Mecp2 promotes the anti-inflammatory effect of alpinetin via epigenetic modification crosstalk.

In recent years, inflammatory disorders have emerged as a significant concern for human health. Through ongoing research on anti-inflammatory agents, alpinetin has shown promising anti-inflammatory properties, including involvement in epigenetic modification pathways. As a crucial regulator of epigenetic modifications, Mecp2 may play a role in modulating the epigenetic effects of alpinetin, potentially impacting its anti-inflammatory properties. To test this hypothesis, two key components, p65 (a member of NF-KB family) and p300 (a type of co-activator), were screened by the expression profiling microarray, which exhibited a strong correlation with the intensity of LPS stimulation in mouse macrophages. Meanwhile, alpinetin demonstrates the anti-inflammatory properties through its ability to disrupt the synthesis of p65 and its interaction with promoters of inflammatory genes, yet it did not exhibit similar effects on p300. Additionally, Mecp2 can inhibit the binding of p300 by attaching to the methylated inflammatory gene promoter induced by alpinetin, leading to obstacles in promoter acetylation and subsequently impacting the binding of p65, ultimately enhancing the anti-inflammatory capabilities of alpinetin. Similarly, in a sepsis mouse model, it was observed that homozygotes overexpressing Mecp2 showed a greater reduction in organ damage and improved survival rates compared to heterozygotes when administered by alpinetin. However, blocking the expression of DNA methyltransferase 3A (DNMT3A) resulted in the loss of Mecp2's anti-inflammatory assistance. In conclusion, Mecp2 may augment the anti-inflammatory effects of alpinetin through epigenetic 'crosstalk', highlighting the potential efficacy of a combined therapeutic strategy involving Mecp2 and alpinetin for anti-inflammatory intervention.

Overexpression of transcription factor TBX5 inhibits the activation of YAP1-TEAD1 pathway to promote ferroptosis in lung cancer cells.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for more than 80 % of lung cancer (LC) cases, making it the primary cause of cancer-related mortality worldwide. T-box transcription factor 5 (TBX5) is an important regulator of embryonic and organ development and plays a key role in cancer development. Here, our objective was to investigate the involvement of TBX5 in ferroptosis within LC cells and the underlying mechanisms. METHODS: First, TBX5 expression was examined in human LC cells. Next, overexpression of TBX5 and Yes1-associated transcriptional regulator (YAP1) and knockdown of TEA domain 1 (TEAD1) were performed in A549 and NCI-H1703 cells. The proliferation ability of A549 and NCI-H1703 cells, GSH, MDA, ROS, and Fe2+ levels were measured. Co-immunoprecipitation (Co-IP) was performed to verify whether TBX5 protein could bind YAP1. Then TBX5, YAP1, TEAD1, GPX4, p53, FTH1, SLC7A11 and PTGS2 protein levels were assessed. Finally, we verified the effect of TBX5 on ferroptosis in LC cells in vivo. RESULTS: TBX5 expression was down-regulated in LC cells, especially in A549 and NCI-H1703 cells. Overexpression of TBX5 significantly decreased proliferation ability of A549 and NCI-H1703 cells, downregulated GPX4 and GSH levels, and upregulated MDA, ROS, and Fe2+ levels. Co-IP verified that TBX5 protein could bind YAP1. Moreover, oe-YAP1 promoted proliferation ability of A549 and NCI-H1703 cells transfected with Lv-TBX5, upregulated GPX4 and GSH levels and downregulated MDA, ROS, and Fe2+ levels. Additionally, oe-YAP1 promoted FTH1 and SLC7A11 levels and inhibited p53 and PTGS2 levels in A549 and NCI-H1703 cells transfected with Lv-TBX5. However, transfection with si-TEAD1 further reversed these effects. In vivo experiments further validated that TBX5 promoted ferroptosis in LC cells. CONCLUSIONS: TBX5 inhibited the activation of YAP1-TEAD1 pathway to promote ferroptosis in LC cells.

The Inhibitory Effect and Mechanism of Ferula akitschkensis Volatile Oil on Gastric Cancer.

Ferula akitschkensis volatile oil (FAVO) has a good inhibitory activity on gastric cancer cell proliferation, but the mechanism of action is not yet clear. In this study, we tested the antigastric cancer efficacy and mechanism of FAVO using both in vivo and in vitro models. The results showed that FAVO effectively inhibited the proliferation, migration, and invasion of human gastric cancer SGC-7901 cells, the formation of small tubules of human umbilical vein endothelial cells as well as zebrafish intersegmental vessel and intestinal vein angiogenesis. In vivo experiments showed that FAVO significantly delayed the growth of SGC-7901 tumor-bearing nude mice and induced higher serum IL-2 and IFN-γ and reduced serum IL-6. Western blot results showed that FAVO reduced the expression of HIF-2α, VEGF, VEGFR2, P-VEGFR2, Akt, and P-Akt in SGC-7901 cells with CoCl2 induced hypoxia. We further clarified the main chemical components of FAVO through GC-MS analysis. In summary, FAVO may inhibit tumor growth and angiogenesis via inhibiting the HIF-2α/VEGF signaling pathway.

Role of Episamarcandin in Promoting the Apoptosis of Human Colon Cancer HCT116 Cells through the PI3K-Akt Signaling Pathway.

This study identifies the active ingredients of Ferula sinkiangensis and investigates the role and mechanism of episamarcandin in colon cancer cells. The silica gel column chromatography was utilized to separate the chemical components of Ferula sinkiangensis. Sephadex LH-20 and semipreparative HPLC were adopted for further separation and purification. The compound episamarcandin showed good anticolon cancer activity among the 13 monomeric compounds obtained. Its effects on the apoptosis, cell cycle, and invasion and migration of colon cancer HCT 116 cells and PI3K-Akt signaling pathway were further investigated. The results showed that, similar to positive control cisplatin, episamarcandin inhibited the proliferation, promoted the apoptosis, arrested cells at G0/G1 phase, and suppressed migration and invasion of HCT 116 cells. A large number of apoptotic HCT 116 cells were observed under a transmission electron microscope. Fluorescence real-time quantitative PCR and western blot analysis showed that episamarcandin increased the expression of PTEN, p53, and Bax and decreased the expression of P-Akt, Akt, mTOR, Bcl-xl, and Bcl-2. Conclusively, episamarcandin may inhibit cell proliferation, migration, and invasion and promote the apoptosis of human colon cancer HCT 116 cells possibly through the PI3K-Akt signaling pathway.

Overexpression of T-box Transcription Factor 5 (TBX5) Inhibits Proliferation and Invasion in Non-Small Cell Lung Carcinoma Cells.

T-box transcription factor 5 (TBX5), a member of the conserved T-box transcription factor family that functions in organogenesis and embryogenesis, has recently been identified as a critical player in cancer development. The aim of this study was to determine the role of TBX5 in non-small cell lung carcinoma (NSCLC). Immunohistochemistry was used to detect the correlation between levels of TBX5 and clinicopathological features of NSCLC patients in tissue microarray. Expression of TBX5 in NSCLC tissues and cell lines was evaluated by quantitative PCR and Western blot. The role of TBX5 in regulating proliferation, colony formation, invasion, and apoptosis of NSCLC cells was evaluated in vitro. Finally, a tumorigenicity assay was performed to determine the effect of TBX5 on tumor growth in vivo. The levels of TBX5 in NSCLC tissues were significantly correlated with the TNM stage (p = 0.016), histopathologic type (p = 0.029), and lymph node status (p = 0.035) of NSCLC. TBX5 overexpression markedly suppressed in vitro NSCLC cell proliferation, colony formation, and invasion and induced apoptosis. In vivo tumor growth was significantly suppressed by TBX5. TBX5 has a tumor-suppressing effect in NSCLC and may serve as a therapeutic target for diagnoses and treatment of NSCLC.

Alpinetin inhibits LPS-induced inflammatory mediator response by activating PPAR-γ in THP-1-derived macrophages.

Alpinetin, a novel plant flavonoid derived from Alpinia katsumadai Hayata, has been reported to have anti-inflammatory properties. However, the anti-inflammatory mechanism of alpinetin has not been fully elucidated. The purpose of this study was to investigate the anti-inflammatory mechanism of alpinetin in modifying lipopolysaccharide (LPS)-induced signaling pathways in human THP-1 macrophages. The cells were stimulated with LPS in the presence or absence of alpinetin. The pro-inflammatory cytokines were evaluated by ELISA and qRT-PCR. Toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), inhibitory kappa B (IκBα) protein, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and PPAR-γ were determined by Western blotting. The results showed that alpinetin inhibited TNF-α, IL-6 and IL-1ß expression in LPS-stimulated human THP-1 macrophages in a dose-dependent manner. Western blot analysis showed that alpinetin suppressed LPS-induced NF-κB activation, IκBα degradation, phosphorylation of ERK, JNK and P38. Furthermore, alpinetin could significantly down-regulated the expression of TLR4 stimulating by LPS. We also found that alpinetin could activate PPAR-γ and the anti-inflammatory effects of alpinetin can be reversed by GW9662, a specific antagonist for PPAR-γ. These results suggest that alpinetin activates PPAR-γ, thereby attenuating TLR4 expression and TLR4 mediated NF-κB and MAPK activation and the release of pro-inflammatory cytokines. These findings suggest that alpinetin may be a therapeutic agent against inflammatory diseases.