N6‐methyladenosine (m6A) has emerged as the most prevalent post‐transcriptional modification on mRNA that contributes prominently to tumorigenesis. However, the specific function of m6A methyltransferase methyltransferase‐like 3 (METTL3) in colorectal cancer (CRC) remains elusive. Herein, we explored the biological function of METTL3 in CRC progression. Clinically, METTL3 was frequently upregulated in CRC tissues, cell lines, and plasma samples and its high expression predicted poor prognosis of CRC patients. Functionally, knockdown of METTL3 significantly repressed CRC cell proliferation and migration in vitro, while its overexpression accelerated CRC tumor formation and metastasis both in vitro and in vivo. Mechanistically, METTL3 epigenetically repressed YPEL5 in an m6A‐YTHDF2‐dependent manner by targeting the m6A site in the coding sequence region of the YPEL5 transcript. Moreover, overexpression of YPEL5 significantly reduced CCNB1 and PCNA expression. Collectively, we identified the pivotal role of METTL3‐catalyzed m6A modification in CRC tumorigenesis, wherein it facilitates CRC tumor growth and metastasis through suppressing YPEL5 expression in an m6A‐YTHDF2‐dependent manner, suggesting a promising strategy for the diagnosis and therapy of CRC.

Folium Microcos (FM), the leaves of Microcos paniculata L., shows various biological functions including antioxidant activity and α‐glucosidase inhibitory effect. However, its therapeutic potential in acute liver injury is still unknown. This study investigated the hepatoprotective effect and underlying mechanisms of the polyphenol‐enriched fraction (FMF) from Folium Microcos. FMF exhibited strong free radical scavenging activities and prevented HepG2/Hepa1–6 cells from hydrogen peroxide‐ (H₂O₂‐) induced ROS production and apoptosis in vitro. Antioxidant activity and cytoprotective effects were further verified by alleviating APAP‐induced hepatotoxicity in mice. Western blot analysis revealed that FMF pretreatment significantly abrogated APAP‐mediated phosphorylation of MAPKs, activation of proapoptotic protein caspase‐3/9 and Bax, and restored expression of antiapoptotic protein Bcl2. APAP‐intoxicated mice pretreated with FMF showed increased nuclear accumulation of nuclear factor erythroid 2‐related factor (Nrf2) and elevated hepatic expression of its target genes, NAD(P)H:quinine oxidoreductase 1 (NQO1) and hemeoxygenase‐1(HO‐1). HPLC analysis revealed the four predominantly phenolic compounds present in FMF: narcissin, isorhamnetin‐3‐O‐β‐D‐glucoside, isovitexin, and vitexin. Consequently, these findings indicate that FMF possesses a hepatoprotective effect against APAP‐induced hepatotoxicity mainly through dual modification of ROS/MAPKs/apoptosis axis and Nrf2‐mediated antioxidant response, which may be attributed to the strong antioxidant activity of phenolic components.

A polyphenol‐enriched fraction (PEF) from Acalypha wilkesiana, whose leaves have been traditionally utilized for the treatment of diverse medical ailments, was investigated for the anti‐inflammatory effect and molecular mechanisms by using lipopolysaccharide‐ (LPS‐) stimulated RAW 264.7 macrophages and acetaminophen‐ (APAP‐) induced liver injury mouse model. Results showed that PEF significantly attenuated LPS‐induced nitric oxide (NO) and prostaglandin E₂ (PGE₂) production and suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX‐2) in RAW 264.7 macrophages. PEF also reduced the secretion of proinflammatory cytokines including tumor necrosis factor‐α (TNF‐α), interleukin‐ (IL‐) 1β, and IL‐6 in LPS‐stimulated RAW 264.7 macrophages. Moreover, PEF potently inhibited LPS‐induced phosphorylation of mitogen‐activated protein kinases (MAPKs) as well as the activation of nuclear factor‐κB (NF‐κB) by preventing the degradation of inhibitor κB‐α (IκB‐α). In vivo, PEF pretreatment ameliorated APAP‐induced liver injury and hepatic inflammation, as presented by decreased hepatic damage indicators and proinflammatory factors at both plasma and gene levels. Additionally, PEF pretreatment remarkably diminished Toll‐like receptor 3 (TLR3) and TLR4 expression and the subsequent MAPKs and NF‐κB activation. HPLC analysis revealed that two predominantly polyphenolic compounds present in PEF were geraniin and corilagin. These results indicated that PEF has an anti‐inflammatory effect, and its molecular mechanisms may be involved in the inactivation of the TLR/MAPK/NF‐κB signaling pathway, suggesting the therapeutic potential of PEF for inflammatory diseases.

The fruit of Rosa laevigata Michx. (FR), a traditional Chinese herb utilized for the treatment of a variety diseases, has notably diverse pharmacological activities including hepatoprotective, anti-oxidant, and anti-inflammatory effects. Despite ongoing research on illustrating the underlying anti-inflammatory mechanism of FR, the principal mechanism remained inadequately understood. In this study, we investigated in depth the molecular mechanism of the anti-inflammatory actions of the ethanol extract of FR (EFR) and its potential targets using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages in vitro. We showed that EFR effectively ameliorated the overproduction of inflammatory mediators and cytokines, as well as the expression of related genes. It was further demonstrated that LPS-induced activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) were significantly inhibited by pretreatment with EFR, accompanied by a concomitant decrease in the nuclear translocation of the p65 subunit of NF-κB and activator protein 1 (AP-1). In addition, EFR pretreatment potently prevented LPS-induced decreased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Our data also revealed that the activation of AMPK and subsequent inhibition of the mammalian target of the rapamycin (mTOR) signaling pathway was probably responsible for the inhibitory effect of EFR on LPS-induced inflammatory responses, evidenced by reverse changes observed under the condition of AMPK inactivation following co-treatment with the AMPK-specific inhibitor Compound C. Finally, the main components with an anti-inflammatory effect in EFR were identified as madecassic acid, ellagic acid, quinic acid, and procyanidin C1 by LC–MS and testified based on the inhibition of NO production and inflammatory mediator expression. Taken together, our results indicated that EFR was able to ameliorate inflammatory responses via the suppression of MAPKs/NF-κB signaling pathways following AMPK activation, suggesting the therapeutic potential of EFR for inflammatory diseases.