Phytomedicine最新文献

Background: Liver fibrosis represents a dynamically reversible pathological process arising as an adaptive repair response to chronic hepatic insults. Scoparone (SCO), an active constituent of artemisia, has demonstrated therapeutic potential across diverse liver diseases, but its antifibrotic mechanism remains unclear.

Purpose: This study aims to elucidate the molecular mechanism by which SCO ameliorates liver fibrosis through m⁶A epitranscriptomic regulation of hepatic stellate cell (HSC) ferroptosis.

Methods: Murine liver fibrosis models and human HSC cells were employed to evaluate the therapeutic effects of SCO on liver fibrosis. Single-cell sequencing, spatial transcriptome sequencing, transcriptome sequencing, immunoprecipitation and laser confocal were used to investigate the potential molecular mechanisms.

Results: Animal experiments and cellular studies showed that SCO exhibited potent antifibrotic effects, which was attributed to the induction of HSC ferroptosis through m⁶A modification. Integrative transcriptomic and bioinformatic analyses identified BECN1 as a key target for m⁶A methylation regulation of ferroptosis. Mechanistically, SCO may interact with the ASN462 residue of YTHDF2, enhancing its protein stability and expression. Elevated YTHDF2 can facilitate translation of BECN1 mRNA by recognizing m⁶A methylation at the A100 site within the 5'-UTR, leading to SLC7A11 activity inhibition and subsequent ferroptotic cell death in HSCs. Clinically, YTHDF2 and BECN1 expression was downregulated in fibrotic liver tissue specimens, which was associated with a poor prognosis.

Conclusions: These results reveal a novel epitranscriptomic mechanism by which SCO induces HSC ferroptosis to attenuate liver fibrosis by promoting the formation of BECN1-SLC7A11 complex through YTHDF2-mediated m⁶A modification. Thess findings molecular insights and therapeutic rationales for SCO-based antifibrotic therapies.

Background: Obesity-induced adipose tissue expansion is characterized by capillary rarefaction and hypoxia, which disrupts angiogenesis and impairs beige adipogenesis. While angiogenesis is known to be crucial for beiging, the functional link between impaired vascularization and defective browning remains poorly understood. How natural compounds like berberine (BBR) links angiogenesis with beige adipogenesis remains unexplored.

Methods: Using both diet-induced obese (DIO) C57BL/6 J and leptin-deficient (ob/ob) murine models, we administered intraperitoneal BBR for 4 weeks. Adipose tissue remodeling was evaluated through histomorphometry, immunofluorescence, and flow cytometry. RNA sequencing of adipose tissue was performed to identify the potential targets. Chemical hypoxia was induced using CoCl₂ in preadipocytes to examine its effects on browning.

Results: BBR improved adipose tissue dysfunction in both the DIO model and the ob/ob model. It increased CD34⁺CD31⁺ endothelial progenitor cells and enhanced protein levels of VEGF/VEGFR2, PRDM16, PPAR-γ, and UCP-1, indicating simultaneous promotion of angiogenesis and adipose browning. Transcriptomic analysis revealed glutathione peroxidase 3 (GPx3) as a novel target through which BBR alleviates adipose dysfunction. GPX3 knockdown in vivo impaired angiogenesis and suppressed browning markers. BBR reversed chemical hypoxia-induced impairment of beige adipocyte differentiation independently of UCP-1 upregulation by inhibiting HIF-1α activation.

Conclusions: This study unveils that BBR counteracts obesity-associated adipose tissue dysfunction: it upregulates GPx3 to reduce oxidative stress, which in turn normalizes HIF-1α levels and activates the PRDM16 signaling, thereby concurrently restoring adipose angiogenesis and promoting beige adipogenesis. This breaks the vicious cycle of hypoxia-impaired angiogenesis and suppressed thermogenesis, positioning BBR as a promising multi-target therapy for obesity.

Background: Crocetin (CRT), one of the active ingredients in saffron, exerts health-promoting effects on body systems such as neuroprotective, cardioprotective and hepatoprotective properties.

Purpose: In the present study, the effects of CRT and lansoprazole (LAP), as a reference drug, were investigated on indomethacin (IND)-induced gastric ulcer and related anxiety.

Methods: Thirty rats were divided into five groups of six. Groups 1 and 2 received vehicle and groups 3, 4 and 5 received CRT (5 and 20 mg/kg) and LAP (30 mg/kg) for seven consecutive days. All groups were deprived of food on day 6. On day 7, group 1 was treated with vehicle and groups 2, 3, 4 and 5 received 50 mg/kg IND. Anxiety and locomotor activity were recorded, and then the animals were euthanized and stomach and hippocampus samples were taken. The effects of the aforementioned treatments were studied in 24 intact rats in four equal groups.

Results: CRT (20 mg/kg) and LAP restored IND-induced alterations in the gastric content volume and pH and ulcer index and protection and cyclooxygenases 1 and 2 and prostaglandin E2 and gastric mucosal and hippocampal superoxide dismutase, malondialdehyde, tumor necrosis factor-alpha, interleukin-1β and caspase-3 and hippocampal brain derived neurotrophic factor. Histopathological alterations in the gastric mucosa and hippocampus were improved, and anxiety was suppressed. Intact rats were not influenced.

Conclusions: CRT and LAP caused protective effects against IND-induced gastric ulcer and by antioxidative, anti-inflammatory, anti-apoptotic and PGE₂-increasing activities. Anxiolytic effects of CRT and LAP were also observed.

Background: Lysosomal acidification deficits are increasingly recognized as a convergent pathological mechanism driving both age-related cognitive decline (ARCD) and early Alzheimer's disease (AD) progression, creating a self-reinforcing cycle of cellular aging and Aβ dyshomeostasis. Despite demonstrated neuroprotective effects of Da-Bu-Yin-Wan (DBYW) in Parkinson's disease models, its therapeutic potential for lysosomal dysfunction in ARCD and AD remains an uncharted area of investigation.

Purpose: This present work aimed to elucidate the mechanistic basis by which DBYW mitigates both ARCD and AD pathology through functionally rescuing impaired lysosomal acidification.

Methods: Cell-based D-galactose and Aβ-induced in BV2 cells to study lysosomal acidification. Molecular analyses combined immunofluorescence localization studies with quantitative immunoblotting of lysosomal and Wnt signaling proteins. In vivo, DBYW treatment effects were systematically evaluated in both D-gal-induced and APP/PS1 transgenic models using cognitive behavioral followed by immunohistochemical and biochemical assessment of brain tissues lysosomal parameters and Wnt signaling activity.

Results: DBYW attenuated the mechanistic basis of ARCD and AD pathology by functionally rescuing impaired lysosomal acidification. Overexpression of β-catenin could modulate D-galactose or Aβ-induced dysregulation of the Wnt/β-catenin pathway and restore lysosomes with abnormal acidification, while DBYW could regulate lysosomal function by promoting Wnt/β-catenin signaling. In addition, in D-gal-induced aging and AD model mice, DBYW treatment activated Wnt/β-catenin signaling to restore lysosomal acidification, while spatial memory deficits in ARCD and AD models were improved, and pathology in mouse attenuation and APP/PS1 mouse brain tissue was inhibited.

Conclusion: DBYW shows a potential dual efficacy in improving cognitive decline in ARCD and AD models. It makes DBYW a promising disease-modifying intervention targeting the shared lysosomal pathophysiology of aging-associated neurodegeneration.

Background: Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancer. Although traditional treatment methods such as surgery, chemotherapy, and radiotherapy can extend patient survival to some extent, they still present significant challenges due to their limited efficacy and substantial side effects. Ferroptosis, a form of iron-dependent programmed cell death, has been shown to exhibit considerable potential in the treatment of NSCLC. However, the molecular mechanisms underlying ferroptosis and how to safely and effectively induce it remain to be fully explored. This study aims to investigate the mechanism by which the natural flavonoid compound Quercetagitrin (Que) regulates the ferritinophagy-ferroptosis pathway to suppress NSCLC and to identify its molecular targets.

Methods: This study evaluated the selective toxicity of Que against NSCLC cells (A549, PC9) and normal lung epithelial cells (BEAS-2B) using in vitro assays, including CCK-8, colony formation, and flow cytometry. Key pathways related to ferritinophagy and ferroptosis were identified through transcriptomic analysis and KEGG pathway analysis. Fluorescence imaging, Western blot (WB) and BODIPY C11 staining were used to assess the levels of ferritinophagy and ferroptosis in cells. Limited proteolysis-mass spectrometry (LiP-MS) and molecular dynamics simulations were employed to identify the direct targets of Que. Gene knockdown and overexpression experiments were conducted to verify that Que targets eukaryotic translation initiation factor 3 subunit D (EIF3D) and regulates the activation of nuclear receptor coactivator 4 (NCOA4) -mediated ferritinophagy. In vivo experiments using xenograft mouse models assessed the antitumor effect and safety of Que.

Results: Que selectively inhibited the proliferation and colony formation of NSCLC cells while showing minimal toxicity to normal lung epithelial cells. It promoted the release of Fe²⁺ and lipid peroxidation by activating the NCOA4-dependent ferritinophagy pathway, while simultaneously inhibiting the expression of ferroptosis markers such as glutathione peroxidase 4 (GPX4). LiP-MS and molecular dynamics simulations confirmed EIF3D as a direct target of Que. Knockdown of EIF3D mimicked the antitumor effect of Que, whereas overexpression of EIF3D diminished its antitumor effect. In vivo, Que significantly inhibited tumor growth without observable toxicity, accompanied by upregulation of NCOA4 and LC3 II, and downregulation of EIF3D and GPX4.

Conclusion: Que exerts significant antitumor effects in NSCLC by targeting EIF3D to activate NCOA4-mediated ferritinophagy and ferroptosis. This study reveals a novel mechanism involving the EIF3D-NCOA4 axis in the regulation of ferritinophagy-dependent ferroptosis, providing a potential therapeutic strategy for the treatment of NSCLC.

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with marked female predominance. Lupus nephritis (LN), one of its most severe manifestations, is strongly associated with aberrant activation of signal transducer and activator of transcription 3 (STAT3). Estrogen receptor β (ERβ) has been reported to exert immunoregulatory effects, but its role in restraining STAT3 signaling in LN remains unclear.

Purpose: This study aimed to investigate whether genistein, a phytoestrogen with selective affinity for ERβ, can modulate the ERβ-STAT3 axis to attenuate lupus nephritis.

Methods: The therapeutic effects of genistein were evaluated in MRL/lpr and pristane-induced lupus mouse models and in LPS-stimulated macrophages. Macrophage polarization, oxidative stress, mitochondrial function, and ERβ-STAT3 signaling were assessed using flow cytometry, biochemical assays, immunoblotting, and bioinformatic analyses.

Results: Genistein significantly ameliorated renal injury, reduced proteinuria, and decreased serum autoantibody and IL-6 levels in lupus models. Mechanistically, genistein suppressed M1 macrophage polarization by activating ERβ and inhibiting STAT3 and NF-κB signaling. Genistein also attenuated oxidative stress by preserving mitochondrial membrane potential, reducing reactive oxygen species production, and restoring antioxidant capacity. Pharmacological blockade of ERβ markedly attenuated the anti-inflammatory effects of genistein, confirming ERβ-dependent regulation of STAT3 signaling.

Conclusion: This study identifies ERβ as a negative regulator of STAT3-driven inflammation and demonstrates that genistein therapeutically engages this axis to suppress macrophage-mediated renal injury, offering a promising therapeutic strategy for lupus nephritis.

Background: Skin photo-aging induced by ultraviolet radiation (UVR) leads to aesthetic alterations, structural degradation, and loss of barrier function. Ferroptosis has been implicated upon UVR stress but the driving modifiers remain largely undefined. Naringin has been reported to exert protective effects against UVR damage, however, the underlying mechanisms remain incompletely understood.

Purpose: To explore the driving factors of UVR-induced ferroptosis and to comprehensively evaluate the effects and underlying mechanisms of naringin in repressing UVR-induced photo-aging.

Methods: A mouse model in which the dorsal skin, as well as a cell model using HaCaT keratinocytes, were exposed to UVR to simulate daily sun exposure. Lentivirus-mediated knockdown, ChIP-seq, and RNA-seq analysis were used to evaluate the role of NR4A1 in UVR-induced ferroptosis. RNA-seq and metabonomics were performed to elucidate the underlying mechanisms of naringin against photo-aging. Molecular dynamics simulations/DARTS/CETSA, and co-IP assays were employed to investigate the mechanism by which naringin regulates NR4A1 expression.

Results: Reduction of NR4A1 leads to excessive lipid metabolism and initiates ferroptosis in UVR-induced photo-aging. Naringin directly binds to NR4A1, enhancing its stability by preventing ubiquitin-mediated degradation, transcriptionally represses EGR1 and LDLR expression, thereby suppressing lipid peroxidation and ferroptotic damage. Remarkably, both genetic deficiency and pharmacological inhibition of NR4A1 across diverse models abolish the effects of naringin against photo-aging.

Conclusion: Our findings emphasize the critical role of NR4A1 in ferroptosis driven by dysregulated lipid metabolism and reveal the therapeutic potential of targeting NR4A1 with naringin in UVR-induced photo-aging, as well as in the other relevant lipid metabolism dysfunction disorders.