BACKGROUND:Estrogen-induced intrahepatic cholestasis (EIC) is characterized by toxic bile acid accumulation and hepatic inflammation. Farnesoid X receptor (FXR), a key nuclear receptor governing bile acid homeostasis, plays a pivotal role in cholestasis progression. Geniposidic acid (GPA), a natural iridoid glucoside, exerts hepatoprotective effects against various liver injuries, but its therapeutic potential in EIC remains obscure. PURPOSE:To investigate the importance of FXR signaling in EIC progression and clarify the therapeutic efficacy and mechanism of GPA against EIC. METHODS:Synthetic estrogen 17α-ethinylestradiol (EE) was used to establish EIC models both in vivo and in vitro. The protective effect of GPA on EE-treated mouse primary hepatocytes (MPHs), HepG2 and wild-type and FXR⁻/⁻ mice was evaluated by liver injury indicators and H&E staing. SPR, LanthaScreen TR-FRET, and hFXR transactivation assays were employed to characterize GPA as an FXR agonist. Co-administration with metformin, an AMP-activated protein kinase (AMPK) activator, was performed to confirm AMPK-FXR crosstalk in the protective mechanism of GPA. RESULTS:GPA directly bound FXR ligand-binding domain via Tyr361 and His447 residues, activating FXR signaling to restore bile acid homeostasis and attenuate oxidative stress and inflammation in an FXR-dependent manner. FXR deficiency abolished GPA's hepatoprotection in vitro and in vivo. Mechanistically, EE-induced AMPK hyperactivation suppressed FXR, whereas GPA-activated FXR counter-regulated AMPK phosphorylation via negative feedback. This protection was partially diminished by co-administrated with the AMPK activator Metformin. CONCLUSIONS:GPA acts as a natural FXR agonist, and targeting AMPK-FXR crosstalk represents a promising therapeutic strategy for EIC.

Gentiana straminea Maxim. (GSM), a cornerstone medicinal plant in Tibetan ethnopharmacology, has been utilized for over two millennia. This species exhibits a wide distribution across China, predominantly in the northwest. Its roots and flowers characterized by bitter, pungent taste and neutral properties are used medicinally. Traditional applications include treating rheumatoid arthritis, icteric hepatitis, leprosy, and “toxic heat” syndromes. Recent research has identified critical bioactive constituents: secoiridoids (gentiopicroside, swertiamarin, sweroside), loganic acid, flavonoids (vitexin, isovitexin), volatile compounds, and saccharides. GSM demonstrates significant pharmacological activities, including anti-inflammatory, analgesic, antioxidant, hepatoprotective, cardioprotective, anti-hypoxic, anti-bacterial, and insecticidal effects. By systematically reviewing domestic and international literature from the past two decades, this study summarizes the morphological characteristics, resource distribution, breeding practices, cultivation methods, chemical composition, and pharmacological actions of GSM. The aim is to provide a scientific basis for its cultivation, identification, rational clinical application, and to promote its development and utilization. Botany, pharmacological effects, and chemical composition of Gentiana straminea Maxim.

By employing a molecular networking analysis strategy, we successfully guided the isolation of alkaloids from the ethyl acetate extract of Paeonia lactiflora roots. This approach led to the discovery of previously undescribed indole alkaloids, (+)/(-)-paeonialkaloid A [(+)/(-)-1], paeonialkaloids B and C (2 and 3), along with one known alkaloid (4). The structures were fully established through comprehensive spectroscopic methods, including 1D/2D NMR, HRESIMS, UV, IR, and theoretical calculations of electronic circular dichroism (ECD) spectra. Indole alkaloids have been rarely reported from the Paeonia genus. In this study, the discovery of (+)/(-)-1, 2 and 3 provides only the second report of such compounds. In addition, (+)-1, (-)-1, 2 and 3 are moderate inhibitors of human carboxylesterase 2 (hCE2), with IC₅₀ values of 13.65 ± 0.64, 13.92 ± 0.72, 14.45 ± 0.43, and 14.16 ± 1.05 μM, respectively, which was revealed through the molecular docking studies.

Background:Myocardial ischemia-reperfusion injury (MIRI) remains a major clinical challenge in the management of acute myocardial infarction. Ginsenoside Rg1, a bioactive component from Panax ginseng, exhibits cardioprotective properties but suffers from poor bioavailability and limited tissue targeting. Methods:We designed a novel DNA nanocarrier, Rg1@pTDN, by loading Rg1 onto a tetrahedral DNA nanostructure (TDN) modified with the myocardial-targeting peptide CREKA. The physicochemical characteristics of Rg1@pTDN were evaluated by DLS, zeta potential analysis, AFM, and gel electrophoresis. Biodistribution, biosafety, and cellular uptake were assessed in vitro and in vivo. Cardioprotective efficacy was evaluated in a murine MIRI model and a H/R injury cell model. Mechanistic studies focused on oxidative stress and endoplasmic reticulum (ER) stress pathways. Results:Rg1@pTDN exhibited uniform nanoscale structure, high Rg1 loading efficiency, and good colloidal stability. In vivo imaging revealed preferential accumulation in cardiac tissue following intravenous administration. Rg1@pTDN was well tolerated and improved survival, cardiac function, and myocardial histology in MIRI mice. It significantly reduced serum CK-MB concentrations and oxidative stress markers (MDA), while increasing antioxidant enzyme activities (SOD, GSH-Px). In vitro, Rg1@pTDN suppressed ROS accumulation and H/R-induced apoptosis in H9c2 cells. Furthermore, Rg1@pTDN alleviated H/R-induced ER stress, as shown by decreased GRP78 and CHOP mRNA expression and reduced phosphorylated PERK and CHOP protein levels. Conclusion:Rg1@pTDN represents a promising nanotherapeutic strategy for myocardial ischemia-reperfusion injury through targeted delivery and dual inhibition of oxidative and ER stress. This DNA-based platform offers a versatile approach for enhancing the efficacy of natural compounds in cardiovascular disease.

Chronic heart failure (CHF) is a leading cause of morbidity and mortality, characterized by the heart’s progressive inability to maintain adequate circulation. While adverse cardiac remodeling, encompassing cardiomyocyte hypertrophy, fibrosis, and ultimately, cardiomyocyte loss, is central to CHF pathogenesis, the precise mechanisms driving this cellular demise remain incompletely understood. Dysregulation of programmed cell death (PCD) pathways plays a critical role. Beyond apoptosis, the canonical form of PCD, diverse modalities including necroptosis, mPTP-dependent necrosis, pyroptosis, ferroptosis, cuproptosis, disulfidptosis, and autophagy-dependent cell death contribute to cardiomyocyte loss and adverse remodeling, exacerbating CHF progression. These pathways are intricately interconnected, forming a complex “cell death interactome” in which activation of one death program can influence others, shaping the balance between adaptive and maladaptive responses. This review first provides core definitions for each PCD modality, followed by an analysis of their spatiotemporal dynamics, etiology-specific activation patterns, and crosstalk within the interactome. By integrating molecular, pathological, and preclinical evidence, we delineate the key regulatory nodes of the cell death interactome in CHF, highlight promising therapeutic targets, and ultimately accelerate the translation of these mechanistic findings into clinical interventions.

This study aims to meet the therapeutic needs of rheumatoid arthritis(RA)by focusing on the traditional anti-arthritic medicinal plant Gentiana straminea.An integrated strategy combining characterization of absorbed components,network pharmacology,molecular docking,and molecular interaction verification was employed to systematically investigate the pharmacodynamic material basis and mechanism of this herb against RA.Ultra-high performance liquid chromatography-quadrupole-time of flight-tandem mass spectrometry(UHPLC-Q-TOF-MS/MS)was performed,which identified gentiopicroside,swertiamarin,and loganic acid as the core components absorbed into blood.Network pharmacology prediction and target mapping revealed that these components were primarily involved in RA-related biological processes such as inflammatory response and immune cell activation.Molecular docking suggested that the core components exhibited favorable binding potential with key targets including STAT3,EGFR,and MMP9.Further quantitative validation with bio-layer interferometry demonstrated that gentiopicroside(KD=50.1 nmol·L-1)and swertiamarin(KD=87.7 nmol·L-1)specifically bound to STAT3 with high affinity.The results indicate that G.straminea exert anti-RA effects through its iridoids by targeting STAT3 and modulating related inflammatory pathways,providing a scientific basis for the clinical application of G.straminea and the development of natural anti-RA drugs.

Litcubanine A (LA), an isoquinoline alkaloid characterized by a specific C-1 methyl group and an N → O moiety, exhibits significant anti-inflammatory activity, suggesting its potential as a lead compound for the development of novel macrophage-targeted anti-inflammatory drugs. However, the low natural abundance of LA in plants poses challenges for extraction and isolation to meet the demands of subsequent drug development. To overcome this limitation, we developed a concise and efficient total synthesis strategy. Utilizing a classical Bischler-Napieralski cyclization followed by the N-oxidation reaction, the synthesis of LA was accomplished in only four steps, providing multigram quantities of the target compound with an overall yield of 21.7%. The anti-inflammatory activity of LA, along with those of key synthetic intermediates and structural analogues, we subsequently evaluated.

Chemotherapy-related cognitive impairment (CRCI), colloquially termed “chemobrain,” remains a debilitating and underaddressed sequela of cancer treatment. Despite its prevalence and profound impact on quality of life, the precise pathophysiological mechanisms remain incompletely understood. This review synthesizes emerging evidence positioning mitochondrial quality control (MQC) dysfunction as a central mechanistic hub in CRCI pathogenesis. We critically evaluate how diverse chemotherapeutic agents, including anthracyclines, alkylating agents, platinum compounds, antimetabolites, and microtubule inhibitors, converge on distinct yet overlapping pathways of MQC impairment. These agent-specific mechanisms collectively compromise the five fundamental pillars of MQC: biogenesis, mitophagy, dynamics, and proteostasis, along with the formation of mitochondria-derived vesicles. MQC failure subsequently drives a feed-forward cycle of neuroinflammation, blood-brain barrier disruption, synaptic loss, and ultimately, cognitive dysfunction. We further examine promising therapeutic strategies targeting MQC, encompassing mitochondria-targeted antioxidants, metabolic regulators, biogenesis activators, mitochondrial dynamics modulators, mitophagy activators, multi-targeted drugs, as well as physical and nutritional interventions that collectively enhance neuronal mitochondrial resilience. By elucidating the mechanistic centrality of MQC in CRCI, this review provides a robust framework for developing targeted interventions that may preserve cognitive function without compromising anticancer efficacy, thereby addressing a critical unmet need in cancer survivorship care and accelerating the transition towards precision neuroprotection in oncology.

The microbiota is being increasingly recognized for its ability to regulate host physiology through the production of small bioactive molecules. However, how host-derived nutrients are metabolically transformed by root-associated microbes to influence plant immunity remains poorly understood. Here, we show that vitamin B3 (VB3; niacin) secreted by plant roots shapes the assembly of a functionally specialized root microbiota, which, in turn, metabolizes VB3 into an immune-active signal that enhances plant disease resistance. VB3 secretion selectively increases the abundance of root-associated bacteria harboring a conserved nic biosynthetic gene cluster (BGC), which enables the conversion of VB3 into 6-hydroxynicotinate (6-OHNA), a previously uncharacterized microbial metabolite involved in plant-microbe interactions. Microbially produced 6-OHNA is transported from roots to shoots, where it primes systemic immune responses in a salicylic acid-dependent manner. Disruption of the microbial nic BGC abolishes immune priming, whereas increased VB3 exudation from plant roots enhances disease resistance. Together, these findings reveal a metabolically mediated dialog between plant hosts and their microbiota that links host nutrient secretion to microbial functional specialization and the activation of systemic plant immunity.

Eight new ent-pimarane diterpenoids (1-8), along with three known compounds (9-11), were isolated from the aerial parts of Sigesbeckia pubescens. The structures of the new ent-pimarane diterpenoids were established by extensive spectroscopic techniques, X-ray diffraction crystallography, ECD calculations and Mo2(OAc)4-induced ECD. The isolated compounds were evaluated for their myocardial protective activities in an H9c2 cell hypoxia/reoxygenation (H/R) induced myocardial ischemia-reperfusion injury model. Bioassay results showed that pubescens B (2), pubescens H (8) and darutigenol (9) enhanced the cell viability at concentrations of 1, 10, and 50 µM and molecular docking explored their binding mode with H/R connected protein Ubiquitin C-terminal hydrolase L5 (UCHL5).

Gentiopicroside (GPS) is a natural component with anti-inflammatory, hepatoprotective, and other activities. However, its short half-life and insufficient residence time limit its clinical application. In this study, GPS was identified as a hydrophilic drug based on pre-formulation studies, and two sustained-release preparations were successfully developed, including gentiopicroside microporous osmotic pump tablets (GPS-MPOP) and gentiopicroside matrix sustained-release tablets (GPS-MRT). GPS-MPOP and GPS-MRT were prepared using single-factor experiments. In vitro release studies demonstrated that both preparations exhibited sustained release for 12 h. The release curve followed the Weibull model, and the release mechanism was governed by a combination of diffusion and erosion. In vivo pharmacokinetic study in New Zealand rabbits showed that the Tmax of reference preparations (GPS-OT), GPS-MRT and GPS-MPOP were 0.25 h, 1.00 h (p ≤ 0.01) and 1.50 h (p ≤ 0.01); the Cmax were 1108.11 ± 14.56 μg/L, 714.71 ± 10.24 μg/L (p < 0.0001) and 850.53 ± 4.80μg/L (p < 0.0001), and the t1/2 were 1.30 ± 0.07 h, 5.36 ± 1.39 h (p < 0.0001) and 4.86 ± 0.28h (p < 0.0001), respectively. Compared with reference preparations, the relative bioavailability was 103.24% for GPS-MRT and 116.47% for GPS-MPOP, respectively. Both of the two sustained-release preparations prolonged drug release and reduced plasma concentration fluctuation, which provides a new strategy for clinical application of GPS.

ABSTRACT Natural volatile components (VCs) are extensively applied in medicine, food, and daily chemicals. Characterizing their chemical compositions is essential for fundamental research. Reversed‐phase preparative chromatography is among the most widely used and efficient separation approaches. Nevertheless, the poor thermal stability and steam‐volatile nature of VCs pose substantial challenges for laboratory‐scale preparation and recovery. To address this problem, we report a laboratory‐grade liquid–liquid extraction‐assisted reversed‐phase preparative solution recovery (LERPSR) method designed to enhance the recovery efficiency and stability of VCs during reversed‐phase chromatography. Cost‐effective solvents were screened based on phase separation and miscibility. Ten VCs representing four categories were selected to evaluate the universality of LERPSR, while zedoary turmeric oil was used to validate its feasibility in complex matrices. The mechanism was investigated using computational chemistry. Results demonstrated that n ‐hexane outperformed isooctane. Compared with the direct vacuum recovery method, the LERPSR method with n ‐hexane improved the recovery of all 10 VCs, with seven showing statistical significance ( p < 0.05). The recovery weight of characteristic components significantly increased in zedoary turmeric oil, exhibiting enhanced stability. Computational results aligned with experimental findings. Thus, LERPSR effectively improves the recovery and stability of VCs, offering a promising laboratory‐grade approach for preparation, quality control, and identification of VCs.

Chronic heart failure (CHF) impairs cognitive function. Xijiaqi Formula (XJQ), a traditional Chinese medicine (TCM) used clinically to treat CHF, demonstrates potential for improving cognition in CHF patients. However, its precise mechanism in treating post-CHF cognitive dysfunction remains unclear. This study systematically investigates XJQ's effects on post-CHF cognitive dysfunction and the underlying mechanisms. The components of XJQ were identified through liquid chromatography-mass spectrometry. CHF was induced in rats via ligation of the left anterior descending coronary artery, followed by six weeks of XJQ treatment. Cardiac function was evaluated through echocardiography and hemodynamic parameters, while cognitive function was assessed using Morris water maze (MWM) and open field tests (OFT). XJQ treatment enhanced both cardiac and cognitive functions in CHF rats. Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses, inflammation, and phosphodiesterase 4 (PDE4)-dependent cyclic adenosine monophosphate (cAMP) signaling. XJQ inhibited microglial and astrocyte activation, decreased proinflammatory cytokines, and mitigated neuronal damage. Notably, XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP, protein kinase A (PKA), cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), PSD95, and synapsin I levels. Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin, kaempferol, isorhamnetin, and darutoside to PDE4. In conclusion, XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway. These findings provide valuable insight into the heart-brain axis.

China has made remarkable achievements in the science and technology innovation of traditional Chinese medicine(TCM)since the 18th National Congress of the Communist Party of China.The modernization of TCM is advancing steadily,contributing significantly to public health and well-being,while accumulating valuable experience for the development of TCM in the new era.Based on the current research status of TCM modernization in the new era,this study systematically identifies key factors influencing the achievements in TCM innovation,and puts forward targeted recommendations to address existing challenges,aiming to provide novel insights for optimizing the mechanism of heritage-driven innovation and development in TCM,offer theoretical foundations and decision-making support for the national science and technology deployment in the TCM sector,and promote high-quality development of TCM driven by scientific and technological innovation.

The flagellar hook subunit FlgE of Pseudomonas aeruginosa (Pa-FlgE) is a core component of the bacterial surface flagellum. It is also identified as an important virulence factor capable of modulating host inflammatory response. Herein, we report the high-resolution crystal structures of Pa-FlgE domain I (D-I) and domain II (D-II), both of which adopt predominantly β-structure. Structural comparison among Pa-FlgE and its orthologs shows that D-I and the core-barrel of D-II are highly conserved. Two peripheral insertions of variable length and structure, however, are identified in FlgE D-II. In Pa-FlgE, these two insertions fold as a loop element and a β-hairpin element, respectively. Notably, these two elements are solvent-exposed and extend towards one another, and deletion of the two elements either simultaneously or individually is shown to abolish the immunomodulation activity of Pa-FlgE. While the loop element is present in other FlgE orthologs, the β-hairpin is unique to Pa-FlgE, suggesting that P. aeruginosa has evolved this distinctive β-hairpin in flagellar hook to modulate the inflammatory response during infection.

To study the prototype components and metabolites at different time points in the serum of rats after oral administration with Shaoyao Gancao Decoction (SGD), and to analyze their metabolism regularities in vivo. The UPLC-Q-TOF-MS/MS method was used to analyze the drug-containing serum samples at different time points. The mass spectrometry data were preliminarily processed using Analyst® TF 1.7.1 Software, followed by advanced analysis and visualization by PeakView 2.0 and Masterview1.0 to determine the retention time and relevant details of prototype components and metabolites. The MetabolitePilot™1.5 was employed to analyze the prototype components and metabolites in drug-containing serum samples at different time points, systematically summarizing their in vivo metabolic profiles. A total of 79 prototype components and 527 metabolites were detected in serum samples collected at 10 different time points, including flavonoids, terpenoids, volatile oils, organic acids, alkaloids, coumarins, etc. Of these, 11 prototype components were detected at all time points in the positive ion mode, and 19 were detected in the negative ion mode. Specifically, seven key components, including glycyrrhetinic acid, isoglycyrrhetinic acid, macedonic acid, diisobutyl phthalate, dibutyl phthalate, vitexin, and linoleic acid, were detected in both ion modes. This article is the first to analyze the metabolites of drug-containing serum at 10 different time points. The predominant metabolic processes in vivo included oxidation, reduction, hydrolysis, glucuronidation, sulfation, acetylation, methylation, and amino acid conjugation. The study revealed detailed data about the effective substances in SGD having a potential protective role against liver injury, which will support further investigation of the effective ingredient group of SGD and associated mechanism(s).

To the editor: The comprehensive exploration of natural products and metabolites is essential for unraveling the complexities of natural drug thera-pies.Inadequate tracking and separation methods result in increased research costs and reduced scientific output,significantly hindering the healthy advancement of related research fields.

IntroductionA combination of Corydalis Rhizoma (the dried tuber of Corydalis yanhusuo W.T. Wang) and Paeoniae Radix Alba (the root of Paeonia lactiflora Pall.) has been traditionally employed for analgesia. However, the underlying pharmacological mechanisms have not been clarified. The aim of the present study was to investigate the anti-inflammatory and analgesic effects of YB60, the 60% ethanol elution fraction derived from the combination of Corydalis Rhizoma and Paeoniae Radix Alba, and the explore the underlying mechanism.MethodsLipopolysaccharide-induced cellular inflammation model and chronic compression injury (CCI) rat model were used to study the anti-inflammatory and analgesic effects of YB60. Proteomics and molecular biology experiments were applied to explore the potential analgesic mechanism of YB60.ResultsThe results demonstrated that YB60 significantly decreased inflammatory cytokine levels both in cellular models and rat serum, while concurrently elevating pain thresholds in CCI rats. Proteomic analysis indicated that YB60 could upregulate the expression of Membrane Bound O-Acyltransferase Domain Containing 2 (Mboat2), a newly confirmed marker of ferroptosis. Furthermore, YB60 prevented ferroptosis in the spinal cords of CCI rats. Western blotting and immunofluorescent dual staining further revealed that YB60 increased the expression of Mboat2 and its upstream signaling molecule Androgen receptor (AR). Results in PC12 cells in vitro showed that YB60 reversed the downregulation of AR and Mboat2, and ameliorated ferroptosis induced by Erastin, while knockdown of AR eliminated the above effects of YB60.ConclusionThese findings indicated that YB60 exerted its analgesic effect by inhibiting ferroptosis in spinal cord neurons via modulation of the AR/Mboat2 pathway.

Platelet factor 4 (PF4), also referred to as CXCL4, is a significant component of the C-X-C chemokine family, predominantly localized within the alpha granules of platelets. It is recognized for its anti-heparin and anti-angiogenic properties. However, the involvement of PF4 in inflammatory processes has not been extensively investigated. This article aims to explore the diverse functions of PF4 in the context of inflammatory diseases, emphasizing its potential dual regulatory roles across various immune cell types and pathological conditions. Recent research has enhanced our comprehension of PF4, revealing its production not only in platelets but also in macrophages and activated T cells, thereby extending its functional repertoire beyond its conventional roles. Consequently, this review provides a thorough analysis of PF4's influence on inflammatory diseases and offers perspectives and recommendations for future research endeavors.

Ferroptosis induced by ferrous ions (Fe2+) and lipid peroxidation accumulation is a novel form of regulated cell death that has become a hot topic in tumor therapy research. Identifying small-molecule drugs that can induce ferroptosis in tumor cells is a very attractive therapeutic strategy. Here, we screened a natural product, acevaltrate (ACE), which rapidly and strongly induces ferroptosis in colorectal cancer cells. ACE not only increases Fe2+ levels in colorectal cancer cells by targeting iron chaperones PCBP1/2 and reducing their expression but also disrupts the antioxidant system of colorectal cancer cells by targeting GPX4 and inhibiting its enzymatic activity, leading to its ubiquitin-mediated degradation. This dual effect of ACE makes it significantly more effective than classical ferroptosis inducers in inducing ferroptosis. Our animal experiments revealed that the therapeutic effect of ACE surpasses that of established ferroptosis-inducing drugs and is superior to that of first-line clinical drugs such as capecitabine and TAS-102. Importantly, ACE also demonstrated superior inhibitory effects in colorectal tumor organoids versus at the cellular level, underscoring its potential for clinical application. This study pioneers the discovery of a small molecule inhibitor that targets both PCBP1/2 and GPX4, offering a novel therapeutic strategy for eliminating cancer cells through ferroptosis.