Background: While recipient cytochrome P450 (CYP) genetic polymorphisms are established modulators of tacrolimus (TAC) pharmacokinetics, the combined effects of donor-derived hepatic and recipient intestinal CYP3A4/5 and CYP2C19 genotypes during voriconazole (VRC)-mediated CYP3A inhibition remain inadequately elucidated in liver transplantation. Objectives: This study evaluated the impact of donor and recipient CYP3A4/5 and CYP2C19 polymorphisms on TAC pharmacokinetics during VRC co-therapy in liver transplant recipients. Design: A retrospective study was conducted on 139 liver transplant patients receiving TAC-based immunosuppressive therapy at the First Affiliated Hospital of Sun Yat-sen University from December 2016 to June 2025. Methods: The liver transplant recipients were stratified into a VRC co-therapy group (n = 33) and a non-VRC control group (n = 106). TAC dose-corrected trough concentrations (C-0/D) were analyzed in relation to donor and recipient genotypes of CYP3A4*1G (rs2242480), CYP3A5*3 (rs776746), CYP2C19*2 (rs4244285), and CYP2C19*3 (rs4986893). Results: During VRC co-therapy, dual donor-recipient CYP3A4*1G CC carriers exhibited a 73% increase in TAC C-0/D compared with TT/TC genotypes (6.83 vs 3.95, p = 0.0031). Recipients grafted from CYP3A5 non-expresser donors exhibited 34% higher TAC C-0/D than those from CYP3A5 expressers (6.35 vs 4.75, p = 0.0196). Recipient CYP2C19 poor metabolizers demonstrated 36% elevated TAC C-0/D compared to extensive or intermediate metabolizers (6.47 vs 4.76, p = 0.0401). The magnitude of TAC-VRC interaction was modulated by both donor and recipient genotypes. Comparing with the control group, VRC co-therapy increased TAC C-0/D by 3.80- and 2.75-fold increases in CYP3A5 expresser and non-expresser recipients, respectively, and by 3.44- and 3.53-fold in recipients grafted from CYP3A5 expresser and non-expresser donors, respectively. Post-VRC discontinuation, TAC C-0/D remained significantly elevated for 5 days before returning to baseline level by day 6 (p < 0.0001). Conclusion: In summary, Donor and recipient CYP3A4/5 and CYP2C19 genotypes jointly influence TAC pharmacokinetics during VRC co-therapy. Genotype-guided dosing strategies integrating both donor and recipient genotypes may improve TAC dosing precision. TAC dose reinstatement may be deferred until day six following VRC discontinuation to avoid overexposure.

The timing of immunotherapy administration has been linked to variations in clinical outcome across multiple cancers, but its effect on clinical outcome in nasopharyngeal carcinoma (NPC) remains unstudied. In this single-center retrospective cohort study, patients with recurrent/metastatic (R/M) NPC who received first-line anti-PD-1-based immunochemotherapy (June 2019–December 2024) were included. The primary endpoint was progression-free survival (PFS), and overall survival (OS) was the secondary endpoint. Data regarding the time of day of administration (ToDA) during the initial four cycles were collected for each patient. Survival was estimated by the Kaplan–Meier method and compared with log-rank tests. Multivariable Cox models were adjusted for prespecified covariates. Propensity score matching (PSM) was performed between patients from different ToDA groups. The ToDA cutoff was derived from the data without a prespecified hypothesis, using a data-driven approach. Among the 334 screened patients, 312 met the eligibility criteria. The median follow-up was 24.9 months. The median PFS was 25.0 months, and the mOS was not reached. A data-driven optimal ToDA cutoff of 12:00 was identified. Patients who received immunotherapy after 12:00 had significantly longer PFS (31.2 vs. 18.3 months, p = 0.006) and OS (both not reached, p = 0.011). After PSM at a 1:2 ratio, PFS (36.1 vs. 18.3 months, p = 0.003) and OS (both not reached, p = 0.018) were still significantly improved in patients who received immunotherapy after 12:00. Multivariate analysis demonstrated that a ToDA after 12:00 was independently correlated with improved PFS (HR=0.63; 95

Objectives: This study compared controlled ovarian hyperstimulation (COH) outcomes and chromosomal euploidy results between the Utrogestan-based progesterone-primed ovarian stimulation (PPOS) and gonadotropin-releasing hormone antagonist (GnRH-Ant) protocols in preimplantation genetic testing for monogenic disorders (PGT-M) cycles, and assessed the efficacy and safety of the Utrogestan-based PPOS protocol. Methods: In this retrospective single-center cohort study, 176 PGT-M cycles managed with the Utrogestan-based PPOS protocol were compared with 176 GnRH-Ant cycles using 1:1 direct caliper matching without replacement. Embryos were classified as euploid, mosaic, aneuploid, or no-call according to next-generation sequencing results. The primary outcomes were euploidy rate and chromosomal aberration patterns; secondary outcomes included COH outcomes and pregnancy outcomes. Results: Baseline characteristics were comparable after matching. The total gonadotropin (Gn) dose was significantly lower in the Utrogestan-based PPOS group (2100 (1500–3000) vs. 2250 (1800–3000), p = 0.035). PGT analysis revealed comparable rates of euploidy, aneuploidy, mosaicism, and “No-call” between the Utrogestan-based PPOS (n = 586) and GnRH-Ant (n = 605) groups. The unadjusted difference in euploidy rate per MII oocyte between groups (18.98% vs. 16.36%, p = 0.045) was no longer statistically significant after multivariable adjustment (p = 0.194). In addition, patterns of aneuploidy and chromosomal involvement were similar between groups. The Utrogestan-based PPOS group showed numerically higher clinical pregnancy rate (70.67% vs. 63.22%) and live birth rate (62.67% vs. 51.72%), and a lower early abortion rate (5.66% vs. 12.73%), but none of these differences were statistically significant. Conclusions: Compared with the GnRH-Ant protocol, the Utrogestan-based PPOS protocol required a significantly lower total Gn dose while exhibiting comparable euploidy rate, analogous chromosomal abnormality spectrums, and pregnancy outcomes. The Utrogestan-based PPOS protocol may be a feasible alternative ovarian stimulation strategy in PGT-M cycles.

[This corrects the article DOI: 10.3389/fphar.2026.1840717.].

Aristolactam I (AL-I), as a metabolite of AA-I, exhibits toxicity that remains a subject of significant debate. AL-I exhibits detectable distribution in both traditional Chinese medicines and environmental samples. Therefore, understanding the safety of AL-I, particularly its long-term toxicity, is crucial. The detection rate of AL-I were detected in wheat samples obtained from Serbia was 100%, with a maximum concentration of 0.409 ng/g, cumulative exposures could matter. In long-term toxicity testing, no animals in AL-I groups died. At week 24 administration, no pathological changes similar to AA-I group were found in AL-I-H group. However, mild renal tubular injury was observed in discontinuation period. Localized mild renal interstitial collagen deposition was noted in 80% kidneys at weeks 50 discontinuation, but no pathological changes were observed in other tissues and AL-I-L group. Additionally, results of bone marrow micronucleus assay for AL-I-H group were negative, and no SNP mutation changes were observed in kidney/liver/stomach tissues compared with the control. A variety of metabolites were detected in AA-I group, including intermediates with carcinogenic risks. However, the metabolites in AL-I group were only AL-Ia and its glucuronide/sulfated derivatives, and AL-I was not detected in kidneys. We infer the nephrotoxicity of AL-I is much lower than that of AA-I, and no obvious tumorigenic or mutagenic effects were observed, which could be associated with metabolism in the body. Meanwhile, AL-I accumulation in environmental samples from Balkan region does not reach levels associated with nephrotoxicity, suggesting minimal toxicological risk. However, it is essential to control dosage and duration of use when applying medicines containing AL-I in clinical practice.

BACKGROUND:Chronic atrophic gastritis (CAG) is a common chronic digestive disorder associated with the occurrence and development of gastric cancer (GC). Euodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang (Fructus evodiae) is a traditional Chinese medicinal material often used to treat gastrointestinal diseases. However, the therapeutical effects of Fructus evodiae in CAG and underlying mechanisms remain unelucidated. PURPOSE:This study aimed to determine the efficacy of the water decoction of fructus evodiae in the treatment of CAG, reveal its mechanism of action, clarify its pharmacological material basis and regulatory pathways in the treatment of CAG, and provide a scientific basis for the clinical treatment of CAG with fructus evodiae. METHOD:First, we established CAG rat model and administered fructus evodiae decoction for treatment, monitoring serum inflammatory factors, hormones, and histopathology. Then, components of fructus evodiae decoction were determined using UHPLC-Q Exactive Orbitrap HRMS. Subsequently, the mechanism of fructus evodiae in the treatment of CAG were explored by proteomics analysis, network pharmacology and molecular docking. Finally, in vivo and in vitro validation was taken by western blot (WB) assays, ELISA, CCK-8, immunofluorescence staining, hematoxylin and eosin (HE) measurement, bile acid (BAs) analysed. RESULTS:Data showed that 25 compounds were identified in fructus evodiae decoction. The proteomics analysis, network pharmacology, and molecular docking results showed evodiamine (EVO) is a major active ingredient and PI3K/AKT/NF-κB pathway and gastrointestinal motility are key regulating pathways in fructus evodiae decoction used to treat CAG. In vivo and in vitro experiments confirmed that Fructus evodiae decoction and EVO significantly reduced the expression levels of IL-1β, IL-6, TNF-α, Gastrin-17 (G-17), somatostatin (SS), caudal type homeobox 2 (CDX2), and mucin 2 (MUC2) protein by inhibited PI3K/AKT/NF-κB signaling. Moreover, fructus evodiae decoction and EVO increased the expression of the gastrointestinal excitatory neurotransmitters ACh and 5-HT, promoted gastric emptying rate and small intestinal propulsion rate, and reduced the level of BAs in the stomach, thereby reducing further damage to the gastric mucosa. CONCLUSION:Fructus evodiae decoction exerts anti-CAG effects primarily by suppressing chronic inflammation and intestinal metaplasia through inhibition of the PI3K/AKT/NF-κB signaling pathway, thereby reducing bile acid accumulation and restoring gastrointestinal function. Importantly, evodiamine was identified as a key bioactive alkaloid of Fructus evodiae and was further validated as a critical mediator of these effects via targeted in vivo and in vitro experiments. By integrating proteomics, network pharmacology, molecular docking, and single-compound mechanistic validation, this study establishes evodiamine-centered regulation of the PI3K/AKT/NF-κB axis as a unifying mechanism underlying the therapeutic action of Fructus evodiae in MNNG-induced chronic atrophic gastritis.

BACKGROUND:Lung cancer is the most common and deadliest malignancy worldwide, with about 85% of cases being non-small cell lung cancer (NSCLC). Although targeting PD-1/PD-L1 with immune checkpoint inhibitors has revolutionized NSCLC treatment, a substantial proportion of patients still experience intrinsic or acquired resistance. Understanding the mechanisms of immune evasion and resistance and identifying novel therapeutic targets remain critical challenges. METHODS:Using RNA sequencing, qRT-PCR, and Western blotting, we discovered and validated that the long non-coding RNA (lncRNA) AFAP1-AS1 activates the interferon signaling pathways and upregulates PD-L1 and IDO1 expression in NSCLC cells. Through mass spectrometry analysis combined with Western blotting and sucrose density gradient separation of polyribosomes, it was found that AFAP1-AS1 binds to the translation initiation factor EIF4A1 and promotes the translation of the tyrosine kinases JAK2 and TYK2. In vitro, CD8+ T cell killing ability after coculture was assessed by flow cytometry. In a mouse subcutaneous tumor model, the immunotherapeutic efficacy of JAK2/TYK2 inhibitors and a PD-1 monoclonal antibody against AFAP1-AS1-overexpressing tumors was evaluated. RESULTS:In this study, we demonstrate that elevated AFAP1-AS1 expression correlates with poor response to anti-PD-1 therapy and is inversely associated with CD8+ T-cell infiltration. Mechanistically, AFAP1-AS1 interacts with EIF4A1 to enhance the translation of JAK2 and TYK2, thereby promoting STAT1 phosphorylation and nuclear translocation, which activate interferon signaling pathways. This cascade upregulates the immunosuppressive checkpoints PD-L1 and IDO1, ultimately suppressing CD8+ T cell cytotoxicity and promoting T cell apoptosis. Importantly, in preclinical models, pharmacological inhibition of JAK2 and TYK2 synergistically enhances the efficacy of anti-PD-1 immunotherapy. CONCLUSIONS:Our findings reveal a novel mechanism through which AFAP1-AS1 promotes immunotherapy resistance in NSCLC by binding to the translation initiation factor EIF4A1 to enhance JAK2 and TYK2 translation. This highlights AFAP1-AS1 and its downstream tyrosine kinases, JAK2/TYK2, as potential therapeutic targets to improve immunotherapy efficacy in NSCLC.

Lung cancer remains a leading cause of cancer-related mortality worldwide, yet the molecular mechanisms driving its progression remain incompletely understood. Here, analysis of the GSE31210 dataset identified UCHL1 as a markedly upregulated deubiquitinase in lung cancer. Its high expression was validated in TCGA cohorts, clinical tissues, and lung cancer cell lines, and was associated with poor prognosis. Functional assays showed that UCHL1 promoted lung cancer cell proliferation, migration, invasion, and tumor growth in vivo. Mechanistically, UCHL1 interacted with YAP1 and stabilized YAP1 protein by reducing its ubiquitination without affecting YAP1 mRNA expression. YAP1 restoration significantly reversed the inhibitory effects of UCHL1 knockdown, indicating that YAP1 is a critical downstream effector of UCHL1. Transcriptomic and untargeted lipidomic analyses further revealed that UCHL1 regulates lipid metabolism, particularly ceramide metabolism. UCHL1 silencing induced ceramide accumulation, accompanied by increased CERS4 and decreased CERK expression, whereas YAP1 restoration partially reversed these changes. Moreover, UCHL1 knockdown or pharmacological inhibition with LDN57444 significantly suppressed xenograft tumor growth. Together, our findings identify UCHL1 as an oncogenic deubiquitinase that promotes lung cancer progression by stabilizing YAP1 and remodeling ceramide metabolism, highlighting the UCHL1–YAP1–ceramide axis as a potential therapeutic target.

Background Nasopharyngeal carcinoma (NPC) is considered a typical “hot” tumor, yet its immune evasion mechanisms remain poorly defined, and immunotherapy efficacy is suboptimal. Attenuation of intrinsic tumor cell immunogenicity to evade T cell recognition and cytotoxicity represents a major route of tumor immune evasion, whose mechanistic basis is largely unelucidated.Methods Multiplex immunofluorescence and immunohistochemistry were used to assess correlations between mitochondrial leucyl-transfer RNA synthetase 2 (LARS2) expression, CD8+ T cell infiltration and immunotherapy response in NPC tissues. In vitro CD8+ T cell co-cultures, immunodeficient nude mice and immunocompetent murine models were used to explore LARS2-dependent CD8+-mediated antitumor immunity. Blue native polyacrylamide gel electrophoresis (BN-PAGE), extracellular flux and other mitochondrial functional assays were performed to characterize the roles of LARS2 and leucine in electron transport chain (ETC) translation and oxidative phosphorylation (OXPHOS) activity. Chromatin immunoprecipitation-quantitative PCR, ELISA and flow cytometry analyzed epigenetic modifications, major histocompatibility complex class I (MHC-I) expression and antigen presentation. Leucine supplementation combined with anti-programmed cell death protein-1 (PD-1) therapy was tested in mouse models to evaluate in vivo therapeutic efficacy against NPC immune escape.Results We demonstrated that LARS2, a gene mapped to the 3p21 chromosomal region, was significantly downregulated in NPC, and its expression is positively correlated with patient prognosis and response to immunotherapy. Through in vitro and in vivo experiments, we demonstrated that restoration of LARS2 expression accelerates the translation of mitochondrial ETC subunits, enhances OXPHOS, and upregulates MHC-I expression via an epigenetic mechanism. These effects work together to enhance tumor antigen presentation and augment CD8+ T cell-mediated cytotoxicity. Furthermore, we demonstrated that a high-leucine diet increases LARS2 expression and improves the effectiveness of anti-PD-1 immunotherapy.Conclusions This study uncovers a novel mechanism by which the tumor suppressor LARS2 inhibits immune evasion in NPC through upregulation of MHC-I, and highlights a high-leucine diet as a promising strategy to sensitize tumors to immunotherapy.

Arrhythmia is a critical clinical manifestation of cardiovascular disease; however, current therapeutic strategies are limited by significant side effects or high invasiveness. Kuanxiong aerosol (KXA), a traditional Chinese medicine (TCM) formulation clinically used for the relief of angina pectoris, exhibits multi-component and multi-target characteristics that suggest potential antiarrhythmic properties. However, direct cellular-level electrophysiological evidence is lacking. This study established an in vitro myocardial sensing model based on microelectrode array (MEA) technology. This platform supports non-invasive, real-time monitoring with parallel multi-site recording capability and has been used to systematically evaluate KXA’s intervention effects on various types of arrhythmias. We successfully constructed an MEA-based sensing platform using primary rat cardiomyocytes and determined a safe and effective KXA concentration. On this basis, we developed pathological models simulating chronic degenerative lesions and acute drug-induced bradycardia to assess the regulatory effects of KXA on myocardial electrical activity. Experimental results demonstrated that KXA effectively increased cardiomyocyte firing rate, enhanced electrical signal amplitudes, and restored the rhythmicity of calcium transients. This study reveals KXA’s multidimensional intervention effects on arrhythmias and successfully integrates advanced MEA biosensing technology into the dynamic pharmacodynamic evaluation of TCM compounds, providing an innovative bioengineering method for assessing the cardiac function of complex drug systems.

Mitochondria are central to health and disease by precisely regulating metabolism and interacting closely with other organelles. Mitochondrial dysfunction contributes to the initiation and development of numerous diseases, including cancer. In cancer cells, metabolic reprogramming, impaired mitochondrial quality control, and mitochondrial DNA damage are linked to tumor initiation, development, and metastasis. Dysregulated mitochondrial function in cells within the tumor microenvironment, such as CD8 + T cells, also promotes cancer progression. Therapeutic approaches targeting mitochondria range from dietary interventions to small-molecule drugs aimed at restoring mitochondrial dysfunction. In this review, we summarize the relationships between mitochondrial dysfunction and cancer from the perspectives of metabolism, quality control, mitochondrial DNA stability, ion homeostasis, and the tumor microenvironment. We also provide updates on mitochondria-targeted therapies, highlighting key translational gaps from bench to bedside. Finally, we discuss future directions for mitochondria-targeted cancer therapy, emphasizing mitochondrial homeostasis as a critical target for improving therapeutic outcomes.

Ethnopharmacological relevance The processing of Panax notoginseng (PN) is a quintessential example of the traditional Chinese medicine principle of "different uses for raw and processed products", embodied in the theory of "raw for dispersing while processed for tonifying". However, few studies are available summarizing the corresponding chemical transformations and pharmacological shifts. Aim This review aims to synthesize current research to elucidate the processing-driven chemical transformations and pharmacological shifts in PN. Methods Focused on the core topic of chemical transformations and pharmacological shifts in PN driven by processing, a systematic search of eligible literature published since 2015 was conducted across several databases, including Scopus, PubMed, Web of Science, the Chinese National Knowledge Infrastructure, the Chinese Biomedical Database, the WanFang Database, and the Chinese Science and Technology Journals Database. Results Key findings indicate that heat-based processing significantly reduces hemostatic components like dencichine while converting native saponins (e.g., ginsenoside Rg1, Rb1, Rd, Re, notoginsenoside R1) into rare saponins (e.g., ginsenoside Rg3, Rg5, Rk1, Rk3, Rh4). This compositional remodeling underpins the efficacy transition that raw PN excels in hemostasis and blood activation, whereas the processed form exhibits enhanced blood-nourishing, immunomodulatory, and anti-tumor activities. However, critical gaps persist, including the lack of dedicated quality standards for processed products, non-standardized processing protocols reliant on empirical judgment, and a fragmented understanding of the systemic mechanisms linking compositional changes to holistic efficacy. Conclusion This review summarizes critical advances in understanding the inherent chemical transformations and pharmacological shifts in PN driven by processing. To advance the field, future research must focus on processing standardization through objective chemical endpoints, establishing quality markers based on multiple rare saponins, investigating processing-chemistry-efficacy-mechanism relationships, and translating laboratory findings into clinical evidence. These further studies are essential for transforming traditional wisdom into precision science, ensuring clinical efficacy and facilitating the global recognition of PN.

Background:Caspofungin, micafungin, and anidulafungin are three commonly used echinocandins recommended for the treatment of invasive candidiasis. This study aimed to comprehensively evaluate the safety profiles of these three agents to assist clinicians in making appropriate therapeutic decisions. Methods:A cross-sectional pharmacovigilance study based on the FDA Adverse Event Reporting System (FAERS) database was performed. Adverse event (AE) reports were collected from January 2004 to March 2025. The reporting odds ratio, proportional reporting ratio, and Bayesian confidence propagation neural network were used to identify, assess, and compare AE signals of the three echinocandins. Data from the VigiAccess database were used for external validation. Results:A total of 2343, 2338, and 406 cases associated with caspofungin, micafungin, and anidulafungin, respectively, were extracted from the FAERS database. Caspofungin exhibited a tendency toward higher reporting frequencies of hepatobiliary disorders and skin and subcutaneous tissue disorders compared with micafungin and anidulafungin. Hepatobiliary signals observed for anidulafungin should be interpreted cautiously, as they may reflect confounding by indication related to preferential use in patients with underlying hepatic dysfunction rather than direct drug toxicity. A range of AEs that were not highlighted in the labels were identified. Logistic regression analyses indicated that skin and subcutaneous tissue disorders associated with caspofungin or micafungin were significantly associated with hospitalization reporting. Supplementary PT-level analyses further identified several clinically relevant AEs associated with hospitalization, including drug reaction with eosinophilia and systemic symptoms for caspofungin, renal failure for micafungin, and hepatic failure for anidulafungin. Higher disproportionality signals related to caspofungin and micafungin were observed in patients aged≥65 years and females. Additionally, the sensitivity analyses demonstrated that this study possessed good robustness. The median time-to-onset of AEs was significantly longer for caspofungin at 4 days (IQR: 0-11 days) than for micafungin at 2 days (IQR: 0-8 days, P < 0.001) and anidulafungin at 1 day (IQR: 0-10 days, P = 0.001). The results in VigiAccess were broadly consistent with FAERS findings. Conclusion:This study provides a comparative pharmacovigilance overview of the safety profiles of three echinocandins using FAERS and VigiAccess data. Further prospective studies are needed to validate these observations.

BACKGROUND:Reliable biomarkers for risk stratification and treatment monitoring in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) treated with first-line chemo-immunotherapy remain limited. This study evaluated the prognostic value of baseline computed tomography (CT)-derived body composition parameters and their early dynamic changes. METHODS:In this single-center retrospective cohort study, patients with R/M NPC receiving first-line chemo-immunotherapy were included. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Associations between body composition and outcomes were analyzed. RESULTS:A total of 199 patients were included, and 99 with post-treatment CT after two cycles were further analyzed for dynamic changes. Higher baseline skeletal muscle area (SMA) was independently associated with longer PFS (HR = 0.56, 95% CI: 0.37-0.85, p = 0.006) and OS (HR = 0.46, 95% CI: 0.23-0.93, p = 0.03), and with higher ORR (82.8% vs 70.0%, p = 0.033) and DCR (98.0% vs 91.0%, p = 0.031). During early treatment, a ≤ 1.3% decrease or an increase in SMA was independently associated with longer PFS (HR = 0.53, p = 0.045) and OS (HR = 0.27, p = 0.018). A greater decline in visceral adipose tissue density (ΔVATD < -0.9%) was also associated with more favorable PFS and OS, whereas no significant difference in ORR was observed. CONCLUSION:Baseline SMA and early changes in SMA and VATD have prognostic value in R/M NPC treated with first-line chemo-immunotherapy. CT-based body composition assessment may serve as a practical imaging biomarker for risk re-stratification and individualized management. IMPLICATIONS FOR PRACTICE:CT-based body composition assessment may provide a practical approach for individualized management of patients with recurrent/metastatic nasopharyngeal carcinoma receiving chemo-immunotherapy. Incorporating body composition assessment into routine CT imaging analysis may further improve risk stratification and facilitate early identification of patients with poor prognosis. For patients with low skeletal muscle reserve or significant early muscle loss during treatment, timely nutritional assessment, exercise support, and closer clinical monitoring may be considered to optimize supportive care and treatment management.

Background: Dangguibuxue decoction (DD), containing Angelica sinensis (Oliv.) Diels (AS) and Astragalus membranaceus (Fisch.) Bge. (AM) (1:5), is a well-known traditional Chinese medicine (TCM) used for strengthening qi and nourishing the blood. DD has shown therapeutic effects in nephropathy patients. However, the underlying mechanisms based on the traditional efficacy are still not fully elucidated. Methods: The chemical constituents in DD were identified using UPLC-MS/MS. Network pharmacology analysis was applied to predict the potential target genes and associated signaling pathways. A renal fibrosis mouse model was induced by the intraperitoneal injection of aristolochic acid I (AA I) at 3.0 mg/kg. Mice were treated with AM, AS, and DD at two dosages by oral gavage for 30 days. Body weights, serum biochemistry, hematology, and histopathology observations were assessed. The key targets predicted were validated using qRT-PCR and Western blotting. The active constituents were screened by molecular docking, and their anti-fibrotic effects were evaluated through in vitro assays. Results: DD effectively improved renal functions and alleviated AA I-induced renal fibrosis. DD alleviated anemia and upregulated the expression of Erythropoietin (EPO). Network pharmacology analysis indicated the involvement of signaling pathways, including the PI3K/Akt, hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-β (TGF-β) signaling pathways. Experimental validation further demonstrated that DD reduced the protein expression of HIF-1α, collagen I, and TGF-β, and the ratios of phosphorylated Smad2/3 to total Smad2/3. Molecular docking and in vitro assays suggested that rutin may be a potential bioactive compound in DD. Conclusions: This research indicated that DD ameliorated AA I-induced renal fibrosis in mice, which may be associated with the modulation of HIF-1α and TGF-β/Smad signaling pathways. Rutin may be a potential bioactive compound in DD with anti-fibrotic activity, but further studies are still needed to clarify the content of rutin in DD, the amount of its exposure in the body, and its contribution to the effects of DD.

Curcuma is a traditional Chinese medicine that has been utilized for centuries in the treatment of various diseases. Terpenoids, particularly monoterpenes and sesquiterpenes, constitute the primary bioactive components of the essential oil derived from Curcuma species. Among these, curdione-one of the key active constituents-has been identified in 25 Curcuma species, with the highest concentration reported in the rhizome essential oil of Curcuma trichosantha Gagnep. Curdione can also be synthesized through chemical methods, and its regio- and stereo-selectivity can be further optimized via chemo-bio transformations. This compound demonstrates significant therapeutic potential, including anticancer, anti-thrombotic, anti-inflammatory, anti-viral, anti-fungal, anti-diabetic, and multi-organ protective properties. Despite these promising biological activities, its clinical application is hindered by poor water solubility and potential toxicity. This review summarizes current knowledge on the natural sources, chemical synthesis, chemo-bio transformations, metabolism, pharmacokinetics, pharmacological effects, potential toxicities, and molecular mechanisms of curdione. Furthermore, perspectives on future drug development are discussed with the aim of promoting the clinical translation of this promising natural compound.

Background Patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) exhibit heterogeneous short-term responses despite induction chemotherapy plus concurrent chemoradiotherapy, and effective plasma protein prognostic markers are lacking. This study aimed to screen and validate differentially expressed proteins (DEPs) associated with short-term response using plasma proteomics and machine learning, to support personalized treatment. Methods 107 newly diagnosed LA-NPC patients (stage III-IVA) from Hunan Cancer Hospital were enrolled (October 2023-June 2025) and divided into a discovery cohort (n = 6) and a validation cohort (n = 101). Plasma samples were collected before treatment, after induction chemotherapy, and after radiotherapy. Data-independent acquisition (DIA) mass spectrometry-based proteomics was performed. LASSO regression and random forest were employed to identify key DEPs. Candidate proteins were validated by ELISA in the validation cohort. Predictive performance was assessed by ROC curve, multivariate ordinal logistic regression, Kaplan-Meier survival analysis, and multivariate Cox regression. Results Proteomics identified 67 DEPs between patients with complete response (CR) and stable disease (SD) before treatment, enriched in endoplasmic reticulum protein processing, ribosome, and neurodegenerative disease pathways. Intersection of LASSO (4 DEPs) and random forest (139 DEPs) yielded two key DEPs: BAK1 and GAA. ELISA confirmed that pre-treatment BAK1 was significantly higher in CR and partial response (PR) groups compared to SD (P < 0.05); post-treatment, BAK1 increased in SD but decreased in CR/PR groups. GAA showed no significant differences. Pre-treatment BAK1 predicted short-term response with an AUC of 0.902. Multivariate ordinal logistic regression showed BAK1 was significantly associated with response stratification (P = 0.039). Based on the optimal cut-off, the BAK1 high-expression group had significantly better distant metastasis-free survival (DMFS) and progression-free survival (PFS) (P < 0.05), and BAK1 was an independent factor for both. Conclusion This study is the first to discover and validate plasma BAK1 as a novel predictive biomarker for short-term response to induction chemotherapy plus concurrent chemoradiotherapy in LA-NPC, with additional prognostic value for DMFS and PFS. BAK1 holds promise for early risk assessment and individualized treatment strategies.

Triple-negative breast cancer (TNBC) is highly aggressive and lacks specific targeted therapeutic targets. Its immunosuppressive “cold” tumor microenvironment severely limits the efficacy of conventional chemotherapy and immunotherapy, resulting in unsatisfactory clinical outcomes. To address the challenges, we developed a biomimetic nanoplatform (M@Ba-Fe/Al NPs) by coating Fe3+/Al3+-baicalin cores with homologous tumor cell membranes. Benefiting from the inherent homologous targeting capability, the nanoplatform efficiently accumulates in tumor tissues and penetrates the dense cancer-associated fibroblast barrier to achieve deep tumor infiltration. Mechanistically, M@Ba-Fe/Al NPs induce tumor ferroptosis by triggering Fenton-like reactions to deplete intracellular glutathione and accelerate lipid peroxidation, while simultaneously activating immunogenic cell death (ICD). Additionally, Al3+ acts as an immune adjuvant to promote dendritic cell maturation and increase intratumoral CD8+ T-cell infiltration, thereby comprehensively remodeling the immunosuppressive tumor microenvironment. By synergistically integrating ferroptosis and ICD dual antitumor pathways, the designed nanoplatform effectively suppresses tumor progression with favorable biosafety, providing a promising and translatable strategy for chemodynamic-immunotherapy of TNBC.