Liu Y, Zhou J, Bai G
… +7 more, Zhang Y, Song Q, Zeng C, Huang H, Wang Z, Cai W, Wang Y
Phytomedicine
· 2026 Jun · PMID 42372594
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BACKGROUND: Kawasaki disease (KD) is a childhood systemic vasculitis of unknown etiology, with its most severe complication being the formation of coronary artery aneurysms. The pathogenesis of KD remains incompletely un...BACKGROUND: Kawasaki disease (KD) is a childhood systemic vasculitis of unknown etiology, with its most severe complication being the formation of coronary artery aneurysms. The pathogenesis of KD remains incompletely understood, and there is an ongoing need to develop new therapeutic agents for its treatment. PURPOSE: This study aims to identify biomarkers and potential drug targets for KD, screen natural products with therapeutic potential based on these findings, and elucidate their mechanisms of action in depth. METHODS: Key genes associated with KD were identified through comprehensive bioinformatics analysis. Virtual screening was subsequently performed using molecular docking, ADMET property evaluation, metabolomics analysis, molecular electrostatic potential (MEP), and frontier molecular orbital (FMO) calculations. The stability and binding free energy of the complexes were assessed via molecular dynamics simulations. Proton nuclear magnetic resonance spectroscopy was employed to verify compound purity. Surface plasmon resonance and cellular thermal shift assays were used to detect the binding affinity between compounds and proteins. Serum levels of sCD137L and sTNF-α in children with KD and healthy controls were compared using ELISA. Finally, therapeutic efficacy and underlying mechanisms were evaluated in a KD cell model. RESULTS: CD137 was identified as a biomarker and potential drug target for KD. Hinokiflavone (HF) was identified as a candidate therapeutic agent, forming a stable complex with CD137 under physiological conditions. Serum levels of sCD137L and sTNF-α were significantly elevated in children with KD compared to healthy controls. In vitro experiments demonstrated that HF, by targeting and binding to CD137, inhibits the activation of the NLRP3 inflammasome signaling pathway induced by KD serum. siRNA-mediated knockdown of CD137 further confirmed that this intervention enhances the inhibitory effect of HF on pyroptosis, and that the pyroptosis process is dependent on CD137. CONCLUSION: Our findings highlight the efficacy of HF in treating KD and demonstrate its broader therapeutic potential through targeted inhibition of CD137.
Zhu H, Han S, Xue C
… +13 more, Hou Z, Peng X, Sun H, Zhang B, Zhang L, Qiao X, Wang L, Feng G, Zhang Y, Liu J, Liu Z, Jin Z, Duan W
Phytomedicine
· 2026 Jun · PMID 42365698
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BACKGROUND: Sepsis-induced crosstalk between macrophages and cardiomyocytes is a critical pathogenic mechanism underlying cardiac dysfunction. However, clinically effective pharmacological interventions to mitigate the a...BACKGROUND: Sepsis-induced crosstalk between macrophages and cardiomyocytes is a critical pathogenic mechanism underlying cardiac dysfunction. However, clinically effective pharmacological interventions to mitigate the associated cytokine storm remain limited. PURPOSE: In this study, we aimed to investigate the role of thymol, a natural small-molecule bioactive compound, in regulating macrophage function in septic cardiomyopathy (SCM). METHODS: The following methodologies were employed to investigate the cardioprotective effects of thymol in sepsis and its underlying mechanisms. For in vivo studies, a septic mouse model was established via cecal ligation and puncture (CLP), followed by thymol administration. Cardiac function and macrophage responses were assessed using survival analysis, echocardiography, hematoxylin and eosin (HE) staining, TUNEL assay, flow cytometry, and immunofluorescence staining. In vitro, a co-culture system of RAW264.7 macrophages and HL-1 cardiomyocytes stimulated with lipopolysaccharide (LPS) was used to examine macrophage‑cardiomyocyte interactions. Mechanistic exploration involved proteomic sequencing, western blotting, quantitative polymerase chain reaction (qPCR), and biochemical analyses. Key signaling pathways were further validated by chromatin immunoprecipitation (ChIP) and co‑immunoprecipitation (Co‑IP). Additionally, Krüppel-like factor 4 (Klf4) knockout mice, RNA sequencing (RNA-Seq), liquid chromatography‑tandem mass spectrometry (LC‑MS/MS)‑based proteomics, molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) assay, and surface plasmon resonance (SPR) were utilized to identify the direct molecular target of thymol and elucidate its regulatory role in downstream signaling pathways. RESULTS: Thymol treatment ameliorated cardiac dysfunction and promoted macrophage polarization toward the M2 phenotype. Furthermore, thymol reduced the secretion of tumor necrosis factor-α (TNF-α) by macrophages, thereby inhibiting cardiomyocyte pyroptosis. Mechanistically, RNA-Seq analysis revealed that thymol upregulated KLF4 expression, and macrophage-specific deletion of Klf4 abolished the beneficial effects of thymol on heart failure. We also identified phosphorylase kinase alpha 2 (PHKA2) as a direct binding target of thymol at GLU 546. This interaction enhanced PHKA2 kinase activity, leading to phosphorylation of the downstream transcription factor forkhead box A1 (FOXA1). Importantly, phosphorylated PHKA2 translocated into the nucleus and bound to the promoter region of Klf4, facilitating its transcriptional activation. CONCLUSIONS: Our findings demonstrate that thymol alleviates the cytokine storm in SCM, highlighting its potential as a therapeutic candidate for this condition.
Liu Q, Tang Q, Ye W
… +7 more, Chen B, Zhong Y, Song Y, Wang S, Zhou K, Jiang X, Wang J
Phytomedicine
· 2026 Jun · PMID 42365697
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BACKGROUND: Immunosuppressive tumor-associated macrophages (TAMs) in the malignant ascites contribute to Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance in ovarian cancer (OC). PURPOSE: This study aimed to inve...BACKGROUND: Immunosuppressive tumor-associated macrophages (TAMs) in the malignant ascites contribute to Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance in ovarian cancer (OC). PURPOSE: This study aimed to investigate the activation efficacy of micelle loaded curcumol (MC) on TAMs and its impact on the resistance of OC cells to Niraparib. METHODS: Firstly, ID8-bearing mice with malignant ascites were treated with vehicle or MC, and single-cell RNA sequencing (scRNA-seq) was conducted to profile the immune cells' transcriptome of the ascites. Then, macrophages derived from ascites of patients with recurrent high-grade serous OC undergoing PARPi therapy (ROCAMs), were comprehensively analyzed after MC treatment, including measurements of lactate and ATP, oxygen consumption rate (OCR) assay, and Complex Ⅰ and Ⅳ activity assays. Meanwhile, conditioned culture medium (CCM) from MC-treated ROCAMs was used to co-culture with Niraparib-resistant A2780 cells (A2780), followed by LC-MS/MS analysis. Finally, based on the LC‑MS/MS results, candidate cytokines that potentially reverse Niraparib resistance in OC cells were screened. The effects of these cytokines on A2780 cells were assessed by the CCK-8 assay. RESULTS: Intravenous injection of MC markedly reduced malignant ascites in ID8 tumor-bearing mice, as evidenced by decreased ascites volume, reduced abdominal circumference, and fewer tumor lesions. Analysis of the ascites cells by scRNA-seq showed that macrophages were a major immune cell population, with reduced immunosuppressive clusters (Hmox1 and Gab2) in the MC-treated group. Further analysis using average gene expression scoring showed that MC treatment led to a significant reduction in M2 scores. In vitro treatment of patients' ROCAMs with MC resulted in enhanced expression of TNF-α and suppressed expression of TGF-β, IL-6 and CD206, indicating that MC promotes transition of ROCAMs from an M2-like immunosuppressive state to an M1-like immunoactive state. Metabolic analysis of MC-treated ROCAMs and THP-1 showed that MC led to significant reductions in lactate production, ATP generation, OCR, and Complex IV activity, revealing that MC inhibits OXPHOS. NDUFA4, an essential structural protein of Complex IV, was found to be downregulated in both MC-treated ROCAMs and THP-1. Overexpression of NDUFA4 or restoration of NDUFA4 expression following MC treatment abrogated the inhibitory effect of MC on OXPHOS and partially reversed the MC-induced immune-active macrophage phenotype. Meanwhile, CCM from MC-treated ROCAMs enhanced the sensitivity of A2780 cells to Niraparib, with the IC decreasing from 110.94 ± 22.52 μM to 65.98 ± 21.59 μM. IL-1β and IL-18 were identified as potential candidates by LC-MS/MS, and co-treatment with IL-1β and IL-18 sensitized A2780 cells to Niraparib (IC was 39.25 ± 1.44 μM). CONCLUSION: Our study reveals that MC could promote macrophage activation by inhibiting NDUFA4 and increase the sensitivity of OC cells to Niraparib.
Xiong F, Xu Y, Wang X
… +8 more, Peng Y, Tang T, Jiang K, Wang R, Wu Y, Wang H, Li C, Gao H
Phytomedicine
· 2026 Jun · PMID 42365696
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INTRODUCTION: Apigenin, a naturally occurring flavone widely present in the plant kingdom, possesses antioxidant, anti-inflammatory, and metabolic regulatory activities. Metabolic-associated fatty liver disease (MAFLD),...INTRODUCTION: Apigenin, a naturally occurring flavone widely present in the plant kingdom, possesses antioxidant, anti-inflammatory, and metabolic regulatory activities. Metabolic-associated fatty liver disease (MAFLD), a chronic liver disorder driven by metabolic stress, currently lacks effective pharmacological therapies. Given these pharmacological properties, apigenin may represent a promising candidate for MAFLD intervention. OBJECTIVE: This study aimed to evaluate the therapeutic potential of apigenin in MAFLD and to elucidate the underlying mechanisms linking the gut microbiota and host lipid metabolism. METHODS: A methionine-choline deficient (MCD) diet-induced mouse model of MAFLD, combined with lipidomic profiling, microbiota analysis, and metabolite assessment, was used to determine the beneficial effects of apigenin. RESULTS: Apigenin markedly ameliorated hepatic steatosis in MCD-fed mice, as demonstrated by reduced hepatic triglyceride accumulation, improved liver function markers, and alleviated hepatic inflammation and oxidative stress. Lipidomic profiling showed decreased hepatic saturated and polyunsaturated fatty acids accompanied by an increase in monounsaturated fatty acids and their related lipid species. Apigenin remodeled the gut microbiota, characterized by increased Lactobacillus abundance and decreased Akkermansia abundance. Further analyses identified homocysteine (HCY) as a key microbiota-associated metabolite that induced oxidative stress and reproduced the lipid dysregulation observed in MAFLD, thereby linking microbial alterations to hepatic lipid metabolism. CONCLUSION: These findings demonstrate that apigenin alleviates MAFLD by remodeling the gut microbiota-metabolite network, lowering HCY levels, and subsequently improving hepatic function, lipid metabolism, and oxidative stress, highlighting its potential as a phytochemical-based therapeutic strategy.
Li Z, Li X, Yu X
… +10 more, Lam Y, Wang M, Gu J, Lu C, Zhong J, Zhu Y, Jiang X, Yuan Z, Zhang S, Yin P
Phytomedicine
· 2026 Jun · PMID 42365695
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BACKGROUND: Bone is the most common metastatic site in Breast cancer, where osteoclast activation contributes to osteolytic destruction. Bufalin (BU) has shown anti-tumor activity in several cancers, but its effects on b...BACKGROUND: Bone is the most common metastatic site in Breast cancer, where osteoclast activation contributes to osteolytic destruction. Bufalin (BU) has shown anti-tumor activity in several cancers, but its effects on breast cancer bone metastasis remain unclear. PURPOSE: This study aimed to investigate whether BU suppresses breast cancer-induced osteoclast differentiation and osteolytic bone metastasis, and to explore its underlying mechanism. METHODS: In vivo murine models of breast cancer bone metastasis were used to evaluate the effects of BU on metastatic progression. Osteoclast differentiation and resorptive function were assessed using in vitro and in vivo assays. Biochemical, biophysical, and genetic approaches were employed to identify and validate the direct molecular target of Bu, and downstream signaling pathways regulating osteoclastogenesis were investigated. The clinical relevance of SEC13 (SEC13 homolog, nuclear pore and COPII coat complex component) was analyzed using breast cancer tissue specimens and patient outcome data. Potential combinatorial effects of BU with the RANKL inhibitor denosumab were also briefly evaluated. RESULTS: BU markedly suppressed bone metastasis and inhibited tumor-induced osteoclastogenesis. SEC13 was identified as a molecular target associated with BU treatment and was highly expressed in breast cancer tissues, correlating with poor clinical outcomes. Genetic ablation or pharmacological inhibition of SEC13 in tumor cells significantly reduced osteoclast differentiation and metastatic burden. Mechanistically, SEC13 promoted osteoclastogenesis via HMGB1 release and subsequent activation of the TLR4/NF-κB signaling axis in the bone microenvironment, a process effectively disrupted by BU. Notably, combined treatment with BU further strengthened the suppressive effects of denosumab on osteoclast differentiation and bone metastasis. CONCLUSIONS: BU demonstrates potent pharmacological activity against breast cancer bone metastasis by targeting SEC13 and suppressing tumor-induced osteoclast differentiation. This effect is mediated through inhibition of HMGB1 release and blockade of the TLR4/NF-κB signaling axis, leading to reduced osteoclast formation and inhibition of metastatic progression.
Chen H, Zhang Y, Peng XJ
… +5 more, Zhang LJ, Ward R, Yang Y, Xiang C, Xu TR
Phytomedicine
· 2026 Jun · PMID 42365694
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BACKGROUND: Parkinson's disease (PD) still lacks therapies that can simultaneously improve symptoms and slow neurodegenerative progression, making the screening of natural products with well‑defined mechanisms of action...BACKGROUND: Parkinson's disease (PD) still lacks therapies that can simultaneously improve symptoms and slow neurodegenerative progression, making the screening of natural products with well‑defined mechanisms of action a promising strategy. The biflavonoid amentoflavone (AMF), which is present in plants including Ginkgo biloba L., has been shown to exert neuroprotective effects in PD models. However, its direct protein target remains unidentified. PURPOSE: This study aimed to investigate the anti‑parkinsonian activity of AMF and to elucidate its potential direct target and molecular mechanisms. METHODS: A multidisciplinary integrated strategy was employed. The protective effects of AMF on motor function and dopaminergic neurons were evaluated in MPTP-induced zebrafish and mouse models of PD. Potential target identification and signaling pathway analysis were performed by integrating multi-source target prediction, machine-learning-based reverse virtual screening, and transcriptomic analysis of the substantia nigra (SN) from AMF-treated mice. Compound-target interactions were validated using molecular docking, molecular dynamics simulations, and biophysical techniques including cellular thermal shift assay (CETSA), solvent-induced precipitation (SIP), and fluorescence correlation spectroscopy (FCS). Furthermore, immunofluorescence staining was conducted on mouse substantia nigra brain sections, signaling pathway validation was carried out at the cellular level, and siRNA interference was employed for in vitro target validation. RESULTS: AMF significantly improved motor deficits, alleviated neuroinflammation, and protected dopaminergic neurons in the substantia nigra in both zebrafish (100, 200, and 400 µM) and mouse models (15, 30, and 60 mg/kg, i.p.). Integrated machine‑learning screening and transcriptomic correlation analysis identified the dopamine D3 receptor (D3R) as a key target of AMF, with the model showing excellent classification performance (Voting Classifier AUC: 0.99). Molecular docking and dynamics simulations revealed that AMF stably binds to the orthosteric pocket of D3R. CETSA, SIP, and FCS experiments confirmed the stable binding and specific antagonistic activity of AMF toward D3R, with Asp110 and Tyr373 identified as critical binding residues. Furthermore, transcriptomic analysis combined with GO and KEGG enrichment suggested that beyond direct D3R antagonism, AMF may exert synergistic neuroprotective effects by targeting the PI3K/Akt signaling axis. Critically, D3R knockdown abolished the protective effects of AMF against MPP⁺-induced injury in vitro. CONCLUSIONS: This study systematically demonstrates for the first time that the natural biflavonoid AMF is a structurally novel D3R antagonist with anti‑parkinsonian potential. The work establishes and validates an integrated "computational prediction - experimental verification" framework for natural product target discovery, providing a new lead compound and a methodological paradigm for PD drug development.
Teixidor-Vilà E, Encinar JA, Martin-Castillo B
… +5 more, Lupu R, Bosch-Barrera J, Menendez JA, Verdura S, Cuyàs E
Phytomedicine
· 2026 Jun · PMID 42365692
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BACKGROUND: The adaptive upregulation of the immune-checkpoint PD-L1 in response to interferon-γ (IFNγ) protects solid tumors from cytotoxic lymphocytes and undermines adoptive cell immunotherapies. Currently, pharmacolo...BACKGROUND: The adaptive upregulation of the immune-checkpoint PD-L1 in response to interferon-γ (IFNγ) protects solid tumors from cytotoxic lymphocytes and undermines adoptive cell immunotherapies. Currently, pharmacologically interrupting the trafficking of nascent PD-L1 to the surface of cancer cells is not feasible in a clinical setting. HYPOTHESIS/PURPOSE: We investigated whether silibinin (SBN), the primary bioactive flavonolignan found in Silybum marianum (milk thistle) seeds, could impede the post-translational glycomaturation of PD-L1 and enhance T-cell-mediated antitumor cytotoxicity. METHODS: We assessed the effects of SBN on PD-L1 glycomaturation by integrating electrophoretic mobility shifts, Endo-H/PNGase-F glycosidase sensitivity mapping, transcript-level glyco-enzyme arrays, computational molecular dynamics (MD), biochemical cross-linking, AlphaLISA binding, and flow cytometry. Co-cultures of cancer cells with cytokine-activated T cells were performed using SBN as a single agent or in combination with the small-molecule PD-L1 inhibitor BMS-1166. RESULTS: SBN converted nascent PD-L1 into an Endo H-sensitive, 43 kDa, high-mannose species that becomes trapped in the endoplasmic reticulum (ER), regardless of STAT3 status. SBN did not alter CD274/PD-L1 transcription or global N-glycosylation. MD predicted, and BS3 cross-linking confirmed, weak but significant SBN-induced PD-L1 dimerization which diminished PD-1 binding. SBN increased the ability of BMS-1166, which also induces PD-L1 dimerization and ER retention of underglycosylated PD-L1, to block PD-1/PD-L1 interaction and to eradicate IFNγ-elicited plasma-membrane PD-L1. SBN was synthetically lethal with BMS-1166, causing multiple cancer types to become highly responsive to the immunocytolytic activity of T cells. CONCLUSION: SBN is a plant-derived molecular glue that intercepts PD-L1 glycomaturation co-translationally in the ER. When combined with canonical PD-L1 dimerizers, SBN collapses adaptive PD-L1 expression and renders cancer cells exquisitely susceptible to the cytolytic insults of T cells. Due to its favorable safety profile and oral bioavailability, SBN is a promising "glycotherapeutic" phytochemical for T-cell-based immunotherapy, particularly in IFN-rich tumors with reactive PD-L1 expression programs.
Jiang Y, Sun Y, Li J
… +4 more, Ma C, Chen H, Tang R, Zuo X
Phytomedicine
· 2026 Jun · PMID 42365690
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BACKGROUND: Endothelial pyroptosis is a critical contributor to the development of atherosclerosis. Baicalein (BAI) exhibits anti-atherosclerotic potential; however, whether it alleviates atherosclerosis by modulating en...BACKGROUND: Endothelial pyroptosis is a critical contributor to the development of atherosclerosis. Baicalein (BAI) exhibits anti-atherosclerotic potential; however, whether it alleviates atherosclerosis by modulating endothelial pyroptosis and the underlying molecular mechanisms remain unclear. PURPOSE: This study aimed to elucidate the mechanism by which baicalein attenuates atherosclerosis, with a particular focus on Cylindromatosis (CYLD)-mediated deubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). METHODS: Atherosclerosis was induced in ApoE⁻/⁻ mice, and ox-LDL was used to trigger pyroptosis in HUVECs. Serum lipid levels were measured, and aortic pathological changes were evaluated by Oil Red O, H&E, and Masson's trichrome staining. Endothelial injury, inflammasome activation, Gasdermin D cleavage, and TRAF6 ubiquitination were assessed using immunofluorescence, immunohistochemistry, western blotting, and co-immunoprecipitation. Pyroptosis was quantified by flow cytometry. CYLD knockdown, molecular docking, microscale thermophoresis (MST), and cellular thermal shift assays (CETSA) were performed to verify the interaction between baicalein and CYLD. RESULTS: Baicalein significantly alleviated dyslipidemia, reduced aortic lipid deposition and plaque formation, and increased collagen content in ApoE⁻/⁻ mice. Baicalein also attenuated endothelial injury and suppressed the elevated expression of NF-κB, NLRP3, Caspase-1, and Gasdermin D in aortic tissues. In vitro, baicalein improved ox-LDL-induced HUVEC injury and markedly inhibited pyroptosis. Mechanistically, baicalein reduced TRAF6 ubiquitination by targeting CYLD, thereby suppressing Caspase-1 activation and Gasdermin D cleavage. Molecular interaction analyses confirmed direct binding of baicalein to the CYLD protein. CONCLUSIONS: This study demonstrates that baicalein attenuates atherosclerosis by inhibiting endothelial pyroptosis through the CYLD-TRAF6-Caspase-1/Gasdermin D signaling axis, highlighting CYLD as a potential therapeutic target for atherosclerosis.
Ning F, Xu Y, Xu L
… +8 more, Zhang Y, Zhou L, Chen H, Shao J, Hu C, Wang Z, Gan W, Wang Y
Phytomedicine
· 2026 Jun · PMID 42365689
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BACKGROUND: Acute pancreatitis (AP), a common gastrointestinal emergency, lacks specific treatments. β-elemene (ELE), a sesquiterpene derived from Curcuma phaeocaulis, has attracted attention for its anti-inflammatory an...BACKGROUND: Acute pancreatitis (AP), a common gastrointestinal emergency, lacks specific treatments. β-elemene (ELE), a sesquiterpene derived from Curcuma phaeocaulis, has attracted attention for its anti-inflammatory and immunomodulatory properties beyond its known antitumor effects. However, its potential protective role in AP and the underlying mechanisms remain incompletely elucidated. PURPOSE: In this study, we investigated the protective effect of ELE against AP and elucidated its potential mechanism of action. METHODS: Ceruletide and L-arginine-induced AP mice were used to evaluate the protective effect of ELE on the pancreas of mice. In the mechanism study, RNA sequencing was used to identify potential signaling pathways in pancreatic tissues from AP mice. Subsequently, pull-down, SPR, and DARTS experiments were performed to identify the binding sites between ELE and IL-17RA. Ixekizumab, a clinically available IL‑17RA monoclonal antibody, was used to confirm IL‑17RA as ELE's key target in the AP mouse model. RESULTS: Our research revealed that ELE effectively alleviated pancreatic damage in AP mice. Pancreatic tissue RNA sequencing revealed a pronounced association with the IL-17 signaling pathway following ELE administration. Further in vivo and in vitro studies revealed that ELE mitigated the inflammatory response in mouse pancreas and bone marrow-derived macrophages by inhibiting the IL-17RA signaling and subsequent NF-κΒ activation. Mechanistically, ELE directly targeted the F534 of the IL-17RA protein. The IL-17RA-neutralizing antibody, ixekizumab, and ELE alleviated AP with comparable efficacy, without a significant difference, suggesting that ELE exerts its protective effects, at least in part, through the IL‑17RA receptor. CONCLUSION: Our research revealed that ELE effectively alleviates AP by modulating the IL-17RA-NF-κΒ signaling axis-mediated inflammatory response. These findings suggest that ELE may be a potential therapeutic approach for the anti-inflammatory treatment of AP.
Kim NY, Jung YY, Yang MH
… +3 more, Um JY, Sethi G, Ahn KS
Phytomedicine
· 2026 Jun · PMID 42364563
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BACKGROUND: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, driven in part by persistent activation of pro-survival pathways such as STAT3 and NF-κB. AIM: Cannabidiol (CB...BACKGROUND: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, driven in part by persistent activation of pro-survival pathways such as STAT3 and NF-κB. AIM: Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has emerged as a potential anti-cancer agent; however, its mechanisms in NSCLC remain incompletely defined. In particular, CBD has not been systematically investigated for its ability to simultaneously suppress both constitutive and inducible STAT3/NF-κB activation, while coordinating apoptosis and autophagy in NSCLC. Furthermore, its role as a chemosensitizer in combination with paclitaxel remains to be validated in vivo. METHODS: Human NSCLC cell lines (A549, PC9, and H1299) were treated with cannabidiol (CBD), alone or in combination with paclitaxel. Apoptosis and autophagy were evaluated via caspase-3/7 activity, Western blotting, and immunocytochemistry. The effects of CBD on STAT3 and NF-κB signaling were assessed using EMSA, luciferase reporter assays, and nuclear translocation analysis. Anti-tumor efficacy was further validated in a xenograft mouse model. RESULTS: Here, we demonstrate that CBD reduced cell viability in NSCLC cells (A549 and PC9), while showing less cytotoxicity in normal lung fibroblasts. Mechanistically, CBD induced apoptosis and autophagy and suppressed STAT3 and NF-κB activation at the levels of phosphorylation, nuclear localization, and transcriptional activity. These effects were also observed in inducible signaling models using IL-6-stimulated H1299 cells. Importantly, CBD enhanced the efficacy of paclitaxel, a commonly used chemotherapeutic agent, by synergistically inducing apoptosis and autophagy and further suppressing STAT3/NF-κB signaling. In a xenograft mouse model, CBD treatment significantly reduced tumor growth without affecting body weight, and combination therapy with paclitaxel led to the most pronounced tumor suppression. Tumor tissue analyses confirmed that CBD downregulated phosphorylated STAT3 and p65, reduced proliferation marker Ki-67, and increased expression of cleaved PARP, LC3 II, and other cell death-associated proteins. CONCLUSION: Our findings provide preclinical evidence that CBD exerts potent anti-tumor activity in NSCLC by coordinating inhibition of oncogenic signaling and activation of programmed cell death pathways. To our knowledge, this study provides evidence that CBD concurrently inhibits STAT3 and NF-κB signaling, affecting both constitutive and inducible activation in NSCLC, and enhances paclitaxel efficacy in vivo, thereby establishing a novel mechanistic and translational basis for its therapeutic potential. These results support the therapeutic effect of CBD as a potential adjuvant in lung cancer treatment.
Phytomedicine
· 2026 Jun · PMID 42364562
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BACKGROUND: Dietary polyphenols exhibit diverse biological activities, yet many parent compounds rarely reach peripheral target organs at pharmacologically relevant concentrations following oral intake. This discrepancy...BACKGROUND: Dietary polyphenols exhibit diverse biological activities, yet many parent compounds rarely reach peripheral target organs at pharmacologically relevant concentrations following oral intake. This discrepancy highlights the need to understand how these compounds exert systemic efficacy. PURPOSE: This review aims to critically evaluate the concept of "indirect pharmacology" in the context of dietary polyphenols, referring to mechanisms in which biological effects are mediated predominantly through gut microbiota-dependent biotransformation and intermediary signaling molecules rather than direct systemic exposure of the intact parent compounds at pharmacologically relevant concentrations. STUDY DESIGN: A comprehensive narrative review and conceptual synthesis of current evidence regarding polyphenol-microbiota interactions and their interorgan signaling pathways. METHODS: The study evaluates key mechanisms, including microbial biotransformation, the modulation of the intestinal barrier, and the multi-layered signaling network of shared mediators across major cross-organ axes. Evidence from in vitro systems, animal models, metabolomic analyses, and available human intervention studies was comparatively evaluated to assess the mechanistic and translational strength of current evidence. RESULTS: Current evidence suggests that unabsorbed polyphenols undergo extensive microbial biotransformation to generate bioactive mediators, including short-chain fatty acids (SCFAs), secondary bile acids, and specific phenolic derivatives. Together with the modulation of the microbial architecture itself, these mediators reinforce the gut barrier to reduce endotoxemia. By entering the systemic circulation, these metabolites may influence host receptor signaling and interorgan communication across the gut-liver, gut-adipose, and gut-brain axes, thereby contributing to the regulation of systemic inflammation and glucose-lipid metabolism. However, in many cases, causal validation remains incomplete, and the relative contribution of direct versus microbiota-mediated mechanisms is still unresolved. CONCLUSION: The physiological efficacy of dietary polyphenols is heavily driven by a multi-target, microbiota-mediated regulatory network. Although the indirect pharmacological framework provides an integrative perspective for understanding microbiota-mediated polyphenol activity, substantial translational challenges remain, including interindividual microbiome variability, limited causal validation, and insufficient long-term clinical evidence.
Zhou Y, Huang J, Liu H
… +9 more, Luo J, Du Y, Wan J, He H, He H, Huang X, Yang P, Ye P, Xia J
Phytomedicine
· 2026 Jun · PMID 42364561
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BACKGROUND: Marfan syndrome (MFS) is a genetic disorder predominantly caused by mutations in the FBN1 gene, leading to thoracic aortic aneurysm (TAA) and a lack of effective pharmacological treatments. However, the role...BACKGROUND: Marfan syndrome (MFS) is a genetic disorder predominantly caused by mutations in the FBN1 gene, leading to thoracic aortic aneurysm (TAA) and a lack of effective pharmacological treatments. However, the role of metabolic alterations in this process remains poorly understood. PURPOSE: We aim to investigate the regulatory roles of metabolites in MFS. METHODS: Fbn1 mice were utilized as a TAA mouse model of MFS. Untargeted metabolomic screening of aortic tissues was conducted to identify metabolites in Fbn1 mice compared to controls. Echocardiographic and EVG staining were performed to evaluate TAA. Vascular smooth muscle cells (VSMCs) were isolated from mice for in vitro experiments. Proteomic sequencing was conducted to identify target mediators. Rescue experiments were carried out using recombinant LDHA in vitro. RESULTS: Stachydrine (STA) was upregulated in Fbn1 mice aorta compared with controls. Administration of STA notably mitigated thoracic aortic dilation and medial degeneration in MFS mice. Furthermore, STA significantly diminished the elevated expression of matrix metalloproteinases and the excessive activation of the transforming growth factor-β (TGF-β) signaling pathway in vivo and in vitro. Proteomic analysis revealed that STA treatment led to a reduction in lactate dehydrogenase A (LDHA) expression. Rescue experiments further confirmed that LDHA acts as a critical mediator downstream of STA. CONCLUSIONS: STA attenuated TAA in MFS by inhibiting LDHA, thereby modulating TGF-β signaling and maintaining extracellular matrix homeostasis. These findings highlight STA as a protective metabolite and suggest LDHA as a potential therapeutic factor for TAA in MFS.
Guo R, Niu Z, Chen F
… +10 more, Zheng L, Li J, Qi L, Wu G, Wang X, Xu F, Cho JY, Hu W, Zhu H, Gu F
Phytomedicine
· 2026 Jun · PMID 42364560
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BACKGROUND: Excessive or aberrant activation of the NLRP3 inflammasome is implicated in the initiation and progression of various inflammatory diseases. PURPOSE: This study aimed to investigate whether piperine (PIP) inh...BACKGROUND: Excessive or aberrant activation of the NLRP3 inflammasome is implicated in the initiation and progression of various inflammatory diseases. PURPOSE: This study aimed to investigate whether piperine (PIP) inhibited NLRP3 inflammasome activation and disrupting the NEK7-NLRP3 interaction, and to evaluate its anti-inflammatory effects in vivo. METHODS: We identified NLRP3 as a potential target of PIP through COMET database and RNA sequencing. A classic NLRP3 inflammasome activation model was established in immortalized bone marrow-derived macrophages (iBMDMs) primed with lipopolysaccharide (LPS) and then activated with nigericin. Protein interactions and binding modes were analyzed using co-immunoprecipitation and molecular modeling. The protective effects of PIP were evaluated in mouse models of acute lung injury and colitis. RESULTS: PIP effectively inhibited NLRP3 inflammasome activation without affecting NLRC4 or AIM2 inflammasome. Furthermore, PIP blocked NLRP3 protein oligomerization and ASC recruitment, and inhibited inflammasome assembly by interfering with NEK7-NLRP3 interaction. Molecular simulation confirmed that PIP binds noncovalently to NLRP3 at lysine 232 via a hydrogen bond, and mutating this residue to alanine eliminated its inhibitory effect on the NEK7-NLRP3 interaction. In vivo, PIP markedly alleviated LPS-induced acute lung injury and dextran sulfate sodium-induced colitis by reducing inflammatory responses. CONCLUSION: These findings demonstrate that PIP inhibited NLRP3 inflammasome activation by targeting Lys232 and exerted potent anti-inflammatory effects in vivo, supporting its potential as a therapeutic candidate for NLRP3-driven inflammatory diseases.