Phytomedicine [JOURNAL]
Sun
200 papers
Ma-Xing-Shi-Gan decoction alleviates allergic asthma by modulating the gut microbiota-tryptophan metabolism-ILC2 axis.
Lv M, Wang C, Hong Y … +7 more , Ye F, Cao X, Zheng Z, Zhang E, Liu J, Jia A, Peng G
Phytomedicine · 2026 Aug · PMID 42287819 · Publisher ↗
BACKGROUND: Ma-Xing-Shi-Gan decoction (MXSG) shows clinical efficacy in asthma, yet how it shapes gut-lung immunity-particularly type 2 innate lymphoid responses-remains poorly defined. PURPOSE: To investigate whether MX...
BACKGROUND: Ma-Xing-Shi-Gan decoction (MXSG) shows clinical efficacy in asthma, yet how it shapes gut-lung immunity-particularly type 2 innate lymphoid responses-remains poorly defined. PURPOSE: To investigate whether MXSG mitigates asthma by restraining group 2 innate lymphoid cells (ILC2s) via a gut microbiota-tryptophan metabolic pathway, and to identify microbiota-dependent active compounds. METHODS: An asthma mouse model was used. ILC2 in the lung and intestinal lamina propria were assessed by flow cytometry. Rag1 mice were used to assess T and B cell-independent effects. Untargeted fecal metabolomics and antibiotic-mediated microbiota depletion were conducted to evaluate metabolic and microbial contributions. Microbiota-dependent MXSG constituents were traced using anaerobic fecal fermentation coupled with LC-MS/MS profiling, followed by in vivo validation. RESULTS: MXSG significantly alleviated pulmonary inflammation, reduced bronchoalveolar lavage eosinophils and improved histopathology. It decreased ILC2s populations in lung and gut. These effects were preserved in Rag1 mice but abolished with antibiotics pretreatment, indicating microbiota dependence. Metabolomics revealed that MXSG reprogrammed tryptophan metabolism, restoring tryptamine and rebalancing kynurenine, indole, and serotonin-related branches. Anaerobic fermentation and LC-MS/MS profiling identified microbiota-dependent flavonoids, and isorhamnetin partially reproduced the anti-inflammatory and ILC2-modulating effects in vivo. CONCLUSION: MXSG exerts its anti-asthmatic effects via the gut microbiota-tryptophan metabolism-ILC2 axis. These findings reveal a novel gut-lung mechanism centered on type 2 innate immunity and microbiota-derived indole metabolism.
Cepharanthine triggers immunogenic cell death in solid tumors by suppressing protein kinase C zeta-mediated poly(ADP-ribose) polymerase 1 expression and synergizes with immunotherapy.
Chen K, Gui L, Chen P … +5 more , Wang Z, Zheng Z, Luo W, Gao WQ, Ma B
Phytomedicine · 2026 Aug · PMID 42287818 · Publisher ↗
BACKGROUND: Immunogenic cell death (ICD) represents a promising strategy to suppress tumor growth and potentiate immunotherapy efficacy, driving the demand for novel and clinically translatable ICD inducers. Here, we inv...
BACKGROUND: Immunogenic cell death (ICD) represents a promising strategy to suppress tumor growth and potentiate immunotherapy efficacy, driving the demand for novel and clinically translatable ICD inducers. Here, we investigated the potential of cepharanthine (CEP) for inducing ICD in multiple representative solid tumors. METHODS: The ICD-inducing potential of a series of natural alkaloids was screened by flow cytometry. CEP's activity and mechanism were characterized using flow cytometry, western blot, immunofluorescence, ATP quantification, cell thermal shift assay (CETSA), surface plasmon resonance (SPR), bulk and single-cell RNA sequencing. The translational potential of CEP, either as monotherapy or in combination with other immunotherapies, was evaluated in both syngeneic mouse tumor models and patient-derived organoid systems. Toxicity in mice was assessed through hematological and biochemical parameters. RESULTS: CEP effectively induced ICD in multiple representative solid tumor models (breast cancer, colorectal cancer, esophageal cancer, liver cancer, lung cancer) by promoting damage-associated molecular patterns (DAMPs) release, enhancing phagocytosis by antigen-presenting cells, and activating T cell-mediated immunity. Mechanistically, CEP directly bound to protein kinase C zeta (PKCζ), leading to the inhibition of NF-κB signaling via suppressing p65 nuclear translocation, and downregulation of poly ADP-ribose polymerase 1 (PARP1) transcription. PARP1 downregulation triggers intracellular reactive oxygen species (ROS) accumulation, subsequently inducing DNA damage and endoplasmic reticulum (ER) stress. Furthermore, CEP synergized with PD-1 blockade and OX40 agonism, thereby enhancing antitumor efficacy in vivo. CONCLUSIONS: CEP is a potent and preclinically well-tolerated ICD inducer that acts by targeting the PKCζ/NF-κB/PARP1 axis. Its synergy with immune checkpoint inhibitors and co-stimulatory agonists underscores its translational potential for combination cancer immunotherapy.
Curcumin: A therapeutic phytochemical in multi-target hallmarks of cancer.
Tamilselvan P, Aishwarya S, Praveen Kumar PK
Phytomedicine · 2026 Aug · PMID 42287817 · Publisher ↗
BACKGROUND: Cancer remains a major global health challenge due to its complex molecular heterogeneity, therapeutic resistance, and severe treatment-associated toxicities. In recent years, increasing attention has been di...
BACKGROUND: Cancer remains a major global health challenge due to its complex molecular heterogeneity, therapeutic resistance, and severe treatment-associated toxicities. In recent years, increasing attention has been directed toward natural bioactive compounds as complementary or alternative anticancer agents. Curcumin, a polyphenolic compound derived from Curcuma longa, has emerged as a promising multi-targeted phytochemical with broad anticancer potential. OBJECTIVE: This review aims to comprehensively summarize the chemical, molecular, pharmacological, and computational insights into curcumin's anticancer mechanisms and to evaluate its potential role in modern precision oncology. KEY FINDINGS: Extensive preclinical and computational studies demonstrate that curcumin modulates multiple oncogenic pathways involved in cancer initiation, progression, and metastasis. Curcumin regulates key transcription factors such as NF-κB and STAT3, induces apoptosis through both intrinsic and extrinsic pathways, and suppresses angiogenesis and tumor invasion. However, its clinical translation has been limited by poor bioavailability and rapid systemic elimination. Recent advances in nanotechnology, targeted delivery systems, and computational modelling offer promising strategies to overcome these limitations. CONCLUSION: This review highlights that curcumin demonstrates strong mechanistic and preclinical activity across multiple cancer hallmarks, but its translational relevance remains uneven and strongly dependent on formulation, delivery strategy, and cancer context. By integrating hallmark biology with computational oncology, systems-level analysis, and translational nanomedicine, this review provides a more structured and contemporary phytomedicine-based perspective for cancer therapy.
Sweroside attenuates heart failure with preserved ejection fraction via targeting PCSK9-CD36 interaction to reduce cardiac-hepatic lipotoxicity.
Wang D, He A, Gao K … +6 more , Yu X, Li F, Jiang F, Pu H, Chang J, Guo S
Phytomedicine · 2026 Aug · PMID 42287816 · Publisher ↗
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is characterized by cardiac and hepatic lipotoxicity, necessitating effective therapeutic strategies. Sweroside, a natural compound with significant phar...
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is characterized by cardiac and hepatic lipotoxicity, necessitating effective therapeutic strategies. Sweroside, a natural compound with significant pharmacological activity, is widely investigated in pharmacological studies of cardiovascular and fatty liver diseases. However, its effects and mechanisms against HFpEF remain unclear. OBJECTIVE: To investigate the effects of sweroside on cardiac function and cardiac/hepatic lipotoxicity in HFpEF mice, and to explore the underlying molecular mechanisms and targets. METHODS: An HFpEF mouse model was established using a high-fat diet and l-NAME. Echocardiography, lipidomics, Masson staining, and Oil Red O staining were employed to assess the cardioprotective effects of sweroside, including the reduction of inflammation and inhibition of cardiac and hepatic lipid deposition in HFpEF mice. The effects of sweroside on lipotoxicity and inflammation induced by palmitic acid (PA) and oleic acid (OA) in H9c2, AC16, AML12, and HepG2 cells were investigated using immunofluorescence, flow cytometry, and Oil Red O staining. Western blot, co-immunoprecipitation, molecular docking, SPR, and LC-MS/MS were used to identify the direct binding of sweroside to CD36 and its impact on the PCSK9-CD36 complex. Finally, the regulatory role of sweroside on CD36 was confirmed using CD36-siRNA-transfected H9c2 cardiac cells and CD36-KO HepG2 cells. RESULTS: Sweroside significantly improved cardiac function and inhibited cardiac lipid deposition in HFpEF mice. Lipidomics results indicated that the improvement in cardiac function by sweroside was associated with the inhibition of inflammation and regulation of mitochondrial function. Consequently, sweroside significantly reduced the mitochondrial aggregation of the NLRP3 inflammasome in cardiac tissue, thereby suppressing the levels of IL-1β and IL-18. In both HFpEF mice and PA+OA-stimulated H9c2 and AC16 cardiac cell models, the ability of sweroside to inhibit lipid deposition, reduce NLRP3 inflammasome activation, and improve myocardial mitochondrial oxidative phosphorylation was potentially related to the downregulation of CD36. Furthermore, sweroside exerted a positive effect on hepatic lipid deposition in HFpEF mice. Similar effects were observed in PA+OA-stimulated AML12 and HepG2 cells, and this action was found to depend on the formation of the PCSK9-CD36 complex. Through methods including molecular docking, SPR, and LC-MS/MS, CD36 was identified as a potential direct binding target of sweroside. In CD36-siRNA-transfected H9c2 cardiac cells and CD36-KO HepG2 cells, the ability of sweroside to alleviate lipid deposition and inflammation was inhibited. CONCLUSION: This study reveals the pharmacological mechanism by which sweroside, by targeting the PCSK9-CD36 complex, inhibits the mitochondrial accumulation of the myocardial NLRP3 inflammasome, reduces inflammatory responses, reverses the hepatic lipid deposition phenotype, and improves cardiac function in HFpEF mice. Collectively, these findings provide a solid experimental basis for the development of anti-HFpEF therapeutics.
Patchouli oil and its main component patchouli alcohol inhibit colorectal cancer by activating ectopic olfactory receptor.
Zhao H, Jin M, Yu S … +8 more , Zhao C, Yang J, Du H, Mao Z, Cao L, Huang S, Bai L, Miao M
Phytomedicine · 2026 Aug · PMID 42287815 · Publisher ↗
BACKGROUND: Growing evidence suggests that ectopic olfactory receptors are involved in regulating various physiological functions, including the progression of colorectal cancer (CRC). Patchouli oil, the primary bioactiv...
BACKGROUND: Growing evidence suggests that ectopic olfactory receptors are involved in regulating various physiological functions, including the progression of colorectal cancer (CRC). Patchouli oil, the primary bioactive volatile fraction of Pogostemon cablin (Blanco) Benth (P. cablin), demonstrates potent anti-colorectal cancer activity, though its precise mechanism of action remains incompletely understood. OBJECTIVE: This project aims to investigate the anti-CRC effects of patchouli oil, with a focus on elucidating its regulatory mechanisms involving the ectopic olfactory receptor OR13G1, the CaMKK2/AMPK signaling pathway, and ferroptosis, and to identify its crucial active constituents. METHODS: An AOM/DSS-induced CRC mouse model was used to evaluate patchouli oil's effects on tumor development, inflammation, and pathological changes. Differential protein expression and pathways were analyzed via 4D-FastDIA proteomics. Mechanisms related to OR13G1, CaMKK2/AMPK, and ferroptosis were further examined in CT26 and HCT116 cell lines. Chemical constituents were identified via GC-MS, followed by the quantification of anti-tumor bioactive components. Patchouli alcohol was subsequently identified as the key active ingredient through screening in HCT116 cell models. The in vivo and in vitro efficacy and mechanisms were validated using a mouse model in conjunction with inhibitors/agonists of ferroptosis or relevant signaling pathways. RESULTS: Patchouli oil significantly improved survival, suppressed tumor growth, attenuated inflammation, and alleviated pathological damage. It up-regulated OR13G1, activated the CaMKK2/AMPK pathway, and induced ferroptosis. In vitro, it inhibited proliferation, migration, and colony formation while promoting ferroptosis. Patchouli alcohol was identified as the crucial anti-CRC constituent, exerting effects through OR13G1-CaMKK2/AMPK axis modulation and ferroptosis induction. CONCLUSION: Patchouli oil inhibits CRC progression by upregulating OR13G1, modulating CaMKK2/AMPK signaling, and inducing ferroptosis, with patchouli alcohol as its primary active constituent.
Saikosaponin A restores the IDO1-driven gut-testis kynurenine axis to alleviate oligozoospermia.
Li Y, Zhang B, He G … +14 more , Shen C, Chang F, Yang J, Wang S, Wang Y, Zong J, Luo Y, Wang N, Sun Y, Sui Y, Wu M, Lu D, Li C, Zhou X
Phytomedicine · 2026 Aug · PMID 42287814 · Publisher ↗
BACKGROUND: Busulfan (Bus)-induced oligozoospermia still lacks a disease-modifying therapy, and its pathogenesis has been largely attributed to germ-cell DNA damage. Emerging evidence indicates that microbiota-derived me...
BACKGROUND: Busulfan (Bus)-induced oligozoospermia still lacks a disease-modifying therapy, and its pathogenesis has been largely attributed to germ-cell DNA damage. Emerging evidence indicates that microbiota-derived metabolites are key determinants of spermatogenic failure. Saikosaponin A (SSA), a major triterpenoid from Bupleurum, has never been evaluated in male infertility. Consequently, its regulatory role in the gut microbiota-metabolite axis and causal efficacy remain completely undefined. PURPOSE: To determine whether SSA rescues Bus-induced oligozoospermia via the gut microbiota-metabolite axis, and to uncover a novel pathogenic mechanism of Bus, beyond the known germ-cell DNA damage pathway, revealing a gut microbiota-metabolite-mediated regulatory axis. METHODS: Bus-induced oligozoospermia was established in male C57BL/6 J mice and followed by SSA treatment. Sperm count, testis index, and histology were assessed; spermatogenic proteins were quantified by Western blot. Microbiota and metabolites were profiled via 16S rDNA sequencing; serum metabolomics; and fecal microbiota transplantation (FMT) from SSA donors. Testicular transcriptome sequencing identified differentially expressed pathways. Indole-3-carboxaldehyde (ICA) administration and Kynurenine (Kyn) supplementation were performed in parallel. Indoleamine 2,3-dioxygenase 1 (IDO1) protein level and activity were measured by Western blot and ELISA. ICA-IDO1 interaction was verified by molecular docking and surface plasmon resonance (SPR). The l-tryptophan/L-kynurenine ratio was determined by targeted liquid chromatography-mass spectrometry (LC-MS/MS). RESULTS: SSA restored sperm count, testis index, and tubular architecture while increasing DDX4, DAZL, and SYCP1/3. It reversed Bus-induced Lactobacillus expansion, decreased colonic ICA, relieved ICA-mediated IDO1 inhibition, thereby restoring colonic IDO1 activity, and elevated Kyn. FMT from SSA donors reproduced these protective effects. Transcriptomics showed up-regulation of AKT-mediated targets: pro-growth (CCND1), antioxidant (NRF2), and anti-apoptotic (Bcl-2), with down-regulation of pro-apoptotic genes. Mechanistically, SSA reshaped the gut microbiota, lowered colonic ICA, relieved ICA-mediated IDO1 inhibition, and restored Kyn-dependent testicular antioxidant and anti-apoptotic signaling. CONCLUSION: By reshaping the gut microbiota, reducing colonic ICA and relieving ICA-mediated IDO1 inhibition, SSA restored Kyn-driven testicular antioxidant and anti-apoptotic signaling. This suggests a microbiota-directed, non-hormonal candidate preclinical approach for Bus-induced oligozoospermia; the gut microbiota-ICA-IDO1-Kyn axis offers a framework awaiting human validation.
Licochalcone A protects against cisplatin-induced acute kidney injury via the modulation of Nrf2/Keap1-mediated ferroptosis and apoptosis.
Li C, Yang H, Chen M … +4 more , Wang S, Wang Y, Yuan P, Shen F
Phytomedicine · 2026 Aug · PMID 42287813 · Publisher ↗
BACKGROUND: The use of cisplatin (CP), a widely used chemotherapeutic agent, is severely limited by the high incidence of CP-induced acute kidney injury (AKI). Licochalcone A (Lico A) is a natural chalcone isolated from...
BACKGROUND: The use of cisplatin (CP), a widely used chemotherapeutic agent, is severely limited by the high incidence of CP-induced acute kidney injury (AKI). Licochalcone A (Lico A) is a natural chalcone isolated from Glycyrrhiza inflata that has multiple beneficial effects, but its potential role in CP-induced AKI through apoptosis and ferroptosis remains unclear. PURPOSE: To investigate the therapeutic effects of Lico A on CP-induced AKI and clarify the underlying molecular mechanisms. MATERIALS AND METHODS: In vivo and in vitro models of CP-induced AKI were established using male C57BL/6 mice and human renal proximal tubular epithelial HK2 cells, respectively, to systematically evaluate the renoprotective effects of Lico A. Renal function parameters and kidney injury biomarkers were measured in the mice. Mitochondrial function, oxidative stress, lipid peroxidation, and key indices related to apoptosis and ferroptosis were also assessed. RESULTS: Lico A treatment significantly ameliorated CP-induced AKI, accompanied by reduced serum levels of urea nitrogen and creatinine, downregulated expression of kidney injury molecule-1 and neutrophil-gelatinase-associated lipocalin, and attenuated renal histopathological damage. In vivo and in vitro, Lico A reduced CP-triggered renal apoptosis and the expression of apoptosis-related proteins. Additionally, Lico A mitigated ferroptosis by suppressing iron overload, oxidative stress, lipid peroxidation and mitochondrial dysfunction. Lico A also markedly activated nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling. Notably, pharmacological inhibition of Nrf2 with ML385 abolished the renoprotective effect of Lico A, as well as its suppression of apoptosis and ferroptosis. CONCLUSION: This study demonstrated that Lico A exerts significant renoprotective effects against CP-induced AKI. The underlying renoprotective mechanism involves activation of the Nrf2/Keap1 pathway, which in turn inhibits apoptosis and ferroptosis in renal tubular epithelial cells. Lico A therefore shows promise as a potential therapeutic candidate for the prevention and treatment of CP chemotherapy-associated kidney injury.
Ethyl acetate fraction of Chaidangbo prescription (EAFC) improves hippocampal neural plasticity in CUMS mice: involving glucocorticoid receptors and Akt-related signaling pathway.
Zeng J, Tang Y, Zhao A … +8 more , Yang J, Zhang X, Qi H, Peng Q, Su Y, Liu R, Peng X, Zeng N
Phytomedicine · 2026 Aug · PMID 42284647 · Publisher ↗
BACKGROUND: The Chaidangbo prescription is an antidepressant traditional Chinese medicine (TCM) prescription derived by simplifying Xiaoyaosan (a classic antidepressant TCM prescription) through dismantling research. Whi...
BACKGROUND: The Chaidangbo prescription is an antidepressant traditional Chinese medicine (TCM) prescription derived by simplifying Xiaoyaosan (a classic antidepressant TCM prescription) through dismantling research. While it shows promising antidepressant efficacy, its material basis and mechanism remain unelucidated. PURPOSE: This study sought to identify the material basis and mechanisms by which EAFC enhances hippocampal neuroplasticity in CUMS mice. METHODS: The active ingredients in EAFC were quantified using HPLC. Depressive-like behaviors in CUMS mice were assessed behavioral test, alongside evaluation of hippocampal neuronal morphology, synaptic signaling, apoptosis, and neurogenesis. Integrated non-targeted metabolomics and network pharmacology predicted EAFC's mechanisms for restoring neuroplasticity in depression, with enrichment-derived targets and pathways validated. In vitro studies on CORT-stimulated HT22 cells, combined with MK-2206 (Akt inhibitor) or ANA-12 (TrkB inhibitor) treatment, further confirmed EAFC's effects and mechanisms. RESULTS: HPLC analysis identified ferulic acid, saikosaponin A, and rosmarinic acid as the main constituents of EAFC. EAFC significantly attenuated depression-like behaviors including anhedonia, behavioral despair and reduced exploration; improved synaptic structure and functional plasticity in the mouse hippocampus, maintained neuronal integrity, and restored neurogenesis. Furthermore, metabolomics identified disturbances in apoptosis and mTOR signaling, while network pharmacology predicted AKT1 and NR3C1 as key targets, with the PI3K/Akt pathway as a hub-findings which were subsequently validated by Western blot. In vitro research demonstrated that EAFC reduced structural damage and apoptosis in HT22 cells while enhancing DCX expression. More importantly, MK-2206 but not ANA-12 reversed the effect of EAFC on GR nuclear translocation, and further findings revealed that EAFC increases the binding between GR and Akt. CONCLUSION: In summary, EAFC alleviates depressive behaviors and restores neuroplasticity by activating the TrkB/PI3K/Akt axis to enhance neuroplasticity, and independently, by increasing Akt-GR interaction to restrain GR nuclear translocation. This dual mechanism highlights a novel coordinated integration between neurotrophic and glucocorticoid systems.
Screening and enrichment of quercetin from Tetrastigma hemsleyanum Diels & Gilg toward targeted micellar delivery for lung cancer therapy.
Wang D, Ye J, Wang Z … +3 more , Zou J, Yu B, Cong H
Phytomedicine · 2026 Aug · PMID 42284646 · Publisher ↗
BACKGROUND: Lung cancer is one of the malignant tumors with the highest mortality in the world. Quercetin (Qu) is a flavonoid compound isolated from Tetrastigma hemsleyanum Diels & Gilg (SYQ), which has multi-target anti...
BACKGROUND: Lung cancer is one of the malignant tumors with the highest mortality in the world. Quercetin (Qu) is a flavonoid compound isolated from Tetrastigma hemsleyanum Diels & Gilg (SYQ), which has multi-target anti-tumor activity. However, there are problems such as low extraction purity, poor water solubility, and difficulty in targeted delivery. Its anti-lung cancer mechanism remains to be elucidated. OBJECTIVE: To investigate the enrichment of Qu by molecularly imprinted polymers (MIPs) and to construct targeted micelles to improve its solubility, tumor targeting, and bioavailability and to explore its anti-lung cancer mechanism by in vitro cell experiments and in vivo animal models. METHODS: The static adsorption performance of Qu in SYQ extract was evaluated by MIPs. Key targets and pathways were predicted by network pharmacology and molecular docking. The targeted micelles were constructed, and their particle size, morphology, drug loading, and release behavior were characterized. The cytotoxicity and migration inhibition of free Qu and drug-loaded micelles on H1299 and A549 cells were evaluated by MTT assay, crystal violet staining, live/dead cell staining, and scratch healing assay. The uptake efficiency of Qu and the change of intracellular reactive oxygen species level were observed by confocal microscopy. The expression of the PI3K/AKT pathway protein was detected by Western blot, and the H1299 tumor-bearing mouse model was established to evaluate the in vivo distribution and anti-tumor effect. RESULTS: Qu was isolated and identified from SYQ extracts using ¹HNMR, MALDI-TOF, Q-TOF LC/MS, and FTIR. When the ratio of Qu to acrylamide was 1:7, the equilibrium adsorption capacity for Qu reached 393.26 μg/g. In network pharmacology, Qu and non-small cell lung cancer (NSCLC) shared 111 common target proteins, with a binding energy of -8.71 kcal/mol between Qu and the BCL-2. The HPP@Qu micelles exhibited a particle size of 107.75 nm, a drug loading capacity of 6.57%, and a cumulative release rate of 55.15% at 72 h. HPP@Qu significantly inhibited the viability and migration of H1299 cells, increased intracellular reactive oxygen species (ROS) levels, downregulated p-PI3K, p-AKT, and BCL-2 proteins, and upregulated cleaved caspase-3. Furthermore, HPP@Qu effectively accumulated in tumor tissues, suppressed tumor growth in tumor-bearing mice, and showed no obvious toxicity to major organs. CONCLUSION: MIPs selectively enrich high-purity Qu from SYQ. Targeted micelles enhance Qu's solubility and tumor targeting, effectively inhibiting tumor growth. Qu induces H1299 cell apoptosis by elevating ROS levels, suppressing the PI3K/AKT pathway, downregulating BCL-2, and activating Caspase-3. These findings reflect the research value of Qu as a potential natural anticancer candidate drug.
Simiao Yongan decoction alleviates sepsis-induced liver injury by modulating macrophage polarization via gut-derived ursodeoxycholic acid.
Yu T, Liu Z, Liu Y … +6 more , Gao M, Guo F, Liu Y, Xiong J, Jiang Y, Yan S
Phytomedicine · 2026 Aug · PMID 42284645 · Publisher ↗
BACKGROUND: Sepsis-induced liver injury (SLI) is a severe complication of sepsis; however, its pathogenesis remains incompletely understood, and effective therapeutic agents are still lacking. PURPOSE: This study was to...
BACKGROUND: Sepsis-induced liver injury (SLI) is a severe complication of sepsis; however, its pathogenesis remains incompletely understood, and effective therapeutic agents are still lacking. PURPOSE: This study was to analyze alterations in metabolic profiles in patients with sepsis and to elucidate the mechanisms by which the traditional Chinese medicine formula Simiao Yongan (SMYA) Decoction ameliorates SLI through an integrated multi-omics approach. METHODS: An integrated multi-omics approach, including metabolomics, transcriptomics, 16S rRNA sequencing, and mass spectrometry, was employed to investigate metabolic alterations in sepsis and to elucidate the protective mechanisms of SMYA against sepsis-induced liver injury. Subsequently, immunofluorescence staining, Western blot analysis, and Surface plasmon resonanc (SPR) were performed to evaluate the regulatory effects of SMYA and ursodeoxycholic acid (UDCA) on macrophage polarization. Finally, an ApoB-modified liposome delivery system was constructed to enhance drug delivery efficiency and therapeutic efficacy. RESULTS: We observed that serum UDCA levels were markedly reduced in patients with sepsis and were inversely correlated with the expression of pro-inflammatory mediators. SMYA ameliorated SLI by enhancing intestinal UDCA biosynthesis. Mechanistically, UDCA inhibited TLR4/NF-κB-mediated macrophage polarization, thereby attenuating hepatic inflammatory responses. In addition, an ApoB-modified liposome delivery system significantly enhanced the therapeutic efficacy of UDCA. CONCLUSION: we elucidated that the Gut microbiota-UDCA-Macrophage axis underlies the hepatoprotective effects of SMYA, offering a promising integrative therapeutic strategy for SLI.
Modulating the neuroendocrine-immune network in depression: Therapeutic targets and pharmacological mechanism of natural products.
Liu J, Sun M, Wang F … +8 more , Gao H, Lu Y, Ma H, Shang R, Zhong X, Yi Y, Yu X, Lv S
Phytomedicine · 2026 Aug · PMID 42284644 · Publisher ↗
BACKGROUND: Major depressive disorder (MDD) represents a significant global public health challenge, yet the complexity of its pathophysiology has long hindered meaningful advancements in clinical precision medicine. Wit...
BACKGROUND: Major depressive disorder (MDD) represents a significant global public health challenge, yet the complexity of its pathophysiology has long hindered meaningful advancements in clinical precision medicine. With the advent of systems biology, the dysregulation of the neuroendocrine-immune (NEI) network has been identified as the core pathological foundation mediating the onset and progression of depression. This discovery provides a critical entry point to overcome the limitations of single-target therapies. Plant-derived natural products, with their unique advantages of multicomponent synergy, multitarget action, and multipathway regulation, show significant therapeutic potential by indirectly remodeling NEI network homeostasis through modulation of key physiological intermediates. However, a comprehensive review detailing the specific role of the NEI network in the pathogenesis of depression, and the mechanisms by which natural products systematically regulate this network, is currently lacking in the literature. PURPOSE: This review aims to systematically elucidate the pivotal role of the NEI network in the pathology of depression, explore the molecular mechanisms and key targets of natural product interventions within this network, and critically assess current challenges related to toxicological evaluation, mechanistic understanding, and clinical translation. Ultimately, the review seeks to provide a solid theoretical foundation and strategic guidance for the development of novel antidepressant drugs based on natural products. METHODS: To investigate the primary pharmacological mechanisms by which natural products regulate the NEI network to treat depression, we conducted a comprehensive search across multiple databases, including PubMed, Web of Science, and ScienceDirect. We then categorized and synthesized the relationship between the NEI network and depression, as well as the regulatory mechanisms of natural products. RESULTS: Numerous studies indicate that abnormalities in the NEI network play a central role in the pathology of depression and that modulation of this network is intrinsically linked to the efficacy of antidepressants. Natural products, including flavonoids, terpenoids, saccharides, and saponins, regulate the NEI system through various multidimensional pathways to exert antidepressant effects. CONCLUSIONS: We have consolidated the role of natural products in regulating the NEI network within the context of antidepressant therapy, offering a unique perspective on their application. Nevertheless, it is crucial to invest substantial efforts in both clinical and preclinical research to further elucidate the mechanisms by which antidepressant agents influence the NEI network. This step is essential for the development of effective therapeutic interventions.
Chikusetsusaponin V improves vascular endothelial dysfunction by binding to ITGB1 and mediating PURA-eNOS activation in mice with diabetes mellitus.
Zuo D, Lv D, Zhao G … +9 more , Chen Y, Chen Z, Pu L, Luo M, Tang M, Wang M, He A, Xiong W, Li X
Phytomedicine · 2026 Aug · PMID 42284643 · Publisher ↗
BACKGROUND: Vascular endothelial dysfunction is a core pathological feature of diabetes-associated vascular complications, primarily driven by impaired nitric oxide (NO) bioavailability due to dysregulated endothelial ni...
BACKGROUND: Vascular endothelial dysfunction is a core pathological feature of diabetes-associated vascular complications, primarily driven by impaired nitric oxide (NO) bioavailability due to dysregulated endothelial nitric oxide synthase (eNOS) activity. While pharmacological strategies targeting the eNOS pathway have shown promise, the discovery of natural compounds capable of restoring endothelial function through novel molecular targets remains an important research direction. PURPOSE: The aim of this study was to investigate the targets and molecular mechanisms of Chikusetsusaponin V (CsV) in regulating vascular endothelial function in diabetes mellitus (DM). METHODS: The DM models were constructed using db/db mice and high-glucose cultured human aortic endothelial cells (HAECs). The vasodilatory function was investigated using techniques such as metal wire microvascular tension measurement and ultrasonography after intervention with CsV. Modern techniques such as affinity chromatography, mass spectrometry, molecular docking and microscale thermophoresis (MST) test were used to identify the direct targets of CsV. The key pathways and downstream transcription factors involved in the improvement of vasodilatory function of CsV were screened using RNA-Seq. Subsequent validation was performed using a dual luciferase assay. Knockdown adenoviral vectors, quantitative polymerase chain reaction (qPCR), and Western blot (WB) were used to elucidate the molecular mechanism of CsV in regulating the vasodilatory function in DM. RESULTS: The results showed that CsV down-regulated blood glucose and increased the expression of eNOS and p-eNOS (S1177), which improved vasodilatation and reduced vascular stiffness in DM mice. Additionally, CsV increased NO release and tube-forming capacity of HAECs. CsV can directly bind to the membrane protein ITGB1. In vivo and in vitro experiments showed that administration of CsV after knockdown of ITGB1 or inhibiting PI3K significantly down-regulated the expression of p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, NR4A3, PURA, and p-eNOS (S1177)/eNOS, decreased NO levels, and affected angiogenesis and endothelial cell function. In contrast, overexpression of ITGB1 produced the opposite results. Moreover, knockdown NR4A3 inhibited NR4A3/PURA/eNOS expression and affected endothelial function, whereas overexpression produced the opposite result. CONCLUSIONS: CsV improves endothelial function in DM vasculature by targeting ITGB1, enhancing eNOS phosphorylation via the PI3K/AKT pathway, and promoting PURA/eNOS expression through PI3K/AKT/mTOR/NR4A3. These findings support CsV's potential use for improving diabetes vascular function.
Lipid-mediated broad-spectrum antiviral mechanism of alpha-linolenic acid against respiratory enveloped viruses.
Feng Y, Benma L, Li J … +5 more , Shi X, Zhao J, Zeng H, Tang J, Zhu H
Phytomedicine · 2026 Aug · PMID 42284642 · Publisher ↗
BACKGROUND: α-Linolenic acid (ALA), an essential plant-derived polyunsaturated fatty acid with high safety, has been preliminarily shown to possess antiviral activity in vitro. However, the lack of in vivo activity evalu...
BACKGROUND: α-Linolenic acid (ALA), an essential plant-derived polyunsaturated fatty acid with high safety, has been preliminarily shown to possess antiviral activity in vitro. However, the lack of in vivo activity evaluation and mechanism research has limited the understanding of its precise antiviral mechanism and therapeutic potential. PURPOSE: This study elucidates the mechanism by which ALA disrupts viral lipid envelopes, conferring broad-spectrum antiviral activity, and evaluates its feasibility as a natural botanical agent against respiratory enveloped viruses. METHODS: ALA (100 μM) was tested against H1N1, H3N2, and HCoV-229E in vitro. Its protective effect on the lungs were evaluated via intranasal and intraperitoneal administration in vivo. Raman spectroscopy, transmission electron microscopy, immunohistochemistry, and other techniques were employed to investigate the effects of ALA on viral envelopes, host membrane lipid signaling, pulmonary surfactant, lipoxygenases, and B-cell function. Additionally, a simulated mask application was tested to evaluate its practical antiviral potential. RESULTS: ALA exhibited differential effects on viral and host membranes. Transmission electron microscopy and Raman spectroscopy confirmed that it disrupts viral envelopes while restoring the lipid balance of host membranes. Intranasal administration reduced viral loads and tissue damage in H1N1-infected mice, enhanced pulmonary surfactant and lipoxygenase levels independently of B-cell activation. ALA also showed broad-spectrum activity against HCoV-229E and H3N2, and further simulated mask tests confirmed that ALA significantly impaired viral infectivity. CONCLUSION: This work establishes a unique dual mode of viral membrane destruction and host membrane protection for ALA. It innovatively reveals the lipid-targeted antiviral advantage of natural plant lipids, offering novel mechanistic insights and support for developing phytomedicine-based antiviral interventions.
Lysine β-hydroxybutyrylation: A metabolic-epigenetic interface in health and disease.
Chen C, Chen X, Lyu X … +4 more , Yao L, Ge S, Yu M, Sang R
Phytomedicine · 2026 Aug · PMID 42284641 · Publisher ↗
BACKGROUND: Lysine β-hydroxybutyrylation (Kbhb) is a β-hydroxybutyrate-derived lysine acylation that connects ketone-body metabolism with chromatin regulation and non-histone protein function. Initially described as a fa...
BACKGROUND: Lysine β-hydroxybutyrylation (Kbhb) is a β-hydroxybutyrate-derived lysine acylation that connects ketone-body metabolism with chromatin regulation and non-histone protein function. Initially described as a fasting-responsive histone mark, Kbhb is now implicated in immune memory, metabolic adaptation, cancer metabolism and neuroprotection. PURPOSE: This Review reframes Kbhb as a context-dependent metabolic acylation system. We discuss the metabolic origin of β-hydroxybutyryl-CoA, the writer, reader and eraser machinery of Kbhb, its crosstalk with acetylation, lactylation and crotonylation, and the evidence standards required to distinguish Kbhb-driven mechanisms from broader β-hydroxybutyrate biology. MAJOR ADVANCES: Recent studies have identified p300/CBP as a Kbhb writer, HDACs and sirtuins as erasers, and ENL as an H3K9bhb reader. Kbhb has also been linked to CD8 T-cell memory, fasting-responsive chromatin remodeling, tumor metabolic rewiring and non-histone protein regulation. However, shared enzymes, overlapping acylation programs and pleiotropic BHB signaling complicate causal attribution. CONCLUSION: Kbhb should not be viewed as uniformly beneficial or pathological. Instead, its effects depend on donor availability, site specificity, reader engagement, tissue context, disease stage and competing acylations. Future work should prioritize site-resolved mass spectrometry, validated chromatin profiling, parallel acylome analysis, functional perturbation and clinically interpretable biomarkers to define which Kbhb events are causal and therapeutically actionable.
Eupatilin inhibits non-small cell lung cancer metastasis by suppressing Netrin-1-mediated epithelial-mesenchymal transition.
Xu B, Hu L, Jiang B … +5 more , Qi Y, Yan L, Zhang J, Yu Y, Miao Q
Phytomedicine · 2026 Aug · PMID 42284640 · Publisher ↗
BACKGROUND: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, primarily attributed to distant metastasis. The trimethoxyflavone eupatilin (Eup), a major flavonoid derived from the leaves...
BACKGROUND: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, primarily attributed to distant metastasis. The trimethoxyflavone eupatilin (Eup), a major flavonoid derived from the leaves of Artemisia argyi, exhibits potential antitumor properties. However, its effects and underlying mechanisms in NSCLC have been inadequately elucidated. PURPOSE: To investigate the efficacy of Eup against NSCLC and elucidate its molecular targets and mechanisms, particularly focusing on its effects on epithelial-mesenchymal transition (EMT). METHODS: A lung metastasis model was established via tail vein injection of NCI-H1299 cells. In vitro, Eup's effects on proliferation, migration, invasion, and cell cycle in NCI-H1299/H23 cells were assessed using CCK-8, colony formation, wound healing, Transwell, EdU, and flow cytometry assays. Western blotting was employed to analyze EMT markers (E-cadherin, N-cadherin, Vimentin, Snail), PCNA, and phosphorylation of PI3K/AKT pathway components (p85, Akt, GSK3β, S6). Target identification integrated molecular docking, RNA-seq, Cellular Thermal Shift Assay (CETSA), and Surface Plasmon Resonance (SPR). Co-immunoprecipitation validated Netrin-1-UNC5B and UNC5B-PI3K interactions, while Netrin-1 modulation and rescue experiments clarified its functional role. In vivo efficacy and safety were evaluated in NCI-H1299 xenograft models. RESULTS: In the lung colonization and metastasis model, Eup significantly suppressed NCI-H1299 cell colonization and metastasis. In vitro assays demonstrated that Eup inhibited NSCLC cell proliferation and migration while inducing G0/G1 phase cell cycle arrest. Further analysis revealed that Eup reversed EMT by upregulating E-cadherin and downregulating N-cadherin, Vimentin, Snail, and PCNA. Mechanistically, recombinant Netrin-1 protein activated the PI3K/AKT pathway, an effect that was abrogated upon UNC5B knockdown. Eup binds to Netrin-1 and suppresses Netrin-1/UNC5B-mediated PI3K/Akt signaling and phosphorylation of downstream GSK3β (Ser9) and S6 (Ser235/236). Functional assays showed that Netrin-1 overexpression antagonized the antitumor effects of Eup. In the subcutaneous xenograft model, Eup significantly suppressed tumor growth and counteracted the pro-tumorigenic effect of Netrin-1 without inducing obvious systemic toxicity. CONCLUSION: This study demonstrates that Eup binds to Netrin-1 to suppress Netrin-1/UNC5B-mediated PI3K/Akt signaling, thereby inhibiting EMT-driven metastasis in NSCLC, and provides preclinical evidence supporting its potential as a candidate therapeutic for metastatic NSCLC.
Yulin Yangchao formula improves premature ovarian insufficiency by inhibiting granulosa cell apoptosis through the PI3K/AKT/p53 signaling axis.
Huang Y, Liu J, Wu H … +2 more , Li Y, Dai Y
Phytomedicine · 2026 Aug · PMID 42284639 · Publisher ↗
BACKGROUND: Abnormal apoptosis of ovarian granulosa cells (GCs) represents a crucial pathological foundation of premature ovarian insufficiency (POI). Yulin Yangchao Formula (YLYCF) has demonstrated favorable clinical ef...
BACKGROUND: Abnormal apoptosis of ovarian granulosa cells (GCs) represents a crucial pathological foundation of premature ovarian insufficiency (POI). Yulin Yangchao Formula (YLYCF) has demonstrated favorable clinical efficacy in the treatment of POI. Nevertheless, its mechanism of action remains elusive. PURPOSE: This study aimed to investigate the relevant target sites and potential molecular mechanisms of YLYCF in the treatment of POI. METHODS: Cyclophosphamide (CTX) was employed to stimulate adult female mice and GCs (KGN) to establish in vivo and in vitro models of POI. Following YLYCF treatment, mouse ovarian function was evaluated in vivo by assessing the estrous cycle, hormone levels, follicular development, pregnancy rate, cell apoptosis, and embryos yield. KGN cell proliferation and apoptosis were examined in vitro. Besides, active components in YLYCF were identified, and its possible targets for treating POI were identified by network pharmacology, which were related to the PI3K/AKT/p53 axis. Moreover, proteins involved in this axis were analyzed in the CTX-mediated KGN cells and ovarian tissues of POI mice. Moreover, rescue experiments were carried out alongside PI3K/AKT pathway inhibitor MK-2206 and p53 activator Nutlin-3a for validating the specific mechanism through which YLYCF enhances ovarian function. RESULTS: Following CTX induction, mice with POI exhibited disruptions in the estrous cycle and estrogen secretion, accompanied by a reduced pregnancy rate and litter size, as well as an increased rate of apoptosis in ovarian tissue. KGN cells exposed to CTX demonstrated decreased proliferation and increased apoptosis. YLYCF significantly ameliorated the aforementioned POI-related characteristics. Based on the findings of component identification and network pharmacology analysis, the active components glyuranolide, 3'-Methoxyglabridin, glyasperin B, and naringenin in YLYCF exhibit strong binding affinities with AKT1 and TP53. Additionally, YLYCF treatment significantly activated the PI3K/AKT signaling pathway and inhibited p53 expression in both in vivo and in vitro POI models. However, MK-2206 or Nutlin-3a reversed the benefits induced by YLYCF against GC apoptosis and ovarian function. CONCLUSION: YLYCF suppressed GC apoptosis via PI3K/AKT pathway activation, which then down-regulated p53, thereby enhancing ovarian function in cases of POI.
Mechanism study of HuanglianKushen decoction intervention in DSS-induced ulcerative colitis mice based on integrative omics.
Chen B, Xu J, Chen Y … +8 more , Li M, Xu Y, Hu Y, Su M, Wang Q, Huang A, Chen F, Zhang L
Phytomedicine · 2026 Aug · PMID 42284638 · Publisher ↗
BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by variable extent colon and rectum inflammation. The pathogenesis is not yet clear, with no curative treatments available. HuanglianKush...
BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by variable extent colon and rectum inflammation. The pathogenesis is not yet clear, with no curative treatments available. HuanglianKushen decoction (HKD) is derived from Puji Fang (Prescriptions for Universal Relief) which records its effect for improving symptoms of acute severe UC. However, weak research on its efficacy and pharmacological mechanism limits its clinical application. PURPOSE: This study aims to establish the quality control method for the HKD aqueous extract and explore its mechanism of action on UC through intestinal microbiota and transcriptomics. METHODS: We employed high-performance liquid chromatography (HPLC) technology to develop the specific chromatogram of HKD aqueous extract. The UC model was induced by allowing free access to a solution of dextran sulfate sodium salt (DSS). Three doses of HKD were administered simultaneously for intervention. General signs were observed to score the disease activity index (DAI). The lengths of colon and small intestine tissues were detected and the colon tissues were subjected to histopathological examination. The weight indexes of spleen and thymus tissues was measured. The mRNA expression of inflammatory factors in colon tissues were assessed. After the efficacy was determined, the expression of key proteins for maintaining intestinal barrier integrity in colon tissues was detected and 16S rRNA sequencing was performed on the cecal contents. Meantime, high-throughput transcriptome sequencing of the colon tissues was performed to identify differentially expressed genes (DEGs) and the signaling pathways that regulated by HKD intervention. Based on the transcriptome results, the molecular mechanisms were further investigated by Western blotting (WB), Real-time quantitative PCR (RT-qPCR), and TdT-mediated dUTP nick-end labeling (TUNEL) staining of colonic tissue. RESULTS: The HPLC specific chromatogram of HKD aqueous extract was established; 21 common peaks were identified and nine components were qualitatively determined. Pharmacodynamic studies have shown that HKD intervention improved the macroscopic pathological characterization of the UC mice and the pathological morphology of colon tissue. It also restored the immune organ indices and exerted anti-inflammatory effects. 16S rRNA sequencing results showed that HKD intervention improved the dysbiosis of gut microbiota. Colonic transcriptome sequencing results showed that the DEGs regulated after HKD intervention were primarily enriched in the IL-17 signaling pathway, Forkhead box protein O (FoxO) signaling pathway and p53 signaling pathway, etc. And the restoration of the mRNA expression of 14 DEGs in these three pathways after HKD intervention was validated. CONCLUSION: This study preliminarily established a quality control method for HKD aqueous extract and provided a research basis for the pathogenesis of UC and the anti-UC mechanism of HKD by demonstrating that HKD improved the pathological characteristics and intestinal barrier damage, regulated the dysbiosis of the gut microbiota, and suppressed the apoptosis of IECs probably by inhibiting the apoptosis-related FoxO1 signaling pathway in UC mice.
Integrated network pharmacology and UHPLC-Q-TOF LC-MS/MS phytochemical profiling demonstrate tilianin-mediated restoration of PDE10A/cAMP/PKA/CREB signaling in an MK-801-induced schizophrenia-like model.
Cho YE, Park HB, Chelliah R … +13 more , Kim SY, Cho SY, Lee SJ, Lee YW, Lee SW, Lee NH, Liu XQ, Son SH, Lee S, Ryu JH, Oh DH, Bae HJ, Park SJ
Phytomedicine · 2026 Aug · PMID 42284637 · Publisher ↗
BACKGROUND: Schizophrenia is a complex neuropsychiatric disorder characterized by impairments in cognition, perception, and social behavior. Current antipsychotic medications primarily target dopaminergic signaling but o...
BACKGROUND: Schizophrenia is a complex neuropsychiatric disorder characterized by impairments in cognition, perception, and social behavior. Current antipsychotic medications primarily target dopaminergic signaling but often exhibit limited efficacy in treating negative and cognitive symptoms. Moreover, long-term antipsychotic therapy is frequently associated with clinically relevant adverse effects, including metabolic syndrome and extrapyramidal symptoms (EPS). Phosphodiesterase 10A (PDE10A) has emerged as a promising non-dopaminergic therapeutic target involved in regulating cyclic nucleotide signaling in the striatum. However, several synthetic PDE10A inhibitors have shown safety and tolerability limitations. This study therefore investigated the antipsychotic-like potential of the ethanol extract of Dracocephalum moldavica (EEDM) and its major flavone glycoside, tilianin, in an MK-801-induced schizophrenia-like mouse model and explored the underlying molecular mechanisms. METHODS: Tilianin content in EEDM was quantified using HPLC, and phytochemical constituents were comprehensively characterized by UHPLC-Q-TOF LC-MS/MS. The inhibitory effect of EEDM and tilianin on PDE10A activity was evaluated using in vitro enzyme assays, supported by molecular docking. Behavioral tests, including the open field test (OFT), acoustic startle response (ASR), novel object recognition, and social interaction test (SIT), were performed in MK-801-induced schizophrenia-like mice. Mechanistic insights were explored through network pharmacology analysis and further validated by analyzing the cAMP/PKA/CREB signaling in the prefrontal cortex using Western blot analysis. RESULTS: HPLC analysis identified tilianin as the major constituent of EEDM, while UHPLC-Q-TOF LC-MS/MS profiling revealed a diverse phytochemical profile comprising multiple flavonoids and phenolic compounds. Molecular docking predicted stable, high-affinity binding of tilianin to the PDE10A catalytic site (docking score: -11.857 kcal/mol), and this prediction was supported by an enzymatic assay showing PDE10A inhibition by both EEDM (IC = 346.6 μg/ml) and tilianin (IC = 11.25 μg/ml; 25.20 μM). Tilianin ameliorated MK-801-induced hyperlocomotion, rescued prepulse inhibition (PPI) deficits, and reversed impairments in cognitive and social functions. Network pharmacology identified PDE10A, CREB1, ESR1, and MAPK1 as key hubs modulating synaptic plasticity. Furthermore, tilianin restored the disrupted cAMP/PKA/CREB signaling in the prefrontal cortex. CONCLUSION: These findings suggest that tilianin may act as a network-informed modulator associated with PDE10A inhibition and downstream neuroplastic signaling, providing a potential mechanistic basis for addressing the limited efficacy of conventional antipsychotic strategies in schizophrenia.
The neutral and acidic polysaccharides from Ginseng are metabolized by specific gut microbial taxa and confer immunomodulatory effects.
Zhao J, Zuo M, Cao L … +7 more , Li Q, Zhang R, Wu H, Yuan J, Lv C, Yu Y, Lu J
Phytomedicine · 2026 Aug · PMID 42275884 · Publisher ↗
BACKGROUND: Ginseng (Panax ginseng C. A. Mey.) exerts immunomodulatory effects partly mediated by its polysaccharides and interactions with gut microbiota. However, due to the structural complexity of ginseng polysacchar...
BACKGROUND: Ginseng (Panax ginseng C. A. Mey.) exerts immunomodulatory effects partly mediated by its polysaccharides and interactions with gut microbiota. However, due to the structural complexity of ginseng polysaccharides, knowledge of their oral fate and direct microbiota interactions remains limited. PURPOSE: This study aims to elucidate the oral fate of neutral and acidic polysaccharides in ginseng, analyze core gut microbiota genera and their immunomodulatory effects mechanisms. METHODS: Structural analysis was conducted on neutral and acidic polysaccharides from ginseng. Thereafter, in vitro digestion and fermentation were performed, with metagenomic and metatranscriptomic profiling. The results were validated in conventional and pseudo‑germ-free immunosuppressed mouse models, and the immunomodulatory mechanisms of the core gut microbiota were investigated. RESULTS: The in vivo and in vitro findings indicated that neutral and acidic polysaccharides exhibit different digestive properties and gut microbiota degradation patterns, differ in short-chain fatty acid production tendencies, bind to GPR-41/43 receptors, upregulate MAPK-p38 phosphorylation, and promote proliferation of intestinal immune cells. CONCLUSION: This work systematically elucidated the digestive characteristics of ginseng polysaccharides and laid the groundwork for future studies on the specificity and structure-function relationships of plant-derived polysaccharides.
Jianpi Huayu decoction suppresses hepatocellular carcinoma invasion and metastasis by inhibiting SIRT5-regulated Nrf2 activation and mitochondrial metabolic reprogramming.
Zhao X, Zhu X, Chen X … +10 more , Liu S, Ying B, Zhao Y, Liu S, Huang H, Yao R, Shi H, Luo R, Lai Y, Zhong C
Phytomedicine · 2026 Aug · PMID 42275883 · Publisher ↗
BACKGROUND: Hepatocellular carcinoma (HCC) and its subsequent lung metastasis represent a significant clinical challenge with limited therapeutic options. Jianpi Huayu Decoction (JPHYD) is an empirically effective formul...
BACKGROUND: Hepatocellular carcinoma (HCC) and its subsequent lung metastasis represent a significant clinical challenge with limited therapeutic options. Jianpi Huayu Decoction (JPHYD) is an empirically effective formula derived from our clinical practice in treating hepatocellular carcinoma, demonstrating significant efficacy in inhibiting metastasis and improving prognosis. PURPOSE: The research aims to evaluate the therapeutic potential and elucidate the underlying mechanisms of JPHYD against HCC progression and metastasis. STUDY DESIGN AND METHODS: The anti-tumor efficacy of JPHYD was evaluated in an HCCLM3 xenograft model, whereas its anti-metastatic activity was assessed in an H22 experimental lung metastasis model. Proteomics and network pharmacology combined analysis were employed to identify key molecular targets. Functional validation was performed in HCCLM3 and HepG2 cells in vitro. The regulatory effect of JPHYD on the interaction between SIRT5 and Nrf2 was confirmed by co-immunoprecipitation and immunofluorescence. Functional rescue was achieved through transient transfection of a SIRT5 overexpression plasmid in HCCLM3 and HepG2 cells, and the interaction between JPHYD's bioactive compounds and the identified target was verified by molecular docking simulations. RESULTS: JPHYD treatment significantly inhibited the growth of primary HCC tumors and suppressed lung metastasis in vivo. Proteomic and functional analyses identified sirtuin 5 (SIRT5) as a key functional target candidate of JPHYD against HCC. Downregulation of SIRT5 by JPHYD impaired oxidative phosphorylation (OXPHOS) and promoted apoptosis, while molecular docking supported the stable binding of JPHYD-derived bioactive components to SIRT5. Mechanistically, JPHYD disrupted the SIRT5/Nrf2 protein interaction, which suppressed Nrf2 nuclear translocation and decreased its downstream antioxidant proteins. Consequently, this led to reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and diminished ATP production. Crucially, SIRT5 overexpression partially reversed the anti-metastatic effects of JPHYD, highlighting its pivotal role in the drug's mechanism of action. CONCLUSION: Our findings demonstrated that JPHYD effectively inhibited HCC growth and lung metastasis by dually modulating the SIRT5/Nrf2 signaling axis. This action simultaneously induced oxidative stress and disrupted mitochondrial metabolic reprogramming. JPHYD thus presents a promising multi-target therapeutic strategy for advanced HCC.
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