Space exploration introduces unique health challenges for astronauts, including musculoskeletal degradation, immune dysregulation, oxidative stress, and cardiovascular alterations, primarily due to microgravity and space radiation. Conventional solutions like synthetic drugs face limitations such as side effects and storage constraints during long missions. Phytomedicine, derived from plant bioactive compounds, offers a promising alternative to address these challenges through multitargeted therapeutic actions. However, most evidence on these plant-based interventions comes from terrestrial preclinical and clinical studies, with only sparse data from microgravity or space analog environments, so their relevance to spaceflight must be interpreted cautiously. This review article explores the potential integration of phytomedicine into space health protocols to enhance astronaut well-being and mission success. The review synthesized findings from diverse studies on the health effects of microgravity and the therapeutic potential of phytomedicines. Relevant literature was sourced from scientific databases notably Scopus and Web of Science (2012-2025). Key bioactive compounds and their mechanisms were evaluated in relation to space-relevant conditions and their feasibility for use in space environments, while noting that the vast majority of included studies were conducted under terrestrial conditions. The findings were synthesized to propose phytomedicine as a viable addition to astronaut healthcare protocols. Phytomedicines demonstrate significant potential in mitigating space-induced health issues. Resveratrol and curcumin support bone and muscle health, flavonoids and sterols enhance cardiovascular resilience, and compounds like Ginkgo biloba and ashwagandha provide neuroprotective and adaptogenic benefits. Phytomedicines' advantages include multitargeted actions, compact storage, and alignment with sustainable exploration goals, such as bioregenerative cultivation systems. These benefits, however, are inferred largely from Earth-based models and patient populations, and should therefore be viewed as preliminary indicators rather than space-validated countermeasures. Challenges like stability, integration with protocols, and standardization were also identified. Phytomedicine represents a transformative approach to astronaut healthcare, offering holistic and sustainable solutions to counteract the adverse effects of space travel including musculoskeletal loss, immune dysregulation, oxidative stress, and neurocognitive strain. While promising, its integration requires further research, development of space-specific formulations, and interdisciplinary collaboration. Addressing these gaps could revolutionize space medicine and support the success of long-duration space missions.
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Zanthoxylum zanthoxyloides is a medicinal plant employed in the production of phytomedicines in Burkina Faso, including FACA®, which is used for the treatment of sickle cell disease. A chemometric spectral-prediction approach was applied to classify Z. zanthoxyloides organ powders according to organ type, including leaves, stem bark, and roots. The characteristic FTIR spectral profile of Z. zanthoxyloides powders revealed spectral bands of interest between 800 and 1750 cm-1, enabling discrimination among the analyzed powders. A Partial Least Squares-Discriminant Analysis (PLS-DA) model was constructed using spectral data from 75 powder samples representing three plant organs, collected from three sites in Burkina Faso. The PLS-DA model, validated through ANOVA and permutation tests, demonstrated excellent performance, achieving 93.33% overall classification accuracy and an ROC-AUC exceeding 0.90 across the three organ classes. This statistical model enabled the determination of the botanical affiliation of 33 new plant powders by accurately assigning them to their respective organ classes of Z. zanthoxyloides. Chemical characterization of powders using their FTIR spectral profiles represents a green analytical approach contributing to the standardization of botanical raw materials. Integrating chemometric and multivariate data-analysis tools into raw-material quality-control routines will enhance the safety and reliability of locally produced phytomedicines.
Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited treatment options. While natural products offer a vast chemical space for drug discovery, the literature at the oncology-phytochemistry interface remains fragmented. This study provides a high-resolution bibliometric curation to map research trends and pharmacological hotspots in HCC therapy over the last decade. A systematic search was conducted via Scopus for studies published between 2015 and 2025. Following manual curation of 1477 eligible articles, VOSviewer and the Bibliometrix R-package were utilized for analysis. A distinctive feature was the integration of taxonomic validation and manual text mining to ensure high accuracy of botanical and phytochemical data. Our findings reveal an exponential growth in scientific production, led by China, the USA, and India. The editorial landscape spans over 400 journals and 90 publishers, such as Elsevier, Frontiers, MDPI and Wiley. Phytomedicine and Journal of Ethnopharmacology were the most prolific journals. We identified over 700 distinct phytochemicals, notably quercetin, curcumin, and resveratrol, and approximately 600 plant species. Thematic clustering demonstrated that these compounds modulate critical cellular events, including apoptosis, oxidative stress, cell-cycle checkpoints, epithelial-mesenquimal transition, and distinct but complementary signaling pathway, such as Bax-Bcl-2, PI3K/Akt, mTOR, VEGF, SIRT1/NRF2, MAPK/ERK, CHOP and GRP78, and also different classes of miRNAs. Nanotechnology-based delivery systems emerged as a major trend to overcome bioavailability challenges. This bibliometric curation provides a mapping of the field, identifying critical thematic transitions and current knowledge gaps. The systematic cataloging of authors, institutions, publishers, journals, and phytochemicals offers a foundation for prioritizing molecules in future trials, providing objective insights for drug discovery and potential novel targeted therapies for HCC.
Doxorubicin (Dox) is a highly effective chemotherapeutic agent, but its clinical use is limited by cumulative cardiotoxicity. Panax notoginseng, a traditional medicinal herb, exhibits well-documented cardioprotective properties; however, the therapeutic application of its bioactive constituents is constrained by poor bioavailability and potential toxicity. Plant-derived extracellular vesicles (EVs) have emerged as natural nanocarriers facilitating cross-kingdom delivery of bioactive metabolites. In this study, we investigated whether P. notoginseng-derived EVs (PEVs) could mitigate Dox-induced cardiotoxicity (DIC) and explored the underlying mechanisms. PEVs were isolated from P. notoginseng rhizomes and systematically characterized, with metabolite profiling performed by UPLC-MS. Cellular uptake, biodistribution, and cardioprotective effects were evaluated in Dox-injured cardiomyocytes and a chronic mouse model of DIC. Mechanistic insights were obtained using transcriptomic analysis, molecular docking, and biochemical assays. PEVs were stable nanosized vesicles enriched with characteristic P. notoginseng metabolites, including triterpenoid saponins and dencichine. PEVs were efficiently internalized by cardiomyocytes and preferentially accumulated in injured myocardium. Functionally, PEVs attenuated Dox-induced inflammation, apoptosis, myocardial atrophy, fibrosis, and cardiac dysfunction, with efficacy comparable to dexrazoxane. Mechanistically, transcriptomic and molecular analysis identified p53 as a central regulatory target. PEVs-derived metabolites targeted the p53 DNA-binding domain, suppressing p53 phosphorylation and transcriptional activation of pro-apoptotic and inflammatory genes. Notably, p53 activation attenuated PEVs-mediated protection, whereas p53 inhibition or silencing abolished additional protective effects, indicating a p53-dependent mechanism. PEVs protect against DIC by delivering bioactive metabolites to injured myocardium and inhibiting p53-driven oxidative, inflammatory, and apoptotic pathways, highlighting their potential as a phytomedicine-based cardioprotective strategy.
Diabetes mellitus is a chronic metabolic disorder characterised by hyperglycaemia due to insulin resistance and insufficient insulin production. Currently, multiple drugs exist for managing diabetes mellitus. However, the demand for herbal medicines is still required as the present treatments have a few challenges like toxicity, drug resistance and side effects. Therefore, in order to identify potent natural drug candidates, the NPASS database was selected for structure-based virtual screening. Lipinski's rule of five and PAINs removing filters were applied for pre-processing, prior to actual screening. Subsequently, filtered molecules were subjected to three modes of molecular docking, viz. HTVS, SP and XP, where the topmost 10%, 20% and 30% molecules were selected, respectively, followed by binding free energy calculations. Based on dock score evaluation and protein-ligand interaction analysis, the top five candidates were processed for ADME predictions along with the reference drug, sitagliptin. Out of which, two hits, NPC14706 and NPC319625, and Sitagliptin, showing respective ∆GMMGBSA values of - 49.53, - 50.93, and - 27.97 kcal/mol, respectively, with acceptable pharmacokinetic properties (ADME), were subjected to investigate MD simulation studies of about 100 ns. The MD results revealed that compound NPC14706 showed an average RMSD value of ~ 2.5 nm that remained stable throughout the trajectory, while compound NPC319625 exhibited an average RMSD value of ~ 2.9 nm with some fluctuations in between the trajectory. Therefore, the present study indicated that the lead compound NPC41706 could be further assessed for its potential inhibitory activity against the human DPP-IV enzyme through appropriate in-vitro, ADME and Phytomedicine studies for the management of diabetes mellitus.
When arsenic combines with oxygen, chlorine and sulfur, it forms inorganic arsenic compounds. Studies have found that exposure to inorganic arsenic can cause pathological cardiac hypertrophy. MK7 is a long-chain menaquinone with superior bioavailability and extended half-life compared to other vitamin K2 homologues. BCL2-related ovarian killer (BOK) belongs to the BCL2 family and regulates mitochondrial membrane permeability to determine whether to initiate apoptosis. Early growth response 3 (EGR3) is a type of transcription factor that can specifically recognize and bind to its downstream regulatory gene promoter region, thereby exerting transcriptional regulation. We investigated the underlying mechanism of MK7 as a prophylactic treatment for inorganic arsenic-induced pathological cardiac hypertrophy. Inorganic arsenic exposure caused pathological cardiac hypertrophy in mice. MK7 inhibited the increase of the surface area of mouse cardiomyocytes, apoptosis, the expression of ANP and BNP, and the abnormalities of myocardial enzyme spectrum and cardiac function caused by inorganic arsenic, which were reversed by BOK and EGR3 overexpression. CHIP and dual luciferase reporting system results demonstrated that BOK was the direct target gene of EGR3. MK7 alleviates inorganic arsenic-induced pathological cardiac hypertrophy by downregulating the EGR3-mediated transcriptional activation of BOK, thereby inhibiting the mitochondrial apoptosis pathway in cardiomyocytes.
Despite existing reports on the hepatoprotective effects of limonin (Lim), its specific impact on hepatic fibrosis and cellular senescence in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. The precise molecular mechanisms and direct targets underpinning its pharmacological activity are also poorly defined. This research aimed to investigate the therapeutic potential of Lim against MASH-related hepatic fibrosis and senescence, and to delineate the underlying molecular pathways. A murine MASH model was generated by feeding a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). To elucidate the mechanism of action of Lim, an integrated strategy was adopted, comprising AAV8-mediated gene manipulation, RNA sequencing (RNA-seq), and pharmacological interventions with agonists or inhibitors. The direct protein targets of Lim were identified using human proteome microarrays and validated through molecular docking, pull-down assays, and site-directed mutagenesis. Our findings indicate that Lim effectively alleviates hepatic fibrosis and senescence in MASH mice, while suppressing galectin-3 expression and mechanistic target of rapamycin complex 1 (mTORC1) activation. Notably, targeted knockdown of galectin-3 in the liver hindered aging-related changes in MASH mice, with mTORC1 functioning as a downstream effector. Further results revealed that mTORC1 acts as a key mediator of Lim's protective effects against hepatic fibrosis and senescence in MASH mice. Mechanistically, Lim binds to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3 (STAT3), inhibiting its activity and leading to reduced galectin-3 expression and mTORC1 activation. Moreover, the application of STAT3 inhibitor has been shown to alleviate hepatic fibrosis and senescence in MASH mice, further corroborating the suppression of galectin-3 and mTORC1 activity. In conclusion, our study provides compelling evidence for the efficacy of Lim in ameliorating hepatic senescence and fibrosis in MASH mice, elucidating the involvement of the STAT3/galectin-3/mTORC1 signaling in these processes.
Kaempferol has been shown to be beneficial in the treatment of Alzheimer's disease (AD) in animal models. However, the action mechanism remains unclear. AKR1B1 has been identified as a target of kaempferol, initially suggested by the Therapeutic Target Database, DrugBank, and PubChem, and subsequently confirmed through experimental validation. Kaempferol treatment facilitated the expression of AKR1B1 in PC12 cells exposed to Aβ1-42. Kaempferol treatment mitigated the Aβ1-42-induced increases in Fe2+, MDA, and lipid ROS and Aβ1-42-induced decreases in GSH synthesis and SOD activity. The reduction in ferroptosis-related proteins (GPX4, NQO1, SLC7A11, AKR1C1, and AKR1C3) and the inhibition of Nrf2 nuclear translocation and Nrf2/HO-1 signaling caused by Aβ1-42 were also reversed by kaempferol. Overexpressing AKR1B1 led to decreased levels of Fe2+, MDA, and lipid ROS, along with increased GSH synthesis and SOD activity in Aβ1-42-treated cells, although these effects were negated by Nrf2 inhibition. The upregulation of GPX4 and AKR1C3 by AKR1B1 overexpression was also reversed when Nrf2 expression was inhibited. Notably, silencing AKR1B1 counteracted the protective effects of kaempferol against Aβ1-42-induced neuronal ferroptosis. In vivo studies revealed that kaempferol improved cognitive impairments, reduced deposition of Aβ and p-Tau, and alleviated neuronal ferroptosis in the hippocampal tissues of an AD mouse model in a dose-dependent manner, effects that were diminished by inhibiting AKR1B1 expression. Following kaempferol treatment, the levels of GPX4 and AKR1C3 in the hippocampus of AD mice were found to be reduced. Overall, our findings indicate that kaempferol treatment enhances cognitive function and mitigates pathological alterations in AD mice by inhibiting neuronal ferroptosis through the activation of the Nrf2/HO-1/GPX4/AKR1C3 signaling via upregulation of AKR1B1. This research supports the need for further investigation and clinical exploration of kaempferol.
Reflux esophagitis involves esophageal inflammatory injury associated with mitochondrial dysfunction and apoptosis. The role of AMPK/FUNDC1-mediated mitophagy in this process remains unclear. This study investigated whether Chaihu Shugan San (CHSG) ameliorates reflux esophagitis by regulating AMPK/FUNDC1-dependent mitophagy and mitochondrial metabolism. We integrated in vivo rat models, in vitro cellular assays, network pharmacology, molecular docking, and AMPK genetic knockout models. CHSG was administered to esophagitis-induced rats to evaluate esophageal injury, inflammation, and mitochondrial function. Network pharmacology and docking analyses identified potential targets, followed by in vitro validation using AMPK siRNA and knockout mice. CHSG markedly attenuated inflammation, enhanced mitochondrial energy production, and promoted FUNDC1-mediated mitophagy while inhibiting apoptosis. AMPK was identified as a core target, and its genetic ablation abolished the protective effects of CHSG. CHSG mitigates reflux esophagitis through AMPK-driven activation of FUNDC1 mitophagy, restoration of mitochondrial function, and suppression of apoptosis, providing a mechanistic basis for its therapeutic application.
Mitochondrial cristae ultrastructure enables ATP synthase organization for adaptive energy production. This process is critical for regulating microglia mediated neuroinflammation in ischemic stroke pathology. However, therapeutic strategies targeting cristae remodeling remain unexplored. We identified a chemical probe, icariin II (ICS), which restores mitochondrial cristae by targeting triose phosphate isomerase 1 (TPI1). ICS-induced TPI1 conformational switching recruits ATP5MF to drive F1Fo-ATP synthase dimerization, thereby resulting in cardiolipin-mediated membrane curvature generation for cristae morphogenesis. Functionally, TPI1-targeted intervention reprograms microglial immunometabolism by rescuing oxidative phosphorylation, suppressing mtDNA-STING neuroinflammation, and promoting M2 polarization. In vivo, pharmacologically targeting TPI1 inhibits microglial activation to reverse the pathological processes in a middle cerebral artery occlusion rat model (male only). Further, evidence from stroke patients suggests an association between TPI1 and microglial activation. Collectively, our findings reveal that cristae plasticity is a promising therapeutic target for mitochondrial disorders, with TPI1 as a central regulator for ischemic stroke.
Aortic dissection (AD) is a fatal cardiovascular emergency for which effective pharmacological treatments are lacking. Increasing evidence suggests that spicy diets exert beneficial effects on cardiovascular diseases. However, whether a spicy diet can attenuate AD, and the mechanisms by which it might do so, remain unclear. This study was performed to investigate the role of dietary capsaicin in AD and to elucidate its underlying mechanisms. Fifty patients with AD (AD group) and 50 volunteers with risk factors for AD (NP group) were enrolled to examine associations among spicy food consumption, serum capsaicin levels, and AD. In addition, a β-aminopropionitrile-induced AD mouse model and a lipopolysaccharide-induced M1 macrophage polarisation model were established to investigate the impact of capsaicin on AD and elucidate its underlying mechanisms. Patients with AD exhibited lower spicy food consumption, reduced serum capsaicin concentrations, and gut microbiota dysbiosis compared with the NP group. Dietary capsaicin attenuated AD pathogenesis in mice, suppressed M1 macrophage polarisation, and restored gut microbiota homeostasis. Mechanistically, in vitro transcriptomic sequencing and small interfering RNA experiments demonstrated that capsaicin activates TRPV1 to suppress TLR4/MyD88/NF-κB signalling, thereby inhibiting M1 macrophage polarisation. Importantly, the TRPV1 antagonist capsazepine abrogated the protective effects of capsaicin in vivo, confirming TRPV1 dependence. These findings elucidate the mechanistic basis of the protective effects of dietary capsaicin against AD and provide the first evidence that dietary capsaicin attenuates AD by inhibiting M1 macrophage polarisation, an effect accompanied by the restoration of gut microbiota homeostasis and improved intestinal barrier function. Collectively, this work supports dietary capsaicin as a promising therapeutic strategy for AD.
Ovarian cancer remains a highly lethal gynecologic malignancy with limited responsiveness to immune checkpoint blockade and few well-tolerated strategies for improving antitumor immunity. Here, we developed a nanocrystalline berberine formulation (nanoBBR) using high-pressure homogenization and evaluated whether nanocrystal reformulation is associated with enhanced antitumor activity and improved responsiveness to programmed cell death protein 1 (PD-1) blockade. NanoBBR retained the crystalline structure of berberine and exhibited stable dispersion under the tested conditions. Across two-dimensional ovarian cancer cell models, three-dimensional human ovarian cancer organoids, and an immunocompetent intraperitoneal ID8-luc mouse model, nanoBBR showed greater inhibitory activity than conventional berberine (BBR). Transcriptomic analyses revealed immune-related pathway enrichment associated with nanoBBR treatment, including cytokine signaling and T cell receptor-related programs. In combination studies, nanoBBR plus anti-PD-1 antibody produced greater tumor suppression than either monotherapy, accompanied by increased intratumoral CD8⁺ T cell abundance and altered inflammatory and immune-related marker profiles. CXCL10 emerged as a prominently upregulated candidate chemokine in the combination group and showed spatial association with CD8⁺ T cell enrichment. These findings identify nanocrystalline berberine as a formulation strategy associated with enhanced antitumor activity and support further investigation of nanoBBR as a potential immunomodulatory adjunct to PD-1 blockade in ovarian cancer.
Liver fibrosis can be accelerated by oxidative stress and inflammatory damage. The effect of liquiritigenin (LQ) on ferroptosis in liver fibrosis is what this research intends to explore. Mouse models of liver fibrosis were created through intraperitoneal injection of carbon tetrachloride (CCl4) and silencing of NR1D1. Subsequently, RNA sequencing was employed to infer the liver fibrosis signaling network. 16S rRNA analysis was used to assess LQ's efficacy in improving liver fibrosis. AML12 cells were treated with LQ and H2O2/Erastin, and siRNA-NR1D1 was transfected into mouse primary hepatocytes in vivo. The interplay between NR1D1 and SLC7A11 promoter was investigated via dual-luciferase assay. Mouse bone marrow-derived macrophages (BMDMs) were treated with LPS/Erastin and LQ, and siRNA-NR1D1 was transfected into them. RNA sequencing indicated that in the mouse models induced by CCl₄, the NR1D1/ SLC7A11/ferroptosis/mitophagy pathway changed significantly, which was crucial for LQ-mediated hepatoprotection. LQ could effect on gut microbiota diversity and composition. After knocking down NR1D1 via shRNA, the protein and mRNA levels of SLC7A11 in mouse livers decreased significantly, and ferroptosis was exacerbated. The absence of NR1D1 in hepatocytes impaired the inhibitory effect of LQ on the SLC7A11-mediated ferroptosis pathway. It was shown that NR1D1 can directly bind to the SLC7A11 promoter. Moreover, LQ can reduce ferroptosis in BMDMs, thereby diminishing the inflammatory response. These findings suggest that LQ can inhibit ferroptosis by modulating the NR1D1-SLC7A11 signaling pathway in liver fibrosis. LQ represents a promising therapeutic candidate and its mechanism offers a novel strategy for treating liver fibrosis.
Pulmonary fibrosis (PF) is a progressive and fatal disease with limited therapies. Anemoside B4 (AB4), an oleanane-type pentacyclic triterpenoid saponin isolated from the roots of Pulsatilla chinensis (Bunge) Regel, exhibits anti-inflammatory and anti-apoptotic activities, yet its mechanisms of action in PF have yet to be elucidated. This study aimed to define the protective effects of AB4 against PF, focusing on the Keap1/Nrf2 axis, NLRP3-mediated pyroptosis, and epithelial-mesenchymal transition (EMT). A bleomycin (BLM)-induced PF model was established in wild-type and Nlrp3-/- mice. AB4's efficacy was evaluated through pulmonary function, histology, and biochemical assays. Bulk RNA-seq, scRNA-seq, molecular docking, Co-IP, CETSA, and nuclear-cytoplasmic fractionation were utilized to dissect mechanisms. Key pathways were validated with HO-1and NLRP3 inhibitors ZnPP and MCC950, respectively. AB4 ameliorated weight loss, improved lung function, and reduced collagen deposition in the BLM challenge. It directly bound Keap1, disrupting the Keap1-Nrf2 complex and promoting Nrf2 nuclear translocation, which upregulated HO-1 and attenuated oxidative stress. AB4 subsequently inhibited NLRP3 inflammasome activation and pyroptosis. Single-cell analysis confirmed suppression of EMT. AB4's anti-fibrotic effect depended on HO-1 activity and was phenocopied in Nlrp3-deficient mice. This study first identifies AB4 as a preventive, rather than therapeutic, agent against PF. AB4 targets Keap1 to activate Nrf2-driven antioxidant responses, inhibits NLRP3-dependent pyroptosis, and attenuates secretome-driven EMT. AB4 thus presents a novel, mechanism-based candidate for clinical translation, specifically for the prevention or early intervention of progressive PF.
Asthma, as a persistent inflammatory airway disease, constitutes a significant burden in the field of global public health. Fritillaria Bulbus is a traditional Chinese medicine with efficacy in treating coughs, dissolving phlegm, and alleviating asthma. Sipeimine (SIP) is one of its isosteroidal alkaloids, has demonstrated antitussive, anti-inflammatory, and pulmonary protective effects. Nevertheless, the efficacy of SIP in asthma and its potential mechanisms have not yet been fully clarified. The research seeks to investigate the therapeutic potential and action mechanism of SIP for asthma using a comprehensive multi-omics strategy. The asthma rat model was induced using ovalbumin. Subsequently, SIP was administered orally for 14 consecutive days. Biochemical assays and pulmonary histopathological examinations assessed anti-asthmatic efficacy. An integrated strategy combining metabolomics, 16S rRNA sequencing, and transcriptomics was employed to identify potential mechanisms underlying SIP treatment in asthma. Real-time quantitative PCR and western blotting were used to validate key genes and proteins. SIP significantly alleviated histological damage in lung tissue, including inflammation, collagen deposition, and mucus secretion. Metabolomics analysis indicated that SIP normalized metabolite profiles and modulated pathways associated with ferroptosis. Additionally, SIP improved gut microbiota dysbiosis by restoring Lactobacillus abundance, reducing the richness of Muribaculaceae, Romboutsia, and Clostridium_sensu_stricto_1 genera. Transcriptomic analysis revealed that SIP ameliorated asthma by suppressing the IL-17 signaling pathway. SIP exhibits significant therapeutic effects against asthma, potentially by reducing inflammation, altering gut microbiota and metabolites, and inhibiting ferroptosis and IL-17 signaling.
Allergic contact dermatitis (ACD) is an immunological disorder elicited by antigen exposure, which activates the immune system and leads to T cell-mediated inflammation. This study aimed to investigate the role of Xiao-Feng Powder (XFP)-loaded thermosensitive composite hydrogel in alleviating ACD and elucidated its underlying mechanisms in HaCaT cell induced by TNFα/IFNγ. SADBE-induced ACD mouse and TNFα/IFNγ-induced damage to HaCaT cells were established. CFB expression was knocked down in HaCaT cells via shRNA plasmid transfection. UPLC-MS was employed to analyze the chemical composition of the TCM compound XFP. The composite F127-PEG200/XFP@SA-GEL-PVP was prepared by encapsulating XFP in microspheres via a blend of sodium alginate (SA), gelatin (GEL), and polyvinylpyrrolidone (PVP), followed by their integration into a hydrogel matrix of Pluronic F127 (F127) and PEG200. Scratching behavior, skin fold thickness, spleen-thymus index, histological analysis, photoacoustic imaging system were used to evaluate the effect of F127-PEG200/XFP@SA-GEL-PVP. Finally, expression levels of CFB, RANKL, IL4, IL13, TSLP, and IL25 were analyzed by immunohistochemistry and western blot. CFB regulates Th2-type cytokine expression via C3 in the TNFα/IFNγ-induced HaCaT cells. F127-PEG200/XFP@SA-GEL-PVP exhibited stable physicochemical properties and favorable biocompatibility. Treatment with F127-PEG200/XFP@SA-GEL-PVP significantly reduced scratching behavior, skin fold thickening, and inflammatory infiltration in ACD mice, inhibited mast cell degranulation, restored vascular morphology and local blood flow in skin and spleen tissues, and downregulated the expression levels of Th2-type cytokines (IL4, IL13, TSLP) and pro-inflammatory mediators (CFB, RANKL, IL25). These findings demonstrate that F127-PEG200/XFP@SA-GEL-PVP exerts protective effects in ACD. Silencing CFB restored HaCaT cell viability after TNFα/IFNγ treatment and the modulation of the C3 pathway reduced Th2-type cytokine expression.
Ischemic stroke remains a lethal disease with high morbidity and disability, yet effective therapeutic options for chronic recovery are still limited. Angiogenesis facilitates post-stroke blood supply restoration by reconstructing vascular networks, which helps rescue the penumbra and recover neurological function. Rhodiosin is a bioactive compound derived from rhodiola crenulata, exhibiting multiple pharmacological activities. However, whether rhodiosin exerts protective effects by promoting angiogenesis after stroke, as well as the underlying mechanisms, remains unclear. This study aimed to investigate whether rhodiosin promotes cerebral angiogenesis and neurological functional recovery after stroke, and to explore the underlying mechanisms. Stroke was induced in mice by distal middle cerebral artery occlusion (dMCAO). Rhodiosin was administered intraperitoneally daily post-surgery. Therapeutic efficacy was assessed based on neurological deficits and infarct volume. Microvascular density and pericyte/astrocyte coverage were evaluated using immunofluorescence staining. Cerebral blood flow (CBF) was monitored by laser speckle imaging. Two-photon microscopy was employed to measure dynamic changes in cerebrovascular diameter and density. RNA sequencing was performed to identify rhodiosin-associated pathways. PI3K/Akt pathway factors were examined by Western blot and qRT-PCR. The human cerebral microvascular endothelial cells (hCMEC/D3) were utilized to explore the underlying mechanisms in vitro. Rhodiosin enhanced neurological recovery and reduced infarct volume post-stroke. It improved CBF and increased vascular diameter and density in the penumbra. It also promoted angiogenesis by increasing BrdU⁺/CD31⁺ cells and enhancing pericyte/astrocyte coverage around microvessels. Moreover, rhodiosin facilitated endothelial cell migration and tube formation under OGD conditions. Rhodiosin upregulated PI3K/Akt phosphorylation and the expression of their downstream targets (HIF-1α, Ang1, VEGF). These effects were partially or fully reversed by PI3K/Akt inhibition (LY294002/MK-2206 in vivo, shRNA transfection in vitro). Integrating RNA-seq with experimental validation, we confirmed that activation of PI3K/Akt mediates rhodiosin's pro-angiogenic effect. Rhodiosin promotes neurological recovery post-stroke by enhancing cerebral angiogenesis via PI3K/Akt pathway activation, highlighting its potential as a therapeutic candidate for ischemic stroke during the subacute/chronic recovery phase.
Hyperhomocysteinemia (HHcy) is characterized by disrupted methionine and one-carbon metabolism. Although epigallocatechin gallate (EGCG) can lower homocysteine levels, how it regulates methionine metabolism in vivo, especially at the intestinal level, remains unclear. This study aimed to determine whether EGCG alleviates HHcy by modulating methionine availability. An HHcy model was established in Drosophila melanogaster using a high-methionine diet. The effects of tea extracts and catechins were first evaluated using metabolic and physiological indicators. Methionine metabolism and N-EGCG formation were then characterized using targeted metabolomics and LC-MS/MS. Finally, transcriptomic and epigenetic analyses were performed to examine downstream regulatory changes. Green tea, which contains the highest EGCG level, showed the strongest protection against HHcy. EGCG significantly improved HHcy phenotypes in a dose-dependent manner. It reduced homocysteine levels by approximately 55%. This indicates a strong effect on methionine metabolism. It also significantly extended lifespan. Importantly, EGCG reduced intestinal methionine levels by approximately 58% and promoted the formation of N-EGCG in vivo. These changes were accompanied by recovery of metabolic pathways. Transcriptional and epigenetic patterns were also normalized. EGCG alleviates HHcy by limiting intestinal methionine availability and restoring one-carbon metabolism. This study reveals a gut associated metabolic mechanism. It links dietary polyphenols to systemic metabolic regulation. It also highlights a potential target for dietary intervention of HHcy.
Colorectal cancer (CRC) remains a significant clinical challenge, with progression largely driven by tumor microenvironment (TME) remodeling. Cancer-associated fibroblasts (CAFs), key stromal components, promote CRC progression and metastasis via paracrine signaling. Solanum nigrum L. (SNL), a traditional medicinal plant rich in steroidal glycoalkaloids, is recognized for its health-promoting potential. This study aimed to systematically investigate the bioactive chemical constituents of an aqueous SNL extract, evaluate its biological effects in multiple CRC models, and link the extract's chemical profile to its functional outcomes, focusing on elucidating its anti-metastatic molecular mechanisms. We evaluated the in vivo efficacy of SNL in subcutaneous xenograft, APCMin/+, and experimental metastasis models. Phytochemical analysis identified its major active components. By integrating single-cell RNA sequencing (scRNA-seq) of human CRC with TMT-based proteomics of CRC cells, we identified and validated key molecular targets of SNL. We employed drug-target interaction assays, genetic modulation, and molecular analyses to elucidate its mechanism of action. SNL markedly inhibited tumor growth and lung/liver metastasis in vivo. Phytochemical analysis identified solasonine and solamargine as the major glycoalkaloids responsible for the biological activity. Multi-omics analysis identified Annexin A2 (ANXA2) as a key SNL-regulated target. Mechanistically, SNL disrupted CAF-induced signaling, reversed epithelial-mesenchymal transition (EMT), and suppressed invasion by modulating the STAT3-ANXA2-Cortactin axis. While SNL did not bind ANXA2 directly, its active components, solasonine and solamargine, directly interacted with STAT3, blocking its phosphorylation and nuclear translocation, thus repressing ANXA2 transcription. Reduced ANXA2 levels prevented the ANXA2-Cortactin complex formation and inhibited Src/Cortactin phosphorylation, thereby impairing cytoskeletal remodeling and cell motility. Genetic modulation confirmed ANXA2 as a functional mediator of SNL's anti-metastatic effects. These findings provide molecular evidence supporting SNL as a source of multifunctional bioactives capable of reshaping the tumor microenvironment and highlight its potential as a plant-derived therapeutic candidate for metastatic colorectal cancer.