinocembrin (PIN), a natural dihydroxyflavanone has been shown to have anti-melanoma effects, but the detailed mechanisms remain unresolved. PURPOSE: This study aimed to elucidate the effect of PIN on the reduction of PD-L1 expression and the enhancement of anti-PD-1 therapy by inhibiting Ets1-mediated Smad3 transcription to determine the role of PIN in anti-melanoma. METHODS: To investigate the pharmacological mechanism of PIN, we employed B16 cells for in vitro assays and established a syngeneic tumor-bearing mouse model for in vivo studies. These analyses integrated multiple approaches, including RNA-seq, bioinformatics prediction, Dual Luciferase Reporter and ChIP-qPCR, site-directed mutagenesis, CRISPR/Cas9, lentivirus-mediated stable overexpression cell lines, RT-qPCR, and Western blot. Furthermore, the proportion of immune cells within tumor tissues was determined by flow cytometry, ELISA was performed to quantify IFN-γ secretion. RESULTS: PIN significantly inhibited melanoma growth, proliferation, migration, and PD-L1 expression. RNA-seq analysis revealed marked inhibition of the TGF-β signaling pathway, with Smad3 identified as a core downstream target. Using bioinformatics analysis, Dual Luciferase reporter assay, and ChIP-qPCR, we demonstrated that Ets1 directly bound to four specific regions within the Smad3 promoter and activated its transcriptional activity, all of which were suppressed by PIN treatment. Ets1 overexpression restored Smad3 and PD-L1 expression and reversed the tumor-suppressive effects of PIN. Moreover, Ets1 overexpression failed to restore PD-L1 expression in Smad3-deficient B16 cells. We further demonstrated that PIN exerted its anti-tumor effect primarily on tumor cells and also modulated the immune composition of the melanoma microenvironment. Notably, combining PIN with αPD-1 increased pro-tumor immune populations, reduced inhibitory subsets, and enhanced immune-mediated melanoma killing. CONCLUSION: PIN can effectively inhibit the malignant progression of melanoma and the expression of PD-L1 through Ets1/Smad3 axis. Combined with αPD-1, PIN can further enhance its immunomodulatory function.
Natural small molecule evodiamine alleviates liver fibrosis by targeting the ANXA2-p110α axis in hepatic stellate cells.
Sun Y, Liu Z, Zhang Y … +10 more , Xiao J, You H, Xiao G, Wei L, Ding Z, Mo Y, Ren H, Ling N, Hu P, Peng M
Phytomedicine · 2026 Jun · PMID 42361759 · Publisher ↗
BACKGROUND: Liver fibrosis is a common consequence of chronic liver injury, whereas pharmacological interventions that directly impede fibrogenesis remain limited. PURPOSE: This study aimed to screen natural compounds th...
BACKGROUND: Liver fibrosis is a common consequence of chronic liver injury, whereas pharmacological interventions that directly impede fibrogenesis remain limited. PURPOSE: This study aimed to screen natural compounds that inhibit hepatic stellate cell (HSC) activation from clinically effective antifibrotic traditional Chinese medicine (TCM) formulas and to elucidate the underlying mechanisms. STUDY DESIGN AND METHODS: Using network pharmacology integrated with a TGF-β1-induced HSC activation model to screen natural small molecules, followed by in vivo validation in CCl₄-, DDC-, and HFD+CCl₄-induced mouse fibrosis models. Direct target identification and mechanistic analyses were conducted by drug affinity responsive target stability (DARTS), biolayer interferometry (BLI) and RNA sequencing. RESULTS: Among 23 prioritized candidates, evodiamine (EVO) significantly suppressed HSC activation and proliferation in human LX-2 and rat HSC-T6 cells. In three mouse models, EVO (50 mg/kg) markedly improved liver function and fibrotic pathology without inducing overt toxicity. Annexin A2 (ANXA2) was identified as a direct binding target of EVO, and was enriched in activated HSCs and upregulated in fibrotic mouse livers and human fibrotic specimens. Mechanistically, EVO bound to ANXA2 at a site involving Ser22 and Val27, and promoted NEDD4L-mediated K48-linked ubiquitination and degradation of ANXA2. Furthermore, EVO disrupted the interaction between ANXA2 and the PI3K catalytic subunit p110α, resulting in the suppression of PI3K-AKT signaling in HSCs. CONCLUSION: These findings identified EVO as an active antifibrotic compound and uncovered a previously unrecognized mechanism whereby EVO targets the ANXA2-p110α axis in HSCs to alleviate liver fibrosis.
Mitochondria-mediated apoptosis induced by acetogenins from Porcelia macrocarpa (Annonaceae) in K562 chronic myeloid leukemia cells.
Lopes RM, Antoniolli G, Frutuoso BA … +9 more , Urushima FY, Grabauskas LA, Ferreira D, Brito IA, Ferreira LEM, Soares SR, Ruiz JLM, Rodrigues T, Lago JHG
Phytomedicine · 2026 Jun · PMID 42361758 · Publisher ↗
BACKGROUND: Acetogenins from Annonaceae species are widely recognized for their potent cytotoxic and antitumor properties. Some acetogenin derivatives, such as bullatacin, have been reported to impair mitochondrial funct...
BACKGROUND: Acetogenins from Annonaceae species are widely recognized for their potent cytotoxic and antitumor properties. Some acetogenin derivatives, such as bullatacin, have been reported to impair mitochondrial function, including inhibition of mitochondrial respiratory chain complex I. However, the cytotoxic effects of acetogenin derivatives isolated from Porcelia macrocarpa in leukemia cells remain poorly explored, as do the mitochondrial mechanisms underlying their biological activity. PURPOSE: The present study aimed to evaluate the cytotoxic potential of three acetogenins, namely (2S,3R,4R)-3‑hydroxy-4-methyl-2-(n‑eicos-11'-yn-19'-enyl)butanolide (1), (2S,3R,4R)-3‑hydroxy-4-methyl-2-(n‑eicos-11'-ynyl)butanolide (2), and (2S,3R,4R)-3‑hydroxy-4-methyl-2-(n‑eicos-11'-yn-19'-epoxy)butanolide (3), isolated from the seeds of Porcelia macrocarpa and to investigate the molecular mechanisms underlying the cytotoxic activity of the most active compound in K562 chronic myeloid leukemia cells. STUDY DESIGN: A combined phytochemical, in silico, and In vitro experimental approach was employed to investigate the physicochemical and predicted pharmacokinetic properties, cytotoxic activity, and cellular responses associated with acetogenin exposure. METHODS: Acetogenins 1 - 3 were isolated and structurally characterized by NMR and HR-ESI-MS. In silico analyses were conducted to predict physicochemical properties, pharmacokinetic parameters, and toxicity profiles. Cytotoxicity was evaluated in Philadelphia chromosome positive K562 human chronic leukemia cells using MTT and trypan blue assays, while mitochondrial superoxide production, mitochondrial membrane potential, and cytosolic calcium levels were analyzed by flow cytometry. Apoptotic signaling was assessed by Western blot analysis of BAX, BCL-2, and caspase activation of caspase 9 and caspase 3. RESULTS: In silico predictions indicated favorable gastrointestinal absorption and limited blood-brain barrier permeability for the evaluated acetogenins. In vitro assays demonstrated structure-dependent cytotoxicity, with acetogenins 1 and 3 significantly reducing leukemia cell viability, whereas compound 2 showed minimal activity. Mechanistic studies revealed that acetogenin 1 increased mitochondrial superoxide production, partially dissipated mitochondrial membrane potential, disrupted calcium homeostasis, and it was associated with modulation of the BAX/BCL-2 ratio and activation of caspase-9 and caspase-3, consistent with intrinsic apoptotic signaling. CONCLUSION: These findings indicate that acetogenin 1 exposure is associated with mitochondrial alterations and intrinsic apoptotic signaling in K562 chronic myeloid leukemia cells and provide mechanistic insights into the cellular responses induced by acetogenins isolated from Porcelia macrocarpa.
Corrigendum to "Indole-3-carbinol attenuates cisplatin-induced premature ovarian failure by activating Nrf2 through competitive binding of Keap1" [Phytomedicine volume 154 (2026)/158040].
Zhu F, Zhang R, He Z … +7 more , Zhang N, Li F, Li J, Chen H, Liu X, Cheng L, Zhong F
Phytomedicine · 2026 Jun · PMID 42349223 · Publisher ↗
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Liqi Huoxue dripping pills alleviate myocardial ischemia-reperfusion injury with improved mitochondrial biogenesis and reduced ferroptosis: Involvement of S100A8/A9-TLR4-ERK signaling.
Hao Q, Yue J, Li P … +1 more , He Q
Phytomedicine · 2026 Jun · PMID 42349222 · Publisher ↗
BACKGROUND: S100A8/A9, a critical danger-associated molecular pattern, amplifies inflammatory responses and exacerbates myocardial ischemia-reperfusion injury (MIRI) through Toll-like receptor 4 (TLR4) signaling. Althoug...
BACKGROUND: S100A8/A9, a critical danger-associated molecular pattern, amplifies inflammatory responses and exacerbates myocardial ischemia-reperfusion injury (MIRI) through Toll-like receptor 4 (TLR4) signaling. Although S100A8/A9-TLR4-related signaling has been implicated in MIRI pathogenesis, effective pharmacological interventions for MIRI remain limited. PURPOSE: This study investigated whether Liqi Huoxue Dripping Pills (Lqhxdw), a traditional Chinese medicine, alleviates MIRI in association with modulation of the S100A8/A9-TLR4-ERK-related signaling axis and elucidated the downstream mechanisms involving mitochondrial dysfunction and ferroptosis. METHODS: A rat MIRI model was established by temporary LAD ligation, followed by 7-day Lqhxdw treatment. An in vitro hypoxia/reoxygenation (H/R) model was established using drug-containing serum. Transcriptomic profiling, network pharmacology, and molecular docking were performed to identify candidate therapeutic targets. Rescue experiments with recombinant S100A8/A9 (rS100A8/A9), pharmacological pathway validation using U0126, ferroptosis inhibitor rescue using ferrostatin-1, and in vivo pharmacological validation using TAK-242 were performed to support the proposed mechanistic framework. Mitochondrial function and ferroptosis were assessed by Seahorse XF analysis, biochemical assays, fluorescent probes, and transmission electron microscopy. RESULTS: Lqhxdw treatment dose-dependently improved cardiac function, attenuated histopathological damage, and reduced myocardial injury biomarkers. Transcriptomic analysis identified S100a8/S100a9 as significantly upregulated genes following MIRI, with negative correlations to mitochondrial Complex I subunits. Molecular docking predicted favorable binding affinity of Lqhxdw components to TLR4. Experimentally, Lqhxdw reduced S100A8/A9-TLR4 co-localization, suppressed TLR4/ERK phosphorylation, and restored the PGC-1α/NRF1/NDUFA9 axis. Seahorse analysis demonstrated restored mitochondrial respiration. Ferroptosis markers were markedly attenuated by Lqhxdw treatment. Critically, exogenous rS100A8/A9 partially reversed these protective effects. Pharmacological validation using U0126 partly restored PGC-1α and NRF1 expression under rS100A8/A9 stimulation, supporting the involvement of ERK upstream of mitochondrial regulatory changes. Ferrostatin-1 rescue experiments provided functional support for the involvement of ferroptosis. In vivo validation with TAK-242 showed regulatory directions broadly consistent with those of Lqhxdw on iron homeostasis markers and NF-κB-associated inflammatory readouts. CONCLUSION: This study provides pharmacological and functional evidence supporting a mechanistic framework in which Lqhxdw attenuates MIRI in association with suppression of S100A8/A9-TLR4-ERK-related signaling, restoration of PGC-1α-mediated mitochondrial biogenesis, and attenuation of ferroptosis. These findings identify S100A8/A9-TLR4-ERK as a biologically relevant signaling framework in MIRI and support the potential clinical application of Lqhxdw in ischemic heart disease.
Corrigendum to "Salvigenin mitigates neuronal ferroptosis by binding to PI3K and enhancing the interaction between VCP and PI3K in the repair of spinal cord injury" [Phytomedicine, Volume 147, 2025, 157181].
Yu Y, Xie X, Zhang Y … +5 more , Xiao S, Dan F, Liu J, Liu Z, Zhou R
Phytomedicine · 2026 Jun · PMID 42349221 · Publisher ↗
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Corrigendum to "Differential and complementary effects of Baizhu and Fuling on spleen deficiency syndrome by regulating microbiota-gut-metabolite axis" [Phytomedicine 150 (2026) 157690].
Xu Y, Yang W, Yang Z … +4 more , Pan Y, Zhu Y, Shen B, Chen J
Phytomedicine · 2026 Jun · PMID 42349220 · Publisher ↗
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Lithospermic acid-induced gut microbiota remodeling alleviates intraplaque inflammation.
Wu C, Zheng T, Huang S … +8 more , Meng C, Wang W, Li M, Cheng H, Ju Z, Wang Y, Mao W, Zhou X
Phytomedicine · 2026 Jun · PMID 42341529 · Publisher ↗
BACKGROUND: Atherosclerosis is a leading cause of mortality worldwide. The gut microbiota (GM) plays a significant role in the initiation and progression of atherosclerosis, making its modulation a promising therapeutic...
BACKGROUND: Atherosclerosis is a leading cause of mortality worldwide. The gut microbiota (GM) plays a significant role in the initiation and progression of atherosclerosis, making its modulation a promising therapeutic strategy for atherosclerotic cardiovascular disease. Salvia miltiorrhiza, a traditional Chinese medicine renowned for its therapeutic effects in treating cardiovascular diseases, contains lithospermic acid (LA) as one of its key active constituents. PURPOSE: To elucidate whether LA can alleviate atherosclerosis and its mechanism. STUDY DESIGN AND METHODS: Atherosclerosis was induced in Apolipoprotein E knockout mice through a Western diet, followed by a 12-week treatment with LA. In a separate model, low-density lipoprotein receptor knockout mice were fed a Western diet for 8 weeks prior to receiving LA for an additional 12 weeks. The role of GM in LA-mediated alleviation of atherosclerosis was assessed using fecal microbiota transplantation (FMT) models coupled with 16S rRNA gene sequencing. Furthermore, serum metabolomics was employed to elucidate the mechanism by which LA modulates serum metabolites via GM to attenuate atherosclerosis. RESULTS: LA administration significantly attenuated the development of atherosclerosis in both models. FMT experiments further indicated that the GM contributes to the anti-atherosclerotic effects of LA. 16S rRNA gene sequencing revealed that LA modified the composition of the GM. Metabolomic analysis demonstrated that LA reduced serum levels of lysophosphatidylcholine (LysoPC), a metabolite critical for macrophage function. CONCLUSION: Collectively, these findings highlight the therapeutic potential of LA in the treatment of atherosclerosis.
Compound Danshen Dripping Pills retards the progression of cerebral cavernous malformations via strengthening vascular integrity and ameliorating inflammatory response.
Chen L, Zheng W, Ma J … +7 more , Zuo Y, Ren J, Li J, Choi JP, Yu S, Lu Y, Zhao Y
Phytomedicine · 2026 Jun · PMID 42341528 · Publisher ↗
BACKGROUND: Cerebral cavernous malformations (CCMs) are characterized by abnormal clusters of dilated, thin-walled capillaries in the brain that are prone to bleeding, which give rise to a range of neurological symptoms...
BACKGROUND: Cerebral cavernous malformations (CCMs) are characterized by abnormal clusters of dilated, thin-walled capillaries in the brain that are prone to bleeding, which give rise to a range of neurological symptoms including seizures and stroke. Current therapeutic strategies are restricted to surgical resection, highlighting the requirement for effective and efficient treatments. OBJECTIVE: In this study, we investigated the therapeutic potential of Compound Danshen Dripping Pills (CDDP) as a traditional Chinese medicine (TCM) against the progression of CCMs. METHODS: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to characterize the chemical composition of CDDP and identify its brain-penetrating ingredients. Lesion burden was assessed by macroscopic observation, micro-computed tomography (microCT), and histological analysis. Vascular integrity and function were evaluated by immunofluorescence staining. Blood flow was assessed by laser speckle contrast imaging and permeability was examined using Evans blue dye and FITC-dextran. Multi-omics approaches, including RNA sequencing (RNA-seq), proteomics, and metabolomics, were conducted to decipher molecular mechanisms. Western blot and quantitative Real-time PCR (qPCR) were performed to detect key signaling pathways. Brain-penetrating components were identified by UPLC-MS/MS, followed by molecular docking and molecular dynamics simulations for target proteins (MEKK3 and NF-κB). Surface plasmon resonance (SPR) assay was performed to validate the direct binding affinity of the identified key components to their respective target proteins. The functional impacts of target binding were assessed in HEK293T cells overexpressing MEKK3 (HEK293T/MEKK3-OE) by examining the phosphorylation levels of downstream mediators. KRIT1-knockdown human cerebral microvascular endothelial cells (HCMEC/D3) stimulated by lipopolysaccharide (LPS) were treated with identified components (ginsenoside F3 and tanshinone I), and assessed for trans-endothelial electrical resistance (TEER) and expression of critical inflammatory cytokines. RESULTS: UPLC-MS/MS identified 36 ingredients in CDDP, including phenolic acids, alkaloids, and ginsenosides. CDDP treatment dose-dependently reduced CCM lesion burden in Krit1 mice, with 0.2 g/kg demonstrating optimal efficacy comparable to propranolol. Immunofluorescence revealed that CDDP significantly enhanced vascular integrity by upregulating Claudin-5 and VE-cadherin expression, increasing pericyte coverage, and normalizing basement membrane support. Functional assays demonstrated that CDDP restored cerebral blood flow and reduced vascular permeability. Integrated transcriptomics, proteomics, and metabolomics analysis revealed that CDDP significantly downregulated the MEKK3-MEK5-ERK5-KLF2/4-p-MLC2 signaling axis and suppressed inflammatory networks involving NF-κB, ICAM1, VCAM1, IL-6, IL-1β, and neutrophil extracellular traps (CitH3). Diprovocim-induced exacerbation of CCM lesions was effectively reversed by CDDP, confirming the involvement of MAPK and NF-κB pathways. Brain tissue analysis identified 11 brain-penetrating components, including salvianolic acids and ginsenosides. Molecular docking and molecular dynamics simulations revealed that ginsenoside F3 exhibited optimal binding affinity with NF-κB, while tanshinone I strongly bound to MEKK3. SPR assay further confirmed the direct binding, with ginsenoside F3 binding to NF-κB and tanshinone I binding to MEKK3. Functional validation in HEK293T/MEKK3-OE cells demonstrated that tanshinone I markedly suppressed MEKK3-driven phosphorylation of MEK5 and ERK5, while ginsenoside F3 significantly attenuated NF-κB phosphorylation. Administration of ginsenoside F3, tanshinone I, or their combination in Krit1 mice led to reductions in cerebellar hemorrhagic lesions and vascular leakage, with the combination group exhibiting the most prominent therapeutic effect. In vitro validation in KRIT1-knockdown HCMEC/D3 cells demonstrated that ginsenoside F3, tanshinone I, and their combination significantly restored TEER values and reduced IL-1β and IL-6 expression, with the combination showing synergistic effects. CONCLUSION: CDDP exerts therapeutic effects against CCM progression by strengthening vascular integrity, restoring endothelial barrier function, and suppressing inflammation through inhibition of the MEKK3-MEK5-ERK5-KLF2/4-p-MLC2 and NF-κB signaling pathways. Brain-penetrating components, particularly ginsenoside F3 and tanshinone I, directly targeted key proteins (NF-κB and MEKK3) and synergistically protected endothelial function. These findings provide preclinical evidence supporting CDDP as a promising multi-target therapeutic strategy for CCMs.
Corrigendum to "Guipi Tang alleviates vascular dementia by regulating purine metabolism via gut microbiota-derived pantothenic acid" [Phytomedicine volume 148 (2025) 157297].
Ren Y, Sun Y, Liu Q … +11 more , Chen JL, Chen YH, Sun L, Cui Z, Yan SY, Cheng L, Li N, Wang SS, Li GB, Yang ZS, Yuan JL
Phytomedicine · 2026 Jun · PMID 42341527 · Publisher ↗
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Corrigendum to "Hyperoside ameliorates the progression of osteoarthritis: An in vitro and in vivo study" [Phytomedicine/volume80 (2021)/153387].
Sun K, Luo J, Jing X … +6 more , Xiang W, Guo J, Yao X, Liang S, Guo F, Xu T
Phytomedicine · 2026 Jun · PMID 42341526 · Publisher ↗
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Therapeutic effects of jaceosidin on atopic dermatitis via ubiquitin-mediated JAK1 degradation.
Wei R, Cheng W, Zhang J … +4 more , Zou Q, Tan Y, Zhang Z, Wang H
Phytomedicine · 2026 Jun · PMID 42341525 · Publisher ↗
BACKGROUND: Atopic dermatitis (AD) is a prevalent inflammatory skin disease with substantial clinical burden. Jaceosidin (JAC), a trihydroxy-dimethoxy flavone primarily isolated from Artemisia genus and several other pla...
BACKGROUND: Atopic dermatitis (AD) is a prevalent inflammatory skin disease with substantial clinical burden. Jaceosidin (JAC), a trihydroxy-dimethoxy flavone primarily isolated from Artemisia genus and several other plants, possesses potent immunomodulatory and anti-inflammatory activities with therapeutic potential for inflammatory skin diseases. However, its precise anti-AD mechanism remains unclear. PURPOSE: This study aimed to investigate the therapeutic efficacy of JAC against AD and elucidate its underlying mechanisms. METHODS: A murine AD model was established by repeated topical calcipotriol application, followed by topical JAC treatment for 7 consecutive days. Therapeutic efficacy was evaluated by ear thickness, dermatitis severity, and histopathology. TNF-α/IFN-γ-stimulated HaCaT cells and reconstructed human epidermis (RHE) models were further used for phenotypic validation and mechanistic analyses. RNA sequencing, co-immunoprecipitation, and ubiquitination assays were performed. RESULTS: JAC significantly alleviated AD-like pathological manifestations in mice by reducing ear edema, mast cell infiltration, and Th2 cytokine production, while restoring epidermal barrier protein expression. Similar therapeutic effects were observed in TNF-α/IFN-γ-stimulated HaCaT cells and RHE models. Mechanistically, transcriptomic analysis identified SOCS4 as a key upstream regulator induced by JAC. JAC promoted SOCS4-mediated ubiquitin-proteasomal degradation of JAK1, leading to suppression of JAK1/STAT1 activation. CONCLUSION: This study provides the first experimental evidence supporting the anti-AD effects of JAC across multiple preclinical models. JAC mitigates AD progression by restoring epidermal barrier integrity and modulating immune dysregulation through SOCS4-mediated degradation of JAK1 and subsequent suppression of JAK1/STAT signaling. These findings position JAC as a promising therapeutic candidate for AD.
Corrigendum to "Gut microbiota metabolite Urolithin B inhibits chondrocyte ferroptosis by rewriting iron homeostasis via FGFR3/NCOA4/FTH1 axis, alleviating osteoarthritis" [Phytomedicine (Volume 148, 25 November 2025, 157292)].
Li Y, Gu H, Jiang X … +11 more , Li J, Li Q, Song K, Kong X, Meng Q, Shi A, Lin J, Chen B, Wang G, Zhang H, Xu Q
Phytomedicine · 2026 Jun · PMID 42341524 · Publisher ↗
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Myricetin prevents lethal enterovirus infection by broadly targeting a conserved surface-exposed loops on the VP1 capsid.
Zhang J, Zhang Y, Li J … +7 more , Wang W, Wang M, Liu Z, Chen S, Lin Y, Cai X, Liu L
Phytomedicine · 2026 Jun · PMID 42341523 · Publisher ↗
BACKGROUND: Enteroviruses impose a significant global health burden, causing outbreaks of Hand, Foot, and Mouth Disease (HFMD) and severe neurological complications. Currently, no specific and broadly effective antiviral...
BACKGROUND: Enteroviruses impose a significant global health burden, causing outbreaks of Hand, Foot, and Mouth Disease (HFMD) and severe neurological complications. Currently, no specific and broadly effective antiviral therapeutics are available due to the rapid mutation and co-circulation of diverse viral strains. The viral capsid protein VP1 is critical for viral integrity and host cell entry, making it an attractive target for drug development. Myricetin (MC) is a highly safe, naturally occurring flavonol widely distributed in medicinal plants (e.g., Myrica rubra) with well-documented ethnopharmacological applications and antiviral properties. However, its specific interaction with non-enveloped enteroviruses remains elusive. PURPOSE: This study aimed to comprehensively investigate the broad-spectrum antiviral efficacy of MC against diverse, highly pathogenic enteroviruses, structurally and functionally elucidate its molecular mechanism targeting the VP1 capsid protein, and evaluate its preclinical therapeutic potential in vivo. METHODS: The antiviral activity of MC was evaluated in vitro using cytopathic effect (CPE) reduction assays, plaque viral reduction assays, and RT-qPCR against a diverse panel of viral strains (EV-A71, CV-A16, EV-D68, CV-B3, CV-A6, and human coronavirus OC43 [HCoV-OC43]). The mechanism of action was investigated utilizing time-of-addition and temperature-shift attachment assays. Target engagement was mapped through continuous drug-resistance selection, whole-genome sequencing, and reverse genetics (via a mutant reporter virus construction). Structural interactions were modeled via molecular docking, 100-ns molecular dynamics (MD) simulations, and the binding affinity was quantitatively validated using Biolayer Interferometry (BLI). In vivo efficacy was assessed in a lethal EV-A71-infected neonatal ICR mouse model. RESULTS: MC exhibited robust, broad-spectrum antiviral activity against all tested enteroviruses (IC in the low micromolar range) with a favorable, dose-dependent safety margin (high CC). Time-of-addition and temperature-shift assays revealed that MC functions as a viral entry inhibitor, directly blocking the initial attachment of the virus to host cells. Crucially, viral passaging identified a non-synonymous E98K escape mutation on the EV-A71 VP1 capsid protein, which was proven via reverse genetics to completely abrogate the antiviral efficacy of MC. BLI analysis confirmed a direct, strong interaction (Kd = 16.66 µM) between MC and purified VP1. Computational analyses elucidated this broad-spectrum capability, revealing that MC specifically binds to a conserved surface-exposed region formed by the flexible BC, DE, and HI loops within the VP1 protein, distinct from classical deep-pocket binders. In vivo, systemic administration of MC (100 mg/kg) successfully rescued mice from lethal EV-A71 infection, alleviating extreme weight loss and severe hind-limb paralysis, while significantly clearing viral RNA loads from the brain, lungs, and muscle tissues. CONCLUSION: MC acts as a novel, naturally derived, broad-spectrum enterovirus capsid binder that physically intercepts viral entry by targeting evolutionarily conserved surface-exposed loops on the VP1 protein. Supported by clear ethnopharmacological relevance, definitive mechanistic clarity, and robust translational efficacy in vitro and in vivo, MC represents a highly valuable natural antiviral lead for the management of current and emerging enterovirus outbreaks.
Huang-Lian-Jie-Du Decoction alleviates cognitive deficits in Alzheimer's disease via aromatase-mediated regulation of Aβ metabolism.
Sun M, Ye D, Min P … +7 more , Guo M, Zhao X, Zhou Y, Xu L, Wu Y, Meng Z, Wang G
Phytomedicine · 2026 Jun · PMID 42341522 · Publisher ↗
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and pathological accumulation of amyloid-β (Aβ). Hippocampal aromatase (AROM), a key enzyme for local es...
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and pathological accumulation of amyloid-β (Aβ). Hippocampal aromatase (AROM), a key enzyme for local estrogen biosynthesis, has emerged as an important regulator of Aβ metabolism. Huang-Lian-Jie-Du Decoction (HLJD), a classical traditional Chinese medicine formula, has shown therapeutic potential in AD; however, its molecular mechanism remains largely unclear. METHODS: The effects of HLJD on cognitive function and Aβ metabolism were evaluated in APP/PS1 transgenic mice and Aβ-induced HT22 cells. Behavioral performance was assessed using the Morris water maze. Aβ burden and the expression of Aβ-related metabolic enzymes (BACE1, IDE, and NEP) were analyzed by western blotting, qRT-PCR, and immunofluorescence. Network pharmacology was applied to predict potential targets and pathways of HLJD. Gain and loss of function experiments targeting AROM were performed to determine its mechanistic involvement. RESULTS: HLJD significantly improved learning and memory deficits and reduced hippocampal Aβ accumulation in APP/PS1 mice without altering APP expression. In both in vivo and in vitro models, HLJD significantly upregulated AROM expression. HLJD suppressed Aβ production by downregulating BACE1 while enhancing Aβ degradation through upregulation of IDE and NEP. Importantly, AROM knockdown largely abolished the regulatory effects of HLJD on Aβ metabolism, whereas AROM overexpression reproduced its protective actions. CONCLUSION: These findings demonstrate that HLJD alleviates cognitive impairment in AD models by activating hippocampal aromatase and restoring Aβ homeostasis through coordinated regulation of Aβ production and degradation. This study identifies AROM as a critical mediator of HLJD's neuroprotective effects and highlights AROM-dependent modulation of local estrogen synthesis as a promising therapeutic strategy for Alzheimer's disease.
Icariin ameliorates sarcopenia via activation of the estrogen receptor α/fatty acid transport protein 1 pathway.
Song L, Li Y, Li W … +7 more , Lin B, Xiao W, Xia Y, Wang F, Ye M, Wang W, Wang N
Phytomedicine · 2026 Jun · PMID 42341521 · Publisher ↗
BACKGROUND: Sarcopenia is a prevalent disorder among postmenopausal women, representing a debilitating condition with limited treatment options. Icariin (ICA), a prenylated flavonol glycoside, is commonly used in conditi...
BACKGROUND: Sarcopenia is a prevalent disorder among postmenopausal women, representing a debilitating condition with limited treatment options. Icariin (ICA), a prenylated flavonol glycoside, is commonly used in conditions associated with estrogen deficiency; however, its efficacy and mechanism in postmenopausal sarcopenia remain undefined. PURPOSE: This study aimed to evaluate the therapeutic effect of ICA on postmenopausal sarcopenia and to elucidate its underlying mechanism, with a focus on the estrogen receptor α/fatty acid transport protein 1 (ERα/FATP1) pathway. STUDY DESIGN: An integrated approach was employed, combining in vivo pharmacological evaluation, multi-omics analyses, and in vitro mechanistic validation. METHODS: The in vivo therapeutic effect of oral ICA was assessed by evaluating muscle function, histology, and senescence markers. Human muscle transcriptome datasets and mouse single-cell RNA sequencing data were analyzed. In vitro validation was performed in D-galactose-induced senescent C2C12 myoblasts. Target engagement was confirmed by molecular docking, cellular thermal shift assay, and surface plasmon resonance, and mechanistic validation was performed via FATP1 knockdown. RESULTS: Oral administration of ICA significantly improved muscle mass, function, and fiber cross-sectional area, while attenuating lipid deposition and cellular senescence. Single-cell RNA sequencing revealed a diminished myoblast pool with downregulated ERα in aged muscle. This finding aligns with human transcriptome data, linking reduced ERα/FATP1 signaling and dysregulated fatty acid metabolism to sarcopenia. Metabolomic analysis identified FATP1 as a critical transporter of eicosapentaenoic acid and docosapentaenoic acid, which activated the protein kinase B/ mammalian target of rapamycin pathway to promote myogenesis. Importantly, ICA functioned as a dual-target agonist, directly binding to and upregulating both ERα and FATP1, thereby elevating eicosapentaenoic/ docosapentaenoic acid levels and reactivating the protein kinase B/ mammalian target of rapamycin/ myogenic differentiation 1 axis. The specificity of this pathway was confirmed, as FATP1 knockdown completely abrogated the protective effects of ICA. CONCLUSION: This study identifies the ERα/FATP1 axis as a pivotal therapeutic target for sarcopenia. ICA, acting as a first-in-class dual agonist of this pathway, represents a promising candidate for sarcopenia treatment by synchronously modulating estrogen signaling and fatty acid metabolism.
Corrigendum to "Combination of andrographolide and baicalin inhibited influenza A virus infection through suppressing RORγt-IL-17A pathway" [Phytomedicine 156 (2026) 158277].
Cui Y, Yue Y, Lin H … +12 more , Yang W, Zhou C, Li Q, Shi J, He Q, Xi J, Li J, Li J, Liu X, Dong S, Wang S, Guo L
Phytomedicine · 2026 Jun · PMID 42341520 · Publisher ↗
Abstract loading — click title to view on PubMed.
Psoralen ameliorates sepsis-induced acute lung injury by regulating microbiota-dependent tryptophan metabolism.
Kong Y, Feng J, Xu H … +8 more , Chen X, Huo W, Pan S, Wang Q, Chen J, Liu Y, Li J, Lu Y
Phytomedicine · 2026 Jun · PMID 42335643 · Publisher ↗
BACKGROUND: Sepsis frequently leads to acute lung injury (ALI). Despite the documented anti-inflammatory effects of Psoralen (PSO), the exact mechanism by which it confers protection against septic ALI remains poorly und...
BACKGROUND: Sepsis frequently leads to acute lung injury (ALI). Despite the documented anti-inflammatory effects of Psoralen (PSO), the exact mechanism by which it confers protection against septic ALI remains poorly understood. PURPOSE: This research explored the protective efficacy and mechanistic aspects of PSO in sepsis-induced ALI. METHODS: Lipopolysaccharide (LPS) was employed to create a murine ALI model. Pathological and inflammatory responses were evaluated. The dependency on gut microbiota was assessed through intestinal flora ablation and fecal microbiota transplantation. The aryl hydrocarbon receptor (AhR) engagement was demonstrated by its agonist FICZ and antagonist CH-223191. RESULTS: In a septic ALI model, PSO ameliorated the histopathological damage and attenuated the inflammatory response. Evidence for this included a lower lung neutrophil percentage and decreased amounts of the proinflammatory mediators tumor necrosis factor-α, interleukin-6, interleukin-1β, as well as MPO-DNA complexes. Additionally, PSO downregulated the abundance of key markers in pulmonary tissue, including peptidylarginine deiminase 4, colony-stimulating factor 2, citrullinated histone H3, and MPO, thereby suppressing neutrophil extracellular trap formation. Furthermore, PSO altered gut microbial diversity, an effect that relied on tryptophan metabolism originating from the gut microbiota. The treatment raised the relative abundance of indole-3-propionic acid (IPA) in serum, which subsequently triggered the AhR/CYP1A1 pathway and thereby alleviated ALI. Moreover, PSO enhanced intestinal tight junction protein expression. Nonetheless, these protective effects were abolished by the AhR inhibitor CH-223191.
Metapath-guided transfer learning with clinical validation for identifying herb-drug interactions.
Lee WY, Mo KH, Kim S … +11 more , Keum DH, Jin BH, Kim S, Han Y, Kim Y, Park SD, Yoo HH, Park MS, Hoshi N, Kim CO, Kim YW
Phytomedicine · 2026 Jun · PMID 42335642 · Publisher ↗
BACKGROUND: Drug co-administration can alter metabolism and cause clinically important pharmacokinetic interactions. Herb-drug interactions (HDIs) are particularly hard to identify because validated cases are scarce and...
BACKGROUND: Drug co-administration can alter metabolism and cause clinically important pharmacokinetic interactions. Herb-drug interactions (HDIs) are particularly hard to identify because validated cases are scarce and herbal products are chemically complex. PURPOSE: We aimed to develop Meta-HDI, a metapath-guided transfer-learning framework that utilizes large drug-drug interaction graphs to improve HDI prediction and interpretability, and to prospectively confirm its predictions at the clinical pharmacokinetics level. STUDY DESIGN: This study integrates the development of a computational deep learning framework with a prospective clinical crossover trial involving 18 participants and in vitro human liver microsome assays. METHODS: Meta-HDI combines a GCN encoder and shortest-path LSTM with hierarchical attention mechanisms to generate interpretable mechanistic chains. We benchmarked the model against baselines across three in vivo HDI classes and clinical cases. The predicted interaction between donepezil and the herbal formulas Gami-soyosan and Ojeok-san was evaluated in the crossover study, followed by mechanistic validation using microsome assays. RESULTS: Meta-HDI improved the micro-averaged AUROC to 0.95 (from ≤0.60) and correctly classified all eight clinical cases. Ablation studies highlighted the essential role of protein-protein and drug-protein edges. In the clinical trial, co-administration increased donepezil exposure (1.6-fold C; 1.5-fold AUC) without serious adverse events. Attention weights and microsome assays identified falcarinol and glabranin as CYP2D6 inhibitors (IC 45 µM and 4.5 µM). CONCLUSION: Meta-HDI mitigates HDI data scarcity while providing mechanistic, clinically interpretable predictions. Our framework demonstrated its potential for decision support in herb-drug co-administration, though broader validation across diverse drugs and herbal products is needed.
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