Phytomedicine [JOURNAL]
Sun
200 papers
Bushen Huoxue Decoction alleviates osteoporosis by promoting the osteogenic differentiation of BMSCs by targeting the OTUD5/PDCD5/p53 signaling pathway.
Chen X, Han H, Tian N … +11 more , Jin J, Sun Y, Guo Z, Zhou M, Wang J, Liao T, Xu Z, Teng J, Song Y, Wu L, Li Z
Phytomedicine · 2026 Jun · PMID 42385430 · Publisher ↗
BACKGROUND: A decline in the osteogenic differentiation capacity of bone marrow mesenchymal stem cells (BMSCs) constitutes a central event in the disruption of bone homeostasis in osteoporosis (OP). Bushen Huoxue Decocti...
BACKGROUND: A decline in the osteogenic differentiation capacity of bone marrow mesenchymal stem cells (BMSCs) constitutes a central event in the disruption of bone homeostasis in osteoporosis (OP). Bushen Huoxue Decoction (BSHXD), a traditional Chinese medicinal formula, has demonstrated clinical efficacy; however, its specific therapeutic effects and underlying mechanisms in the treatment of OP remain to be fully elucidated. PURPOSE: This work aimed to elucidate the mechanisms by which BSHXD mitigates OP and to explore its therapeutic potential. METHODS: First, the bioactive constituents of BSHXD were identified using LC-MS/MS analysis. In vivo, the effects of BSHXD on bone mineral density and microarchitecture were evaluated in an ovariectomized (OVX) mouse model through micro-CT, H&E staining, and IHC analysis. In vitro, the pro-osteogenic effects of BSHXD on the differentiation of BMSCs into osteoblasts were assessed using ALP staining, Alizarin Red S staining, Western blotting, and RT-qPCR. Furthermore, to elucidate the underlying mechanisms by which BSHXD regulates osteogenic differentiation of BMSCs, proteomic sequencing, protein co-expression network analysis, network pharmacology, Co-IP, and lentiviral-mediated overexpression assays were performed. RESULTS: In vivo experiments demonstrated that medium- and high-dose BSHXD significantly increased bone mineral density in OVX mice, enhanced bone formation, and attenuated OVX-induced bone loss. In vitro, BSHXD treatment markedly promoted the osteogenic differentiation capacity of BMSCs. Proteomic analysis coupled with protein co-expression network analysis indicated that OTUD5 may represent a key therapeutic target in OP. Mechanistically, at the protein level, BSHXD downregulated OTUD5 expression and facilitated the ubiquitin-dependent degradation of PDCD5, thereby suppressing p53 activation and upregulating osteogenesis-related genes, ultimately enhancing the osteogenic differentiation of BMSCs. Notably, OTUD5 overexpression abrogated the therapeutic effects of BSHXD. CONCLUSION: Collectively, BSHXD exerts a promoting action on BMSCs osteogenic differentiation via the OTUD5/PDCD5/p53 signaling pathway, thereby alleviating osteoporotic bone metabolic imbalance. These observations highlight the therapeutic potential of targeting BMSCs for OP treatment and provide mechanistic evidence supporting the use of BSHXD in the prevention and management of OP.
Epigallocatechin gallate targets the hexokinase 2-voltage-dependent anion channel 1 axis in myofibroblasts to attenuate pulmonary fibrosis.
Geng Q, Qiu F, Zhang X … +7 more , Yan L, Zhang X, Liu X, Cao Z, Yuan S, Liang C, Lu C
Phytomedicine · 2026 Jun · PMID 42385429 · Publisher ↗
BACKGROUND: Pulmonary fibrosis (PF) is sustained by apoptosis-resistant myofibroblasts that undergo a metabolic shift toward aerobic glycolysis. Hexokinase 2 (HK2) couples these two features: it catalyzes the first commi...
BACKGROUND: Pulmonary fibrosis (PF) is sustained by apoptosis-resistant myofibroblasts that undergo a metabolic shift toward aerobic glycolysis. Hexokinase 2 (HK2) couples these two features: it catalyzes the first committed step of glycolysis and, by occupying voltage-dependent anion channel 1 (VDAC1) on the outer mitochondrial membrane, physically excludes the pro-apoptotic effector Bcl-2 Associated X protein (BAX) from VDAC1, thereby raising the apoptotic threshold. Epigallocatechin gallate (EGCG), a principal green tea catechin, exhibits anti-fibrotic activity in preclinical models, yet its direct molecular target and mechanism of action in myofibroblasts remain undefined. PURPOSE: To identify the direct molecular target of EGCG in myofibroblasts and to delineate how target engagement restores apoptotic competence and metabolic homeostasis in PF. METHODS: Target engagement was assessed using drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR). HK2 stability, ubiquitination, and proteasome dependence were examined alongside mitochondrial complex formation, Bcl-2 Associated X protein (BAX) recruitment, and apoptosis readouts. Anti-fibrotic efficacy and metabolic remodeling were evaluated in a bleomycin (BLM)-induced murine PF model and in HK2-deficient settings. RESULTS: EGCG bound HK2 with high affinity and promoted its ubiquitination-dependent proteasomal degradation rather than functioning solely as an enzymatic inhibitor. Loss of HK2 disrupted the mitochondrial HK2-VDAC1 complex, liberated VDAC1 for BAX engagement, and restored mitochondrial outer membrane permeabilization and apoptosis in transforming growth factor-beta 1 (TGF-β1)-activated myofibroblasts. In BLM-injured lungs, EGCG administration attenuated fibrotic remodeling, suppressed glycolysis-biased metabolic reprogramming, and improved mitochondrial oxidative phosphorylation. Genetic depletion of HK2-both in vivo and in vitro-phenocopied the pro-apoptotic, anti-glycolytic, and anti-fibrotic effects of EGCG, and largely abolished the additional benefit conferred by EGCG treatment, establishing HK2 as an obligatory mediator of EGCG action. CONCLUSION: These findings identify HK2 as a bona fide molecular target of EGCG and establish a mechanistic framework in which EGCG-induced HK2 degradation disrupts the HK2-VDAC1 complex, re-enables BAX-dependent apoptosis, and concurrently corrects pathological glycolytic reprogramming in myofibroblasts. This HK2-VDAC1-BAX axis represents a druggable vulnerability that may inform the development of targeted anti-fibrotic therapies.
Paederoside alleviates rheumatoid arthritis by targeting SMAD4 to suppress histone lactylation through inhibiting lactate transport in senescent macrophages.
Chen J, Zhang J, Ma Y … +5 more , Chen B, Jian S, Chen T, Wang W, Xiao M
Phytomedicine · 2026 Jun · PMID 42385428 · Publisher ↗
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent synovial inflammation and progressive joint destruction. Senescent macrophages are key drivers of RA pathogenesis through...
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent synovial inflammation and progressive joint destruction. Senescent macrophages are key drivers of RA pathogenesis through metabolic reprogramming, leading to intracellular lactate accumulation and histone lactylation, which promotes the expression of pro-inflammatory cytokines and synovial hyperplasia. Paederoside, an iridoid glycoside from Paederia scandens, has demonstrated anti-inflammatory effects, but its precise molecular targets in RA remain unclear. PURPOSE: This study aimed to elucidate the mechanism by which paederoside alleviates RA by targeting the SMAD4-MCT1 axis to suppress lactate transport and histone lactylation in senescent macrophages. METHODS: A senescent RAW264.7 macrophage model was established using bleomycin (BLM). The effects of paederoside on macrophage polarisation, lactate metabolism, and histone lactylation were assessed using ELISA, qRT-PCR, Western blot, and immunofluorescence. Molecular docking, cellular thermal shift assay (CETSA), and dual-luciferase reporter assays were employed to validate the interaction between paederoside and SMAD4. A collagen-induced arthritis (CIA) mouse model was used to evaluate the therapeutic efficacy of paederoside in vivo. RESULTS: Paederoside significantly reduced BLM-induced lactate accumulation and H3K14 lactylation (H3K14la) in senescent macrophages by inhibiting monocarboxylate transporter 1 (MCT1) expression. Mechanistically, paederoside directly binds to SMAD4 at Arg100, blocking its nuclear translocation and transcriptional activation of Mct1. This led to decreased lactate influx, reduced H3K14la levels at the promoters of pro-inflammatory genes, including chemokines (Ccl7, Cxcl1) and matrix metalloproteinase Mmp1, and a shift from pro-inflammatory M1 to anti-inflammatory M2 macrophage polarisation. Consequently, paederoside suppressed the proliferation and invasion of synovial fibroblasts. In the CIA model, paederoside attenuated joint swelling, bone erosion, and synovial inflammation comparably to methotrexate. CONCLUSION: Paederoside alleviates RA by targeting SMAD4 to inhibit MCT1-mediated lactate transport, thereby suppressing histone lactylation and pro-inflammatory macrophage polarisation. These findings highlight the SMAD4-MCT1 axis as a promising metabolic-epigenetic target for RA therapy and support paederoside as a lead compound for the precision treatment of elderly RA patients.
The common mechanism underlying Shuangxinfang's amelioration of post-myocardial infarction depression: Targeting S100A9/NLRP3 to improve mitochondrial energetics.
Ding W, Shao J, Zhao W … +7 more , Hou J, Zhang Y, Sun Z, Liu X, Wang J, Wang C, Zhao H
Phytomedicine · 2026 Jun · PMID 42385427 · Publisher ↗
BACKGROUND: Post-myocardial infarction (post-MI) depression is a common clinical complication affecting approximately 29-40% of post-MI patients, whose pathological mechanism remains incompletely understood. While Shuang...
BACKGROUND: Post-myocardial infarction (post-MI) depression is a common clinical complication affecting approximately 29-40% of post-MI patients, whose pathological mechanism remains incompletely understood. While Shuangxinfang (Psycho-cardiology formula, PCF) has demonstrated efficacy in treating post-MI depression, its specific underlying mechanism of action remains poorly understood. OBJECTIVE: This study seeks to elucidate the common pathological mechanisms underlying myocardial infarction and depression, as well as the therapeutic pathway by which PCF exerts its effects, through an integrated approach combining transcriptomics, cellular experiments, and animal studies. METHOD: Transcriptomic analysis was employed to identify the potential molecular pathways. Cellular models employing H9C2 cardiomyocytes and astrocytes were established and subjected to hypoxia/reoxygenation intervention and S100A9 overexpression plasmid transfection, respectively. A rat model of post-MI depression was established. To validate the key findings, the following analytical methods were employed in the present study: real-time quantitative PCR (qRT-PCR), Western blotting, immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), high-performance liquid chromatography (HPLC), colorimetric assays, and transmission electron microscopy (TEM). RESULTS: Transcriptomic analysis revealed that PCF potentially targets S100A9, the NLRP3 inflammasome, and mitochondrial dysfunction. Both in vivo and in vitro experiments confirmed that PCF primarily inhibits S100A9, thereby reducing S100A9/NLRP3 inflammatory pathway factors (S100A9, NLRP3, Caspase-1, IL-18, and IL-1β) and ameliorating mitochondrial energy metabolism. These effects included enhanced activity of mitochondrial complexes I-V, elevated mitochondrial membrane potential, decreased mitochondrial permeability transition pore opening, improved mitochondrial ultrastructure, facilitated ADP-to-ATP conversion, and ultimately enhanced ATP production. CONCLUSION: S100A9/NLRP3 inflammasome-mediated mitochondrial energetic dysfunction may represent the common pathological mechanism linking post-MI cardiac dysfunction and depression, while simultaneously serving as a therapeutic pathway through which PCF exerts its therapeutic effects.
Qiteng Xiaozhuo granules activate mitophagy to alleviate chronic glomerulonephritis.
Liu T, Zhuang XX, Zhu XL … +6 more , Zhang YT, Wu X, Qin XJ, Wei LB, Gao YC, Gao JR
Phytomedicine · 2026 Jun · PMID 42378805 · Publisher ↗
BACKGROUND: Qiteng Xiaozhuo Granules (QTXZG), a traditional Chinese medicine formula, is widely recognized for its therapeutic effects. Previous studies have demonstrated that the Methyltransferase-like 3 (METTL3)/FOS Li...
BACKGROUND: Qiteng Xiaozhuo Granules (QTXZG), a traditional Chinese medicine formula, is widely recognized for its therapeutic effects. Previous studies have demonstrated that the Methyltransferase-like 3 (METTL3)/FOS Like Antigen 1 (FOSL1) N6-methyladenosine (m6A) axis plays a crucial role in the regulation of mitophagy in chronic glomerulonephritis (CGN) both in vitro and in vivo. However, it remains unclear whether QTXZG exerts its therapeutic effects in CGN through the METTL3/FOSL1 m6A axis to regulate mitophagy. This study aims to investigate the renal protective mechanisms of QTXZG by activating mitophagy in glomerular mesangial cells through the METTL3/FOSL1 m6A axis. METHODS: Adenine-induced CGN mice and lipopolysaccharide-stimulated mouse glomerular mesangial cells were employed as in vivo and in vitro models, respectively. The chemical characterization and quality control of QTXZG were performed using high-performance liquid chromatography fingerprinting, peak assignment, marker quantification, and analytical method validation. Renal function was evaluated via serum creatinine, blood urea nitrogen, immunoglobulin G, and immunoglobulin M quantification. Renal histopathology was analyzed using Hematoxylin and Eosin, Masson, and Periodic Acid-Schiff staining. QTXZG-containing serum concentration and treatment duration were optimized via cell counting kit-8 assays. Inflammation and oxidative stress were assessed by enzyme-linked immunosorbent assay and reactive oxygen species staining. Global m6A levels were quantified by colorimetric assays, and FOSL1 mRNA m6A modifications were validated via methylated RNA immunoprecipitation quantitative PCR. Actinomycin D experiments determined FOSL1 mRNA stability. METTL3/FOSL1 m6A axis and mitophagy were analyzed by western blot, transmission electron microscopy, MitoTracker Red staining, and microtubule-associated protein 1 light chain 3-mitochondria immunofluorescence co-localization. RESULTS: High-performance liquid chromatography fingerprinting of ten QTXZG batches identified sixteen common peaks, assigned them to corresponding herbal sources, and quantified five representative marker compounds. QTXZG improved renal function and suppressed mesangial cell proliferation in CGN mice, while reducing pro-inflammatory cytokines and reactive oxygen species levels and enhancing superoxide dismutase activity. Importantly, QTXZG promoted autophagosome formation and mitigated mitochondrial damage, with enhanced microtubule-associated protein 1 light chain 3-mitochondria/voltage-dependent anion channel 1 co-localization confirming mitophagy induction. Mechanistically, QTXZG inhibited METTL3/FOSL1 expression, reduced global m6A levels and FOSL1 mRNA m6A enrichment, and destabilized FOSL1 transcripts. Critically, METTL3 overexpression reversed QTXZG's effects on inflammation, oxidative stress, mitophagy, and METTL3/FOSL1 m6A axis in lipopolysaccharide-stimulated mouse glomerular mesangial cells. CONCLUSION: This study suggests that QTXZG induces mitophagy in glomerular mesangial cells in CGN by modulating the METTL3/FOSL1 m6A axis. Targeting FOSL1 m6A modification through the writer enzyme METTL3 may provide a potential therapeutic approach for the treatment of CGN.
Efficacy and safety of Tripterygium agents in treatment of psoriasis: a systematic review and network meta-analysis.
Lin NX, He JJ, Gao PB … +15 more , Zhang M, Cao RQ, Sun XY, Zhou YQ, Wang J, Cai XC, Li LH, Yeap JW, Yu YT, Gheyret N, Ling YJ, Jie CX, Li B, Li X, Liu L
Phytomedicine · 2026 Jun · PMID 42378804 · Publisher ↗
BACKGROUND: Psoriasis is a chronic inflammatory disease characterized by skin plaques and scaling. Tripterygium, a traditional Chinese medicinal herb, has been developed into a variety of agents for the treatment of psor...
BACKGROUND: Psoriasis is a chronic inflammatory disease characterized by skin plaques and scaling. Tripterygium, a traditional Chinese medicinal herb, has been developed into a variety of agents for the treatment of psoriasis; however, its efficacy, safety, and optimal treatment regimen remain unclear. OBJECTIVE: To summarize the efficacy and safety of Tripterygium agents in the treatment of psoriasis and compare monotherapy with combination therapy. METHODS: Five databases were searched up to June 30, 2025. R software version 4.3.3 with the "meta" and "Gemtc" packages were used for the data analysis. RESULTS: Forty-three trials were included in the analysis. A meta-analysis showed that TwHF agent combination therapy reduced the Psoriasis Area and Severity Index (PASI) score (mean difference [MD], -3.96; 95% confidence interval [CI], [-5.57, -2.35]; p<0.01) and elevated the total effective rate (odds ratio, 3.02; 95% CI, [2.44, 3.74]; p<0.05), whereas monotherapy of Tripterygium agent showed no significant difference. Adverse events were also observed with combination therapy. Among the combined treatments, Tripterygium glycoside (TG) + acitretin (ACI) (98.41%) ranked first at improving the PASI score, followed by TG + compound glycyrrhizin injection (71.13%) and TG + DiYin capsule (51.30%). LIMITATIONS: All included studies were published in Chinese or English, causing a degree of selection bias. CONCLUSION: Tripterygium agents combination therapy, especially TG+ACI (SUCRA 98.41%), is effective for psoriasis but associated with some adverse events. Further studies should focus on toxicity reduction and expanding clinical options.
Bufalin mitigates corneal damage in herpes simplex keratitis mice via inhibiting viral replication.
Wu J, Liu Y, Zhang Y … +6 more , Chen N, Ji J, Chen L, Nawaz W, Cheng J, Chen D
Phytomedicine · 2026 Jun · PMID 42378803 · Publisher ↗
BACKGROUND: Herpes simplex keratitis (HSK) is an ocular viral infectious disease with limited therapeutic options and increasing resistance, leading cause of infectious blindness worldwide. Bufalin is a cardiotonic stero...
BACKGROUND: Herpes simplex keratitis (HSK) is an ocular viral infectious disease with limited therapeutic options and increasing resistance, leading cause of infectious blindness worldwide. Bufalin is a cardiotonic steroid, more specifically a bufadienolide, which can be found in many plant or animal species, but their main sources are skin and parotid gland secretions of toads (such as Bufo bufo gargarizans Cantor), which constitutes the traditional Chinese medicine preparation known as Chan Su (Venenum Bufonis). Despite its broad pharmacological activities, the potential role of bufalin in controlling HSK progression remains to be systematically investigated. PURPOSE: This study systematically evaluates the antiviral and anti-inflammatory activities of commercial bufalin standards along with the underlying mechanisms in an HSK mouse model, aiming to discover lead compounds for the treatment of drug-resistant HSK. METHODS: In vivo studies were conducted using an HSK mouse model established via corneal infection with either HSV-1F or the clinically acyclovir (ACV)-resistant strain HSV-1/153. In vitro experiments were conducted in ARPE-19 and HCEC cell lines, commonly used in ophthalmic research. Plaque assay, RT-qPCR, Western blot, CCK-8, sodium fluorescein staining, H&E staining, and other related experiments were employed to evaluate the antiviral and anti-inflammatory activities of bufalin. The ocular and systemic toxicities of topical bufalin were evaluated using in vivo confocal microscopy, TUNEL staining, body weight monitoring, and organ index analysis. RESULTS: Bufalin and Chan Su alleviates corneal damage in HSK mice, due to its antiviral and anti‑inflammatory activities both in vitro and in vivo. Bufalin not only inhibits the replication of viruses including HSV-1F and HSV-1/153 strains but also reduces inflammatory infiltration and the expression of inflammatory cytokines (IL-1β and IL-6) in the corneas of HSK mice. RNA-seq analysis reveals that bufalin may act as a potential broad-spectrum antiviral agent by upregulating OAS1 and ISG15 expression, which may represent a distinct antiviral mechanism distinct from ACV. No systemic or ocular toxicity was observed with bufalin at therapeutic doses in this study. CONCLUSIONS: These findings identify the natural product bufalin as a potential candidate against drug-resistant HSK by modulating the expression of broad-spectrum antiviral factors OAS1 and ISG15. This study expands the pharmacological application scope of bufalin, and thereby establishes a novel strategic direction for developing plant-derived bufalin and its derivatives as anti‑herpesvirus agents.
Pan-chloroplast genome of Coptis species reveals genetic divergence and medicinal materials identification.
Wang Y, Yan P, Zhang Q … +9 more , Wang J, Hao F, Xie W, Zhang C, Wang H, Dong W, Cui X, Sun J, Guo L
Phytomedicine · 2026 Jun · PMID 42378802 · Publisher ↗
BACKGROUND: Accurate identification of medicinal plants is fundamental to ensuring the efficacy, safety, and quality control of Traditional Chinese Medicine. Coptis species are the primary botanical sources of the import...
BACKGROUND: Accurate identification of medicinal plants is fundamental to ensuring the efficacy, safety, and quality control of Traditional Chinese Medicine. Coptis species are the primary botanical sources of the important herbal medicine "Huanglian", which is officially derived from Coptis chinensis, Coptis deltoidea, and Coptis teeta. However, their high morphological similarity and the loss of distinguishing features in processed materials have led to long-standing species confusion in the medicinal materials market. Traditional identification methods have limitations, and commonly used universal DNA barcodes often lack sufficient resolution for distinguishing closely related species within the Coptis. METHODS: This study constructed the first genus-level pan-chloroplast genome for Asian Coptis. We sequenced, assembled, and annotated the chloroplast genomes of 172 individuals encompassing nine Asian Coptis species, including two species that were overlooked in previous studies. Through whole-genome alignment, variant analysis, phylogenetic reconstruction, and population genetic structure analysis, we systematically assessed the genetic diversity and divergence within the genus. Furthermore, we screened for hypervariable regions to develop specific molecular markers for authenticating commercially available medicinal materials and patent medicines containing Huanglian (Coptis spp.). RESULTS: The chloroplast genomes of Coptis species were found to be highly conserved in size and structure, yet the distribution of variable sites (3589) was uneven. The inverted repeat regions were the most conserved, while some areas in the small single-copy region exhibited high mutation rates. Significant differences in intraspecific genetic diversity were observed; C. teeta had the highest number of variable sites, whereas no intraspecific variation was detected in species like C. deltoidea. Phylogenetic and population structure analyses clearly revealed the interspecific relationships. Sliding-window analysis identified four hypervariable regions, and the intergenic spacer ndhF-trnL was determined to be the specific DNA barcode for distinguishing Coptis species. Application of this marker successfully corrected misidentifications of commercial samples and identified the Coptis species within patent medicines. CONCLUSION: The pan-chloroplast genome constructed in this study provides a valuable resource for understanding the genetics and evolution of Coptis. The identified ndhF-trnL marker serves as a reliable and efficient tool for the accurate authentication of Coptis medicinal materials, which is significant for ensuring quality, promoting sustainable resource utilization, and regulating the herbal market.
Corrigendum to "Liquiritigenin targets transferrin receptor to potentiate ferroptosis sensitivity in colorectal cancer cells" [Phytomedicine. 154 (2026) 158057].
Li R, Song C, Jia T … +8 more , Xia T, Guo M, Wang Q, Yao Y, Xu X, Bao X, Yang P, Li Z
Phytomedicine · 2026 Jun · PMID 42373351 · Publisher ↗
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Total glycosides of Cistanche deserticola ameliorate alcohol-induced oligoasthenozoospermia via the modulation of gut microbiota-mediated spermidine metabolism.
Yuan S, Hong J, Zhang H … +10 more , Gao P, Yang P, Lei J, He Y, Fang X, Lu Y, Wang B, Tu P, Zhang X, Jiang Y
Phytomedicine · 2026 Jun · PMID 42372605 · Publisher ↗
BACKGROUND: Oligoasthenozoospermia is a major cause of male infertility, with chronic excessive alcohol consumption being a prevalent etiology. Cistanche deserticola Ma., a traditional Chinese medicine historically emplo...
BACKGROUND: Oligoasthenozoospermia is a major cause of male infertility, with chronic excessive alcohol consumption being a prevalent etiology. Cistanche deserticola Ma., a traditional Chinese medicine historically employed for reproductive improvement. However, the role and mechanism in alcohol-induced reproductive dysfunction remains unexplored. PURPOSE: This study aimed to elucidate the protective effect and underlying mechanism of total glycosides of C. deserticola (TGCD) against alcohol-induced oligoasthenozoospermia. METHODS: The effects of TGCD were evaluated using a NIAAA mouse model. Mechanisms were elucidated through multi-omics, fecal microbiota transplantation, Lactobacillus reuteri supplementation, spermidine supplementation, and so on. Translational relevance was assessed by patients with alcohol-induced sperm abnormalities and a public single-cell transcriptome dataset. RESULTS: TGCD administration significantly improved alcohol-impaired sperm quality, restored testosterone levels and testicular architecture. Mechanistically, TGCD selectively enriched L. reuteri, which enhanced spermidine production. Spermidine activated the Nrf2-mediated antioxidant pathway, thereby reducing ROS accumulation and reinstating the expression of key steroidogenic enzymes. Critically, these findings are corroborated by clinical data showing reduced fecal L. reuteri abundance in patients with alcohol-related sperm abnormalities, as well as human testicular single-cell transcriptomic evidence of concurrent downregulation of spermidine and Nrf2 pathways in infertile patients. CONCLUSION: TGCD alleviates alcohol-induced oligoasthenozoospermia via a gut microbiota-dependent mechanism involving L. reuteri-enhanced spermidine production and subsequent activation of the Nrf2 antioxidant pathway. This study not only highlights the therapeutic potential of TGCD for male infertility but also underscores the gut-testis axis as a promising target. Fecal abundance of L. reuteri emerges as a potential biomarker for clinical translation in this context.
Corrigendum to "Phillyrin ameliorates sepsis via targeting microRNA-203a-mediated caspase-4/caspase-11/caspase-B downregulation to suppress endothelial pyroptosis" [Phytomedicine 152 (2026) 157872].
Zhou X, Yang G, Tan W … +8 more , Ding H, Zheng W, Liu Y, Zou L, Su X, Yu L, Li W, Yang L
Phytomedicine · 2026 Jun · PMID 42372604 · Publisher ↗
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Molecular and bioinformatic mechanism of asiaticoside on macrophage-mediated keloid pathogenesis.
Huang J, Yang Y, Li Z … +5 more , Wang W, Wu X, Gao Z, Chen H, Liu W
Phytomedicine · 2026 Jun · PMID 42372603 · Publisher ↗
BACKGROUND: Keloid is a fibroproliferative skin disorder driven by dysregulated inflammation and fibrosis, involving complex interactions between keloid fibroblasts (KFs) and immune cells. Although macrophages are implic...
BACKGROUND: Keloid is a fibroproliferative skin disorder driven by dysregulated inflammation and fibrosis, involving complex interactions between keloid fibroblasts (KFs) and immune cells. Although macrophages are implicated in keloid pathogenesis, the exact mechanisms remain poorly defined. Asiaticoside, a natural triterpene molecule, has shown therapeutic potential for pathological scarring, yet its molecular mechanisms warrant further investigation. PURPOSE: This study aims to elucidate the macrophage subtype-specific contributions to keloid progression and to investigate the anti-inflammatory and anti-fibrotic therapeutic efficacy of asiaticoside. METHODS: In vitro co-culture models were established to assess the interactions between KFs and macrophages. Phenotypic changes, inflammation, fibrogenesis, and macrophage polarization were evaluated. Asiaticoside was tested at various doses for its effects on these pathological phenotypes. Macrophage or human monocyte pre‑treated with asiaticoside were co‑cultured with untreated KFs to determine the indirect inhibitory effect of asiaticoside on KF activation. Proteomic, phosphoproteomic, and molecular docking analyses were conducted to explore underlying mechanisms. RESULTS: Both M1 and M2 macrophages exacerbated KFs proliferation, inflammation, and fibrogenesis, while KFs reciprocally promoted M2 macrophage polarization. Asiaticoside dose-dependently suppressed pathological phenotypes of KFs and macrophages and attenuated their pro-inflammatory and pro-fibrogenic cross-activation. Pre-treatment of macrophages or monocytes with asiaticoside inhibited their ability to activate KFs. Proteomic and phosphoproteomic profiling revealed that asiaticoside disrupted multiple keloid-associated pathogenic pathways. Molecular docking further identified high-affinity interactions between asiaticoside and pro-inflammatory factors. CONCLUSION: Asiaticoside exerts a dual therapeutic mechanism by concurrently inhibiting macrophage-driven inflammation and fibroblast-driven fibrogenesis, positioning it as a promising multi-targeting agent for keloid and related fibrotic diseases.
Xian-Lian-Jie-Du Decoction suppresses colorectal cancer liver metastasis by inhibiting Plaur/Hbegf/EGFR-mediated actin cytoskeleton remodeling.
Zhang Q, Shi Z, Qian J … +7 more , Geng X, Tao Y, Dong D, Shi H, Zhang D, Sun Y, Cheng H
Phytomedicine · 2026 Jun · PMID 42372602 · Publisher ↗
BACKGROUND: Colorectal cancer liver metastasis (CRLM) remains a major clinical challenge. Xian-Lian-Jie-Du Decoction (XLJDD) has shown anti-tumor activity against colorectal cancer, but its mechanism in CRLM remains uncl...
BACKGROUND: Colorectal cancer liver metastasis (CRLM) remains a major clinical challenge. Xian-Lian-Jie-Du Decoction (XLJDD) has shown anti-tumor activity against colorectal cancer, but its mechanism in CRLM remains unclear. PURPOSE: To clarify the anti-metastatic mechanism of XLJDD and identify its Plaur-targeting active constituents in CRLM. STUDY DESIGN: An integrated in vivo, in vitro, transcriptomic, proteomic, and single-cell mechanistic study. METHODS: A CRLM mouse model was established by intrasplenic injection of CT26 cells. Transcriptomic and proteomic analyses were integrated to identify candidate targets. Single-cell RNA sequencing (scRNA-seq) was used to characterize tumor microenvironment changes. Wound-healing, Transwell, phalloidin staining, and an in vivo Plaur-overexpression rescue model were used for functional validation. XLJDD granules and XLJDD-derived compounds in biological samples were profiled by UPLC-MS/MS, and their binding to Plaur was examined by molecular docking, surface plasmon resonance (SPR), and microscale thermophoresis (MST). Hepatic exposure of cyclogalegenin was further quantified by targeted UHPLC-MRM-MS/MS. RESULTS: XLJDD reduced hepatic metastatic burden in metastatic liver tissues. Integrated transcriptomic and proteomic analyses identified the Plaur/Hbegf axis as a candidate target of XLJDD. Mechanistically, Plaur promoted Mmp9-associated Hbegf release, whereas XLJDD suppressed EGFR/ERK signaling and reduced the expression of cytoskeleton-related effectors, including Fscn1 and Cdc42ep1. scRNA-seq revealed that XLJDD reduced a Plaur-high Car6 malignant subpopulation, increased an Ifit1 interferon-reactive state, and weakened Spp1-Cd44 signaling between malignant cells and Thbs1 tumor-associated macrophages. In vivo, Plaur overexpression weakened the anti-metastatic effect of XLJDD. Cyclogalegenin was identified as a tissue-available constituent of XLJDD that directly binds Plaur and suppresses Plaur expression in CT26 cells. Targeted quantification confirmed the presence of cyclogalegenin in liver metastatic tissues after oral XLJDD administration. CONCLUSION: XLJDD suppresses CRLM by targeting Plaur, restraining cytoskeleton remodeling, and remodeling the metastatic tumor microenvironment. Cyclogalegenin may contribute to this activity as a direct Plaur-binding constituent.
Elucidating the NETs-BNIP3-pyroptosis axis in cerebral ischemia-reperfusion injury and the intervention of Bu Yang Huan Wu decoction.
Zhang T, Guo SH, Zheng T … +4 more , Chen X, Xu Z, Zhou X, Gao W
Phytomedicine · 2026 Jun · PMID 42372601 · Publisher ↗
BACKGROUND: Cerebral ischemia‑reperfusion injury (CIRI) leads to poor stroke outcomes, partly due to sustained endothelial damage triggered by neutrophil extracellular traps (NETs) during the subacute phase. However, the...
BACKGROUND: Cerebral ischemia‑reperfusion injury (CIRI) leads to poor stroke outcomes, partly due to sustained endothelial damage triggered by neutrophil extracellular traps (NETs) during the subacute phase. However, the exact downstream pathways through which NETs drive endothelial cell death, and whether Buyang Huanwu Decoction (BHD) intervenes in this process, remain unclear. OBJECTIVE: To investigate how NETs induce endothelial injury in CIRI and to evaluate the protective effects of BHD. METHODS: Chemical profiling of BHD aqueous extract and BHD‑containing serum was performed by UHPLC‑HRMS. A rat transient middle cerebral artery occlusion (tMCAO) model and an in vitro model of primary brain microvascular endothelial cells (BMECs) subjected to oxygen‑glucose deprivation/reperfusion (OGD/R) together with isolated NETs were used. Network pharmacology and transcriptomics were applied to predict key targets. NET formation was dynamically monitored. Functional experiments included a pyroptosis inhibitor, mitophagy modulators, BHD, and lentivirus‑mediated BNIP3 knockdown/overexpression. RESULTS: Absorbable components of BHD included calycosin‑7‑O‑β‑D‑glucoside, hydroxysafflor yellow A, and paeoniflorin. BHD improved neurological deficits, reduced infarct volume, and preserved blood‑brain barrier integrity in tMCAO rats. NETs peaked on day 3 after reperfusion and were suppressed by BHD. Mechanistically, NETs synergized with OGD/R to overactivate BNIP3, leading to dysregulated mitophagic flux and subsequent NLRP3/caspase‑1/GSDMD‑mediated endothelial pyroptosis. BNIP3 knockdown attenuated this cascade, whereas BNIP3 overexpression mimicked the damaging effects. BHD inhibited this NETs‑BNIP3‑pyroptosis cascade. In parallel, BHD partially restored mitochondrial dynamics (p‑DRP1, FIS1, MFN1) and promoted mitochondrial biogenesis (PGC‑1α, SIRT1, TFAM), consistent with its multi‑target regulation of mitochondrial quality control. Furthermore, under BNIP3 overexpression, BHD still reduced mitophagy and pyroptosis markers, indicating BNIP3‑independent protective effects. CONCLUSION: These findings suggest that in CIRI, delayed NET formation overactivates BNIP3‑driven mitophagy and triggers endothelial pyroptosis. BHD exerts neurovascular protection by interfering with this NETs‑BNIP3‑pyroptosis axis while also improving mitochondrial dynamics and biogenesis as parallel protective mechanisms. This study provides experimental evidence for the pathogenic role of NETs and the multi‑target action of BHD in CIRI.
Urolithin A supplementation improves chronic sleep deprivation-induced cognitive impairments and anxiety in mice by suppressing hippocampal ferroptosis via the Nrf2 signaling.
Wang W, Ding Y, Qingji R … +1 more , Zhang Y
Phytomedicine · 2026 Jun · PMID 42372600 · Publisher ↗
BACKGROUND: Sleep deprivation (SD) is now a widespread issue affecting people globally. It adversely impacts individuals of all ages, contributing to cognitive deficits and increased anxiety. Urolithin A (UA) has been fo...
BACKGROUND: Sleep deprivation (SD) is now a widespread issue affecting people globally. It adversely impacts individuals of all ages, contributing to cognitive deficits and increased anxiety. Urolithin A (UA) has been found to address numerous health concerns, including the preservation of brain function. Nonetheless, the exact mechanisms by which UA counters cognitive deficits and anxiety resulting from SD are not well understood. PURPOSE: To investigate the specific molecular mechanisms involving the Nrf2-ferroptosis axis through which UA ameliorates cognitive impairments and anxiety-like behaviors resulting from prolonged SD. METHODS: A murine model of chronic SD was generated by implementing sleep restriction for a duration of 14 consecutive days (n=15 per group). Behavioral experiments were used to assess the success of the SD model and the therapeutic impact of UA. We explored the mechanisms using spatial metabolites and biological functional module network analysis. Furthermore, erastin was utilized to induce ferroptosis in HT-22 cells, creating a model to assess the ferroptosis inhibition effects of UA. RESULTS: UA treatment (100 mg/kg, i.g.) significantly mitigated behavioral abnormalities caused by chronic SD. UA prevented both histopathological alterations and structural injury to hippocampal neurons (P < 0.05, P < 0.01). Further analyses revealed that UA not only attenuated excessive neuroinflammation but also increased dendritic spine density and the protein levels of neurotrophic factors in the hippocampus of chronic SD mice. Mechanistically, spatial metabolomics and target prediction analyses further revealed that the effects of UA were closely associated with the Nrf2 signaling pathway and ferroptosis suppression. UA treatment significantly decreased total iron and Fe levels (P < 0.05, P < 0.01), increased Nrf2, SLC7A11, GPX4, and HMOX1 protein levels (P < 0.01), and decreased ACSL4 expression (P < 0.01) in the hippocampus. In vitro, UA protected HT-22 cells against erastin-induced ferroptosis in a dose-dependent manner (2.5, 5, 10 µM), an effect abolished by the Nrf2 inhibitor ML385. CONCLUSIONS: Overall, supplementation with UA proved beneficial in counteracting chronic SD-induced cognitive deterioration and anxiety-like behaviors by attenuating hippocampal ferroptosis through the Nrf2 pathway. These results suggested that UA represents a potential candidate for future translational studies addressing cognitive impairments and anxiety related to insufficient sleep.
Tongluo Huoxue formula reduces ligamentum flavum fibrosis in lumbar spinal stenosis.
Chen L, Zhang W, Zhang Z … +5 more , Li N, Wang L, Zheng Z, Shen H, Zhang Y
Phytomedicine · 2026 Jun · PMID 42372599 · Publisher ↗
OBJECTIVE: Lumbar spinal stenosis (LSS) caused by ligamentum flavum hypertrophy (LFH) is a common degenerative spinal condition leading to spinal cord and nerve root compression. This study aims to investigate the therap...
OBJECTIVE: Lumbar spinal stenosis (LSS) caused by ligamentum flavum hypertrophy (LFH) is a common degenerative spinal condition leading to spinal cord and nerve root compression. This study aims to investigate the therapeutic effects and underlying mechanisms of Tongluo Huoxue Formula (TLHXF) in treating LSS by modulating the TGF-β/Smad signaling pathway. METHODS: The active compounds of TLHXF were identified using HPLC-MS/MS (high-performance liquid chromatography-mass spectrometry). Network pharmacology was used to predict potential targets, followed by molecular docking to evaluate interactions between the active compounds and key proteins in the TGF-β/Smad signaling pathway. An LFH rat model was established, and ligamentum flavum (LF) thickness was measured using MRI. Histopathological examination, western blot (WB), polymerase chain reaction (PCR), immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA) were performed to assess collagen deposition, inflammation, and fibrosis. RESULTS: HPLC-MS/MS identified five active compounds in TLHXF. Network pharmacology and molecular docking confirmed that these compounds bind to key proteins, such as TGF-β1 and Smad2/3, thereby modulating fibrosis and inflammation. In vivo, TLHXF significantly reduced LF thickness and collagen deposition and inhibited the expression of fibrosis-related proteins (TGF-β1, Smad2/3, and type I collagen), as well as pro-inflammatory cytokines (iNOS, TNF-α, and IL-1β). CONCLUSION: TLHXF shows strong anti-fibrotic and anti-inflammatory effects through the inhibition of the TGF-β/Smad signaling pathway, indicating its potential as a therapeutic agent for LSS caused by LFH.
Ginsenoside F1 as a novel hepatic β3-adrenergic receptor agonist for microbiota-independent cholesterol clearance.
Li W, Ma X, Xia J … +8 more , Qi Y, Zhao X, Ge P, Sheng J, Wei J, Ma Y, Yuan Y, Fan Y
Phytomedicine · 2026 Jun · PMID 42372598 · Publisher ↗
BACKGROUND: Hypercholesterolemia remains a major modifiable risk factor for cardiovascular diseases, calling for innovative strategies to enhance cholesterol clearance beyond conventional approaches. Ginsenoside F1 (GF1)...
BACKGROUND: Hypercholesterolemia remains a major modifiable risk factor for cardiovascular diseases, calling for innovative strategies to enhance cholesterol clearance beyond conventional approaches. Ginsenoside F1 (GF1), a highly bioavailable ginseng metabolite, shows various pharmacological activities, but its cholesterol-lowering potential remains unclear. METHODS: The target of GF1 was identified via cellular thermal shift assay, molecular docking, and RNA interference. Downstream signaling cascade was mapped using network pharmacology and inhibitor assays. Quantitative proteomics revealed the pathways by which GF1 regulates cholesterol metabolism, validated both in vitro and in vivo. Finally, the oral bioavailability of GF1 was assessed using pseudo germ-free mice model and liver high-performance liquid chromatography analysis. RESULTS: Our findings revealed that GF1 directly targeted the hepatic β3-adrenergic receptor (β3-AR) to activate the cAMP/PKA pathway, thereby upregulating SCP2 and CYP7A1 to promote bile acid synthesis and increasing ABCG5/G8 to drive cholesterol excretion. In hypercholesterolemic mice, GF1 demonstrated superior cholesterol-lowering efficacy compared to simvastatin. This effect persisted in germ-free mice, confirming GF1's direct hepatic mechanism of action independent of the gut microbiota following oral administration. CONCLUSIONS: In this study, we demonstrate that GF1 acts as a potent and selective agonist of β3-AR, promoting cholesterol clearance via a gut microbiota-independent mechanism. These findings provide a molecular basis for the potential application of GF1 in the prevention and treatment of hypercholesterolemia.
Corrigendum to "Farrerol alleviates obesity and hepatic steatosis by targeting translational regulation to coordinate cellular stress and lipid metabolism" [Phytomedicine, 158355, Volume 158].
Huang S, Wang J, Ma S … +6 more , Li L, Sun S, Zhou Y, Qian C, Zhang M, Liu Y
Phytomedicine · 2026 Jun · PMID 42372597 · Publisher ↗
Abstract loading — click title to view on PubMed.
The natural isoflavone puerarin mitigates cerebral ischemia-reperfusion injury by directly targeting CaMKⅡδ to block DLG4-Ser654 phosphorylation.
Qian H, Guo S, Tao K … +4 more , Dai S, Zhao H, Mao M, Yuan X
Phytomedicine · 2026 Jun · PMID 42372596 · Publisher ↗
BACKGROUND: Synaptic collapse drives severe neurological deficits following cerebral ischemia-reperfusion (I/R) injury. Puerarin, a bioactive isoflavone from Pueraria lobata, exhibits neuroprotective properties, yet the...
BACKGROUND: Synaptic collapse drives severe neurological deficits following cerebral ischemia-reperfusion (I/R) injury. Puerarin, a bioactive isoflavone from Pueraria lobata, exhibits neuroprotective properties, yet the precise kinase-substrate networks orchestrating its targeted efficacy remain elusive. PURPOSE: To systematically identify the pathogenic kinase networks in I/R injury and elucidate the underlying molecular mechanisms of puerarin's neuroprotection. METHODS: We adopted an integrated pipeline combining quantitative phosphoproteomics, ensemble deep learning-based virtual screening, molecular dynamics, in vitro LC-MS/MS kinase/phosphorylation assays, and in vivo/in vitro experimental validations. RESULTS: Phosphoproteomics and Kinase-Substrate Enrichment Analysis identified aberrant CaMKⅡδ activation, specifically via Thr287 autophosphorylation, as a key pathogenic mediator in I/R-injured rat hippocampi. Ensemble deep learning screening identified puerarin as a potent CaMKⅡδ modulator, while molecular dynamics, SPR, and in vitro kinase assays confirmed that puerarin directly anchors into the CaMKⅡδ ATP-binding pocket to effectively inhibit its kinase activity. Crucially, integrating bioinformatics and in vitro reconstitution, we uncovered Ser654 on the synaptic scaffold DLG4 (PSD-95) as a novel, direct phosphorylation target of CaMKⅡδ. Pathological DLG4-Ser654 phosphorylation is closely associated with the dissociation of AMPA receptors (GluR1/2) and subsequent mitochondria-dependent neuronal apoptosis. In both the NMDA-induced excitotoxicity model in PC-12 cells and MCAO rat models, puerarin suppressed CaMKⅡδ activation, blocked DLG4-Ser654 phosphorylation, restored DLG4-GluR1 interactions, and mitigated infarct volumes and neurological deficits. These protective effects were strictly occluded by CaMKⅡδ silencing or the specific inhibitor KN-93, confirming on-target efficacy. CONCLUSION: Our findings delineate a CaMKⅡδ-DLG4-AMPAR pathological cascade in ischemic stroke and highlight puerarin as a promising structure-based therapeutic candidate to rescue synaptic stability and prevent neuronal apoptosis.
Panax notoginseng saponins attenuate glomerular endothelial glycocalyx degradation in diabetic nephropathy.
Lei YN, Yu Y, Duan XQ … +1 more , Wang JB
Phytomedicine · 2026 Jun · PMID 42372595 · Publisher ↗
BACKGROUND: Glomerular endothelial glycocalyx (eGC) degradation and shedding play key roles in diabetic nephropathy (DN) pathogenesis. Although Panax notoginseng saponins (PNS) have been utilized clinically for diabetes...
BACKGROUND: Glomerular endothelial glycocalyx (eGC) degradation and shedding play key roles in diabetic nephropathy (DN) pathogenesis. Although Panax notoginseng saponins (PNS) have been utilized clinically for diabetes and its complications, the mechanisms by which PNS protects against glomerular eGC degradation, particularly through heparanase-1 (HPSE1)-mediated pathways, remain unclear. PURPOSE: This study investigated whether PNS protects against glomerular eGC injury in DN by regulating the HPSE1/EGFR/STAT3 signaling axis. METHODS: In vitro cell models and in vivo animal models of DN were established using mouse renal glomerular endothelial cells (MRGECs) stimulated with high glucose/high palmitic acid (HGHF) and db/db mice, respectively. The effects of PNS on glomerular eGC integrity and endothelial injury were evaluated. The underlying mechanisms were examined using Western blotting, immunofluorescence staining, transmission electron microscopy, quantitative real-time PCR, siRNA-mediated HPSE1 knockdown, and lentivirus- or adeno-associated virus-mediated HPSE1 overexpression. RESULTS: HGHF stimulation upregulated HPSE1 expression and induced eGC degradation in MRGECs, whereas PNS treatment suppressed HPSE1 expression and preserved eGC integrity. In db/db mice, PNS administration improved renal injury, reduced HPSE1 expression, and attenuated glomerular eGC degradation. Mechanistically, HPSE1 overexpression promoted heparan sulfate (HS) degradation, reduced syndecan-1 (SDC-1) expression, and enhanced EGFR and STAT3 phosphorylation, thereby aggravating eGC injury. In contrast, HPSE1 knockdown or PNS treatment mitigated these changes. Furthermore, AAV-mediated HPSE1 overexpression exacerbated glomerular eGC injury in db/db mice, whereas PNS treatment partially reversed this effect. CONCLUSION: PNS protects against DN-associated glomerular endothelial injury by attenuating eGC degradation, at least in part through suppression of the HPSE1/EGFR/STAT3 signaling axis. This study provides fresh mechanistic insights into how PNS exerts renoprotective effects, suggesting that HPSE1-mediated eGC degradation is a promising target for preventing and treating DN.
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