Phytomedicine最新文献

Background: Wogonin, a flavonoid component derived from Scutellaria baicalensis Georgi roots, exerts considerable therapeutic efficacy against osteoarthritis (OA), yet with unclear precise mechanism.

Purpose: To investigate the therapeutic effect of Wogonin on OA and clarify its potential mechanisms.

Methods: IL-1β-induced C28/I2 cells and mice undergoing destabilization of the medial meniscus (DMM) were constructed to simulate OA. The curative effect of Wogonin was evaluated using pathological staining, micro-CT, Tunel, EdU and migration assay. The repair effect of Wogonin on cartilage injury was assessed by immunohistochemistry, immunofluorescence, toluidine blue and SA-β-gal. The interaction potency between Wogonin and its target protein was validated using RNA-Seq, molecular dynamics simulations (MDs), surface plasmon resonance (SPR), cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS). The mechanism by which Wogonin modulated OA was validated using STAT3 agonist and pcDNA3.1-STAT3.

Results: Wogonin could ameliorate articular cartilage injury, inhibit synovitis and osteophyte formation in DMM mice, promote the proliferation and hinder apoptosis of IL-1β-induced C28/I2 cells. Wogonin could suppress matrix degradation, stimulate matrix synthesis and proteoglycan secretion, enhance CDK and Cyclin transcriptional levels, concomitantly retarded SA-β-gal, senescence-associated secretory phenotype (SASP), γ-H2A.X, P16, P21 and P53. Mechanistically, STAT3 was a direct target of Wogonin. Upregulation of STAT led to significantly increased p-STAT3/STAT3 and PIM1 expression, and simultaneously aggravated cartilage injury and cell senescence. In contrast, Wogonin inhibited its activation by directly binding STAT3 and reversed the above pathological changes.

Conclusion: Wogonin could inhibit chondrocyte senescence, reduce cartilage damage and alleviate OA by targeting the STAT3/PIM1 axis.

Background: Malignant pleural effusion (MPE) is a common and debilitating complication in advanced lung carcinoma, driven by an immunosuppressive tumor microenvironment (TME), where tumor-associated macrophages (TAMs) play a pivotal role. This specialized milieu not only facilitates neoplastic proliferation but also contributes to immune system dysfunction. Preliminary evidence suggests that Xiaoshui Formula (XSF) could inhibit MPE by modulating TAM polarization, a key mechanism underlying T cell dysfunction and compromised tumor surveillance capabilities.

Purpose: This study seeks to elucidate the precise molecular mechanism by which XSF remodels the TME in MPE, with a focus on its regulation of tumor cell signaling and subsequent effects on TAM polarization and T cell function.

Methods: We employed a combination of in vivo MPE mouse models and in vitro cell culture systems. Lewis lung carcinoma cells (LLCs) and bone marrow-derived macrophages were used. Techniques included RNA-seq, Western blot, ELISA, flow cytometry, immunohistochemistry, and qPCR to analyze signaling pathways, cytokine secretion, and immune cell populations.

Results: XSF treatment led to a dose-dependent reduction in pleural effusion volume, marked by a shift in TAM polarization. Transcriptomic and functional analyses revealed that XSF targets tumor cells, inhibiting the expression of Stanniocalcin-1 (STC1), which leads to reduced phosphorylation of the NF-κB subunit p65 and subsequent downregulation of the chemokine CXCL5. This suppression of tumor-derived CXCL5 impaired the recruitment and M2 polarization of TAMs. Consequently, XSF treatment reshaped the TME, leading to an enhancement of anti-tumor T cell function (downregulation of PD-1, CTLA-4, TIM-3 and increased production of IFN-γ and Granzyme B).

Conclusion: Our findings demonstrate that XSF inhibits MPE progression by suppressing the STC1/p65/CXCL5 axis in tumor cells, thereby reprogramming TAMs and potentiating T cell-mediated anti-tumor immunity. This study provides a mechanistic foundation for the clinical application of XSF and highlights the value of targeting tumor cell-intrinsic pathways to modulate the immune TME.

Blueberry anthocyanins, a class of flavonoids with antioxidant and anti-inflammatory properties, were investigated for their role in enhancing intestinal barrier, comparing differential effects between immature and mature enterocytes. Using both wild-type (WT) and Toll-like receptor 4 gene knockout (TLR4^-/-) mice at pup and adult stages, blueberry anthocyanin extract (BAE) was administered via oral gavage, and an ex vivo inflammatory model was established with interleukin-1beta (IL-1β) stimulation. Analysis of 16S rDNA sequencing revealed that BAE modulated gut microbiota in an age- and TLR4-dependent manner, increasing alpha diversity in WT pups but reducing in adults, enriching beneficial Akkermansia in adults. Additionally, BAE elevated total short-chain fatty acid (SCFA) levels, with higher concentrations in WT mice than in TLR4^-/- mice. The SCFA profile was developmentally regulated, marked by the absence of acetate in pups and a BAE-specific induction of valerate in adults. The improvement of the intestinal barrier by BAE was also evidenced by the upregulation of tight junction (TJ) proteins, as well as the suppression of IL-1β-induced pro-inflammatory cytokines and inflammatory mediators. These effects were abolished in TLR4^-/- mice, and pups showed more pronounced inflammatory sensitivity. Furthermore, comparisons between distinct developmental stages revealed that BAE specifically supports the maturation and homeostasis of the intestinal epithelium. Especially, BAE exhibited a distinct pattern of regulation between embryonic-type (e.g., Krt18 and Hbb-γ) and adult-type genes (e.g., Krt20 and Hbb-b1). These findings indicate TLR4 as a critical target, proposing the application of blueberry anthocyanins as a functional ingredient to prevent intestinal barrier dysfunction across life stages.

Objective: Glucocorticoid use is a leading cause of osteonecrosis of the femoral head, with the death of bone marrow mesenchymal stem cells (BMSCs) considered a central cellular event in steroid-induced osteonecrosis of the femoral head (SONFH). However, the underlying mechanisms remain unclear, and effective therapies are lacking.

Method: In this study, we established an in vitro model of SONFH by treating BMSCs with methylprednisolone (MP, 1 mM, 24 h) and screened a natural product library for inhibitors of the steroid-induced cell death (SiCD).

Results: Our results demonstrated that 15 natural products may effectively inhibit SiCD among the screened library, with nuciferine emerging as one of the most potent compounds. Further study showed that nuciferine may predominantly suppress ferroptosis in glucocorticoid treated BMSCs, it may also promote osteogenic differentiation and mitochondrial homeostasis. Mechanistically, integrated bioinformatic analysis and gene knockdown experiments revealed that nuciferine relies on HIF-1α to inhibit ferroptosis and promote osteogenic differentiation. In vivo studies showed that administration of nuciferine effectively ameliorates SONFH in rats.

Conclusions: In summary, our study demonstrates that nuciferine may ameliorate SONFH by activating HIF-1α to suppress ferroptosis in BMSCs. Given that nuciferine is both a medicinal and dietary compound, it may also suggest that nuciferine could be a key dietary component for patients undergoing glucocorticoid treatment.

Background: Glucagon-like peptide-1 (GLP-1), a key incretin produced by intestinal L-cells, plays a vital role in glucose and intestinal homeostasis during type 2 diabetes mellitus (T2DM) management. Large-leaf yellow tea polysaccharide (LYP) exhibits hypoglycemic effects, yet the structural features of LYP-derived bioactive oligosaccharides and their potential effects and mechanisms in promoting GLP-1 secretion remain unclear.

Purpose: This study aimed to isolate an active oligosaccharide from LYP and explore its effects and underlying mechanisms on GLP-1 secretion and intestinal homeostasis in T2DM.

Methods: An oligosaccharide (ELYP) was obtained from enzymatic degradation of LYP guided by activity evaluation. Its structure was characterized, and in situ intestinal perfusion was used to assess GLP-1 secretion in mice. Molecular mechanisms were explored in T2DM mice and STC-1 cells. Intestinal microorganisms and metabolites, intestinal barrier integrity, as well as immunocytes profiles were analyzed.

Results: ELYP primarily consists of 1,4-linked β-GalpA and 1,4-linked β-Glcp, with degrees of polymerization between 3 to 7. It significantly increased plasma GLP-1 levels and upregulated genes related to GLP-1 synthesis, processing, and release synthesis and secretion. ELYP also restored intestinal barrier function by enhancing tight-junction proteins and goblet cell numbers, enriching beneficial gut microbiota and SCFAs composition, and promoting a transition of macrophages and T lymphocytes to an anti-inflammatory phenotype.

Conclusion: ELYP effectively ameliorates T2DM by potently stimulating GLP-1 secretion and restoring intestinal homeostasis. This study not only identifies ELYP as a promising natural product for T2DM management but also provides new insights into the mechanism of tea-derived oligosaccharides.