OBJECTIVE:Chemotherapy-induced fatigue (CIF) remains a clinically challenging condition with limited therapeutic options. This study aimed to elucidate the therapeutic potential and underlying mechanisms of the multiherbal Xinlikang (XLK) capsule against CIF using an integrated strategy that combined network pharmacology prediction with experimental validation. METHODS:A murine CIF model was established using 5-fluorouracil (5-FU). XLK was administered at various doses to evaluate its efficacy through comprehensive assessments, including behavioral tests (weight-bearing swimming, tail suspension, and grip strength), histopathology (hematoxylin-eosin [H&E] and periodic acid-Schiff [PAS] staining), and metabolic indices (lactate and ATP levels). To investigate the mechanisms, an integrated network pharmacology approach was employed to identify bioactive components of XLK, predict their potential targets, and construct a "component-target-pathway" network. Core signaling pathways implicated in CIF were prioritized via protein-protein interaction (PPI) and KEGG enrichment analyses. Key predictions were subsequently verified by Western blot analysis. RESULTS:XLK treatment significantly ameliorated fatigue-like behaviors, improved muscle glycogen storage, and restored lactate and ATP homeostasis in CIF mice (all p  < 0.05). Network pharmacology predicted that the anti-CIF effect of XLK was closely associated with the regulation of energy metabolism-related pathways, particularly the PI3K/AKT-mTOR-FoxO signaling axis. Experimental validation confirmed that XLK significantly modulated the expression and phosphorylation levels of key proteins (e.g., p-PI3K, p-AKT, and p-mTOR) within this pathway in the skeletal muscle or relevant tissues of CIF model mice (all p  < 0.05). CONCLUSION:XLK enhances cellular energy homeostasis by regulating the PI3K/AKT-mTOR-FoxO signaling axis, thereby alleviating CIF. These findings provide a mechanistic rationale for the clinical application of XLK against CIF.

The host microbiota and hepatic drug-metabolizing enzymes are important mediators of the metabolism and biological effects of herbal components. Through bidirectional interactions, herbal medicines can also reshape the host microbial community. The clinical efficacy of Wendan Decoction (WDD) in treating metabolic dysfunction-associated fatty liver disease (MAFLD) has been well established. However, its interactions with the host microbiota through the gut-liver axis remain unclear. This study aimed to investigate the mechanism by which WDD modulates host microbial activity through the gut-liver axis to ameliorate MAFLD. MAFLD models were established by high-fat diet (HFD) feeding and subsequently treated with WDD, Parasutterella excrementihominis (P. excrementihominis), or 7α-OH-T. The ABX group underwent antibiotic-mediated microbiota depletion before treatment. Multi-omics analyses were used to characterize the dynamic trajectories of microbiota-derived metabolites. These analyses included targeted bile acid (BA) profiling of serum, 16S rRNA gene sequencing and untargeted metabolomics of cecal contents, and proteomics and untargeted metabolomics of liver tissue. Hematoxylin and eosin, Oil Red O, and Alcian blue-periodic acid-Schiff staining were used to assess pathological changes in the liver and intestinal tissues during MAFLD. ELISA, Western blotting, and other assays were performed to quantify markers of inflammation and lipid metabolism. Following UPLC/UV detection of 7α-OH-T in portal vein serum, molecular docking and molecular dynamics simulations, together with cellular thermal shift assays (CETSA) and microscale thermophoresis (MST), were used to validate FXR as a target of 7α-OH-T. WDD alleviated hepatic steatosis, intestinal inflammation, and barrier dysfunction in MAFLD, but these effects depended on the integrity of the host microbiota. 16S rRNA gene sequencing showed that WDD promoted the growth of beneficial bacteria, including Bacteroides and Parasutterella. Combined analysis of targeted serum BA metabolomics and untargeted metabolomics of cecal contents indicated that WDD-mediated modulation of the host microbiota reduced the total serum BA load, increased alternative-pathway metabolites, including CDCA and TCDCA, in the liver and intestine, and decreased toxic secondary BAs, including DCA and LCA. Steroid and fatty acid metabolites, such as 7α-OH-T, were also increased. Pearson correlation analysis and P. excrementihominis transplantation experiments suggested that the increase in 7α-OH-T was closely associated with P. excrementihominis. Untargeted liver metabolomics and serological analyses confirmed that gut-derived 7α-OH-T entered the liver through the portal vein and acted on hepatic targets via the gut-liver axis. In animal experiments involving exogenous 7α-OH-T supplementation and in MAFLD THLE-2 cell models treated with 7α-OH-T, 7α-OH-T ameliorated hepatic lipid accumulation and promoted lipid utilization in THLE-2 cells. A series of interaction assays, including CETSA and MST, identified FXR as a target of 7α-OH-T. Furthermore, 7α-OH-T markedly activated the FXR/PPARα/CYP4A12A axis and served as a key messenger through which WDD-mediated regulation of Parasutterella alleviated MAFLD via the gut-liver axis. WDD increased the abundance of P. excrementihominis and the level of the potentially associated metabolite 7α-OH-T. Through the portal circulation, 7α-OH-T promoted gut-liver crosstalk and targeted the FXR/PPARα/CYP4A12A axis, thereby ameliorating MAFLD.

Combination therapy, which integrates diverse treatment modalities to induce synergistic anti-tumor effects, has emerged as a promising strategy in oncology. In this study, we developed a near-infrared (NIR) laser-triggered nitric oxide (NO)-releasing and enzyme-sensitive targeted drug delivery system BNN6/EPI-HA@HP-PDA) for the synergistic treatment of breast cancer via combined chemotherapy, NO gas therapy, and photothermal therapy. The system was constructed based on polydopamine (PDA) nanoparticles modified with hyaluronic acid (HA) and hydroxypropyl-β-cyclodextrin (HP-β-CD), co-loaded with epirubicin (EPI) and the NO donor BNN6 (N, N'-di-sec-butyl-N, N'-dinitroso-1,4-phenylenediamine). The resulting spherical nanoparticles exhibited a uniform size of 180.26 nm and a zeta potential of -27.69 mV, with high drug loading and encapsulation efficiencies of 12.04% and 98.10% for EPI and 46.91% and 88.14% for BNN6, respectively. In vitro release studies confirmed nanoparticles’ responsiveness to hyaluronidase, pH, and NIR irradiation. Cellular assays revealed significantly enhanced cytotoxicity of BNN6/EPI-HA@HP-PDA in both MCF-7 and MCF-7/ADR cells, attributable to the combined effects of PDA-mediated hyperthermia, EPI-induced chemotherapy, and NO-mediated gas therapy. Pharmacokinetic evaluation showed a 4.62-fold increase in the area under the curve of BNN6/EPI-HA@HP-PDA compared to free EPI solution. In vivo experiments further demonstrated potent tumor growth inhibition (96.71%) in MCF-7/ADR tumor-bearing Balb/c mice treated with BNN6/EPI-HA@HP-PDA plus laser irradiation, with no detectable systemic toxicity. In general, BNN6/EPI-HA@HP-PDA presents a combination strategy of photothermal/gas/chemotherapy for the synergistic therapy of breast cancer.

BackgroundThe blood-brain barrier (BBB) is a major obstacle to targeted drug delivery for central nervous system (CNS) diseases. Although liposomes and polymeric nanoparticles have improved brain drug delivery, limitations remain in BBB targeting, long-term biocompatibility, and in vivo clearance. Exosomes are endogenous nanoscale extracellular vesicles with favourable biocompatibility, low immunogenicity, and BBB-crossing potential. Therefore, this bibliometric study summarises the current research status, future research trends, and challenges in the more specific field of exosome-mediated BBB drug delivery.MethodsA comprehensive search was conducted across the Web of Science Core Collection (WoSCC), PubMed, and Embase databases for relevant English-language literature on exosome-mediated drug delivery across the blood-brain barrier from 2015 to 2025. WoSCC served as the primary source for bibliometric analysis. PubMed and Embase databases were used for supplementary validation. Software such as VOSviewer, CiteSpace, and R-bibliometrix was employed for literature visualisation analysis.ResultsThis study included 1,365 relevant articles from the WoSCC database, and the annual publication volume showed a steady upward trend. China and the United States significantly lead in both the number of publications and the number of core contributing institutions in this field. Co-occurrence analysis of keywords showed that research hotspots are mainly focused on exosomes, the blood-brain barrier, drug delivery, and Alzheimer’s disease. PubMed and Embase were used as supplementary validation databases, including 1,089 and 1,517 records, respectively. Their annual publication trends, major countries/regions, core journals, and keywords/themes were generally consistent with WoSCC, supporting the macro-level stability of the bibliometric findings.ConclusionUnlike previous bibliometric analyses that mainly focused on overall trends in CNS exosome research, this study focuses specifically on the direction of exosome-mediated drug delivery across the BBB. The findings show a shift from basic vesicle characterisation toward engineered delivery systems, CNS disease applications, and translational evaluation. Mammalian-derived exosomes remain dominant, while plant-derived vesicles, AI-assisted design, biomimetic hybrid nanovesicles, and gut–brain axis strategies are emerging areas of focus. Future research should prioritise systematic platform comparisons, standardised evaluation, quality control, scalable production, long-term safety, and regulatory pathways.

Duck viral hepatitis (DVH) requires novel therapeutic strategies. This study investigated antiviral miRNAs in separate decoctions of Scutellaria baicalensis Georgi and Chrysanthemum indicum L. High-throughput sequencing identified 14 highly expressed miRNAs, which were chemically synthesized for functional validation. CCK8 assay quantified cytoprotection in duck embryonic hepatocytes (DEHs) and RT-qPCR measured DHAV-1 gene expression, enabling the selection of the most effective miRNAs. Two candidates, novel-miR2 (from S. baicalensis ) and novel-miR10 (from C. indicum ), were selected for detailed study. RT-qPCR along with fluorescent probes assessed miRNA concentrations, stability, and their effects on DEHs biological characteristics. In vivo evaluations included mortality rates, liver histopathology/function, and markers of inflammation/apoptosis. Both miRNAs exhibited differential concentrations in fresh versus dried herbs and demonstrated good thermal stability. In vitro , miRNAs reduced DHAV-1 replication, apoptosis, necrosis, and ROS, while enhancing cell viability. Oral administration improved survival rates in infected ducklings, lowered serum liver enzymes, and alleviated hepatic damage. Specifically, novel-miR2 predominantly reduced apoptosis, whereas novel-miR10 alleviated inflammation. Collectively, novel-miR2 and novel-miR10 suppressed DHAV-1-induced hepatitis, exerting hepatoprotective effects. These findings provided new evidence for clarifying the active constituents of herbal decoctions and their miRNA‑mediated cross‑kingdom antiviral mechanism.

Ethnopharmacological relevance: Cisplatin (DDP)-exacerbated cancer-related fatigue (CRF) and myelosuppression impair patients’ quality of life, yet effective interventions remain limited. Xinlikang Capsule (XLK) is a proprietary Chinese medicine commonly used as adjunctive therapy in oncology, but its effects on CRF and underlying mechanisms are unclear. Aim of the study: This study aimed to investigate the ameliorative effects of XLK on CRF in Lewis lung carcinoma (LLC) tumour-bearing mice and to preliminarily explore its potential molecular mechanisms.Materials and Methods: Mice bearing subcutaneous LLC tumors were assigned to six groups: control, model, DDP, and DDP combined with XLK low‑, medium‑, and high‑dose groups. Four behavioral tests were employed to evaluate fatigue‑related behaviors. Blood cell counts, bone marrow nucleated cell counts, and femoral histopathological changes were examined. ELISA measured serum levels of hematopoietic factors and inflammatory cytokines. Network pharmacology was used to predict core targets and pathways. Key predictions were subsequently confirmed using TUNEL staining and Western blot analysis.Results: XLK treatment significantly ameliorated fatigue-like behaviors, elevated peripheral blood counts, improved femoral marrow histology, and increased bone marrow nucleated cell numbers. Additionally, XLK reversed the aberrant expression levels of EPO, TPO, GM‑CSF, TNF‑α, and TGF‑β1. Network pharmacology suggested that the apoptosis pathway was key pathway. Mechanistic assays confirmed XLK inhibited DDP‑induced marrow apoptosis via downregulated p‑JNK, Bax, cleaved caspase‑3, and upregulated Bcl‑2.Conclusion: XLK effectively alleviates DDP‑exacerbated CRF and myelosuppression in LLC‑tumour bearing mice, and the mechanism is associated with inhibition of JNK‑mediated bone marrow cell apoptosis.

Organic anion-transporting polypeptide (OATP) transporters have a significant influence on the disposition of drugs, significantly influencing their efficacy and toxicity. Humans express two transporters (OATP1B1 and OATP1B3), while murine possess only a single ortholog (Oatp1b2). To elucidate the impact of OATP1B1 and 1B3 on the pharmacokinetics of the hepatoprotective agent glycyrrhizin and its potential drug-drug interactions, we conducted a study utilizing wild-type, murine Oatp1b2 knockout, and newly generated humanized OATP1B1 and OATP1B3 transgenic mice (Slco1b2 -/- ; 1B1/1B3 tg ). These models were characterized physiologically and biochemically, followed by intravenous administration of glycyrrhizin for pharmacokinetic analysis. Compared to wild-type controls, Oatp1b2 knockout mice exhibited a 2-fold decrease in liver AUC0-7h and up to 26.9-fold reduction in liver-to-plasma ratios, indicating impaired hepatic uptake of glycyrrhizin. Additionally, the absence of Oatp1b2 resulted in a 2.8-fold increase in plasma AUC0-7h and enhanced renal distribution of glycyrrhizin. However, the knock-in of human OATP1B1 and OATP1B3 partially or fully restored the impaired hepatic uptake and reduced plasma levels of glycyrrhizin in Oatp1b2 knockout mice. Furthermore, we evaluated drug-drug interactions between glycyrrhizin and glecaprevir/pibrentasvir, a clinically relevant combination. Glecaprevir/pibrentasvir inhibited OATP1B1/1B3-mediated hepatic uptake of glycyrrhizin at therapeutic concentrations, increasing systemic exposure and highlighting drug-drug interaction risks. Our study provides the first in vivo evidence of glycyrrhizin hepatic transport by human OATP1B1 and OATP1B3, emphasizing the need for careful dosing in patients with variable OATP1B/1B3 activity due to transporter-mediated drug-drug interactions. Additionally, this humanized mouse model can serve as a robust in vivo tool for the prediction of human OATP1B1 and 1B3 function.

Duck viral hepatitis (DVH) requires novel therapeutic strategies. This study investigated antiviral miRNAs in separate decoctions of Scutellaria baicalensis Georgi and Chrysanthemum indicum L. High-throughput sequencing identified 14 highly expressed miRNAs, which were chemically synthesized for functional validation. CCK8 assay quantified cytoprotection in duck embryonic hepatocytes (DEHs) and RT-qPCR measured DHAV-1 gene expression, enabling the selection of the most effective miRNAs. Two candidates, novel-miR2 (from S. baicalensis) and novel-miR10 (from C. indicum), were selected for detailed study. RT-qPCR along with fluorescent probes assessed miRNA concentrations, stability, and their effects on DEHs biological characteristics. In vivo evaluations included mortality rates, liver histopathology/function, and markers of inflammation/apoptosis. Both miRNAs exhibited differential concentrations in fresh versus dried herbs and demonstrated good thermal stability. In vitro, miRNAs reduced DHAV-1 replication, apoptosis, necrosis, and ROS, while enhancing cell viability. Oral administration improved survival rates in infected ducklings, lowered serum liver enzymes, and alleviated hepatic damage. Specifically, novel-miR2 predominantly reduced apoptosis, whereas novel-miR10 alleviated inflammation. Collectively, novel-miR2 and novel-miR10 suppressed DHAV-1-induced hepatitis, exerting hepatoprotective effects. These findings provided new evidence for clarifying the active constituents of herbal decoctions and their miRNA‑mediated cross‑kingdom antiviral mechanism.

Cell membrane biomimetic delivery system can reduce the toxicity of encapsulated drugs and prolong systemic circulation. However, current studies have shown that cell membrane often undergo inside-out inversion during the coating process, which may weaken or impair their intrinsic functional properties, such as homologous targeting and long circulation in vivo. To address this, we developed a simple and effective directional membrane coating strategy by screening a peptide that specifically targets phosphatidylserine (PS) on the inner side of the cell membrane and modifying it onto the surface of drug-loaded nanocarriers. This approach preserves the native membrane orientation throughout the coating process. Using this strategy, we engineered red blood cell membrane (RBCm) directional coating bufalin (BF) liposomes (BF/Lip-Pep@RBC). The resulting nanocarrier retained CD47 outward display and PS internalization, reduced macrophage uptake by 79.76%, and extended circulation half-life by 2.24-fold compared to non-directional coating controls. In a breast cancer model, BF/Lip-Pep@RBC exhibited potent antitumor efficacy with favorable biosafety. By resolving the critical and long-overlooked issue of membrane orientation loss, this directional coating strategy establishes a broadly applicable and scalable platform for the rational design of functionally intact cell membrane-coated nanomedicines.

Ulcerative colitis (UC) brings a heavy burden to patients due to its long course, difficulty in cure, high relapse rate, and high carcinoma rate. Limitations of conventional drugs, including poor compliance and high recurrence, are now being addressed by modern approaches like immune-modulating therapies and refined surgical techniques. Therefore, there is an urgent clinical need for a new therapeutic strategy that is safe, long-acting, and has good compliance. In this study, we extracted and fractionated an peptide PAE-P6 with significant anti-inflammatory activity from Periplaneta americana extract (PAE), and it showed certain therapeutic effect in UC mice. To enhance the efficacy and stability of peptides in vivo, we further developed this peptide into a long-acting thermosensitive liposome gel formulation. Following rectal administration, this formulation demonstrated remarkable efficacy in a mouse model of UC by boosting the expression of anti-inflammatory factors, repairing tight junctions, regenerating mucin, and inhibiting the expression of pro-inflammatory factors. This study offers a promising strategy for targeted and sustained drug delivery in UC treatment.

INTRODUCTION:Chan-Hou-Kang-Gao (CHKG) is a classical traditional Chinese medicine (TCM) formula widely used to promote uterine involution and manage postpartum hemorrhage (PPH). However, the pharmacological basis and molecular mechanisms of CHKG in treating PPH remain largely unclear. METHODS:Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was employed to systematically identify the chemical constituents of CHKG. Network pharmacology was used to predict active compounds, potential targets, and relevant signaling pathways. Protein-protein interaction (PPI) analysis and molecular docking were performed to validate the interactions between key compounds and therapeutic targets. RESULTS:A total of 173 compounds were identified in CHKG, including flavonoids, triterpenoids, and phenolic acids. Integration with public databases revealed 67 common targets shared between CHKG-related compounds and PPH-related genes. Enrichment analysis suggested that CHKG may modulate pathways involved in inflammation, immune regulation, and vascular function. TNF, IL6, and PTGS2 were identified as potential key targets. Molecular docking and molecular dynamics (MD) simulations indicated stable binding of ursolic acid, asiatic acid, and kaempferol to these proteins. CONCLUSIONS:This study provides a systems-level prediction of the mechanisms by which CHKG may exert therapeutic effects in PPH, particularly via inflammation- and coagulationrelated pathways. These findings generate mechanistic hypotheses; however, further in vitro or in vivo experimental validation is required to confirm bioactivity and clinical relevance.

Glioma is a highly aggressive malignancy with poor prognosis, largely due to the limited efficacy and systemic toxicity of conventional chemotherapy across the blood-brain barrier (BBB). To address these challenges, we developed dualtargeted nanoparticles (LPPCuP/EPI NPs) for synergistic chemotherapy, chemodynamic therapy (CDT), and photothermal therapy (PTT). The system is constructed from a polydopamine/copper core (CuP NPs) coated with lactoferrin and phenylboronic acidmodified γpolyglutamic acid and loaded with the chemotherapeutic agent epirubicin (EPI). The nanoparticles exhibit uniform spherical morphology (133.7 nm, PDI = 0.009) and high EPI encapsulation efficiency (96.32 %). Both in vitro and in vivo studies demonstrated effective BBB penetration and tumorresponsive release of EPI and Cu²⁺. Released EPI induced apoptosis, while Cu²⁺/Cu⁺ conversion catalyzed a Fentonlike reaction to generate cytotoxic hydroxyl radicals (•OH) for CDT. The photothermal effect of the CuP NPs core further enhanced PTT and promoted •OH production, synergistically amplifying the CDT effect. In vitro and in vivo evaluations confirmed the superior antiglioma efficacy and favorable biosafety profile of LPPCuP/EPI NPs. Together, this work presents LPPCuP/EPI NPs as a robust and promising multimodal nanotherapeutic platform for glioma treatment.

Methicillin-resistant Staphylococcus aureus (MRSA) infections remain a major public health challenge because of limited therapeutic options and the increasing prevalence of multidrug resistance. In this study, carrier-free quercetin-zinc supramolecular assemblies (Qct-Zn NPs) were fabricated through coordination-associated self-assembly and characterized using TEM, UV-Vis spectroscopy, FTIR, DLS, XPS, and zeta potential analyses. Qct-Zn NPs exhibited potent antibacterial activity against multiple MRSA clinical isolates, with enhanced efficacy compared with quercetin or ZnSO4 alone. Time-kill assays demonstrated rapid bactericidal activity, while biofilm assays revealed significant inhibition of biofilm formation and reduction of viable bacteria within mature MRSA biofilms. Mechanistic investigations suggested that Qct-Zn NP treatment was associated with membrane-associated ultrastructural changes, altered intracellular ATP levels, and ROS-associated responses. In vivo studies using murine systemic MRSA infection models showed that Qct-Zn NPs reduced bacterial burdens and systemic inflammatory responses while improving survival outcomes. Importantly, antibacterial efficacy was retained when treatment initiation was delayed to 6 h post-infection under the tested experimental conditions. Together with their favorable hemocompatibility and low cytotoxicity, these findings demonstrate that coordination-driven self-assembly of natural flavonoids and biocompatible metal ions represents a potential strategy for developing antimicrobial materials against drug-resistant staphylococcal infections.

The drug delivery for Alzheimer’s disease (AD) faces substantial obstacles owing to the presence of the blood-brain barrier (BBB). This circumstance highlights the nose-brain route as pivotal for enhancing drug distribution to the brain. As the efficiency of brain entry is constrained by the physiological barrier of the nasal cavity, the development of strategies to efficiently traverse this barrier is imperative for enhancing the effectiveness of AD treatment. In the present study, a cell-penetrating peptide (CPPs) named LK4, which originates from mastoparan-L (MPL), was employed. Its capacity to efficiently penetrate the physiological barrier of the nasal cavity was demonstrated. LK4 was modified into polydopamine (PDA) nanoparticles to construct nanoparticles containing ginsenoside Rg1, ginsenoside Rb1, and notoginseng saponin R1 (TGS), designated as LK4-TGS-PDA. Experiment results reveal that the LK4-TGS-PDA drug delivery system can enhance the uptake of olfactory neurons and promote epithelial transport. In an in vitro nasal mucosal barrier model, LK4 modification increased the apparent permeability coefficients of R1, Rg1, and Rb1 by 1.2-, 1.2-, and 12-fold, respectively, compared to unmodified nanoparticles. Following nasal administration, the brain concentrations of R1, Rg1, and Rb1 increased by 19-fold, 30-fold, and 15-fold, respectively, and the relative brain bioavailability reached 933.1

In this study, we engineered pH/glutathione dual-responsive nanoparticles (LP/CC-Cu-Cur NPs) based on a poly-γ-glutamic acid (γ-PGA)/chitosan (CS) core-shell architecture for synergistic chemo/chemodynamic therapy of glioma. The nanoparticles feature a core of CC-Cu-Cur NPs, formed via Cu2+-coordinated self-assembly of caffeic acid-grafted CS and curcumin (Cur), encapsulated within a phenylboronic acid-conjugated γ-PGA shell through pH-sensitive borate ester bonds. Surface modification with lactoferrin conferred brain-penetrating and glioma-targeting capabilities. The resulting spherical nanoparticles had a uniform size of 235.89 nm, a zeta potential of -22.66 mV, and high Cur loading (6.02%) and encapsulation efficiency (83.09%). Upon exposure to the acidic tumor microenvironment, the nanoparticle shell detaches, reversing surface charge from negative to positive, thereby enhancing cellular uptake and mitochondrial targeting. Intracellular glutathione then triggers core degradation, releasing Cur and Cu2+. Cur induces mitochondrial apoptosis, while Cu2+ catalyzes a Fenton-like reaction, converting endogenous hydrogen peroxide into highly cytotoxic reactive oxygen species. In vitro, the nanoparticles showed enhanced blood-brain barrier penetration, efficient lysosomal escape, and potent cytotoxicity against GL-261 cells (IC50 = 18.34 μg/mL) via a synergistic action of Cu2+ and Cur (CI = 0.28). In vivo, LP/CC-Cu-Cur NPs achieved superior brain accumulation and antitumor efficacy, highlighting their potential as a promising strategy for glioma therapy.

BACKGROUND:Luteal phase defect (LPD) is a prevalent endocrine disorder contributing significantly to female infertility and early pregnancy loss. Nuangong Tiaojing Formula (NTF), a traditional Chinese medicine formula, has demonstrated clinical efficacy in treating LPD, yet its underlying mechanisms remain incompletely elucidated. PURPOSE:This study aimed to explore the curative effects and mechanisms of NTF in LPD-related ovarian endocrine dysfunction and endometrial receptivity defects. METHODS:UPLC-Q-TOF-MS/MS and HPLC technologies were utilized to identify and quantify the chemical components in NTF, respectively. An LPD rat model was established using mifepristone. The therapeutic effects of NTF on estrous cyclicity, serum progesterone (P) and estradiol (E2) levels, and ovarian and uterine histopathology were evaluated. Network pharmacology analysis predicted the underlying biological mechanism modulated by NTF, which were subsequently validated using molecular biology methods, such as Western blotting, ELISA, and TUNEL staining. Component-effect correlation analysis, in silico simulations, and pharmacokinetic study were conducted to identify candidate efficacious ingredients of NTF and their in vivo kinetic characteristics. RESULTS:NTF treatment significantly ameliorated LPD-related pathologies in a dose-dependent manner, including restored estrous cyclicity, increased serum P and E2 levels, and improved ovarian morphology and endometrial receptivity. NTF also reduced the secretion of pro-inflammatory cytokines TNF-α and IL-1β, and modulated lipid peroxidation markers such as SOD and MDA. Mechanistically, the therapeutic effects of NTF on restoring ovarian endocrine function and its downstream endometrial receptivity in LPD was closely associated with the suppression of ovarian inflammatory-apoptotic cascade mediated by the TLR4/MyD88/NF-κB/Bcl-2/Bax/Caspase-3 pathway. Component-effect correlation analysis, in silico simulations, and pharmacokinetic data suggested that Paeoniflorin, Albiflorin, Morroniside, Loganin, Salvianolic acid B, Gallic acid, and Hyperoside were candidate efficacious components of NTF, exhibiting stable binding interactions with core targets of the aforementioned pathway and multi-level exposure characteristics, supporting their potential for synergistic therapeutic effects. CONCLUSION:This study innovatively demonstrates that NTF effectively restores ovarian-uterine axis function in LPD probably by multi-target regulation of the inflammatory-apoptotic cascade, primarily via the TLR4/MyD88/NF-κB/Bcl-2/Bax/Caspase-3 pathway. Our findings present novel mechanistic insights into the curative effect of NTF against LPD.

Allergic rhinitis (AR) poses a major threat to public health, and effective therapeutic strategies are urgently needed. However, persistent exposure to unavoidable allergens and reduced drug retention time caused by the nasal mucociliary clearance system hinder therapeutic effects in AR. Here, we reported an “intranasal nano-mask” named fargesin & cineole self-assembled peptide nanofibers (FCSP@NFs) — a nasal drug delivery system possessing dual functions of “physically intercepting allergens” and “sustained drug release”. The innovation of this strategy lies in designing a novel self-assembling peptide (IIFFSSKKGE-Dopa). On one hand, peptide can assemble into nanofiber network structures, forming a nano-protective layer with mechanical barrier functionality to block allergens from penetrating the nasal mucosa. On the other hand, precise loading of two drugs (fargesin and cineole) was achieved through peptide self-assembly. Furthermore, the introduction of Dopa-modified groups significantly enhanced the adhesive persistence of FCSP@NFs, enabling sustained local drug release and thereby improving the therapeutic efficacy against AR. This dual-function nano-mask system provides a novel technological paradigm for the treatment of respiratory mucosal diseases and can be extended to therapeutic research targeting other mucosal-related pathologies.

Respiratory syncytial virus (RSV) is a ubiquitous respiratory virus that affects individuals of all ages; however, there is a notable lack of targeted treatments. RSV infection is associated with a range of respiratory symptoms, including bronchiolitis and pneumonia. Baicalin (BA) exhibits significant therapeutic effects against RSV infection through mechanisms of viral inhibition and anti-inflammatory action. Nonetheless, the clinical application of BA is constrained by its low solubility and bioavailability. In this study, we prepared BA nanodrugs (BA NDs) with enhanced water solubility utilizing the supramolecular self-assembled strategy, and we further conducted a comparative analysis of this pharmacological activity between free drugs and NDs of BA. Both in vitro and in vivo results demonstrated that BA NDs significantly enhanced the dual effects of viral inhibition and inflammation relief compared to free BA, attributed to prolonged lung retention, improved cellular uptake, and increased targeting affinity. Our study confirms that the nanosizing strategy, a straightforward approach to enhance drug solubility, can also increase biological activity compared to free drugs with the same content, thereby providing a potential ND for RSV treatment. This correlation analysis between the existing forms of drugs and their biological activity offers a novel perspective for research on the active ingredients of traditional Chinese medicine.

Due to the existence of the blood-brain barrier (BBB) and the complicated pathological mechanisms of Alzheimer's disease (AD), current therapeutic approaches for AD show limited efficacy. To overcome these challenges, a multi-strategy drug delivery system (SA-BP-MB/BBR NPs) was developed: photothermal conversion polydopamine nanoparticles (PDA NPs) were decorated with sialic acid-modified bovine serum albumin (SA-BSA) to prepare SA-modified and BSA-stabilized PDA NPs (SA-BP NPs) for targeting the BBB and co-loaded with photosensitizer methylene blue (MB) and berberine (BBR) to target multiple neuropathological factors, including Aβ aggregation and tau hyperphosphorylation. The prepared SA-BP-MB/BBR NPs had spherical morphology with a uniform particle size of 143.43 nm and PDI of 0.095. Drug loading capacities were 6.98 % for MB and 3.50 % for BBR. Our investigations demonstrated that the cellular uptake efficiency of biocompatible SA-BP-MB/BBR NPs increased by 1.74 times when combined with photothermal and photodynamic therapy, which effectively inhibited Aβ aggregation, Aβ fibril depolymerization, and tau hyperphosphorylation. Pharmacokinetics and in vivo biodistribution studies revealed a higher area under the curve (AUC0-t) of SA-BP-MB/BBR NPs (9.75 and 7.52 times higher) than free MB and BBR, and SA modification promoted brain accumulation. Overall, SA-BP-MB/BBR NPs have the potential to be an effective treatment for AD.

Ethnopharmacological relevance Gekko swinhonis Guenther, commonly referred to as Gecko in the following text, belongs to the genus Gekko within the family Gekko. Its dried whole body is a widely utilized traditional Chinese medicine, demonstrating significant efficacy in the treatment of gastrointestinal malignancies, particularly gastric cancer (GC). Nevertheless, the composition of the gecko is complex, necessitating further research into its active ingredients for the treatment of GC. Aim of the study Isolation and characterization of the most active components in Gecko based on their anti-GC mechanisms of vascular endothelial cell inhibition and anti-neovascularization. Materials and Methods We utilized the enzymatic hydrolysate of Geckos to investigate its effectiveness and underlying mechanisms. Initially, we assessed its efficacy in ectopic and in-situ GC tumor-bearing mouse models. Subsequently, we evaluated the effectiveness of peptides, aliphatics, and small molecules derived from Gecko using CCK-8 and 3D tumor spheroid assays. The activities of peptides S1-S4 were further examined through these experiments. Finally, we screened, synthesized, and investigated five potential peptides for their pharmacodynamics in the CCK-8 assay and in the in-situ GC model mice. Results The Gecko can inhibit the formation of blood vessels in the tumor microenvironment, providing a localized treatment for GC. The peptide components significantly inhibit vascular endothelial cells and impede the formation of new blood vessels, with the S2 peptide sections (0.3 KD - 3 KD) demonstrating the most potent inhibitory activity against angiogenesis. One of the active peptides effectively suppresses the growth of in-situ GC in nude mice through angiogenesis inhibition and also modulates immunity, all while exhibiting excellent biosafety. Conclusions We have achieved a significant breakthrough in the local treatment of GC using Gecko. Through pharmacodynamic experiments and a systematic process of isolation and identification, we identified the most effective anti-GC ingredients of Gecko, based on their mechanisms of inhibiting vascular endothelial cells and promoting anti-angiogenesis. Furthermore, we synthesized a lead peptide that demonstrates promising therapeutic efficacy and safety.