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Ablation of the kinases Mst1 and Mst2, orthologs of the Drosophila antiproliferative kinase Hippo, from mouse intestinal epithelium caused marked expansion of an undifferentiated stem cell compartment and loss of secretory cells throughout the small and large intestine. Although median survival of mice lacking intestinal Mst1/Mst2 is 13 wk, adenomas of the distal colon are common by this age. Diminished phosphorylation, enhanced abundance, and nuclear localization of the transcriptional coactivator Yes-associated protein 1 (Yap1) is evident in Mst1/Mst2-deficient intestinal epithelium, as is strong activation of β-catenin and Notch signaling. Although biallelic deletion of Yap1 from intestinal epithelium has little effect on intestinal development, inactivation of a single Yap1 allele reduces Yap1 polypeptide abundance to nearly wild-type levels and, despite the continued Yap hypophosphorylation and preferential nuclear localization, normalizes epithelial structure. Thus, supraphysiologic Yap polypeptide levels are necessary to drive intestinal stem cell proliferation. Yap is overexpressed in 68 of 71 human colon cancers and in at least 30 of 36 colon cancer-derived cell lines. In colon-derived cell lines where Yap is overabundant, its depletion strongly reduces β-catenin and Notch signaling and inhibits proliferation and survival. These findings demonstrate that Mst1 and Mst2 actively suppress Yap1 abundance and action in normal intestinal epithelium, an antiproliferative function that frequently is overcome in colon cancer through Yap1 polypeptide overabundance. The dispensability of Yap1 in normal intestinal homeostasis and its potent proliferative and prosurvival actions when overexpressed in colon cancer make it an attractive therapeutic target.

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.

Taxifolin, a natural flavonoid, consistently exerts cytoprotective effects against various oxidative stresses. In this study, we systematically evaluated its photoprotective efficacy and underlying mechanisms against ultraviolet B (UVB)-induced injury in human immortalized keratinocytes (HaCaT). Cell viability and apoptosis were assessed by MTT, fluorescence staining, and flow cytometry, while integrative transcriptomic and proteomic analyses were employed to identify core pathways and key mediators. Taxifolin exhibited antioxidant capacity comparable to that of ascorbic acid under identical in vitro radical-scavenging assays. Moreover, it displayed a strong absorption peak at 289 nm that overlaps the UVB spectrum (280–320 nm), enabling it to act as a chemical sunscreen. In UVB-challenged HaCaT cells, taxifolin markedly reduced intracellular reactive oxygen species (ROS) and attenuated JNK/p38 MAPK activation, as evidenced by Western blot, thereby breaking the ROS-MAPK vicious cycle. Multi-omics revealed that taxifolin was associated with attenuation of UVB-imposed G1/S arrest concomitant with restored Cyclin expression, while up-regulating MYC, FOXQ1, HMOX1 and AP-1 components c-Jun/c-Fos and thereby switching on a pro-survival transcriptional program. Consequently, apoptosis was suppressed and survival was significantly improved. Collectively, taxifolin integrated chemical filtration, ROS scavenging and signaling modulation to support a multi-target photoprotective network, which provides mechanistic insight into taxifolin-mediated cytoprotection and identifies candidate molecular nodes for further validation.

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.

Aloin, an anthraquinone compound, is naturally abundant in the Aloe . This study comprehensively investigates the photoprotective effects of aloin against UVB-induced damage in HaCaT cells, elucidating its antioxidant capacity and its role in preventing cellular apoptosis. Aloin demonstrated significant antioxidant activity in ABTS and DPPH assays, with a dose-dependent reduction in intracellular reactive oxygen species levels as evidenced by fluorescence analysis. Western blot analysis revealed that aloin inhibited the phosphorylation of both p38 and JNK, with a more pronounced effect on p38. This was further supported by IC50 values, indicating a higher inhibitory potency of aloin against p38 compared to JNK. Assessments using MTT, Hoechst, Calcein/PI staining, and flow cytometry collectively verified that aloin effectively mitigated UVB-induced apoptosis in cells. Proteomic analysis showed that aloin modulated the expression of proteins involved in critical signaling pathways, including PI3K-Akt, p53, TGF-β and pathways in cancer, promoting cell survival. Aloin upregulated proteins associated with cell cycle regulation and antioxidant responses, such as CCND3, GSTM4, GNA12, SKIL, YWHAZ, and PKN3 while downregulating pro-apoptotic protein FOXO3. These findings highlight aloin’s potential as a therapeutic agent for UVB-induced skin damage by effectively modulating cellular stress responses.

In traditional Chinese medicine, the root bark and leaves of Schima argentea are utilized to treat dysentery, parasitic infections, and digestive disorders. In this study, the n-butanol extract of S. argentea (NBA) exhibited potent antioxidant properties, protecting HaCaT cells from UVB-induced damage, and was abundant in phenolic and flavonoid compounds. Using UPLC-QTOF-MS analysis, several antioxidants within NBA were identified. Among these, 3,4-dihydroxybenzoic acid, (+)-catechin, and procyanidin B2 effectively reduced ROS levels after 1 h post-UVB treatment (225 mJ/cm2). Notably, all three compounds significantly decreased the phosphorylation of p38 and JNK in a dose-dependent manner. Additionally, the cell survival rate of these compounds was assessed after 12 h post-UVB treatment (225 mJ/cm2). Both 3,4-dihydroxybenzoic acid and (+)-catechin significantly prevented UVB-induced apoptosis in HaCaT cells, as evidenced by MTT, Hoechst, Calcein/PI staining, and flow cytometry analyses. Proteomic analysis revealed that 3,4-dihydroxybenzoic acid achieved photoprotection by downregulating c-Fos and Jun and modulating cell cycle proteins, while (+)-catechin promoted cell repair through the PI3K-Akt and Wnt signaling pathways. These results demonstrated that both compounds can directly absorb UVB, scavenge ROS, and provide cell photoprotection by modulating multiple signaling pathways. The n-butanol extract of S. argentea holds promising potential for future medical applications.

Background/Objectives: Esterases are widely used in various industrial fields. This study aimed to isolate and characterize esterase genes from Laceyella sacchari HS49-1, a thermophilic bacterium from a hot spring, which can survive at 45–60 °C and pH 5-10 with robust esterase activity. Methods: A genomic shotgun library was constructed to identify three esterase genes: two in family XII (Est2 and Est7) and one in family VIII (Est1). Sequence analysis revealed significant divergence from other genera. Only Est1 was successfully expressed in Escherichia coli. Its activity, optimal conditions, thermostability, and structure were investigated using p-NP butyrate, temperature/pH assays, heating pre-treatment, and fluorescence quenching. Results: Est1 demonstrated high activity (57.43 ± 0.04 U/mg) towards short-chain p-NP butyrate (C4). Molecular-docking analyses revealed that Est1’s catalytic motif (GXSXG) interacts with various p-NP esters, with binding energy and interaction types varying by acyl chain length. The optimal temperature was 60 °C, and the optimal pH was 8. Est1 exhibited excellent thermostability, retaining 90% of its activity after pre-treatment at 50 °C for 8 h and 69.8% after pre-treatment at 80 °C for the same duration. Fluorescence quenching showed that after 1 h at 80 °C, the fluorescence was reduced by only 16.6%, indicating remarkable heat resistance. Additionally, Est1 did not require metal ions as cofactors and maintained 74.8% of its activity in the presence of 0.1% SDS. Conclusions: The unique properties of Est1 from L. sacchari HS49-1 highlight its potential for industrial applications. Further exploration of this thermophilic bacterium could uncover more valuable genes.

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.

Glutamic acid is widely recognized as safe and has various applications in the medical and food industries. This study demonstrated its significant inhibition of tyrosinase, acting as a mixed-type inhibitor according to enzymatic kinetic analysis. Fluorescence spectroscopy analysis and investigation of tyrosinase activity under different pH confirmed that glutamic acid induced changes in the protein structure of tyrosinase, leading to its reduced activity through acidification and binding effects. Additionally, glutamic acid was found to inhibit L-DOPA auto-oxidation, thereby preventing further formation of dopachrome. The IC50 values for glutamic acid inhibiting tyrosinase activity and L-DOPA auto-oxidation were detected to be 4.69 mM and 0.72 mM, respectively. Glutamic acid had a better inhibitory effect on L-DOPA autooxidation than tyrosinase activity. The L-DOPA auto-oxidation process can also lead to the formation of melanin, and its inhibition by glutamic acid further supported its potential in controlling melanin synthesis. Moreover, glutamic acid demonstrated a dose-dependent decrease in melanin production in B16 cells while maintaining cell viability. Western blot analysis revealed decreased protein expression of TYR and TRP-1, both of which are involved in melanin production, with increasing concentrations of glutamic acid. Molecular docking analysis suggested a potential mechanism involving the disruption of copper binding sites on tyrosinase. These findings underscore the potential of glutamic acid as a promising agent for controlling melanin production and associated disorders.

Background Tea ( Camellia sinensis L.) flowers will compete with tea leaves in nutrition and are abandoned as an undesirable by-product. In this study, the biological efficacy of tea flowers was investigated. Further exploration of its antifungal activity was explained. Methods Tea flowers harvested from China were characterized in term of component, antioxidant ability, tyrosinase inhibition, and antifungal ability. Chemical compounds of tea flowers were analyzed by LC-MS. Disinfectant compounds were identified in tea flowers, and 2-ketobutyric acid exhibited antifungal activity against Aspergillus flavus CCTCC AF 2023038. The antifungal mechanism of 2-ketobutyric acid was further investigated by RNA-seq. Results Water-soluble tea flower extracts (TFEs) exhibited free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)(ABTS) as well as a high ferric-reducing ability. However, no inhibition of tyrosinase activity was observed. In the antifungal test, 6.4 mg/mL TFE reached 71.5% antifungal rate and the electrical conductivity of the culture broth increased with increasing concentration of TFE, implying that it damaged the fungal cell membrane by the TFE. Several disinfectants were identified in TFE by LC-MS, and 2-ketobutyric acid was also confirmed to be capable of fungal inhibition. Propidium iodide (PI) staining indicated that 2-ketobutyric acid caused damage to the cell membrane. RNA-seq analysis revealed that 3,808 differentially expressed genes (DEGs) were found in A. flavus CCTCC AF 2023038 treated by 2-ketobutyric acid, and more than 1,000 DEGs involved in the integral and intrinsic component of membrane were affected. Moreover, 2-ketobutyric acid downregulated aflatoxin biosynthesis genes and decreased the aflatoxin production. Conclusions Overall, TFE exhibited excellent antioxidant ability and fungal inhibition against A. flavus CCTCC AF 2023038 due to its abundant disinfectant compounds. As a recognized food additive, 2-ketobutyric acid is safe to use in the food industry and can be utilized as the basis for the research and development of strong fungicides.