Itaconate, derived from the tricarboxylic acid cycle, is recognized as a key regulator of the immune response in mammals. Despite this well-characterized role, its presence and functions within plants have remained largely unexplored. Here, we identify itaconate as an endogenous metabolite in maize and Arabidopsis and investigate its impact on development. Itaconate treatment has dose-dependent effects on growth in maize and Arabidopsis seedlings. To characterize the mechanisms responsible for itaconate's regulation of plant development, we investigated its effects on Arabidopsis roots using analysis of mutants and reporter lines, RNA sequencing, and two forms of protein-metabolite interaction assays. Our results demonstrate that itaconate covalently binds to proteins and substantially influences critical pathways in plants, including central carbon metabolism, phytohormone signaling, and oxidative stress response. This study expands the current understanding of itaconate's roles beyond the animal kingdom, providing a foundation for further research into its complex functions in plants.

Daidzin (DZN) is a natural flavonoid compound derived from soybeans that has recently been recognized for its potential antitumor properties. In traditional Chinese medicine, soybeans and their extracts are extensively used to prevent and treat various diseases. To evaluate the therapeutic efficacy of DZN on human glioblastoma through in vivo and in vitro experiments, and through multi-omics analyses to elucidate potential molecular mechanisms. Cell viability of LN-229 and U-87MG glioblastoma cells was assessed using the CCK-8 assay. Protein and mRNA levels of proliferation and apoptosis-related genes were analyzed via Western blotting and qPCR. Metabolomics and transcriptomics identified key pathways and targets, which were confirmed by in-cell Western blotting and expression correlation analysis. The in vivo antitumor effects of DZN were evaluated in nude mice with LN-229 tumors. DZN treatment reduced cell viability, migration, and survival in a dose-dependent manner, demonstrating strong antitumor effects in both in vitro and in vivo models. Multi-omics analysis identified amino acid metabolism and ubiquitin-mediated proteolysis as key mechanisms. Bioinformatics highlighted LRP5 as a prognostic biomarker in glioblastoma. DZN decreased LRP5 activity, downregulated p-GSK-3β, and promoted c-Myc degradation, thereby inhibiting the Wnt signaling pathway. In vivo, DZN significantly reduced tumor size and Ki67 expression. These findings highlight LRP5 as a promising therapeutic target, with DZN emerging as a potent LRP5 inhibitor and exhibiting significant antitumor effects in glioblastoma.

The aim of this study was to investigate the role of glutathione peroxidase 7 (GPX7) in mitigating oxidative stress-induced cellular ageing and its contribution to intervertebral disc degeneration (IVDD).

Pancreatic and duodenal homeobox protein (PDX)1 is a major transcription factor for the regulation of insulin, glucagon and somatostatin (SST) expression. PDX1 is phosphorylated by CK2 and inhibition of this kinase results in an increased insulin and decreased glucagon secretion. Therefore, we speculated in this study that CK2 also affects SST expression. To test this, we analyzed the effects of the two CK2 inhibitors CX-4945 and SGC as well as of PDX1 overexpression on SST expression and secretion in RIN14B cells by qRT-PCR, luciferase assays, Western blot and ELISA. SST expression and secretion were additionally assessed in isolated murine and human islets exposed to the CK2 inhibitors. Moreover, we determined the expression and secretion of the pancreatic endocrine hormones in CX-4945-treated mice. We found a suppressed SST expression in RIN14B cells due to a methylated SST promoter, which could be abolished by DNA demethylation. Under these conditions, we showed that CK2 inhibition increases SST gene expression and secretion. Additional experiments with overexpression of a CK2-phosphorylation mutant of PDX1 verified that SST expression is regulated by CK2. The exposure of isolated murine and human islets to CX-4945 or SGC as well as the treatment of mice with CX-4945 revealed that CK2 also regulates SST expression under physiological conditions. Taken together, these findings not only demonstrate that CK2 controls SST expression in pancreatic δ-cells but also emphasize the crucial role of this kinase in regulating the main hormones of the endocrine pancreas.

Renal cell carcinoma (RCC) is a malignant neoplasm arising from the renal epithelium and constitutes approximately 2% of global cancer diagnoses and mortalities. With increasing prevalence, RCC remains a pressing clinical challenge, particularly because of its resistance to conventional therapies and poor outcomes in advanced stages. Long noncoding RNAs (lncRNAs) have been proposed as key molecular mediators in RCC, orchestrating critical pathways such as epithelial-to-mesenchymal transition (EMT), cellular proliferation, apoptosis, angiogenesis, and metastasis. Their roles in therapeutic resistance, including chemoresistance and radioresistance, further highlight their impact on treatment outcomes. Additionally, the potential of natural compounds such as curcumin, quercetin, and resveratrol to target lncRNA-mediated pathways has garnered attention, offering insights into novel therapeutic strategies. This review examines the biogenic pathways and multifaceted functions of lncRNAs, shedding light on their influence on RCC pathophysiology and posttranscriptional regulation. In addition, this review emphasizes the repercussions of natural compounds as lncRNA-targeted therapies, thus offering a comprehensive perspective on emerging strategies that may lead to more effective and personalized treatments.

Bladder cancer is the most common malignant tumor of the urinary tract. In this study, 90 lupane triterpene derivatives, previously synthesized in the laboratory, were systematically evaluated for their potential effects against bladder cancer by cytotoxicity screening against five urinary tumor cell lines. Bioinformatics and molecular dynamics methods were used to investigate the mechanism of action of compound 27 in depth. Most of the derivatives effectively inhibited tumor cell growth, and structure-activity relationship analysis revealed that introducing an indole moiety significantly enhanced the biological activity. The peak activity was reached when the dibromoalkyl chain length was C = 5 (IC50 = 1.121 μM). By integrating transcriptomic data and TCGA findings, we identified 11 key targets, among which DUSP5 and SCG2 showed significant differential expression. Further analysis revealed meaningful insights into the clinical association, 10-year survival prognosis, and immune infiltration. The present study further clarified the effects of compound 27 on the expression of DUSP5 and SCG2 in tumor cells after treatment by a combination of RNA-seq and RT-qPCR. Molecular docking confirmed the stable binding of compound 27 to DUSP5, which was confirmed by molecular dynamics simulations. Compound 27 inhibited bladder cancer progression by upregulating DUSP5 expression and negatively regulating the p38 MAPK pathway, modulating the immune response and promoting apoptosis.

Oxaliplatin, a key chemotherapeutic agent, often induces resistance in colorectal cancer (CRC) treatment, highlighting the urgent need for reliable biomarkers to predict treatment efficacy. In this study, we aimed to identify key genes associated with oxaliplatin resistance in CRC and to evaluate their potential as prognostic biomarkers. Using CRC patient data from the TCGA dataset, we categorized patients into oxaliplatin-resistant and -sensitive groups and conducted differential expression analysis. Key feature genes were identified through univariate Cox analysis, LASSO regression, and stepwise multivariate Cox regression. The predictive value of the identified markers was validated using logistic regression, weighted gene co-expression network analysis (WGCNA), and external validation in GEO cohorts. The tumor microenvironment (TME) was assessed using the MCP-counter algorithm, and CRC cell experiments were performed to evaluate changes in drug sensitivity following oxaliplatin exposure. Based on TCGA CRC data, we constructed a prognostic index derived from a three-gene signature associated with oxaliplatin resistance. This index was significantly correlated with progression-free survival (PFS) in oxaliplatin-resistant CRC patients and showed robust prognostic performance, with AUCs of 0.848 and 0.861 in gastric cancer and pancreatic adenocarcinoma cohorts, respectively. Notably, TNFAIP2 knockout significantly reduced clonogenic ability in CRC cells following oxaliplatin treatment. Our results identify TLE4, TNFAIP2, and ARGLU1 as key contributors to oxaliplatin resistance in CRC. The oxaliplatin resistance-related gene signature (ORGSig) serves as a promising tool for predicting treatment response and prognosis in CRC patients receiving oxaliplatin-based chemotherapy. This signature also offers potential for guiding personalized therapy and overcoming drug resistance in clinical practice.

Calcium (Ca) signalling is critical for plant responses to aluminum (Al) stress, with STOP1-mediated ALMT1 expression playing a crucial role in Arabidopsis Al resistance. However, the specific intracellular Ca2+ sensors responsible for transducing Al signals in this process remain unclear. In this study, we identified CPK21 and CPK23, members of the CPK family, as key regulators promoting STOP1-mediated ALMT1 expression under Al stress, significantly influencing malate exudation from roots to limit Al accumulation in root tips. Al stress triggers rapid Ca2+-dependent accumulation of CPK21 and CPK23 in the plasma membrane, cytoplasm and nucleus of root apical cells. The Al-activated CPK21 and CPK23 subsequently phosphorylate STOP1 in both the cytoplasm and nucleus of root apical cells, stabilizing STOP1 by preventing its interaction with RAE1, ultimately enhancing Al resistance. This entire process is Ca2+-dependent. The study unveils a previously undisclosed regulatory network in which CPKs integrate Al-evoked Ca2+ signals and transcriptional reprogramming through the Ca2+-CPK21/23-STOP1 cascade to effectively respond to and adapt to Al stress in plants.

The transcription factor SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1) functions as a crucial integrator of plant responses to various stresses, including aluminum (Al) stress. Its stability and accumulation are modulated by stress-specific post-translational mechanisms such as phosphorylation and ubiquitination. However, the upstream signaling mechanisms governing these modifications remain poorly understood. Here, we reveal that Ca2+ signaling and Ca2+-dependent phosphorylation are essential for Al stress-responsive regulation of STOP1. Al exposure specifically induces rapid, spatio-temporally defined biphasic Ca2+ signals in Arabidopsis roots and concomitantly activates the Ca2+-dependent kinase CPK28. Al-activated CPK28 phosphorylates STOP1 at Ser163, a modification that promotes the nuclear localization of STOP1 and prevents its degradation by inhibiting its interaction with the F-box protein RAE1. This phosphorylation enhances STOP1 accumulation and Al resistance. Our findings identify Ser163 phosphorylation as a key molecular switch and establish a Ca2+-CPK28-STOP1 signaling axis critical for plant adaptation to Al stress.

Listeria monocytogenes is a significant zoonotic pathogen capable of forming biofilms on food and other materials, representing a considerable risk to human health and animal husbandry. The use of bacteriocins as potential new antibacterial and antibiofilm reagents has attracted considerable interest. This study aimed to determine the inhibitory effects of bacteriocin PCM7-4 on L. monocytogenes biofilm formation. In this study, bacteriocin PCM7-4 of SICs (1/16 × MIC, 1/8 × MIC) significantly inhibited the formation of L. monocytogenes biofilm. Bacteriocin PCM7-4 of SICs significantly reduced the production of bacterial extracellular polysaccharides, and could decrease the bacterial motility, meanwhile, PCM7-4 significantly reduced the number and viability of bacteria within the biofilm. RT-qPCR results showed that bacteriocin PCM7-4 significantly reduced the expression of flagella, community sensing and virulence factor genes associated with biofilm formation. The results demonstrated the considerable potential of bacteriocin PCM7-4 as a therapeutic agent for the prevention and treatment of L. monocytogenes biofilms.

The antibiotic minocycline has been suggested as a potential agent in cancer therapy due to its anti-inflammatory properties and effectiveness as an NF-κB inhibitor. In previous studies, we showed that minocycline could effectively block the fusion of breast epithelial cells and cancer cells. However, its influence on breast cancer cell characteristics, including proliferation, migration, and gene expression has not yet been investigated.

Ovarian cancer (OC) is associated with poor prognosis and immune evasion through PD-L1 expression. While anti-PD-L1 therapies have shown limited efficacy, combination strategies may enhance therapeutic outcomes. This study explores the potential of metformin to modulate the immune microenvironment and improve the efficacy of PD-L1 inhibitors in OC. An immunocompetent C57BL/6 mouse model of OC was used to evaluate the effects of metformin and PD-L1 inhibitors on tumor progression, immune cell infiltration, and cytokine expression. Mice received daily metformin treatment for 2 weeks, with PD-L1 inhibitors administered twice weekly. Tumor growth was monitored via volume measurements, immune cell infiltration was assessed by flow cytometry, and cytokine levels (Granzyme B, IFN-γ) were quantified using ELISA. Metformin significantly reduced tumor growth, increased CD8+ T cell infiltration, upregulated RBMS3, and elevated Granzyme B and IFN-γ expression. Additionally, metformin downregulated PD-L1 expression, and its combination with PD-L1 inhibitors further enhanced CD8+ T cell activity. Silencing RBMS3 reversed these effects, underscoring its critical role in immune modulation. These findings suggest that metformin, in combination with PD-L1 inhibitors, may enhance antitumor immune responses and improve treatment outcomes in OC. Targeting RBMS3 could represent a novel therapeutic approach for overcoming immune evasion in OC.

Cisplatin (cis-diamminedichloroplatinum II, CDDP), a widely used chemotherapeutic agent, is clinically limited by nephrotoxicity. Rhein, an anthraquinone from Radix Rhein Et Rhizome, shows nephroprotective potential. This study investigated Rhein's protective effects and mechanisms in CDDP-induced acute kidney injury (AKI).

Lettuce (Lactuca sativa L.) is sensitive to high temperatures, and the growth is inhibited under excessive temperature. Spermidine can improve the ability of lettuce to tolerate high temperatures, however, the molecular mechanism was poorly understood. The molecular mechanism of lettuce response to heat stress (2h) were investigated by physiology, transcriptome, and proteome. The results showed that 781 differentially expressed genes (DEGs) and 255 differentially expressed proteins (DEPs) were detected in lettuce treated with spermidine under heat stress. The DEGs and DEPs of lettuce were treated with 1 mM spermidine under high temperatures stress. There were 718/236 genes/proteins with the same expression trend. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed the genes were mainly enriched in intracellular signal transduction and carbohydrate metabolism pathways, which stimulated the expression of genes/proteins related to hormone and mitogen-activated protein kinase (MAPK) signal transduction pathways, starch and sucrose metabolism, pentose and glucose mutual transformation pathways. It also increased the contents of auxin and cytokinin, starch and soluble sugar. String network analysis showed that spermidine promoted material transport and antioxidant enzyme activity to improve lettuce resist high-temperature stress by removing superoxide radicals, binding and central transport of nuclear pores. In summary, signal transduction and gluconeogenic pathways may be the main ways in which spermidine improve lettuce to tolerate in heat stress. These results increase the understanding of the heat tolerance of lettuce at the transcriptional and protein levels, and provide a better understanding of the heat tolerance mechanism of lettuce.

Aberrant expression of histone deacetylases (HDACs) is associated with cancer drug resistance and tumor progression. While considerable studies and effort have been devoted to developing novel HDAC inhibitors in cancer therapy, hydroxamate-based HDAC inhibitors have gained growing interest for their broad-spectrum anti-tumor properties. We developed a series of HDAC inhibitors featuring a hydroxamate moiety, and WMJ-J-09 was selected due to its potent cytotoxic effect in colorectal cancer (CRC) cells, and its molecular mechanisms driving CRC cell death were characterized. WMJ-J-09 reduced cell viability, arrested the cell cycle at the G2/M phase, and triggered apoptosis. Mechanistically, it activated LKB1-p38MAPK signaling, leading to p53 phosphorylation and acetylation, which elevated p21 and suppressed survivin levels. WMJ-J-09 also acetylated α-tubulin, impaired microtubule assembly, and acetylated survivin, resulting in proteasomal degradation. Both LKB1 siRNA and anacardic acid, a histone acetyltransferase inhibitor, reversed WMJ-J-09-reduced survivin, confirming its dual effects on survivin at transcriptional and post-translational levels. In vivo, the subcutaneous growth of HCT116 CRC xenografts was reduced by WMJ-J-09. In conclusion, WMJ-J-09 causes CRC cell death via the LKB1-p53-survivin signaling pathway and HDAC inhibition, leading to acetylation of α-tubulin, p53, and survivin. This study highlights WMJ-J-09's potential as a promising therapeutic candidate for CRC treatment.

Gastric cancer (GC) is a prevalent digestive tract malignancy, and Huangqi Fuling decoction (HF) has shown potential in enhancing immune function and exhibiting anti-GC activity. However, its mechanisms remain unclear. This study utilized network pharmacology, molecular docking, and in vitro experiments to preliminarily explore the mechanisms by which HF inhibits gastric cancer invasion and metastasis while promoting apoptosis. Public databases identified differentially expressed genes (DEGs), HF targets, and GC-related genes. GO and KEGG analyses revealed signaling pathways. Clinical relevance, immune infiltration, immunotherapy, and molecular docking of hub genes were analyzed. Eight hub genes-PTGS2, MMP9, SELE, CCL2, VCAM1, ICAM1, CXCL2, and CXCL10-associated with the TNF signaling pathway were identified. HF inhibits the invasion and metastasis of GC cells by down-regulating MMP9 and PTGS2 expression, while inducing apoptosis by suppressing BCL-2 expression and promoting BAX expression. Additionally, HF can arrest the cell cycle, blocking AGS cells in the S phase and HGC-27 cells in the G0/G1 phase. This study confirms that HF promotes apoptosis and inhibits metastasis and invasion in GC cells, primarily by modulating the TNF signaling pathway. Additionally, the anti-tumor effects of HF on GC may involve immune regulatory mechanisms, but the mechanism require further experimental verification.

Endocrine resistance is frequently encountered in estrogen receptor-positive (ER+) breast cancer, often because of somatic mutations such as neurofibromin 1 (NF1) loss. The mechanisms by which ER-directed proliferation is lost in such cases are unknown, limiting the potential use of additional endocrine treatments. Here, we performed CRISPR-Cas9 knockout (KO) screens and found that nuclear receptor subfamily 2 group F member 2 (NR2F2), an orphan nuclear receptor, was essential for NF1 loss-induced endocrine resistance. Induction of NR2F2 was observed in ER+ cell line models and patient samples and occurred via activation of the mitogen-activated protein kinase (MAPK) pathway upon NF1 loss or other MAPK pathway genetic alterations. Mechanistically, increased NR2F2 orchestrated a repressed ER transcriptional program by repartitioning the ER cistrome, altering the balance of its associated transcriptional coregulators, and modifying global chromatin accessibility. Accordingly, genetic depletion or pharmacologic inhibition of NR2F2 restored sensitivity to hormone therapies in multiple models, including ER+ cell lines, patient-derived xenografts, and patient-derived organoid-based xenografts harboring diverse endocrine-resistance mechanisms such as NF1, AT-rich interactive domain-containing protein 1A (ARID1A), phoshatase and tensin homolog (PTEN) loss, or Kirsten rat sarcoma virus (KRAS) overexpression. Together, these findings underscore NR2F2 as a critical modulator of the hormone response pathway and suggest its inhibition as a promising strategy to overcome endocrine resistance in breast cancer.

Indisulam, a sulfonamide-based compound, is employed as a second-line therapy for NSCLC due to its anti-tumor activity. However, its clinical efficacy is hindered by acquired resistance, the molecular basis of which remains poorly understood. Here, we demonstrate that hypermethylation of RNA-binding protein 39 (RBM39), a specific target of Indisulam, is closely associated with Indisulam resistance. PRMT6 methylates RBM39 at R92. This methylation inhibits Indisulam-induced ubiquitination and proteasomal degradation of RBM39, increases RBM39 protein levels, promotes alternative splicing and expression of proto-oncogenes, and ultimately leads to malignant proliferation and metastasis of NSCLC cells and tumor growth in xenograft mouse models. Inhibiting PRMT6 with MS023 or mutating the RBM39 methylation site enhances Indisulam sensitivity in NSCLC and significantly improves its anti-tumor efficacy. Our findings identify methylated RBM39 as a key biomarker of Indisulam resistance and suggest a potential therapeutic strategy for NSCLC.

Our previous research demonstrated that curcumin suppresses mouse colorectal cancer (CRC) cell CT26 migration and invasion by inhibiting heparanase (HPSE) mRNA expression. To further elucidate the mechanism of curcumin in human CRC treatment, we hypothesized that HPSE plays a pivotal role in human CRC metastasis and that curcumin inhibits this process by downregulating HPSE expression through epigenetic regulation mediated by non-coding RNAs. For further research, human CRC cells were infected with lentivirus to establish overexpression of HPSE cell lines and corresponding negative control cell lines. In vitro and in vivo experiments showed that curcumin inhibited the proliferation, migration, and metastasis of CRC cancer by inhibiting HPSE expression. In the tumor microenvironment, HPSE played an important role in activating the IL-6/STAT5 axis signaling pathway by destructing the extracellular matrix and releasing large number of cytokines, while changing the tumor microenvironment and EMT process, thus promoting tumor metastasis. RNA-seq analysis combined with qRT-PCR results showed that curcumin's inhibition of HPSE expression involved the regulation of non-coding RNAs. Taken together, our results suggested that HPSE promotes CRC metastasis by activating the IL-6/STAT5 signaling axis, disrupting the ECM, releasing cytokines, and altering the tumor microenvironment to facilitate EMT. Curcumin significantly inhibits CRC cell proliferation, migration, and metastasis by downregulating HPSE expression via non-coding RNAs, which related to IL-6/STAT5 axis signal pathways. This research provides a comprehensive understanding of the molecular mechanisms underlying curcumin's anti-CRC effects, emphasizing the role of HPSE and non-coding RNAs in tumor metastasis. These findings pave the way for the development of novel therapeutic strategies targeting HPSE and its regulatory pathways in CRC.

Uterine sarcoma is strongly associated with poor prognosis. However, its treatment options remain limited. Tazemetostat is a potent and selective EZH2 inhibitor with limited clinical application. Entinostat is one of the strong inhibitors for HDAC1 and HDAC3. This study aimed to assess the effect of dual targeting of EZH2 and HDACs on the phenotype of uterine sarcoma cells in both 2D and 3D culture systems. The uterine sarcoma cell line (MES-SA) was treated with varying concentrations of tazemetostat and/or entinostat for 24, 48 and 72 h. For 3D culture conditions, the cells were combined with Matrigel and seeded in V-bottom plates and incubated for 5 days. Cell proliferation, cell cycle progression and apoptosis were evaluated. Additionally, the RNA expression, IHC staining, wound healing assay, DNMT and HDAC activity measurements were conducted. Our data showed that single-inhibitor treatment with entinostat or tazemetostat significantly increased the cytotoxicity and significantly enhanced apoptosis concomitantly. Furthermore, both inhibitors induced cell cycle arrest in 2D and 3D culture conditions. We also demonstrated that entinostat, but not tazemetostat, suppressed the wound healing in the 2D culture. The combination treatment showed a significantly superior effect compared to single-agent treatment. Our studies demonstrate that treatment with either entinostat or tazemetostat alone showed a potent anti-uterine sarcoma effect in 2D and 3D culture conditions. Importantly, the combination of entinostat and tazemetostat produced superior therapeutic effects, suggesting that dual targeting EZH2 and HDACs may provide a promising treatment option for this aggressive cancer.