Yeast cell-free extracts and supernatants contain several compounds such as β-glucan, mannan, chitin, and mannoprotein with potent antitumor and other health-promoting activities. Candida albicans have been frequently and widely isolated from different habitats compared to other yeasts. The supernatant extracted from this yeast also contains β-glucan, chitin, and mannan compounds. This study investigates the anticancer, apoptosis-inducing, and downregulation of proinflammatory gene expression activities in normal and drug-resistant human stomach cancer cells (EPG and RDB cell lines) after 24 and 48 h treatment.

The GATA transcription factors play multifaceted roles in modulating vital physiological processes in plants. However, the GATA transcription factor family in onion (Allium cepa L.) has been explored to a limited extent. In the present study, a genome-wide survey of the GATA family and the subsequent characterization has been carried out in the onion genome.

Small molecule Menin inhibitor recently has emerged as a new therapeutic by targeting the interaction of histone methyltransferase MLL1 (KMT2A) with Menin. MLL1 is associated with aggressive osteosarcoma (OS) in young adults. The purpose of the study is to explore whether Menin inhibitors have therapeutic effects in OS.To investigate the anti-OS activity of the Menin inhibitor MI-503 in vitro, we performed CCK-8 cell growth and colony formation assay. Cellular thermal shift assay was used to test whether MI-503 binds to Menin in osteosarcoma cells. The expression of oncogenes in MI-503 treated cells were detected by western blotting and Quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay. Finally, we established the OS subcutaneous xenograft mice model to study the anti-OS effect of MI-503 in vivo.The results showed that MI-503 dose-dependently suppressed cell proliferation in 6 OS cell lines, including 143B, HOS, Saos-2, SKES1, MG-63, and U2OS. 143B is the most sensitive cell line with EC50 value 0.13 µM. Cellular thermal shift assay showed that MI-503 binds cellular Menin. RT-qPCR assay showed that MI-503 suppressed the expression of Mcl-1 and c-Myc in 143B cells. Western blotting result showed that MI-503 markedly suppressed the H3K4 methylation, significantly suppressed the expression of Mcl-1 and c-Myc, and increased the expression of p27 and cl-PARP in 143B and Saos-2 cells. In a study with 143B cell-derived xenograft model, we found that MI-503 profoundly inhibited OS tumor growth in mice. Immunohistochemistry (IHC) study showed that MI-503 suppressed the H3K4 methylation and inhibited the expression of the cell proliferation biomarker Ki67 in 143B OS xenograft tissue.Overall, our findings demonstrated the potent anti-OS activity of MI-503 in both in vitro and in vivo models, which also indicated that Menin inhibitor may be a prospective therapeutic strategy for human OS.

Current small-molecule-regulated synthetic gene switches face clinical limitations such as cytotoxicity, long-term side-effects and metabolic disturbances. Here, we describe an advanced synthetic platform inducible by risk-free input medication (ASPIRIN), which is activated by acetylsalicylic acid (ASA/aspirin), a multifunctional drug with pain-relieving, anti-inflammatory, and cardiovascular benefits. To construct ASPIRIN, we repurpose plant salicylic acid receptors NPR1 and NPR4. Through domain truncations and high-throughput mutant library screening, we enhance their ASA sensitivity. Optimized NPR1 fused with a membrane-tethering myristoylation signal (Myr-NPR1) forms a complex with NPR4, which is fused with a DNA binding domain (VanR) and a transactivation domain (VP16). ASA induces dissociation of the Myr-NPR1/NPR4-VanR-VP16 complex, allowing nuclear translocation of NPR4-VanR-VP16 to activate VanR-operator-controlled gene expression. In male diabetic mice implanted with microencapsulated ASPIRIN-engineered cells, ASA regulates insulin expression, restores normoglycemia, alleviates pain and reduces biomarkers of diabetic neuropathy and inflammation. We envision this system will pave the way for aspirin-based combination gene therapies.

Ovarian cancer (OC) is an aggressive malignancy of the female reproductive organs, associated with a low 5-year survival rate. Emerging evidence suggests the pivotal role of microRNAs (miRNAs) in regulating chemoresistance and metastasis in OC, primarily through cancer stem cells (CSCs), also known as cancer stem-like cells (CSLCs). Herein, we demonstrate that miR-379-5p is downregulated in several OC cell populations including both cell lines and patient tumor samples. Furthermore, overexpression of miR-379-5p effectively inhibits CSCs and counteracts cisplatin-induced expansion of CSCs. Further mechanistic investigations identify RAD18, a DNA repair protein involved in translesion DNA synthesis (TLS), as a direct target of miR-379-5p. Moreover, a negative correlation between miR-379-5p and RAD18 expression is observed in ovarian CSCs isolated from OC patients. The downregulation of RAD18 inhibits stem-like phenotypes and enhances the sensitivity of ovarian CSCs to cisplatin treatment. Importantly, miR-379-5p-mediated inhibition of RAD18 prevents the repair synthesis in CSCs by promoting the accumulation of DNA damage. In vivo studies further reveal that miR-379-5p enhances DNA damage, which, in turn, inhibits tumor cell proliferation in athymic nude mice. Remarkably, targeting of RAD18 by miR-379-5p prevents monoubiquitination of proliferating cell nuclear antigen (PCNA), resulting in reduced DNA Polymerase η (a TLS polymerase that helps to bypass DNA lesions) recruitment to lesion sites. In the absence of Polη, the persisting DNA lesions cause activation of cell cycle arrest and apoptosis pathway in CSCs. Therefore, our findings unveil a novel mechanism whereby miR-379-5p overexpression curtails CSCs by modulating the RAD18/Polη axis.

Most land plants engage in arbuscular mycorrhiza (AM) symbiosis with Glomeromycotina fungi for better access to mineral nutrients. The plant hormone ethylene suppresses AM development, but a molecular explanation for this phenomenon is lacking. Here we show that ethylene inhibits the expression of many genes required for AM formation in Lotus japonicus. These genes include strigolactone biosynthesis genes, which are needed for fungal activation, and Common Symbiosis genes, which are required for fungal entry into the root. Application of strigolactone analogs and ectopic expression of the Common Symbiosis gene Calcium Calmodulin-dependent Kinase (CCaMK) counteracts the effect of ethylene. Therefore, ethylene likely inhibits AM development by suppressing expression of these genes rather than by inducing defense responses. These same genes are regulated by SUPPRESSOR OF MAX2 1 (SMAX1), a transcriptional repressor that is proteolyzed during karrikin signaling. SMAX1 is required for suppression of AM by ethylene, and SMAX1 abundance in nuclei increases after ethylene application. We conclude that ethylene suppresses AM by promoting accumulation of SMAX1. SMAX1 emerges as a signaling hub that integrates karrikin and ethylene signaling, thereby orchestrating development of a major plant symbiosis with a plant's physiological state.

RNA-binding proteins (RBPs) have emerged as critical regulators of cancer progression, influencing virtually all hallmarks of cancer. Their ability to modulate gene expression patterns that promote or inhibit tumorigenesis has positioned RBPs as promising targets for novel anti-cancer therapies. This mini-review summarizes the current state of RBP-targeted cancer treatments, focusing on five examples, eIF4F, FTO, SF3B1, RBM39 and nucleolin. We highlight the diversity of current targeting approaches and discuss ongoing challenges including the complexity of RBP regulatory networks, potential off-target effects and the need for more specific targeting methods. By assessing the future potential of novel therapeutic avenues, we provide insights into the evolving landscape of cancer treatment and the critical role RBPs may play in next-generation therapeutics.

Epithelial-mesenchymal transition (EMT) is a highly dynamic cellular process that occurs in development, tissue repair, and cancer metastasis. As a master EMT inducer, transforming growth factor-beta (TGF-β) can activate the EMT program by regulating the expression of key EMT-related genes and triggering other required cellular changes. However, it is unclear whether cell metabolism is involved in TGF-β-induced EMT. Here, we characterized early metabolic changes in response to transient TGF-β stimulation in HaCaT cells and discovered that TGF-β signaling significantly reduces the intracellular polyamine pool. Exogenous addition of spermine, but not other polyamines, attenuates TGF-β-induced EMT. Mechanistically, spermine downregulates the extracellular matrix protein fibronectin. Furthermore, we found that TGF-β activates extracellular signal-regulated kinase to enhance the expression of spermine oxidase, which is responsible for the reduced spermine concentration. This action of TGF-β on EMT via the polyamine metabolism provides new insights into the mechanisms underlying EMT and might be exploited as a way to target the EMT program for therapy.

Valproic acid (VPA) exposure during the gestational period has been found to impair the cognition of the offspring. The study aimed to investigate whether VPA leads to offspring cognitive impairment through disturbing interneuron development.

Chronic atrophic gastritis (CAG) is a precancerous lesion characterised by gastric mucosal atrophy and inflammation. Identifying key molecular mechanisms and potential therapeutic targets is essential to improve patient outcomes. Key modules and differentially expressed genes (DEGs) were recognised in the GSE153224 dataset using weighted gene co-expression network analysis (WGCNA) and examination of differential expression. IGFBP7 was identified as a hub gene by protein-protein interaction (PPI) network and expression validation. CAG patients' blood parameters and gastric mucosal health status were evaluated before and after the treatment of vitamin C (VC). In addition, we investigated the effects of VC and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on GES-1 cells, including cell viability, apoptosis and the expression of inflammatory and angiogenic markers. WGCNA identified that the blue module was significantly associated with CAG with a correlation coefficient 0.924. Among 93 overlapping genes, IGFBP7 was notably underexpressed and selected as a hub gene. ROC analysis confirmed the high diagnostic performance of IGFBP7. CAG patients treated with VC showed significant improvement in blood parameters and improved gastric mucosal health. In vitro, VC increased cell viability, reduced cytotoxicity and apoptosis and lowered COX-2 and apoptosis-related protein expression in MNNG-treated GES-1 cells. Knockdown of IGFBP7 further influenced these effects. MNNG upregulated HIF-1α/VEGF signalling proteins, which VC attenuated. Combined VC and IGFBP7 knockdown showed potential protective effects. This study highlights the regulatory role of VC and IGFBP7 in CAG and demonstrates their potential as therapeutic targets for improving gastric mucosal health and mitigating inflammation.

Neuroblastoma (NB) is the most common solid tumor in children, characterized by high recurrence rates, drug resistance, and significant mortality.

It has demonstrated the indispensable role of ferroptosis in conferring cisplatin resistance in non-small cell lung cancer (NSCLC), as well as the involvement of ubiquitin-specific protease (USP) in regulating ferroptosis. This paper aspired to the mechanism of USP2 and ferroptosis on NSCLC cisplatin resistance.

Hospital and community-acquired infections caused by Methicillin-resistant Staphylococcus aureus (MRSA) have emerged as a significant public health challenge, highlighting the urgent need for novel antibiotics. In response, the antibacterial properties of natural products derived from traditional plants are being investigated as potential treatments for multidrug resistance. This study demonstrates the potent antibacterialimoact of Berberine (BBR), a compound derived from traditional Chinese medicine, against the community-associated MRSA (CA-MRSA) strain USA300 LAC. Through a comprehensive series of in vitro antibacterial experiments and gene-level investigations, we discovered that BBR compromises the integrity of the USA300 LAC cell wall structure. This mechanism of action is likely attributed to the inhibition of the tarO gene, which encodes a critical enzyme in the initial stage of wall teichoic acid (WTA) biosynthesis, thereby suppressing WTA synthesis, an essential component of the cell wall. Additionally, BBR upregulates the expression of lytic enzymes LytM and SsaA, resulting in accelerated hydrolysis of peptidoglycan, a major structural element of the cell wall. This disruption ultimately leads to the destruction of the USA300 LAC cell wall. Moreover, combined antibacterial assays reveal that BBR synergistically enhances the antibacterial effect of Oxacillin against USA300 LAC. Overall, our findings elucidate the antibacterial mechanism of BBR, a traditional Chinese medicine monomer, against MRSA and highlight its promising potential for clinical application in the treatment of MRSA.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a major challenge in the treatment of lung cancer. Cancer associated fibroblasts (CAFs) play a key role in promoting resistance to anti-cancer therapies. This study identified a subpopulation of CAFs characterized by the overexpression of collagen triple helix repeat-containing 1 (CTHRC1) through single-cell RNA sequencing of lung cancer patients undergoing EGFR-TKI treatment. These CTHRC1+ CAFs were enriched in drug-resistant tumors. Mechanistically, CTHRC1+ CAFs enhance the glycolytic activity of cancer cells by activating the TGF-β/Smad3 signaling pathway. Excess lactate produced in the process of glycolysis further upregulates CTHRC1 expression in CAFs through histone lactylation, creating a positive feedback loop that sustains EGFR-TKI resistance. The study also demonstrated that Gambogenic Acid, a natural compound, can disrupt this feedback loop, thereby improving the efficacy of EGFR-TKI therapy. Additionally, the presence of CTHRC1+ CAFs in tumor tissues could serve as a biomarker for predicting the response to EGFR-TKI therapy and patient prognosis. Overall, this study highlights the significant role of CAFs in EGFR-TKI resistance and suggests that targeting CTHRC1+ CAFs could be a promising strategy to overcome drug resistance in lung cancer.

Antibiotic resistance or tolerance of pathogens has become one of the global public crises. Finding new drug targets may open up a way of infection control. Phenazine pyocyanin (PYO) is an important virulence factor produced by the pathogen Pseudomonas aeruginosa. Here we show that a multidrug efflux pump repressor, MexL, acts as a transcriptional activator to enhance phenazines production via binding with a conserved DNA motif within the promoters of phenazines biosynthesis genes. Moreover, PYO functions as a self-regulating ligand of MexL for restricting its own production and the mexL knockout attenuates the virulence and antibiotics tolerance of P. aeruginosa. Based on the structure of MexL we resolve, we find two antimicrobials that can interact with MexL to reduce the PYO production and virulence of P. aeruginosa. Our in vivo studies suggest that the antimicrobials combination by using MexL-antagonists to reduce bacterial virulence and enhance the efficacy of common antibiotics can be an effective way to combat P. aeruginosa infection.

The NAC family is among the most extensive sets of plant-exclusive transcription factors (TFs), which are crucial for various plant development and stress response processes. Although a growing number of studies have been carried out on the NAC family in different species, it has not been characterized in Glycyrrhiza uralensis. To thoroughly understand the effects of methyl jasmonate (MeJA) and sodium chloride (NaCl) inductions on NAC TFs and investigate the underlying regulatory mechanism of NAC TFs in response to MeJA and NaCl on the biosynthesis of metabolites, we used transcriptome sequencing combined with qRT‒PCR to explore differential gene expression. Comparative transcriptomic profiling by RNA sequencing (RNA-seq) revealed differentially expressed NAC TFs between MeJA/CK (Mock Control) and NaCl/CK. KEGG pathway analysis revealed that NAC TFs involved in starch and sucrose, carbohydrate, lipid, and amino acid metabolism, as well as terpenoid, polyketide, and flavonoid pathways, can regulate the MeJA- and NaCl-induced responses of G. uralensis. This research lays the groundwork for a thorough comprehension of the regulatory mechanism of NAC TFs in response to MeJA and NaCl induction and their involvement in the accumulation of secondary metabolites, which can provide a scientific basis for the cultivation of high-quality varieties of G. uralensis.

Genetic and epigenetic modifications of DNA are involved in cancer initiation and progression. Epigenetic modifications change chromatin structure and DNA accessibility and thus affect DNA replication, DNA repair and transcription. Epigenetic modifications are reversible and include DNA methylation, histone acetylation and histone methylation. DNA methylation is catalysed by DNA methyltransferases, histone acetylation and deacetylation are catalysed by histone acetylases and deacetylases, while histone methylation is catalysed by histone methyltransferases. Epigenetic modifications are dysregulated in several cancers, making them cancer therapeutic targets. Epigenetic drugs (epi-drugs) which are inhibitors of epigenetic modifications and include DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi) and bromodomain and extra-terminal motif protein inhibitors (BETi), have demonstrated clinical success as anti-cancer agents. Furthermore, the combination of epi-drugs with standard chemotherapeutic agents has demonstrated promising anti-cancer effects in pre-clinical and clinical settings. In this review, we discuss the role of epi-drugs in cancer therapy and explore their current and future use in combination with other anti-cancer agents used in the clinic. We further highlight the side effects and limitations of epi-drugs. We additionally discuss novel delivery methods and novel tumour epigenetic biomarkers for the screening, diagnosis and development of personalised cancer treatments, in order to reduce off-target toxicity and improve the specificity and anti-tumour efficacy of epi-drugs.

Sepsis-induced acute kidney injury is a fatal, potentially reversible clinical condition. C5a receptor (C5aR) has been implied to play pivotal roles in both autophagy and sepsis-induced organ dysfunction. The aim of this study was to demonstrate the effects of intravenous immunoglobulin preparations on the expression of autophagy markers and investigate possible association between C5aR expression and autophagy in the kidney tissue of septic rats.

Bladder cancer is a prevalent malignancy, ranging from superficial forms to more aggressive types that invade the muscle and require extensive treatment. Imipramine, traditionally used as an antidepressant, has shown potential as an anti-cancer agent.

This study investigated the role of scutellarin (Scu) and Nrf2 in diabetic atherosclerosis, focusing on their effects on FBXL2 and NLRP3 ubiquitination. Human umbilical vein endothelial cells were treated with high glucose (HG) to model diabetic atherosclerosis in vitro. Cell viability, cytotoxicity, pyroptosis, and inflammatory cytokine levels were assessed, and gene interactions were examined by dual-luciferase reporter assays. Ubiquitination and protein levels were analyzed through immunoprecipitation and western blotting. The results revealed that HG treatment decreased Nrf2 and FBXL2 levels and enhanced NLRP3-mediated pyroptosis. However, Scu treatment increased Nrf2 expression, improved cell viability, and inhibited pyroptosis. Nrf2 knockdown downregulated FBXL2 and reversed the protective effects of Scu. Additionally, FBXL2 promoted the ubiquitination-mediated degradation of NLRP3 and suppressed pyroptosis. The activation of NLRP3 reversed the protective effects of Scu on diabetic atherosclerosis. These findings suggest that Scu alleviated diabetic atherosclerosis by increasing Nrf2 and FBXL2 expression, promoting NLRP3 ubiquitination-mediated degradation, and suppressing pyroptosis.