Wound healing is a complex biological process involving inflammation, hemostasis, and tissue regeneration, and its impairment may delay recovery and lead to clinical complications. Medicinal plants have long been used in traditional medicine to support wound repair and control bleeding. Among these, Symphytum officinale L. (comfrey) is widely used in European traditional medicine for the treatment of wounds, fractures, and soft tissue injuries. However, the pharmacological basis of these effects and the contribution of different plant organs remain insufficiently understood. The aim of this study was to characterize the phytochemical composition of extracts obtained from different organs of S. officinale and to evaluate their hemostatic and wound-healing activities in vivo, in order to identify the most active plant parts. Extracts from the roots, leaves, and flowers of S. officinale were prepared using solvents of different polarity. Phytochemical composition was analyzed by spectrophotometric assays and UPLC-MS/MS. Hemostatic and wound-healing activities were evaluated in vivo in rats, and cytological analysis of wound exudate was performed. Distinct organ-specific differences in phytochemical composition were observed, with leaf and flower extracts richer in phenolic compounds and amino acids, while root extracts contained higher levels of pyrrolizidine alkaloids. Leaf (S7) and flower (S13) extracts showed the strongest biological activity. S13 accelerated wound healing, achieving complete wound closure by day 10 compared with day 12 in the reference group, while S7 exhibited the most pronounced hemostatic effect, reducing bleeding cessation time to 44.3 s compared with 64.1 s for the reference preparation and 144.3 s for the control group. Cytological analysis indicated reduced inflammation and enhanced fibroblast activity. The findings support the traditional use of S. officinale in wound treatment and highlight the importance of organ-specific phytochemical composition. Aerial parts showed strong wound-healing and hemostatic effects, suggesting their relevance alongside the traditionally used root and supporting the involvement of multiple constituents in the observed biological activity. The study provides new insights into the organ-specific phytochemical composition and biological activity of S. officinale, thereby supporting further research on the therapeutic potential of its aerial parts.

Symphytum officinale: L. (S. officinale), commonly known as comfrey, has been used in traditional medicine for over 2,000 years to treat wounds, fractures, and inflammatory conditions. This review is the first comprehensive ethnopharmacological synthesis that systematically integrates cross-cultural traditional knowledge with the latest evidence on its phytochemical profile, pharmacological mechanisms, clinical efficacy, and toxicological risks. Unlike previous fragmented reviews that addressed only isolated aspects, we followed PRISMA guidelines to analyze selected studies, with a strong emphasis on developing safe, pyrrolizidine alkaloid (PA)-depleted topical formulations that translate the plant's classic "knitbone" reputation into modern evidence-based phytotherapy. Key bioactive constituents-allantoin, rosmarinic acid, polysaccharides, and lignans-exert anti-inflammatory, tissue-regenerative, and bone-repair effects primarily by inhibiting NF-κB and MAPK pathways and suppressing pro-inflammatory cytokines. Randomized controlled trials demonstrate that topical S. officinale preparations significantly outperform placebo in acute back pain, knee osteoarthritis, ankle sprains, and myalgia, while showing non-inferiority to diclofenac and an excellent safety profile. However, the presence of hepatotoxic PAs (intermedine and lycopsamine) strictly limits internal use. Topical application remains safe owing to minimal systemic absorption. By bridging historical wisdom with rigorous contemporary data and spotlighting PA-depletion strategies, this review offers a balanced framework for safe clinical application and future formulation optimization.

Comfrey (Symphytum officinale L.) was a promising crop in the integrated crop-livestock pattern. However, the impact of long-term irrigation with treated poultry wastewater (TPW) on soil chemical properties and bacterial community, as well as the contribution of comfrey to mitigate N accumulation in soil, remain unclear. This study investigated the changes in chemical and microbiological characteristics of the comfrey soil under six-year TPW irrigation (grassland) in comparison with the adjacent conventional crop soil irrigated with freshwater (farmland). Results showed that N accumulation in comfrey accounted for 66.0% of the N input from TPW irrigation. In grassland, soil pH at all depths increased by one unit and EC in the subsoil increased by 33.5-42.4%, while TN and NO3--N in the surface soil decreased by 26.7% and 64.5%, respectively. The composition and structure of the bacterial community in the grassland dramatically changed, and the relative abundances of nitrite-oxidizing bacteria Nitrospira and ammonifying bacterium Flavobacterium and Pseudomonas increased by 0.1-3.6-, 3.8-11.0- and 0.1-6.0-fold, respectively, while those of saline-alkali-sensitive bacteria Sphingomonas decreased by 72.3-83.2% in the subsoil. Soil pH and NO3--N were the primary factors influencing changes in bacterial communities. These findings revealed that there was no nitrogen accumulation, but alkalization occurred in the comfrey field under long-term TPW irrigation, which highlighted the prospective application of comfrey in the crop-livestock system.

Symphytum officinale L. (Boraginaceae) is a plant with proven anti-inflammatory and analgesic activity on the musculoskeletal system. The traditional use of comfrey primarily refers to its roots, although some literature also mentions the leaves as an alternative plant material. Comparing the therapeutic potential of both plant materials requires additional data on the chemical composition of S. officinale leaves and their biological properties. The aim of the study was to analyze polyphenols in comfrey leaves of different origins and to assess their antioxidant and anti-inflammatory potential against comfrey roots, also collected from different sources. Polyphenol profiles were recognized by 2D TLC and HPLC-DAD-ESI-MS methods, and quantitative analysis was performed by the HPLC-UV/Vis (high performance liquid chromatograph with-ultraviolet/visible detection) method. The antioxidant activity was assessed using DPPH (2,2-diphenyl-1-picrylhydrazyl), FRAP (ferric reducing antioxidant power), and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline- 6-sulfonic acid) diammonium salt) assays, and for leaves also using the TLC-DB (thin layer chromatography-direct bioautography) technique with the DPPH radical. Chemometric analysis to assess the relationship between the antioxidant activity and the origin of comfrey plant raw materials was performed. Factor analysis (FA) confirmed that geographic origin and cultivation conditions influenced the antioxidant content of both plant raw materials. The study results indicate that comfrey leaves can substitute for comfrey roots containing not only caffeic acid derivatives but also flavonoids, and exhibiting stronger antioxidant activity.

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.

This dataset presents flower visitation frequency, pollinator richness, and direct measures of pollination success for four focal plant species from a field experiment in 24 home gardens in the city of Zurich, Switzerland. The home gardens were selected to vary independently in local flowering species richness and the proportion of impervious surface in a 500-m radius around the garden, a common proxy for urban intensity and associated habitat loss. We used a phytometer species approach with the following four insect-pollinated plant species: wild carrot (Daucus carota L.), radish (Raphanus sativus L.), common sainfoin (Onobrychis viciifolia Scop.) and common comfrey (Symphytum officinale L.). We provide the species richness and hourly visitation frequency of 167 flower visitor taxa across multiple taxonomic groups (bees, wasps, beetles, and hoverflies) from multiple sampling dates across the full flowering period of the phytometer species. We collected and identified 5,794 individuals, of which the vast majority (99.5%) were identified to the species or genus level. We provide several functional trait measurements at the individual level. For bees, we measured intertegular distance and proboscis length (the combined lengths of prementum and glossa); for the other taxa, we measured forewing length and the lengths of the labellum, prementum, and fulcrum. We additionally provide seed and/or fruit set, a direct measure of reproductive success for all phytometer plants. Further datasets for these gardens exist, linking soil and soil arthropod diversity data, bird predation data, and plant diversity and properties sampled during the same period. This dataset enables further investigations into the composition of novel anthropogenic pollinator communities, such as analyses comparing multiple cities. The fine temporal resolution of flower visitor frequency additionally provides the opportunity to conduct time series analyses of diurnal pollinator communities across environmental gradients.

Although some studies have investigated the accumulation of radionuclides in honey, other bee products such as wax and bee bread remain insufficiently studied, particularly in terms of seasonal and intra-seasonal dynamics. Spatial patterns of contamination within the foraging area of honey bees, as well as the role of botanical composition of nectar sources, also remain poorly understood. This study examines the dynamics of [137]Cs and [40]K accumulation along the pathway plant-bee-bee product on radioactively contaminated territories in the Bryansk Region during different periods of the honey flow. The results are compared with data collected at low-contamination sites in the Rostov Region. Samples of honey, capping wax, and nectariferous plants were collected in the villages of Vereshchaki and Katichi (Bryansk Region), as well as in the stanitsa of Vyoshenskaya (Rostov Region). The equivalent gamma-dose rate was also measured in the vicinity of the Bryansk apiaries. The activity concentrations of [137]Cs and [40]K in plants and bee products were determined using gamma spectrometry. Statistically significant differences in the activity concentration of [137]Cs in honey samples from the Bryansk and Rostov regions were identified during different phases of the honey flow. In honey collected from contaminated areas (soil contamination density of [137]Cs ranging from 185 to 555 kBq/m[2]), the mean activity concentration of [137]Cs was 44 ± 24 Bq/kg (range: 21-89 Bq/kg), significantly exceeding that of the control group. In capping wax, the mean activity concentration reached 56 ± 33 Bq/kg (range: 29-115 Bq/kg). Pollen analysis and direct foraging tracking linked notably elevated [137]Cs activity concentrations in honey to nectar from Brassica spp. (rapeseed, field mustard), Phacelia tanacetifolia, Melilotus spp. (white/yellow sweet clover), Trifolium spp. (white/yellow clover), Centaurea spp. (cornflower, false-phrygian knapweed), Symphytum officinale (common comfrey), Filipendula ulmaria (meadowsweet), Calluna vulgaris (common heather), and Solidago virgaurea (European goldenrod), indicating the species-specific ability of these plants to accumulate radiocaesium and their potential as bioindicators of localized contamination hotspots. No statistically significant differences in the activity concentrations of [40]K in honey were observed between the regions. Higher variability and greater accumulation of radionuclides were found in capping wax compared to honey, likely due to biophysical filtration processes and differences in the physicochemical properties of honey and wax matrices. Transfer factors for [137]Cs and [40]K along the pathway nectariferous plant-honey/wax were calculated. For [137]Cs, arithmetic mean activity concentrations were used in the control group (homogeneous contamination), while weighted means were applied in the experimental groups (heterogeneous contamination) to account for spatial variability. A marked difference was found in [137]Cs concentrations in plants between the experimental groups (237 Bq/kg) and the control group (45 Bq/kg), while the transfer factors for [137]Cs remained consistent: 0.16-0.19 for honey and 0.24-0.44 for wax, suggesting the stability of these indicators under varying contamination conditions. The weighting of plant sample contributions was based on a digital area estimation of bee foraging zones, using pixel-wise analysis of masked regions on satellite imagery. Transfer factors for [40]K were calculated using pooled samples due to its uniform distribution across all settlements, yielding values of 0.05 for honey and 0.19 for wax. Partitioning analysis in a modern hive system was conducted, reflecting the mass-based distribution of radionuclides within the trophic system of honey bees. These results advance understanding of radionuclide distribution in agroecosystems and confirm the effectiveness of using honey bees and bee products as bioindicators of radioactive contamination across territories with both high and low contamination densities.

Diabetic foot ulcers (DFUs) exhibit impaired healing due to disrupted macrophage polarization, wherein persistent hyperglycemia inhibits the critical M1-to-M2 phenotypic transition, sustaining a pro-inflammatory microenvironment. This investigation elucidates the therapeutic potential of L-shikonin (L-SK), a bioactive phytochemical derived from comfrey with established immunomodulatory properties. In a streptozotocin-induced diabetic murine model, L-SK treatment significantly enhanced wound closure through coordinated anti-inflammatory effects (downregulation of CD86 and tumor necrosis factor-α) and pro-regenerative outcomes (increased collagen deposition and CD31-mediated angiogenesis). At the molecular level, L-SK administration facilitated macrophage polarization towards the regenerative M2 phenotype (upregulated CD163 expression) while activating the pivotal Janus Kinase/phosphatidylinositol-3-kinase/protein kinase B/vascular endothelial growth factor (JAK/PI3K/AKT/VEGF) signaling cascade, as evidenced by enhanced phosphorylation of AKT and PI3K alongside elevated VEGF production. Complementary in vitro studies using human monocytic leukemia cells-derived macrophages confirmed these mechanistic findings, demonstrating consistent modulation of macrophage differentiation markers and secretory profiles. These results position L-SK as a multifaceted therapeutic agent capable of concurrently addressing the immunological and vascular deficiencies characteristic of DFUs, through its dual capacity for macrophage phenotype reprogramming and angiogenic pathway activation. The study provides compelling preclinical evidence for L-SK's potential application in diabetic wound management strategies.

Comfrey (Symphytum officinale L.) is a traditional medicinal plant, and its growth period has an important effect on the accumulation of active components. Phenolic acids and flavonoids are the most important active components in comfrey, but their accumulation in comfrey has not been studied. At present, most research on comfrey focuses on its roots. There is still a lack of systematic research on the comparison of active components and biological activities in the aerial parts of comfrey in different growth periods. To explore the influence of the growth period on the active components of comfrey, non-targeted metabolomics and transcriptomics were used to comprehensively analyze the active components of comfrey during the vegetative period, blooming period, and maturity period and compare the dynamic changes in phenolic acid and flavonoid accumulation during different growth periods of comfrey. The results revealed that the vegetative period presented the highest total phenol and flavonoid contents. The predominant secondary metabolites associated with phenolic acids and flavonoids were integral to the phenylpropanoid, flavonoid, and isoflavonoid biosynthetic pathways. Critical structural genes governing these metabolic processes-PAL, C4H, 4CL, CHS, FLS, and DFR-exhibited marked upregulation during the vegetative growth stage. Comprehensive transcriptomic analysis and weighted gene co-expression network analysis were used to construct a co-expression network of structural genes and transcription factors that affected the accumulation of specific metabolites, and the transcription factors related to the synthesis of flavonoids and phenols were predicted. These findings elucidate the temporal regulatory mechanisms governing the growth-phase-dependent accumulation of bioactive constituents in comfrey, advancing the understanding of phytochemical dynamics in medicinal plants.

This study investigated the influences of comfrey (Symphytum officinale L.) polysaccharides (CPs) in the diet of laying hens on the oxidation stability and fatty acid composition of the egg yolks based on metagenomic and metabolomics techniques. Dietary CPs improved the total phenolic content in fresh and stored eggs. The activity of superoxide dismutase was increased, and the content of malondialdehyde was reduced in the stored eggs of the 1.0 % group of CPs. Dietary supplementation with 1.0 % CPs increased some polyunsaturated fatty acid (PUFA) contents in stored egg yolk, including dihomo-γ-linolenic acid (C20:3n6), arachidonic acid (C20:4n6), and docosahexaenoic acid (C22:6n3). The abundances of Methanobrevibacter, Parabacteroides, and Merdibacter in the caecum were increased in the 1.0 % group of CPs. The content of melatonin was increased, and the contents of palmitic acid and myristic acid in the caecum were decreased by CPs. These results suggested that CPs could improve the antioxidant status and fatty acid composition of egg yolks.

Pyrrolizidine alkaloids (PAs) are toxic specialized metabolites found in several plant lineages with independent evolutionary origins. In comfrey (Symphytum officinale), two independent homospermidine oxidase (HSO) paralogs are responsible for oxidation of homospermidine (Hspd) to the bicyclic pyrrolizidine in roots and young leaves. As PA biosynthesis in S. officinale and Heliotropium indicum (Indian heliotrope) share a common ancestor, we tested whether H. indicum is also able to synthesize PAs, not only in aerial parts but also in roots. H. indicum constitutively synthesizes not only complex PAs, in aerial parts but also simple PAs in roots. Of five copper-containing amine oxidases (CuAOs) identified in H. indicum, three have the ability to convert Hspd to the bicyclic pyrrolizidine in vitro. CRISPR/Cas9 genome editing confirmed that, in planta, only one of these CuAOs is involved in PA biosynthesis in roots, which is identical to the HSO involved in PA biosynthesis in leaves. PA biosynthesis in roots is less efficient than in aerial parts, an observation that allowed the analysis of various pathway intermediates using tracer feeding experiments. The CuAO phylogeny, together with comparative gene structure analyses, suggest a common evolutionary origin of PA-producing CuAOs. However, independent scenarios of PA metabolism were observed in Indian heliotrope and comfrey, adding a further aspect of diversity in the regulation of PA biosynthesis.

In the context of the increasingly serious soil heavy metal pollution， delving deeply into the response mechanisms of plants to heavy metals and their remediation potential is of great significance for the restoration of the ecological environment. This study investigated Symphytum officinale L. via hydroponic pot experiments under single and combined stresses of lead （Pb）， zinc （Zn）， and cadmium （Cd） with different concentration gradients. Through a systematic analysis of growth indicators， antioxidant enzyme activities （superoxide dismutase [SOD]， catalase [CAT]， peroxidase [POD]）， malondialdehyde （MDA） and proline （Pro） contents， as well as heavy metal accumulation patterns， we comprehensively clarified the stress response and accumulation characteristics of comfrey under heavy metal exposure. The results demonstrated that heavy metal stress exerts a significant influence on the growth of Symphytum officinale L.. Its biomass， leaf length， leaf width， and stem length are negatively correlated with the stress concentration， and the inhibitory effect of combined stress is more pronounced. Nevertheless， Symphytum officinale L. shows good tolerance to both single and combined stresses. Only the degree of root inhibition varies according to the type and concentration of heavy metals. At the physiological and biochemical levels， heavy metal stress inhibits the synthesis of chlorophyll and has complex effects on the activities of antioxidant enzymes such as SOD， POD， and CAT， as well as the contents of MDA and Pro. Compared with single stress， combined stress generally has a more intense inhibitory effect on enzyme activities. Under different heavy-metal stresses， each indicator presents different changing trends. Regarding accumulation capacity， the absorption and enrichment amounts of Pb， Zn， and Cd by Symphytum officinale L. increase significantly with the increase of stress concentration. The enrichment amount in roots is significantly higher than that in the aboveground counterparts， and the enrichment ability under single stress is stronger than that under combined stress. Although its transfer effect on heavy metals is not ideal， its enrichment ability far exceeds that of common plants. It has certain tolerance and detoxification abilities and is an excellent germplasm resource for remediating heavy - metal - polluted soil. This study provides crucial support for the application of Symphytum officinale L. in the remediation of polluted soil and the research on related mechanisms.