Phytomedicine [JOURNAL]
Sun
200 papers
Mechanistic study of Hederagenin against liver injury by inhibiting AIM2-mediated PANoptosis via the JAK2/STAT3 signaling pathway.
Zhang Q, Dai H, Cui T … +1 more , Chen S
Phytomedicine · 2026 Aug · PMID 42247941 · Publisher ↗
BACKGROUND: Acute liver injury (ALI) is a severe liver disease induced by various factors, including hepatitis viruses and drug toxicity. Severe and persistent ALI can eventually progress to multiple organ failure in the...
BACKGROUND: Acute liver injury (ALI) is a severe liver disease induced by various factors, including hepatitis viruses and drug toxicity. Severe and persistent ALI can eventually progress to multiple organ failure in the absence of effective intervention. At present, existing treatments for liver injury fail to provide effective and safe long-term management. Therefore, it is urgent to develop new anti-liver injury drugs. PURPOSE: This study aimed to investigate whether Hederagenin (HD) alleviates ALI and to elucidate the mechanism underlying the protective effect of HD against liver injury. METHODS: The intervention efficacy of HD on ALI was assessed using HE staining, TUNEL staining, ROS detection, immunofluorescence, ELISA, and biochemical assays. RNA-seq and proteomic analysis were performed to identify the potential target pathways. Differential gene expression between controls and patients with liver injury was analyzed using the GSE14668 and GSE38941 datasets retrieved from the GEO database. Western blot, qRT-PCR, molecular docking, and immunofluorescence, together with pharmacological inhibitors and agonists, were further applied for verification both in vitro and in vivo. RESULTS: HD was found to significantly alleviate liver injury in mice, including attenuating pathological injury, improving liver function indices and reducing inflammation levels. Subsequent RNA-seq and proteomic analysis results indicated that the protective effect of HD against liver injury was related to the JAK/STAT signaling pathway and PANoptosis. In the GSE14668 and GSE38941 datasets, AIM2 expression was upregulated in liver tissues from patients. By employing the JAK2/STAT3 inhibitor AG490 and the JAK2/STAT3 agonist α7nAChR-JAK2-STAT3 agonist 1, the results demonstrated that HD ameliorated liver injury by regulating the JAK2/STAT3 signaling pathway. Following that, our study found that AIM2 was the downstream target of the JAK2/STAT3 pathway. Using the AIM2 inhibitor ODN TTAGGG and AIM2 overexpression, the protective effect of HD against liver injury was verified to be associated with AIM2-regulated PANoptosis. CONCLUSION: HD exerted a certain ameliorative effect on ALI. In addition, HD protected against liver injury by inhibiting AIM2-mediated PANoptosis through the JAK2/STAT3 signaling pathway.
Multi-dimensional insights into Brucea javanica (L.) Merr. in cancer treatment: current status, challenges and future directions.
Li J, Yan Q, Liu H … +5 more , Wang Y, Liu R, Yao GD, Liu Q, Song SJ
Phytomedicine · 2026 Aug · PMID 42247940 · Publisher ↗
BACKGROUND: Brucea javanica (L.) Merr. (B. javanica) is a medicinal plant with a long history of clinical application and proven antitumor activity. Its oil emulsion (BJOE) is widely used as a cancer adjuvant therapy. Ho...
BACKGROUND: Brucea javanica (L.) Merr. (B. javanica) is a medicinal plant with a long history of clinical application and proven antitumor activity. Its oil emulsion (BJOE) is widely used as a cancer adjuvant therapy. However, a comprehensive understanding of its chemical composition, multi-component synergistic mechanism, key antitumor signaling pathways, formulation optimization challenges, clinical translation bottlenecks, and safety issues remain insufficient, which greatly limits its rational development and precise clinical application. PURPOSE: This review aims to systematically summarize the chemical composition, pharmacological mechanism, antitumor properties, formulation progress, clinical efficacy and safety of B. javanica, and critically point out the current research gaps and key challenges in basic and applied research. STUDY DESIGN AND METHODS: Keywords related to B. javanica, quassinoids, structure-activity relationships, pharmacology, formulations, and clinical aspects to include published studies from 2008-2025 were searched in the following databases: SciFinder, Web of Science, PubMed, China National Knowledge Infrastructure (CNKI) and Wanfang database. Relevant literature in both Chinese and English obtained from the above search was incorporated into this review. RESULTS: Over 100 quassinoids, 48 triterpenoids, and 27 alkaloids have been identified from B. javanica. As the core antitumor components, quassinoids exert pharmacological activities through the regulation of PI3K/AKT, MAPK, NF-κB and various other vital signaling cascades. Targeted nano-formulations can enhance tumor accumulation, but large-scale production is difficult and stability is insufficient. Clinically, BJOE can improve the efficacy of chemo-radiotherapy, but carries risks of allergic reactions and multi-system injury. CONCLUSION: This review clarifies the key antitumor components, signaling pathways, delivery strategies and safety profiles of B. javanica. Despite its significant antitumor potential, instability in quality, unclear synergistic mechanisms, unstable delivery systems, and safety issues remain major challenges. This study provides comprehensive evidence base and identifies key research gaps to support the further rational development of therapies based on B. javanica.
Asperosaponin VI ameliorates osteoporosis via skeletal muscle-derived FGF-2-mediated osteoblast differentiation.
Li J, Liang Y, Li X … +5 more , Chen L, Zhang C, Li Y, Liu Y, Zhou C
Phytomedicine · 2026 Aug · PMID 42241949 · Publisher ↗
BACKGROUND: Skeletal muscle functions as a dynamic endocrine organ, secreting myokines that contribute to systemic physiological homeostasis. Despite the established osteoprotective effects of Asperosaponin VI (AVI), it...
BACKGROUND: Skeletal muscle functions as a dynamic endocrine organ, secreting myokines that contribute to systemic physiological homeostasis. Despite the established osteoprotective effects of Asperosaponin VI (AVI), it remains unknown whether these effects are mediated via the modulation of muscle-derived factors that subsequently regulate bone metabolism. PURPOSE: The present study aims to investigate whether AVI alleviates ovariectomy (OVX)-induced bone loss by modulating muscle-derived signals that exert regulatory effects on osteogenesis. METHODS: Female C57BL/6 OVX mouse models and the co-culture system composed of AVI-treated myotubes and osteoblasts were used. The bone structural microarchitecture, muscle phenotypic changes, bone formation markers were analyzed. Transcriptomics, molecular docking, and cellular thermal shift assays (CETSA) were performed to uncover the core targets and the potential mechanisms involved. RESULTS: AVI significantly improved both trabecular and cortical bone structures in OVX mice, which were associated with simultaneous upregulation of osteogenesis and inhibition of osteoclast activity, along with induction of a phenotypic shift from fast- to slow-twitch muscle fiber types. In vitro studies found that treatment with AVI in myotubes remarkably increased osteogenesis through paracrine action. Mechanistically, AVI bound to and stabilized the transcription factor early growth response 1 (EGR-1) in muscle cells to facilitate rapid EGR-1 nuclear translocation, thus leading to secretion of fibroblast growth factor-2 (FGF-2). Moreover, the key effectors identified in the gene expression profiling, namely fibroblast growth factor receptor 1 (FGFR1), were proven to be required for activation of the osteoblastic Wnt/β-catenin signaling pathway downstream FGF-2. CONCLUSIONS: The present work revealed AVI as an effective therapy in treating post-menopause osteoporosis through direct modulation of EGR-1 in muscle cells to enhance FGF-2 secretion that activated osteoblastic Wnt/β-catenin signaling via FGFR1.
Paeonia lactiflora-derived extracellular vesicles ameliorate diabetic peripheral neuropathy by modulating chemokine-guided immune trafficking in peripheral nerves.
Wang L, Xia S, Lin S … +1 more , Xie X
Phytomedicine · 2026 Jul · PMID 42241812 · Publisher ↗
AIMS: This study investigated the therapeutic potential of Paeonia lactiflora-derived extracellular vesicles (PRA-EVs) for diabetic peripheral neuropathy (DPN), with a particular focus on their immunomodulatory effects o...
AIMS: This study investigated the therapeutic potential of Paeonia lactiflora-derived extracellular vesicles (PRA-EVs) for diabetic peripheral neuropathy (DPN), with a particular focus on their immunomodulatory effects on the CC motif chemokine ligand 21 (CCL21) / CC chemokine receptor type 7 (CCR7) axis. METHODS: PRA-EVs were isolated and characterized. In vitro, their effects on high glucose (HG)-induced Schwann cell apoptosis, CCL21 expression, and CD8⁺ T-cell migration were assessed. In vivo, therapeutic efficacy was evaluated in an STZ-induced DPN mouse model using behavioral testing, histological analysis, and molecular assays. RESULTS: PRA-EVs significantly attenuated HG-induced Schwann cell apoptosis and reduced CCL21 expression. In DPN mice, PRA-EVs improved behavioral and structural abnormalities, including neuropathic pain and myelin injury, with efficacy comparable to mecobalamin. Mechanistically, PRA-EVs were associated with downregulation of CCL21/CCR7 signaling and reduced CCR7⁺CD8⁺ T-cell infiltration in sciatic nerves. In addition, PRA-EVs suppressed CD8⁺ T-cell migration to a degree comparable to the CCR7 pathway inhibitor Cosalane. To our knowledge, this is the first study to link PRA-EVs with the amelioration of DPN in association with modulation of the CCL21/CCR7 axis. CONCLUSION: PRA-EVs ameliorate DPN, at least in part, through modulation of the CCL21/CCR7 axis, thereby attenuating Schwann cell injury and neuroinflammation. These findings support PRA-EVs as a promising multi-target therapeutic strategy for DPN.
Mollugin induces ferroptosis through dysregulation of iron homeostasis and redox balance in non-small cell lung cancer.
Pei Y, Liu Q, Mao Z … +7 more , Liu X, Yin J, He J, Wu M, Chang Q, Zhang L, Cao D
Phytomedicine · 2026 Jul · PMID 42241811 · Publisher ↗
BACKGROUND: Lung cancer remains one of the most prevalent and lethal malignancies worldwide, with non-small cell lung cancer (NSCLC) constituting the predominant subtype, necessitating the development of effective therap...
BACKGROUND: Lung cancer remains one of the most prevalent and lethal malignancies worldwide, with non-small cell lung cancer (NSCLC) constituting the predominant subtype, necessitating the development of effective therapeutic strategies. Although mollugin (MOL) has shown anticancer potential, its specific efficacy and mechanism of action against NSCLC remain unclear. PURPOSE: This study aimed to systematically investigate the anti-NSCLC activity of MOL and to elucidate the underlying molecular mechanisms. STUDY DESIGN: The study combined in vitro experiments using NSCLC cell lines and in vivo efficacy evaluation in a mouse xenograft model. METHODS: The effects of MOL on NSCLC cell proliferation, migration, mitochondrial function, and redox homeostasis were assessed. The role of NCOA4-mediated ferritinophagy and Keap1/Nrf2/GPX4 axis was examined using pharmacological inhibitors and NCOA4 knockdown. RESULTS: MOL significantly inhibited NSCLC cell proliferation, suppressed cell migration, induced mitochondrial dysfunction, and disrupted redox homeostasis. Mechanistically, MOL induced ferroptosis by activating NCOA4-mediated ferritinophagy and modulating the Keap1/Nrf2/GPX4 signaling pathway. This ferroptotic effect was abrogated by NCOA4 knockdown and the Keap1 inhibitor KI696. MOL also showed an enhancing effect on the efficacy of paclitaxel. In vivo, both low and high doses of MOL effectively inhibited lung tumor growth without causing significant systemic toxicity. CONCLUSION: This study identifies MOL as a novel ferroptosis-inducing agent against NSCLC, acting through dual-pathway modulation of ferritinophagy and the Keap1/Nrf2/GPX4 axis. These findings highlight the potential of MOL as a promising therapeutic candidate for NSCLC treatment.
Amorfrutin-A, a membrane-targeting phytochemical active against multidrug-resistant Staphylococcus aureus: In vitro and in vivo activity and mechanism of action.
Lucidi M, Imperi F, Turi M … +13 more , Beccarini M, Ciolfi S, Sacchi A, Visaggio D, Sirignano C, Summa V, Quadrotta V, Polticelli F, D'Intino E, Marianecci C, Rotili D, Taglialatela-Scafati O, Visca P
Phytomedicine · 2026 Jul · PMID 42235358 · Publisher ↗
There is an urgent need to develop new antibiotics to combat multidrug-resistant (MDR) Staphylococcus aureus infections. Amorfrutins are plant-derived prenylated benzoic acids whose antimicrobial potential is largely une...
There is an urgent need to develop new antibiotics to combat multidrug-resistant (MDR) Staphylococcus aureus infections. Amorfrutins are plant-derived prenylated benzoic acids whose antimicrobial potential is largely unexplored. This study aimed to investigate the antibacterial properties of amorfrutins. To this end, the antibacterial activity of ten amorfrutins purified from Glycyrrhiza foetida (Fabaceae) was evaluated by determining their minimum inhibitory concentrations (MICs) against reference bacterial strains, as well as their cytotoxicity in human cell lines. The most promising compound was investigated to identify its target, mode of action (MoA), interactions with standard-of-care anti-staphylococcal antibiotics, and inhibition of biofilm and persister cells. The MoA was corroborated by molecular dynamics simulations and in vitro assays using artificial membranes and cellular models. Toxicity and antibacterial efficacy were also assessed in an insect infection model. Among the tested amorfrutins, amorfrutin-A (AMF-A) exhibited the strongest activity against S. aureus (MIC=4-16 mg/L) without causing detectable cytotoxicity. AMF-A rapidly disrupted S. aureus membranes, eradicated biofilm and persister cells, and displayed an undetectable frequency of resistance development. AMF-A did not antagonize standard-of-care anti-staphylococcal antibiotics and showed synergistic effects with daptomycin, piperacillin, and azithromycin. AMF-A showed no in vivo toxicity and protected Galleria mellonella larvae from lethal S. aureus infection. We conclude that AMF-A is a promising membranolytic phytochemical with potential for treatment of MDR S. aureus infections.
Oleanolic acid alleviates stress-induced alopecia via modulating brain-skin axis: Neuroprotection and dermal papilla cell senescence.
Han B, Wang Y, Yang Z … +5 more , Chen Y, Huang X, Zhang X, Wang H, Zeng X
Phytomedicine · 2026 Jul · PMID 42235357 · Publisher ↗
BACKGROUND: Psychological stress-induced alopecia is becoming increasingly prevalent in younger populations; however, effective nutritional interventions remain limited. OBJECTIVE: To investigate the therapeutic effects...
BACKGROUND: Psychological stress-induced alopecia is becoming increasingly prevalent in younger populations; however, effective nutritional interventions remain limited. OBJECTIVE: To investigate the therapeutic effects and underlying mechanisms of the natural product component Oleanolic acid (OA) on stress-induced alopecia. METHODS: A chronic unpredictable mild stress (CUMS)-induced C57BL/6 J mouse model was established to evaluate the efficacy and potential mechanisms of Oleanolic acid. Evaluation and molecular biology experiments were conducted using pathological staining, commercial assay kits, Western Blot (WB), and LC/MS. In vitro, corticosterone-induced injury models were established in HT22 cells and primary mouse dermal papilla cells. Confocal microscopy, flow cytometry, and WB were employed to explore the mechanisms of OA. RESULTS: Oral administration of OA significantly ameliorated anxiety-like behaviors and reversed the stagnation of hair growth in CUMS mice. Pharmacokinetic analysis confirmed the distribution of OA in both brain and skin tissues. Mechanistically, OA rebalanced neurotransmitter levels (reducing the 5-HIAA/5-HT and Glu/GABA ratios) and downregulated hypothalamic-pituitary-adrenal (HPA) axis hormones (corticosterone, cortisol). In the brain, OA attenuated neuronal degeneration and oxidative stress via the BDNF/CREB signaling pathway. In the skin, OA reduced inflammation and oxidative damage, promoted hair follicle regeneration, and increased skin thickness by activating the Wnt/β-catenin pathway and upregulating GAS6. Furthermore, in vitro studies demonstrated that OA mitigated corticosterone-induced ferroptosis-like changes (restoring SLC7A11 and GPX4 levels) in HT22 cells. In primary dermal papilla cells, OA inhibited stress-induced senescence and cell cycle arrest by modulating P53 and activating Wnt/β-catenin signaling. CONCLUSION: These findings suggest that OA effectively alleviates stress-induced alopecia by regulating the brain-skin axis, highlighting its potential as a functional food ingredient for stress management.
Targeting the virulence factor suilysin: a structure-guided discovery of chebulinic acid as a potent antivirulence agent.
Wang C, Li X, Zhang Z … +6 more , Zhang Z, Liu D, Xiao R, Wang X, Chen H, Tan C
Phytomedicine · 2026 Jul · PMID 42235356 · Publisher ↗
BACKGROUND: The rapid rise of bacterial resistance has compromised conventional antibiotic efficacy, emphasizing the need for antivirulence-based anti-infective strategies. PURPOSE: Targeting the pore-forming toxin suily...
BACKGROUND: The rapid rise of bacterial resistance has compromised conventional antibiotic efficacy, emphasizing the need for antivirulence-based anti-infective strategies. PURPOSE: Targeting the pore-forming toxin suilysin (SLY), this study aimed to establish a surface plasmon resonance (SPR) screening platform to identify candidates that bind to SLY and to evaluate their antivirulence potential. STUDY DESIGN AND METHODS: A total of 159 plant-derived natural compounds were screened to identify SLY-binding candidates. Functional effects were assessed by hemolysis inhibition, biofilm disruption, and bacterial viability assays. The interaction between chebulinic acid (CA) and SLY was further characterized using molecular docking, molecular dynamics, SPR, and isothermal titration calorimetry (ITC) to determine binding properties, and its impact on ATP synthesis, proton gradient, and genes transcription was analyzed. The enhancement of CA with amoxicillin (AMX) was evaluated in a mouse severe infection model, and safety was assessed by cytotoxicity and hemolysis tests. RESULTS: As the candidate compound with the strongest anti-hemolysis activity, CA bound SLY with high affinity and markedly suppressed SLY-mediated hemolysis at 0.25 μg/ml, while its minimal inhibitory concentration (MIC) against S. suis was 1024 μg/ml. CA disrupted preformed biofilms, neutralized hemolytic activity in bacterial supernatants, and damaged embedded bacteria. Mechanistically, CA stabilized SLY via multiple hydrogen bonds, restricted its conformational flexibility, impaired ATP synthesis, and downregulated sly, IL-6, TNF-α, and iNOS expression. In vivo, CA combined with AMX markedly improved survival (from 0 to 90%), reduced bacterial burden and tissue lesions, and suppressed systemic inflammation without observable toxicity. CONCLUSION: These findings reveal the multifaceted antivirulence mechanism of CA and its enhancement therapeutic potential, offering a promising foundation for developing safe and effective "antivirulence + antibiotic" strategies against multidrug-resistant infections.
Targeting the lactate-lactylation-glucose uptake axis: Cryptotanshinone reprograms metabolic-epigenetic crosstalk in gastric cancer.
Ni X, Wang C, Zhang K … +6 more , Zhang M, Guo J, Fan W, Zheng L, Jiang T, Zhang G
Phytomedicine · 2026 Jul · PMID 42235355 · Publisher ↗
BACKGROUND: Gastric cancer remains a leading cause of cancer-related mortality worldwide, with chemotherapy resistance and severe side effects posing significant challenges. Metabolic reprogramming, particularly lactate-...
BACKGROUND: Gastric cancer remains a leading cause of cancer-related mortality worldwide, with chemotherapy resistance and severe side effects posing significant challenges. Metabolic reprogramming, particularly lactate-driven histone lactylation, plays a crucial role in tumor progression. Cryptotanshinone (CTS), a bioactive compound from Salvia miltiorrhiza, has demonstrated anti-tumor properties, yet its mechanisms in regulating lactate metabolism and lactylation in gastric cancer remain unclear. PURPOSE: This study aimed to elucidate the molecular mechanisms by which CTS inhibits gastric cancer progression, focusing on its effects on enolase activity, lactate production, histone lactylation, and downstream metabolic-epigenetic regulation. METHODS: We screened Salvia miltiorrhiza ethanol extract (SME) and identified CTS as a key component targeting enolase. Molecular docking, surface plasmon resonance, and limited proteolysis-mass spectrometry were used to confirm CTS-ENO1 interaction. In vitro and in vivo models, including cell lines, xenografts, and patient-derived organoids, were employed to assess anti-tumor effects. Glycolytic function, histone lactylation, and gene expression were evaluated via seahorse assay, western blot, Cut&Tag, and RNA-seq. RESULTS: CTS directly binds to and inhibits enolase ENO1, reducing phosphoenolpyruvate (PEP) and lactate production. Decreased lactate levels led to reduced global histone lactylation, particularly at H3K18. CTS also enhanced HDAC2-mediated de-lactylation by lowering PEP, which otherwise inhibits HDAC2. Downregulation of H3K18la suppressed MGAT4A expression, impairing GLUT1 membrane localization and glucose uptake, thereby forming a feedback loop that inhibits glycolysis. CTS significantly suppressed tumor growth in xenograft and patient-derived organoid models, effects reversible by exogenous lactate.
Programmed cell death in Naegleria fowleri induced by frutescinol acetate, a polyacetylene from Argyranthemum frutescens.
Aldalaeen SMH, Chao-Pellicer J, Sifaoui I … +6 more , Hernández-Álvarez E, Ben Youssef M, Jiménez IA, Piñero JE, Bazzocchi IL, Lorenzo-Morales J
Phytomedicine · 2026 Jul · PMID 42235354 · Publisher ↗
BACKGROUND: Primary amoebic meningoencephalitis (PAM) caused by Naegleria fowleri remains a highly lethal infection with limited therapeutic options. PURPOSE: In the search for novel amoebicidal compounds of natural orig...
BACKGROUND: Primary amoebic meningoencephalitis (PAM) caused by Naegleria fowleri remains a highly lethal infection with limited therapeutic options. PURPOSE: In the search for novel amoebicidal compounds of natural origin, this study investigates the mechanism of action of a bioactive metabolite from Argyranthemum frutescens, a Canary Islands endemic plant, against Naegleria fowleri. STUDY DESIGN: The present study combined bio-guided fractionation of A. frutenscens to isolate amoebicidal compound followed by elucidation of it mechanism of action against N. fowleri. METHODS: Fractionation of the ethanolic root extract was performed to isolate the bioactive compounds. Activity was tested against N. fowleri in both trophozoite and cyst forms (strains ATCC® 30,808™ and ATCC® 30,215™) and compared to the reference drug miltefosine. Cytotoxicity studies were conducted in a murine macrophage cell line. The onset of programmed cell death in treated cells was investigated through the analysis of keys cellular events including, chromatin condensation, plasma membrane permeability, mitochondrial function, and reactive oxygen species production. RESULTS: The bio-guided fractionation afforded the frutescinol acetate, a polyacetylene that showed strong activity against N. fowleri. Half maximal inhibitory concentration (IC₅₀) values were 4.97 µM and 5.70 µM for trophozoite strains ATCC® 30,808™ and ATCC® 30,215™, respectively, exceeding the potency of miltefosine. The compound was also active against N. fowleri cysts, with an IC₅₀ of 8.53 µM. Cytotoxicity studies revealed a favorable selectivity profile. The compound triggered a cascade of cellular events associated with programmed cell death, including chromatin condensation and increased plasma membrane permeability. These alterations led to mitochondrial dysfunction, overproduction of reactive oxygen species, and consequent oxidative stress. CONCLUSION: Frutescinol acetate exhibits potent amoebicidal activity and induces programmed cell death-like processes in N. fowleri, supporting its potential as a lead for further pharmacological evaluation.
Handelin inhibits osteoclastogenesis and bone loss by targeting lipocalin-2 and restoring autophagy to suppress NF-κB signaling.
Hu S, Li J, Zhang Y … +8 more , Li J, Wang S, Mou Y, Liu J, Sun X, Hu P, Kang H, Zhu M
Phytomedicine · 2026 Jul · PMID 42229383 · Publisher ↗
BACKGROUND: Excessive osteoclastogenesis is a pivotal pathological process in osteoporosis. Identifying compounds that can effectively inhibit osteoclastogenesis without toxicity is of great therapeutic interest. Handeli...
BACKGROUND: Excessive osteoclastogenesis is a pivotal pathological process in osteoporosis. Identifying compounds that can effectively inhibit osteoclastogenesis without toxicity is of great therapeutic interest. Handelin, a guaianolide dimer from Chrysanthemum indicum and other Chrysanthemum spp., possesses known anti-inflammatory and antioxidant properties, yet its role in osteoclastogenesis remains unclear. This study aims to investigate the role and mechanism of Handelin in osteoclastogenesis. METHODS: The effects of Handelin on osteoclast differentiation and function were assessed using Cell Counting Kit-8 (CCK-8), tartrate-resistant acid phosphatase (TRAP) and F-actin ring staining, bone pit assays, real-time quantitative PCR (RT-qPCR), and western blot in vitro. An ovariectomized (OVX) mouse model was employed for in vivo validation, evaluated by Micro-CT, histological staining, and ELISA assays. RNA sequencing (RNA-seq), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) analysis, molecular docking, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), co-immunoprecipitation, immunofluorescence, and autophagy flux assays were employed for mechanistic investigation. Rescue experiments were conducted using recombinant lipocalin-2 (rLCN2) protein and sequestosome-1 (p62) overexpression. RESULTS: Handelin potently inhibited RANKL-induced osteoclast differentiation and bone resorption in vitro without cytotoxicity and alleviated OVX-induced bone loss in vivo. RNA-seq revealed Handelin downregulated LCN2 and activated autophagy while inhibiting the NF-κB pathway. Handelin directly bounded LCN2, reduced its expression at both mRNA and protein levels in cells and tissues, and restored autophagic flux, weakening the interaction between p62-TRAF6 to block NF-κB signaling. The anti-osteoclastogenic effects of Handelin were partially reversed by rLCN2 supplementation or p62 overexpression. Notably, Handelin did not impair osteogenic differentiation. CONCLUSION: This study identifies Handelin as a novel inhibitor of osteoclastogenesis that targets the LCN2-autophagy pathway and suppresses NF-κB signaling, highlighting its potential as a therapeutic agent for osteoporosis and related bone diseases.
Shenqi Tangluo Pill demonstrates protective impacts on kidney damage in mice with type 2 diabetes through modulation of intestinal flora and the microbial metabolic product Trimethylamine N-oxide (TMAO).
Zhang R, Liu M, Yang J … +4 more , Liu F, Duan Y, Zhu X, Bai M
Phytomedicine · 2026 Jul · PMID 42229382 · Publisher ↗
BACKGROUND: Those affected by Type 2 diabetes (T2DM) often encounter microvascular harm, and within this context, the kidneys are especially prone to damage. Among the approaches to manage such microvascular complication...
BACKGROUND: Those affected by Type 2 diabetes (T2DM) often encounter microvascular harm, and within this context, the kidneys are especially prone to damage. Among the approaches to manage such microvascular complications, Shenqi Tangluo Pill (SQTLW), a traditional Chinese herbal formulation, is commonly utilized in clinical settings for preventing and addressing microvascular issues linked to T2DM. Nonetheless, the detailed impacts and working principles of this herbal formulation in alleviating kidney damage caused by diabetes are still not clearly understood. PURPOSE: The aim was to confirm the kidney-protective impacts of SQTLW on T2DM mice, as well as to clarify the fundamental mechanisms related to intestinal microbiota and the microbe-derived metabolite trimethylamine N-oxide (TMAO), especially under the condition of intestinal flora depletion induced by a combination of broad-spectrum antibiotics (ABx). METHODS: Diabetic db/db mice received sustained SQTLW intervention over an 8-week period. Following the 8-week intervention, evaluations were performed on fasting blood glucose levels (FBG), body mass, kidney function, and histopathological changes in renal tissue. Additionally, the makeup of gut microbial communities and the circulating concentrations of metabolites linked to TMAO were assessed. To assess the integrity of the intestinal barrier, histopathological examination of colonic tissue and expression profiles of zonula occludens protein-1 (ZO-1) and Occludin were performed. Expression levels of NOD-like receptor pyrin domain-containing 3 (NLRP3), Smad family member 2/3 (Smad2/3), fibronectin (FN), and α-smooth muscle actin (α-SMA) in renal tissue were examined using immunodetection methods. Next, db/db mice were given a combination of ABx and SQTLW treatments to further examine if the therapeutic outcome is dependent on the regulation of gut microorganisms. RESULTS: SQTLW notably lowered FBG and body weight in db/db mice, ameliorated renal dysfunction, and alleviated histopathological injury of renal tissue, with a notable dose-response relationship. 16S rRNA gene sequencing-based profiling revealed that SQTLW substantially altered the compositional structure of distinct bacterial genera from the phyla Bacteroidota and Firmicutes, particularly Muribaculaceae and Lachnospiraceae. Colonic histopathology and molecular detection indicated that SQTLW effectively preserved intestinal barrier architecture. Targeted metabolomics via LC-MS/MS demonstrated that SQTLW significantly modulated TMAO-related plasma metabolites, including TMAO, choline, and creatinine. Moreover, SQTLW significantly downregulated renal expression of NLRP3 and Smad2/3, thereby attenuating fibrosis-related injury. Importantly, further experiments confirmed that depletion of gut microbiota by ABx partially attenuated the renoprotective effects of SQTLW in db/db mice. CONCLUSIONS: SQTLW confers protective effects against renal injury secondary to T2DM, potentially via modulation of gut microbial composition, preservation of intestinal barrier function, and regulation of TMAO-related metabolic pathways.
Targeting Mitochondrial Dysfunction to Treat Diabetic Osteoporosis: Role of Neoprzewaquinone A.
Chen R, Yang C, Chen C … +8 more , Yang F, Xiao H, Yang A, Peng B, Liu J, Zhao D, Geng B, Xia Y
Phytomedicine · 2026 Jul · PMID 42229381 · Publisher ↗
BACKGROUND: Diabetic osteoporosis (DMOP) involves impaired bone formation driven by mitochondrial dysfunction and osteoblast apoptosis. Current treatments do not address these mechanisms. OBJECTIVE: To evaluate whether N...
BACKGROUND: Diabetic osteoporosis (DMOP) involves impaired bone formation driven by mitochondrial dysfunction and osteoblast apoptosis. Current treatments do not address these mechanisms. OBJECTIVE: To evaluate whether Neoprzewaquinone A (NEO), a natural compound from Salvia miltiorrhiza, can protect bone by restoring mitochondrial integrity and activating survival signaling. METHODS: Bioinformatics, molecular docking, and biophysical assays were combined with in vitro and in vivo studies. Mouse osteoblasts were exposed to glucolipotoxic conditions, and DMOP was induced in C57BL/6 mice. NEO's effects on mitochondrial morphology, mitochondrial membrane potential, ATP production, ROS, apoptosis markers, and PI3K/AKT/mTOR signaling were assessed using imaging, flow cytometry, western blotting, and micro-CT. RESULTS: Glucolipotoxic stress caused mitochondrial damage, ROS accumulation, and suppression of ELF5/PRKD2 and PI3K/AKT/mTOR signaling. NEO bound PRKD2 with high affinity (KD ≈ 10⁻ M), restored pathway activation, reduced ROS, attenuated HGPA-induced mitochondrial depolarization, restored ATP levels, and preserved mitochondrial ultrastructure. In diabetic mice, oral NEO improved bone mineral density, trabecular architecture, and mechanical strength without detectable toxicity. CONCLUSION: NEO mitigates diabetic bone loss by rescuing mitochondrial function and activating the ELF5/PRKD2/PI3K/AKT/mTOR axis. These findings highlight mitochondrial protection as a promising strategy for DMOP therapy and position NEO as a candidate for mechanism-based treatment.
Deacetyl asperulosidic acid methyl ester attenuates renal fibrosis via Hsp90aa1-mediated TGFβR1 degradation.
Zhang L, Li Q, Ni Y … +5 more , Li Z, Wang H, Meng L, Wang L, Li J
Phytomedicine · 2026 Jul · PMID 42229380 · Publisher ↗
BACKGROUND: Renal fibrosis represents a common and critical pathological process underlying chronic kidney disease (CKD), invariably leading to progressive renal dysfunction and ultimately end-stage renal disease. PURPOS...
BACKGROUND: Renal fibrosis represents a common and critical pathological process underlying chronic kidney disease (CKD), invariably leading to progressive renal dysfunction and ultimately end-stage renal disease. PURPOSE: This investigation sought to determine anti-fibrotic efficacy of Deacetyl Asperulosidic Acid Methyl Ester (DA), in ameliorating renal fibrosis, focusing on its interaction with heat shock protein 90 (Hsp90aa1) and its downstream effects on TGF-β/Smad signaling. STUDY DESIGN: The anti-fibrotic efficacy of DA was evaluated in vivo using two murine models of CKD (unilateral ureteral obstruction and adenine-induced nephropathy) and in vitro using TGF-β1-stimulated NRK-49F fibroblasts and TCMK-1 tubular cells. Molecular targets were identified and validated through quantitative proteomics, Specific Pupylation as Identity Reporter (SPIDER) assay, and biophysical interaction analyses. METHODS: Renal function and histological changes were assessed by biochemical analysis, H&E, and Masson's trichrome staining. The expression of fibrotic markers and signaling pathway proteins was determined using IHC, Western blot, and qRT-PCR. The interaction between DA and Hsp90aa1 was verified by Cellular Thermal Shift Assay (CETSA), Drug Affinity Responsive Target Stability (DARTS), and Co-immunoprecipitation (Co-IP). RESULTS: Our data demonstrated that DA administration substantially ameliorated renal dysfunction and attenuated fibrotic progression in both animal and cellular models. Quantitative proteomic profiling results revealed a prominent suppression of extracellular matrix components and TGF-β type I receptor (TGFβRI) following DA treatment. Furthermore, biotin-labeled DA binding combined with SPIDER experiments identified Hsp90aa1 as a direct target of DA. Mechanistically, the binding of DA to Hsp90aa1 disrupts the interaction between Hsp90aa1 and TGFβR1, thereby destabilizing TGFβR1 and promoting its degradation. This regulation effectively impedes the transduction of the downstream TGF-β/Smad signaling cascade, ultimately mitigating renal fibrosis. CONCLUSION: Our findings demonstrate that DA is a potent anti-fibrotic agent that targets Hsp90aa1 to modulate TGFBR1 stability and inhibit the TGF-β/Smad pathway.
Nepetin suppresses HBV-associated hepatocellular carcinoma metastasis by regulating the HBx/HIF-1α-mediated autophagy axis.
Liao M, Du H, Zhong Q … +11 more , Zhang Y, Zhang Y, Wang Z, Qin Y, Chen B, Chen T, Zhang H, Yuan W, Huang D, Zhou H, Tong G
Phytomedicine · 2026 Jul · PMID 42229379 · Publisher ↗
BACKGROUND: Hepatocellular carcinoma (HCC) arising from chronic Hepatitis B virus (HBV) infection has a high metastatic potential, driven largely by the viral oncoprotein Hepatitis B Virus X Protein (HBx) and a hypoxic t...
BACKGROUND: Hepatocellular carcinoma (HCC) arising from chronic Hepatitis B virus (HBV) infection has a high metastatic potential, driven largely by the viral oncoprotein Hepatitis B Virus X Protein (HBx) and a hypoxic tumor microenvironment. Therapeutic strategies targeting these underlying oncogenic mechanisms remain an unmet clinical need. PURPOSE: Nepetin, a naturally occurring flavonoid with known anti-inflammatory and antitumor activities, has not been evaluated for efficacy against HBV-associated HCC metastasis. Therefore, this study aimed to investigate its antimetastatic potential and underlying molecular mechanisms. STUDY DESIGN: The antimetastatic effects and molecular targets of Nepetin were evaluated using complementary in vitro and in vivo models of HBV-associated HCC. METHODS: The antimetastatic effects of Nepetin were assessed in vitro using HBV-positive HCC cell lines and in vivo using an orthotopic liver xenograft model and a tail vein injection metastasis model. Mechanistic studies were conducted using western blotting, molecular docking, cellular thermal shift assay and surface plasmon resonance assays. RESULTS: Nepetin treatment significantly reduced migration and invasion of HBV-HCC cells in vitro by approximately 45% and 50%, respectively, at 10 µM, and suppressed intrahepatic and pulmonary metastasis in vivo, without apparent toxicity. Mechanistically, Nepetin disrupted the interaction between HBx and HIF-1α, leading to reduced hypoxia-inducible factor-1α (HIF-1α), thereby reducing HIF-1α protein stability and transcriptional activity and subsequently suppressed the downstream prometastatic autophagic flux. CONCLUSION: The findings identify Nepetin as a candidate compound that inhibits HBV-HCC metastasis by targeting the HBx/HIF-1α/autophagy signaling cascade. These findings provide a mechanistic rationale for targeting this pathway and support further evaluation of the translational potential of Nepetin in metastatic HBV-HCC.
Liandan Xiaoyan Formula ameliorates DSS-induced ulcerative colitis through altering the metabolism of bile acids by regulating the FXR-FGF15 signaling pathway.
Liu F, Wang Q, Chen Y … +7 more , Zheng B, Li J, Dai P, Zhou R, Wang M, Lin C, Zhu C
Phytomedicine · 2026 Jul · PMID 42229378 · Publisher ↗
BACKGROUND: Ulcerative colitis (UC) is a chronic, non-specific inflammatory disorder that primarily affects the rectal and colonic mucosa and submucosa, and its pathogenesis is closely related to the dysregulation of bil...
BACKGROUND: Ulcerative colitis (UC) is a chronic, non-specific inflammatory disorder that primarily affects the rectal and colonic mucosa and submucosa, and its pathogenesis is closely related to the dysregulation of bile acid (BA) metabolism. Liandan Xiaoyan Formula (LDXYF), a classic Traditional Chinese medicine formula composed of Herba andrographis and Ramulus et folium, widely used for enteritis treatment in China, and its mechanism has not been clarified. PURPOSE: To clarify the effects and mechanism of LDXYF on UC treatment via serum metabolomics and experimental verification. METHODS: The effects of LDXYF on UC was investigated in 3.5 % dextran sulfate sodium (DSS)-induced UC mice. Serum metabolomics strategy was applied for exploring the core mechanism of LDXYF. The regulation of LDXYF on BA metabolism and FXR-FGF15 signaling pathway were further verified by fluorescence reaction, PCR and WB technology. The critical role of FXR for UC treatment of LDXYF was studied via molecular docking, molecular dynamics simulation and FXR knockout (FXR) mice. RESULTS: LDXYF treatment alleviated UC via alleviating body weight loss, reducing disease activity index and the levels of inflammatory factors (TNF-α, MPO), and protecting intestinal barrier. Serum metabolomics revealed that LDXYF notably modulated the levels of 35 metabolites in UC mice, which mainly involved in primary bile acid synthesis, arachidonic acid metabolism, and energy metabolism, hinted the potential mechanism of LDXYF related to regulate BA metabolism by FXR-FGF15 signaling pathway. Bile acid profile showed that LDXYF altered the disorder of BA metabolism. Molecular docking and molecular dynamics simulation presented that a high affinity between active ingredients of LDXYF and FXR protein. We further demonstrated that LDXYF could increase FXR expression in both liver and colon tissues, and then subsequently regulate BA enterohepatic circulation via FXR-FGF15 axis and its target genes for cholesterol hydroxylases and transporters of BA. The effects of LDXYF on BA enterohepatic circulation in UC was dependent on the FXR, which has been demonstrated in FXR mice. CONCLUSION: LDXYF relieved UC via regulation of BA enterohepatic circulation by FXR-FGF15 axis, which provided new insights for the mechanism of LDXYF on UC treatment.
Hedyotis diffusa injection suppresses breast cancer progression and lung metastasis through dual targeting of PTK2B and CCN2.
Ren A, Yang L, Liao Q … +8 more , Ni S, Li X, Chen S, Wang X, Wang Y, Li J, Sun R, Su X
Phytomedicine · 2026 Jul · PMID 42229377 · Publisher ↗
BACKGROUND: Lung metastasis is a leading cause of mortality in patients with breast cancer, especially triple-negative breast cancer (TNBC), where current therapies are limited and toxic. Hedyotis diffusa injection (HDI)...
BACKGROUND: Lung metastasis is a leading cause of mortality in patients with breast cancer, especially triple-negative breast cancer (TNBC), where current therapies are limited and toxic. Hedyotis diffusa injection (HDI) is used clinically as an adjuvant, but its efficacy and mechanisms against lung metastasis remain unclear. PURPOSE: To investigate the antitumour and antimetastatic activities of HDI and its active constituent, asperulosidic acid (ASPA), identify its molecular targets, and assess its potential synergy with gefitinib. METHODS: The antiproliferative, proapoptotic, antimigratory, and anti‑invasive effects of HDI and ASPA were evaluated in 4T1, MDA‑MB‑231, and MCF‑7 cells via CCK‑8, colony formation, flow cytometry, wound‑healing, and Transwell assays. Anti‑tumor efficacy, anti‑lung metastatic effects, and systemic toxicity were assessed in a BALB/c 4T1 orthotopic breast tumor model. Mechanistic studies employed data‑independent acquisition (DIA) proteomics, Western blotting, immunohistochemistry, UPLC-MS, network pharmacology, molecular docking, and microscale thermophoresis. The synergistic activity of HDI with gefitinib was examined in TNBC cells. RESULTS: UPLC-MS identified 1112 constituents in HDI, with deacetylasperulosidic acid, D-(+)-malic acid, and asperulosidic acid among the most abundant compounds. HDI dose- and time-dependently inhibited the proliferation of 4T1, MDA-MB-231, and MCF-7 cells, reduced colony formation, induced apoptosis, and suppressed migration and invasion. In the orthotopic 4T1 breast cancer model, HDI significantly decreased primary tumor growth and lung metastatic burden in a dose-dependent manner, while showing lower systemic toxicity than cisplatin. DIA proteomics identified PTK2B and CCN2 as key downregulated proteins and revealed suppression of focal adhesion-related signaling. Mechanistic validation showed that HDI inhibited PTK2B phosphorylation and CCN2 expression, blocked KRAS-p38 MAPK signaling, reversed EMT, and regulated extracellular matrix remodeling by increasing TIMP2 and decreasing MMP2. Functional activation or overexpression of PTK2B and CCN2 partially weakened the inhibitory effects of HDI, supporting their involvement in HDI action. Asperulosidic acid, a major iridoid glycoside in HDI, reproduced the antitumor and antimetastatic effects of HDI, directly bound PTK2B with a K of 56.7 μM, and suppressed the PTK2B/CCN2-KRAS-p38 axis. HDI also synergized with gefitinib in MDA-MB-231 cells and further inhibited migration, invasion, EMT, and PTK2B/CCN2-associated signaling. CONCLUSION: HDI inhibits breast cancer growth and lung metastasis by dual targeting of PTK2B and CCN2, thereby suppressing KRAS-p38 MAPK signaling, reversing EMT, and modulating TIMP2/MMP2-mediated extracellular matrix remodeling. Asperulosidic acid is identified as an important active constituent contributing to these effects. The favorable safety profile of HDI and its synergistic interaction with gefitinib support its potential application as a multitarget adjuvant therapy for metastatic breast cancer, particularly TNBC.
Corrigendum to " Panax notoginseng saponins ameliorate spinal cord injury by inhibiting JAK2/STAT3-mediated macrophage polarization: Enhanced delivery by ultrasound-targeted microbubble destruction" [Phytomedicine Volume 152, March 2026, 157856].
Shi Y, Chen X, Luo S … +4 more , Chen A, Xie K, Fang M, Zhou J
Phytomedicine · 2026 Jul · PMID 42219855 · Publisher ↗
Abstract loading — click title to view on PubMed.
Novel insights into anti-inflammatory activity-related metabolic markers and biosynthetic regulatory mechanisms between principal and lateral roots of Aconitum carmichaelii Debx. via integrated metabolomics and transcriptomics.
Pei W, He F, Xie Y … +4 more , Wang Z, Li L, Yang L, Zhou H
Phytomedicine · 2026 Jul · PMID 42218859 · Publisher ↗
BACKGROUND: The principal roots (CHW) and lateral roots (FZ) of Aconitum carmichaelii Debx. are widely used medicinal herbs in Asia. Although the two roots are derived from the same plant, they exhibit differences in ant...
BACKGROUND: The principal roots (CHW) and lateral roots (FZ) of Aconitum carmichaelii Debx. are widely used medicinal herbs in Asia. Although the two roots are derived from the same plant, they exhibit differences in anti-inflammatory activity (AIA). In the market, small FZ is frequently passed off as CHW. Therefore, revealing AIA-related markers and biosynthetic regulatory mechanisms between CHW and FZ are critical for the quality control of these medicinal materials. OBJECTIVE: To identify AIA-related markers and reveal the biosynthetic regulatory mechanisms of these markers. METHODS: A "metabolite-gene-efficacy" correlation strategy was adopted. Firstly, verified the AIA difference between CHW and FZ via RAW264.7 cell model and Cyclooxygenase-2 inhibition assay, then integrated metabolomics and transcriptomics to screen AIA-related markers and regulatory genes, finally validated the results via qRT-PCR, AIA assay and molecular docking. RESULTS: 12 AIA-related diterpenoid alkaloid (DA) markers were identified, with 3 components as specific discriminative markers for CHW and FZ. A novel "modular regulatory" mechanism of DA markers biosynthesis was revealed: 8 DA markers in FZ were regulated by highly expressed 3‑hydroxy-3-methylglutaryl-CoA reductase in the mevalonate pathway, while 4 high-accumulation DA markers in CHW were positively driven by 1-deoxy-d-xylulose-5-phosphate reductoisomerase, 1-deoxy-d-xylulose-5-phosphate synthase, ent‑kaurene oxidase, ent‑kaurene synthase and BAHD-type acyltransferase in the methylerythritol phosphate and DA skeleton biosynthesis pathways, and 5 transcription factor families regulated the expression of the above-mentioned synthases. CONCLUSION: This study establishes a "gene regulation → metabolite accumulation → efficacy formation" framework to explain the AIA difference between CHW and FZ, provides specific markers for their quality control, and offers novel insights for DA biosynthetic engineering.
Harpagide alleviates sepsis-induced acute respiratory distress syndrome via gut microbiota modulation.
Sun Y, Xie D, Fu H … +4 more , He M, Li J, Wu C, Pan S
Phytomedicine · 2026 Jul · PMID 42218858 · Publisher ↗
BACKGROUND: Sepsis-associated acute respiratory distress syndrome (ARDS) remains a leading cause of mortality in critically ill patients, with limited therapeutic options beyond supportive care. The gut-lung axis is crit...
BACKGROUND: Sepsis-associated acute respiratory distress syndrome (ARDS) remains a leading cause of mortality in critically ill patients, with limited therapeutic options beyond supportive care. The gut-lung axis is critical in sepsis pathogenesis, yet effective targeting strategies remain scarce. Harpagide (HPG), an iridoid glycoside from Scrophularia ningpoensis, exhibits anti-inflammatory properties, but whether it protects against sepsis-induced ARDS through gut microbiota modulation remains unexplored. METHODS: Sepsis-induced ARDS was established using the cecal ligation and puncture (CLP) model. Gut microbiota dependency was assessed via antibiotic depletion (ABX) and fecal microbiota transplantation (FMT). Ffar2 mice were used to verify receptor necessity. Microbial composition and SCFAs were analyzed by 16S rRNA sequencing and GC-MS. Lung signaling was assessed by RNA-seq, Western blot, and RT-qPCR. Plasma SCFAs were quantified in sepsis-induced ARDS patients (n = 12) and healthy controls (n = 12) by LC-MS/MS. RESULTS: HPG significantly improved survival, attenuated lung injury, and suppressed cytokine storm in septic mice. These effects were abolished by ABX but transferable via FMT, confirming microbiota dependency. HPG enriched acetate-producing taxa, elevating fecal and plasma acetate. Transcriptomic analysis revealed simultaneous suppression of NF-κB signaling and excessive IFN-γ/STAT1 activation. HPG-mediated protection was completely abrogated in Ffar2 mice, and exogenous sodium acetate recapitulated these effects in a Ffar2-dependent manner. Clinically, plasma acetate was significantly depleted in ARDS patients and correlated with disease severity. CONCLUSIONS: HPG alleviates sepsis-induced ARDS by reshaping gut microbiota to boost acetate production, which activates FFAR2 to orchestrate immune reprogramming via NF-κB and IFN-γ/STAT1 pathways, offering a novel microbial-metabolic therapeutic strategy.
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