Gancao decoction ameliorated senecionine-induced Hepatic Sinusoidal Obstruction Syndrome in mice by inhibiting NET formation and senecionine bioactivation in liver.

Exploring time dependent trends and risks of pyrrolizidine alkaloids and their N-oxides in food.

Monocrotaline induces liver injury via TRX1-ASK1-JNK Axis-mediated mitochondrial damage in hepatocytes.

Pyrrolizidine alkaloid contamination in loose tea and its health risk assessment.

Hemoglobin adduction and impaired oxygen transport define the etiology of pyrrolizidine alkaloid-induced pulmonary arterial hypertension.

ABSTRACT This study evaluated the possible cytotoxic properties of the aerial parts of Heliotropium hirsutissimum Weber on MCF‐7 and MDA‐MB‐231 breast cancer cell lines and also investigated its antimicrobial effects. Following the identification of the main components of the extract using gas chromatography–mass spectrometry analysis, molecular docking studies were performed using the PDB 6YD9 and PDB 6BRX targets. The crude methanol extract exhibited the most significant cytotoxicity against the MCF‐7 and MDA‐MB‐231 cell lines, with IC 50 values of 10.03 ± 0.02 and 14.36 ± 0.65 µg/mL, respectively. Among the tested extracts, the n ‐hexane sub‐extract had modest efficacy against Staphylococcus aureus and Bacillus cereus , with a minimum inhibitory concentration of 0.625 mg/mL. In silico studies demonstrated that 3'‐acetyllycopsamine and heliotrine had moderate affinity for the PDB 6YD9 target residue regions, with docking scores of −6.7 and −6.5 kcal/mol, respectively. The docking scores for 3'‐acetyllycopsamine and heliotrine against PDB 6BRX were −6.7 and −6.6, respectively. Quinic acid showed strong affinity for the target residues in PDB 6YD9 and PDB 6BRX, with docking scores of −9.3 and −12.1 kcal/mol, respectively. This study suggests that H. hirsutissimum may have a potential effect on breast cancer. This effect may be attributed to the phenolic compounds and pyrrolizidine alkaloids. These findings indicate that H. hirsutissimum is a promising natural resource for future research in both the anticancer and antimicrobial fields.

Senecio scandens Buch. - Ham.: A comprehensive review of botany, phytochemistry, biological activity, toxicity, quality control, application, and practical domain.

Skin aging, driven by oxidative stress, UV exposure, inflammation, and extracellular matrix degradation, necessitates the discovery of safer, multi-target natural products. We established an integrated pipeline combining UHPLC–MS/MS metabolomics, computational methods (network pharmacology, molecular docking, and dynamics simulation), and in vitro bioassays to efficiently discover and mechanistically characterize anti-aging compounds from novel botanical sources. We applied this pipeline to identify and evaluate Tephroseris flammea, a previously unassessed plant. Metabolomic profiling identified 21 compounds, including flavonoids, phenylpropanoids, and pyrrolizidine alkaloids. These compounds were linked via network pharmacology to 226 skin-aging-related targets, primarily involving inflammation (via AKT1, RELA) and matrix degradation (via MAPK3). Molecular docking and 100 ns molecular dynamics simulations confirmed stable ligand-target interactions with favorable binding energies. Validating these in silico predictions, the T. flammea extract demonstrated significant antioxidant activity and effectively suppressed key inflammatory mediators (IL-6, TNF-α, COX-2) and MMP-1 levels in UVB-exposed fibroblasts, notably without significant cytotoxicity. Collectively, this study validates the utility of our pipeline to mechanistically characterize complex botanicals, revealing that T. flammea contains multifunctional compounds modulating critical inflammatory and matrix-regulatory cascades. This work validates our pipeline for identifying novel, mechanistically defined ingredients from complex botanical sources.

吡咯里西啶生物碱（PAs）是一类植物内源产生的次生代谢产物，具有肝毒性、遗传毒性和致癌性等毒性作用。现有研究覆盖PAs种类有限，且由于同分异构体色谱分离难，大多研究采用加和定量策略。因此，本研究基于超高效液相色谱-三重四极杆质谱法（UHPLC-MS/MS）建立了干茶样本中欧盟法规限量的35种PAs的分析方法，其中有33种目标化合物获得了色谱分离，可以实现单独定量，有2种异构体共流出，进行加和定量。在电喷雾离子源（ESI）正离子模式下电离、多反应监测（MRM）模式下扫描，35种PAs在各自范围内呈现良好的线性关系（r2>0.99），方法的检出限（LOD）和定量限（LOQ）分别为0.2~8.0 µg/kg和0.5~25.0 µg/kg。在1、2和5倍LOQ加标水平下，茶叶基质中均有89%以上的目标化合物平均回收率为70%~130%，3次平行实验相对标准偏差（RSD）小于20%（蓝蓟定和毛果天芥菜碱RSD小于30%）。应用该方法对21份黑茶和30份红茶样本进行检测，黑茶样本中35种PAs检出率为19.05%，总含量为5.07~15.48 µg/kg，红茶样本中无PAs检出。所建立的分析方法可为茶叶样本中PAs的组成、含量及风险评估提供技术支撑。

Pyrrolizidine alkaloids (PAs), found in over 6000 plant species, pose serious risks to food safety and public health due to their potent toxicity. Among them, echimidine, a major PA in Echium vulgare and Symphytum officinale, can account for up to 30% of total PA content in contaminated honey and herbal products. This review summarizes current knowledge on the chemical properties, isolation, and metabolic profiles of echimidine, with an emphasis on its bioactivation by the cytochrome P450 enzyme into reactive pyrrolic intermediates. These intermediates form DNA and protein adducts, contributing to hepatotoxicity, genotoxicity, and developmental toxicity. Human exposure through products such as honey (up to 1 µg/g) and comfrey (5-6 mg/day) raises concern over chronic health effects. This review highlights the urgent need for improved monitoring, standardized analytical protocols, and regulatory interventions to mitigate the widespread hazards associated with echimidine.

Pyrrolizidine alkaloids (PAs) are the most common plant-derived toxins present in numerous herbal and food products, but their environmental transfer pathways and toxicological mechanisms remain unclear. This study establishes a complete contamination pathway from environmental source to molecular target. We identified the invasive plant Bidens alba as a novel PA producer and provided the first evidence of transfer to honey by detecting corresponding PAs and characteristic Bidens alba pollens in local samples. Mechanistically, we demonstrated that PA toxicity fundamentally differs from classic hepatotoxins like acetaminophen. Instead of directly damaging liver cells, PAs first induce red blood cell rupture (hemolysis) by selectively inhibiting glucose-6-phosphate dehydrogenase (G6PD). This hemolytic event precedes observable liver sinusoidal endothelial damage and initiates characteristic vascular liver injury. Our findings establish a new route of food contamination and redefine PA toxicity by identifying blood cells as the primary target, with significant implications for food safety and public health.

ABSTRACTBackgroundThe monocrotaline (MCT) model of cardiac cachexia is a pharmaceutical approach to pulmonary hypertension that has been used to study heart failure and muscle wasting in rodents; however, little is known of how this pyrrolizidine alkaloid leads to peripheral changes in organ function and body mass, and sex differences have not been adequately compared.MethodsTen‐ to 12‐week‐old male and female C57BL/6N mice were treated weekly with MCT (200 mg/kg) for 8 weeks. Body weight, feeding behaviour and stool output were monitored weekly. In the final week, endurance was measured via a treadmill fatigue study. Upon termination, organs were weighed and processed for histochemistry and downstream gene expression analysis.ResultsMales were more susceptible to MCT‐induced weight loss. No change in gross heart or skeletal muscle mass was observed in either sex, though lung mass was elevated in both sexes and cardiomyocyte size was larger in males (p < 0.05). MCT reduced the cross‐sectional area of the tibialis anterior muscle in both sexes (p < 0.05), but this did not correspond to changes in endurance, as the treadmill fatigue study revealed no change in total time or distance run in response to MCT in either sex. RNA‐seq analysis of the gastrocnemius muscle showed no significant changes in gene expression when compared within either the male or female cohort (n = 3), but when pooled (n = 6), MCT reduced gene pathways associated with mitochondrial function, adipogenesis and DNA repair and upregulated pathways associated with inflammation. Total fat mass was reduced by 40% in male mice in response to MCT, mainly because of significant reductions in inguinal white and brown interscapular adipose tissue mass. This was independent of food intake and intestinal distress, as no differences in stool wet:dry output or feeding behaviours were observed in either sex. Gene expression and immunohistochemical analysis of inguinal fat suggest that adipose tissue within males is particularly sensitive to MCT, as Tnfa, Ppargc1a and Zfp516 were upregulated, and there was a significant interaction between sex and MCT on Retn and Pnpl2a (aka Atgl) expression.ConclusionsThese data suggest sex‐dependent physiological responses of mice to MCT, where adipose tissue loss is more pronounced in males as a result of adipose tissue inflammation and metabolic activation. In contrast, conserved atrophic effects of MCT are observed within skeletal muscle, irrespective of sex. Further research using this model should consider sex‐dependent responses.

Hepatotoxic pyrrolizidine alkaloids (HPAs) are environmental and foodborne toxins found in more than 6000 flower plants and are a serious health hazard to humans. Therefore, rapid and accurate on-site detection of HPAs during production, processing, and transportation is a preliminary method to reduce the exposition of HPAs. In this work, a label-free fluorescent aptazyme, named LFAzyme, has been developed for fast, cost-effective, and visual detection of HPAs in real samples. LFAzyme self-assembled by a recognition segment (RS) and a "helper" DNA (HD) has the ability to quench the fluorescence of rhodamine B (RhB) in the presence of hemin and H2O2. With the addition of HPAs, the target would preferentially bind to RS that contains the sequence of the aptamer, yielding the destruction of LFAzyme and the recovery of RhB fluorescence. This assay enabled naked-eye determination of HPAs as low as 0.1 μM within 5 min, and the whole analysis could be completed in 15 min. The limit of detection value of 43 nM was obtained using a microplate reader. Our sensor validation with spiked real samples, including tea and honey, exhibited satisfactory HPA recovery within the range of 97.00-103.15%. Our LFAzyme could potentially be used for the on-site and naked-eye detection of HPAs or other targets with available aptamers.

Herb-induced liver injury (HILI) is an increasingly recognized cause of liver damage, associated with the widespread global use of herbal products. Despite its rising incidence, HILI remains underrecognized and underreported due to the absence of specific biomarkers, limited regulatory oversight, and the complexity of multi-ingredient formulations. Diagnostic efforts rely heavily on the Roussel Uclaf Causality Assessment Method (RUCAM), with clinical presentations often nonspecific and dominated by hepatocellular patterns of injury. Epidemiological data demonstrate regional variation, with notably higher case numbers in Asia and the Americas. Mechanistically, HILI may result from either intrinsic (predictable, dose-dependent) or idiosyncratic (unpredictable, immune-mediated) reactions. Genetic predispositions, including certain HLA alleles, have been identified as risk factors. Hepatotoxicity is often linked to specific phytochemicals such as pyrrolizidine alkaloids, catechins, anthraquinones, and diterpenoids, which may contribute to oxidative stress, mitochondrial damage, or immune activation. Additionally, product inconsistencies and contamination complicate risk assessment and safety evaluation. Current management focuses on immediate discontinuation of the suspected product and supportive care, though severe cases may require liver transplantation. Future directions include the development of specific diagnostic tools, implementation of globally harmonized regulatory standards, improved pharmacovigilance systems, and enhanced public and professional education. Addressing these priorities is crucial for reducing HILI-related morbidity while supporting the safe use of herbal therapies.

ABSTRACTFood contamination poses a significant global health threat with carcinogenic potential, though the molecular pathways connecting contaminants to cancer remain poorly understood. This study sought to identify key molecular targets mediating the carcinogenic effects of nine prevalent dietary contaminants: glyphosate, perfluorooctane sulfonate, nitrosamines, pentabromodiphenyl ethers, methylmercury, dioxins, acrylamide, pyrrolizidine alkaloids, and aflatoxin. Using multiple online databases, we identified target genes associated with these contaminants and pan‐cancer, then conducted protein–protein interaction (PPI) analysis and visualization on intersecting genes. Subsequent gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) functional enrichment analyses were performed to uncover potential mechanisms, with a focus on breast (BRCA), prostate (PRAD), and colon (COAD) carcinomas due to their significant pathway associations. Hub genes were prioritized through an integrative strategy combining topological algorithms in cytoscape (Centiscape, MCODE, and cytohubba's MCC), machine learning validation, and weighted gene co‐expression network analysis (WGCNA). Molecular docking simulations were conducted to examine interactions between contaminants and hub genes. The study identified 69 pan‐cancer‐intersected targets, with enrichment analyses revealing significant cancer‐associated pathways. Hub gene prioritization pinpointed JUN in BRCA, CDC42 in COAD, and MAPK14 in PRAD as critical regulatory targets. Validation using The Cancer Genome Atlas (TCGA) data confirmed statistically significant differential expression patterns (p < 0.05) for these targets across respective malignancies. Gene set enrichment analysis (GSEA) outlined pathway activation profiles consistent with tumor progression mechanisms. Molecular docking simulations demonstrated strong binding affinities (binding energy ≤ −5.0 kcal/mol) between contaminants and structural domains of the identified hub targets, suggesting potential mechanistic links between these food contaminants and cancer development.

Jacobaeae Herba (from Jacobaea cannabifolia and Jacobaea litvinovii): A review of botany, traditional uses, phytochemistry, pharmacology, and toxicology.

Development of LC-MS method enabling full chromatographic separation of 36 pyrrolizidine alkaloids in plant-based matrices.

A HPLC-MS/MS method for the determination of Pyrrolizidine alkaloids (PAs) in green tea, orange pekoe tea, hibiscus flower, chamomile flower, and cardamom seed was developed and validated. Its precision, accuracy, linearity, specificity, LOQ, LOD, and ruggedness were validated following AOAC Guidance for Single Laboratory Validation Procedure. The recovery of the analytes is in a range of 70%–130%. LOQ for 21 PAs in the above botanicals is in a range of 0.8 to 6.5 ppb.

Worldwide, the genus Echium L. (Boraginaceae) is represented by over 60 species of herbaceous plants and shrubs. The species are widely distributed all around the Mediterranean basin, Europe, and the Macaronesian Islands and are known for their analgesic, diuretic, antioxidant, antimicrobial, and antitumor properties. In traditional medicine, they are widely used as a wound-healing and anti-inflammatory agent, for respiratory problems and problems related to mental health, and for general abrasions and fissures of the hands. Four species are naturally distributed in Bulgaria-E. russicum J.F. Gmel., E. vulgare L., E. italicum L., E. plantagineum L., the first three being medicinal. The review aims to summarize the literature describing the content of biologically active substances and the therapeutic effects of Echium spp., with an emphasis on medicinal species distributed in Bulgaria. The content of biologically active substances was monitored, in particular, terpenes, phenolic compounds, flavonoids, naphthoquinones, omega-3 and omega-6 fatty acids, and pyrrolizidine alkaloids. The relationship between bioactive compounds, biological activities, and medicinal uses was researched. After the analysis made in the present review, it can be summarized: Despite extensive research, knowledge of their pharmacological potential is still incomplete. An attempt has therefore been made to outline directions for future research.

The underexplored pulmonary toxicity of pyrrolizidine alkaloids: Emerging hazard from food contamination.