Phytomedicine最新文献

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.

Objective: This study aimed to elucidate the therapeutic mechanisms of the Shengdihuang-Huangqi (SDHHQ) herbal pair in type 2 diabetes mellitus (T2DM) by integrating network pharmacology, transcriptomics, and metabolomics, together with experimental validation, to identify key bioactive compounds and explore their potential targets.

Methods: Active components of SDHHQ were screened from multiple databases, potential targets were predicted through network pharmacology, and a compound-target network was constructed by cross-referencing with T2DM-related genes. KEGG and GO enrichment analyses were then performed to identify key signaling pathways. Transcriptomic profiling of liver tissues from T2DM rats was carried out using RNA sequencing, while serum analysis was conducted via metabolomics. Transcriptomic and metabolomic data were integrated to explore gene-metabolite associations and identify potential pathways of SDHHQ action. Experimental validation involved measurements of fasting blood glucose, serum lipid levels, histopathology, and hepatic gene expression in T2DM rats, as well as glucose uptake and glycogen synthesis assays in insulin-resistant HepG2 cells.

Results: Network pharmacology analysis identified six bioactive compounds-quercetin, kaempferol, formononetin, apigenin, catalpol, and acteoside-as potential major contributors to the therapeutic effects of SDHHQ against T2DM. In vivo experiments demonstrated that SDHHQ significantly ameliorated hyperglycemia, dyslipidemia, and tissue damage in T2DM rats. Multi-omics analysis and qPCR validation further indicated that SDHHQ ameliorates T2DM by modulating the insulin resistance, AMPK, and PPAR signaling pathways, thereby influencing hepatic glycogen synthesis and glucose uptake.

Conclusions: In conclusion, SDHHQ ameliorates T2DM by modulating glucose metabolism through the INS/IRS2/AKT2 and FOXO1 pathways and lipid metabolism via the SREBP1c/FAS/ACC1 and PPARα/CD36 pathways, providing molecular evidence for its therapeutic potential.

Introduction: High fructose is reported to induce lung and hippocampus inflammatory injury. Mulberroside A, derived from the traditional Chinese herb Cortex mori, which is commonly used to treat coughs and bronchitis, has anti-inflammation and neuroprotection.

Objectives: This study aimed to explore whether and how mulberroside A prevent high fructose-induced lung injury and hippocampal inflammation.

Methods: Mice and cultured MH-S, a murine alveolar macrophage cell line were treated with high fructose and/or mulberroside A and positive drug dipyridamole, respectively. Alveolar macrophages (AMs) efferocytosis function, NOD-like receptor family pyrin domain containing 6 (NLRP6) and serum amyloid A3 (SAA3) level were evaluated by Western blot, real-time quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence, respectively. Nlrp6^-/- mice and Nlrp6 overexpression MH-S cells were used to explore the contribution of NLRP6 to AMs efferocytosis dysfunction and hippocampal inflammation under high fructose stimulation, respectively. Simultaneously, a fluorescent anti-GPIbβ Ab (X488) was used to label platelets in mice for measuring lung-derived SAA3 level in platelets.

Results: High fructose caused AMs efferocytosis dysfunction, and up-regulated NLRP6 expression in lung inflammation of mice. SAA3 was found to be abundantly expressed in AMs of fructose-fed mice. Whereas, lung-derived SAA3 transport via platelets induced blood-brain barriers (BBB) injury and hippocampal inflammation in this animal model. Nlrp6 promoted AMs efferocytosis dysfunction and lung-derived SAA3 transport via platelets to induce hippocampal inflammation under high fructose condition. More important, mulberroside A decreased lung NLRP6 expression, and then enhanced AMs efferocytosis function and inhibited lung inflammation. Meanwhile, they blocked lung-derived SAA3-platelet transportation to prevent hippocampal inflammation in high fructose-fed mice.

Conclusion: These results suggested that mulberroside A inhibited NLRP6 to prevent alveolar macrophage efferocytosis and lung-derived SAA3-platelet transport in high fructose-induced hippocampal inflammation.

Background: Polygoni Multiflori Radix (PMR) and its processed form, Polygoni Multiflori Radix Praeparata (PMRP), are two widely used traditional Chinese medicines (TCM). However, in recent years, frequent reports have emerged regarding their hepatotoxicity. Despite numerous studies, the underlying mechanisms of hepatotoxicity and key toxic components remain poorly understood.

Purpose: This study aimed to comprehensively elucidate the hepatotoxic processes of PMR and PMRP and identify the principal toxic components.

Methods: In vivo toxicity tests were carried out to assess the toxicity levels and characteristics of PMR and PMRP. The integration of untargeted serum metabolomics, liver spatial transcriptomics, and liver spatial metabolomics was first employed to elucidate the toxicity mechanisms, which were further validated through metabolite and sensitive index levels and by evaluating protein expression. Mass spectrometry and cytotoxicity tests were utilised to determine the primary toxic components.

Results: The findings revealed that PMR and PMRP primarily regulate tryptophan metabolism, the tricarboxylic acid (TCA) cycle, purine metabolism, and glutathione metabolism. Furthermore, PMR and PMRP can inhibit the expression of bile acid transporters, causing obstruction of bile acid secretion. These modulations trigger oxidative stress, which subsequently leads to cholestasis. The accumulation of bile acids further intensifies oxidative stress, creating a vicious cycle. Furthermore, emodin was identified as the primary toxic component.

Conclusion: PMR and PMRP can induce cholestatic liver injury. They exert hepatotoxic effects by establishing a vicious cycle between cholestasis and oxidative stress, with emodin being the key component responsible for this toxicity.

Background: Antimicrobial resistance (AMR) infection is attracting increasing attention, especially superbug infections. As a result, finding ways to reduce AMR is essential. For the time being, natural compound therapy for reducing AMR is an ideal choice.

Purpose: This study aims to investigate the mechanism of magnolol reducing the AMR of E. coli in vitro and vivo.

Methods: The morphology and function of E. coli under magnolol treatment were assessed using a scanning electron microscope, qPCR, RNA-seq, and other methods. Moreover, the in vivo treatment effects of magnolol combined with antibiotics were evaluated by HE and IHC staining.

Results: In this study, we found that magnolol reduced the resistance of ESBL E. coli to the fourth-generation cephalosporin in vitro via two main mechanisms. Firstly, magnolol disrupts iron ion metabolism by increasing environmental iron uptake significantly (P ≤ 0.01), leading to a significant increase in intracellular ROS (P ≤ 0.01) and membrane damage. Secondly, magnolol significantly inhibits the relative mRNA expression of blaCTX-M-1 (P ≤ 0.01) and the CTX-M-1 enzyme activity in ESBL E. coli. Furthermore, we find that magnolol can inhibit ESBL E. coli in vivo by significantly reducing the TLR4-NFκB p65 pathway (P ≤ 0.01).

Conclusion: In a word, our results indicate that magnolol is a natural antibacterial adjuvant with potent inhibitory activity against bacterial resistance and exerts this activity through multiple pathways, which has particular significance for the further study of the AMR mechanism.