Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal sarcomas of the upper digestive tract. Imatinib is the first-line therapy for patients with metastatic or unresectable GISTs. However, the majority of GIST patients eventually develop imatinib resistance.

BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR::ABL1-targeting TKIs in CML. Unlike their function in reducing drug resistance in many solid tumors, we revealed that neddylation inhibitors counteracted the cytotoxicity of TKIs against CML cells, both in cellular experiments and in animal model. Conversely, neddylation agonist sensitized the function of TKIs. RNA sequencing data revealed that neddylation inhibitor reversed the transcriptomic changes induced by TKI. Co-immunoprecipitation (co-IP) assay identified ABL1 kinase domain as a novel substrate for neddylation. Furthermore, an artificial intelligence (AI) 3-Dimensional spatial structure binding technology was employed to predict the impact of neddylation on the structure of ABL1 kinase domain. Finally, we provided potential evidence showing that TKI therapy decreased the expression of neddylation enzymes in the bone marrow of CML patients. Hence, our study offers new insights into the post-translational modification (PTM)-mediated drug resistance, and highlights the potential clinical benefits of neddylation agonists in improving the responsiveness of BCR::ABL1 TKIs in CML.

Environmental factors may affect gene expression through epigenetic modifications of histones and transcription factors. Here, we report that cellular uptake of sorbate, a common food preservative, induces lysine sorbylation (Ksor) in mammalian cells and tissue mediated by the noncanonical activities of class I histone deacetylases (HDAC1-3). We demonstrated that HDAC1-3 catalyze sorbylation upon sorbate uptake and desorbylation in the absence of sorbate both in vitro and in cells. Sorbate uptake in mice livers significantly induced histone Ksor, correlating with decreased expressions of inflammation-response genes. Accordingly, sorbate treatment in macrophage RAW264.7 cells upon lipopolysaccharide (LPS) stimulation dose-dependently down-regulated proinflammatory gene expressions and nitric oxide production. Proteomic profiling identified RelA, a component of the NF-κB complex, and its interacting proteins as bona fide Ksor targets and sorbate treatment significantly decreased NF-κB transcriptional activities in response to LPS stimulation in RAW264.7 cells. Together, our study demonstrated a noncanonical mechanism of sorbate uptake in regulating epigenetic histone modifications and inflammatory gene expression.

The cGAS-STING pathway is a central signalling mechanism in inflammatory responses and can be activated by cisplatin. Increased autophagic activity has been linked to cisplatin resistance in non-small cell lung cancer (NSCLC); however, how autophagy-STING interactions influence the cisplatin response remains unclear. This study investigates how autophagy modulation affects STING expression and cisplatin sensitivity in NSCLC cells with different basal STING levels. Autophagy was inhibited using chloroquine and induced by serum starvation in Calu-1 and H2030 cells. In Calu-1 cells, cisplatin treatment increased STING expression, activated the cGAS-STING pathway, and induced interferon responses correlated with cisplatin concentration. Autophagy inhibition reduced STING expression and interferon activation while enhancing cisplatin sensitivity. Conversely, autophagy induction caused fluctuations in STING expression and decreased cisplatin sensitivity, with ISG15 expression being selectively increased under serum starvation. In contrast, H2030 cells exhibited low basal STING expression and showed minimal responses to cisplatin or autophagy modulation. These findings suggest that STING expression levels critically influence autophagy-mediated responses to DNA-damaging chemotherapy in NSCLC.

Epigenetic modulators in combination with proapoptotic drugs have become the standard of care treatment in hematological malignancies. Conversely, these combinations have failed to demonstrate clinical efficacy in solid tumors. To address this discrepancy, we conducted a comprehensive analysis of the anti-tumor activity of epigenetic inhibitors in combination with BH3 mimetics that block anti-apoptotic proteins BCL-XL, BCL2 or MCL1 in a large set of solid tumor cell lines derived from patients and mouse models. Treatment with epigenetic drugs targeting DNA methyltransferase, histone methyltransferase, and histone deacetylase enzymes in combination with a BCL-XL inhibitor resulted in marked synergistic in vitro responses both in human and mouse solid tumor cell lines. This unique BCL-XL dependency was in clear contrast to hematological malignancies, which are largely dependent on BCL2 or MCL1 inhibition under epigenetic drug treatment. Mechanistically, co-targeting of epigenetic regulators and BCL-XL induced expression of endogenous retroelements that led to immunogenic cell death. We thus hypothesized that this response may sensitize tumor cells to immune checkpoint blockade (ICB). Accordingly, treatment with a triple combination of epigenetic and BCL-XL inhibitors with an anti-PD-1 monoclonal antibody in vivo reduced tumor growth and prolonged overall survival in a panel of murine syngeneic and orthotopic models of lung, colorectal and breast carcinomas, melanoma, and glioblastoma, as well as in an immunocompetent human colon cancer model. Using flow cytometry and single-cell RNA sequencing of the tumor microenvironment, we found that the broad activity of the triple therapy relied on the expansion of T and NK cells with cytotoxic potential, an increase in the M1/M2 macrophage ratio, and a reduction of immunosuppressive Treg cells, dendritic cells, and B lymphocytes. In conclusion, we report a novel regimen combining epigenetic and BCL-XL inhibitors with ICB that produces potent anti-tumor responses in multiple preclinical models of solid tumors.

Isorhapontigenin is an effective active ingredient in Rheum officinale, which has been reported to have anti-tumor effects. However, its effect and molecular mechanism on non-small cell lung cancer are still unclear. Firstly, potential therapeutic targets of Isorhapontigenin against non-small cell lung cancer were obtained through network pharmacology analysis. Secondly, bioinformatics analysis was conducted to identify key targets and potential signaling pathway mechanisms based on the obtained potential targets. Then, evaluated the binding ability between Isorhapontigenin and key targets by using molecular docking strategies. Finally, in vitro cell experiments were conducted to verify the effects and related targets of Isorhapontigenin on non-small cell lung cancer cells. 104 drug targets and 6688 disease targets were acquired from SwissTarget prediction, BATMAN-TCM, STITCH and Genecards databases.79 potential therapeutic targets were identified through analysis based on online Venn website and PPI interaction analysis was performed on these targets to ultimately obtain 55 key targets. GO and KEGG analysis revealed that Isorhapontigenin targets non-small cell lung cancer mainly through regulation of cell proliferation, cell cycle dynamics, and the PI3K/RELA/cell cycle axis. Molecular docking confirmed that Isorhapontigenin can bind to cell proliferation, cycle related proteins (CCND1, CDK2, PIK3CA, RELA). CCK-8 detection revealed that Isorhapontigenin significantly inhibited the proliferation of PC9 lung cancer cells, Moreover, RT-qPCR detection showed that Isorhapontigenin downregulated the expression of CCND1, CDK2, PIK3CA and RELA genes. CCND1, CDK2, PIK3CA and RELA are highly expressed in NSCLC tissues. Overall survival analysis of patients indicated that key genes in the PIK3CA and NF-κBp65 signaling pathway significantly affected overall survival. Our research has found that Isorhapontigenin can effectively against non-small cell lung cancer, and this effect may be achieved by inhibiting cell proliferation and cycle progression mediated by the PIK3CA/NF-KB signaling pathway. Isorhapontigenin is a new potential therapeutic agent for lung cancer.

Marsdenia tenacissima extract (MTE) from the stem of the Traditional Chinese herbal medicine of Marsdenia tenacissima (Roxb.) Wight et Arn. has been used as an anticancer remedy for decades.

Arsenic is a neurotoxin associated with cognitive impairment following long-term exposure, while Neurotrophin-3 (NT-3) is essential for the survival and development of neurons. This study aims to explore the protective effects of NT-3 on arsenic-caused cognitive impairment and neuronal damage, as well as clarify the underlying mechanisms. In vivo and in vitro results indicated that sodium arsenite impaired cognitive function, reduced neuronal density, and induced apoptosis, which was accompanied by the down-regulation of NT-3 and the PI3K/AKT pathway. Overexpression of NT-3 in HT-22 cells mitigated apoptosis triggered by arsenic and partially restored PI3K/AKT pathway activity. Thus, our findings suggest that NT-3 may counteract the arsenic neurotoxicity by activating PI3K/AKT.

Pharmacological ascorbate (P-AscH, high-dose, intravenous, vitamin C), is a pro-drug that generates hydrogen peroxide (H2O2) and is being investigated as a neoadjuvant treatment for pancreatic adenocarcinoma (PDAC). In a randomized, phase II clinical trial, P-AscH demonstrated encouraging results in terms of efficacy and safety. However, some patients do not respond to P-AscH suggesting that resistance occurs in a subset of patients. The aims of this study were two-fold: first to characterize PDAC cells resistant to P-AscH, and second, determine if these alterations enhance metastatic potential. Resistance to P-AscH increased the ability to detoxify H2O2, altered redox metabolism and cell cycle regulation, however mechanisms to P-AscH resistance were different in the cell lines studied. Transcriptomic analysis demonstrated a significant enrichment of the epithelial-to-mesenchymal gene expression pattern in the cell lines studied, suggesting that upregulation of metastatic phenotypes occur during acquisition of resistance to P-AscH. Cells resistant to P-AscH demonstrated increased invasive potential, more aggressive tumor colonization, and higher abundance of circulating tumor cells in vivo. Our data support that resistance to oxidative stress enhances metastatic disease and indicates a potential route for PDAC to tolerate high levels of P-AscH and may explain why some patients do not respond to this treatment regimen.

Expression of many bacterial genes is regulated by cis- and trans-acting elements in their 5' upstream regions (URs). Cis-acting regulatory elements in URs include upstream ORFs (uORFs), short ORFs that sense translation stress that manifests as ribosomes stalling at specific codons within the uORF. Here, we show that the transcript encoding the Escherichia coli TopAI-YjhQ toxin-antitoxin system is regulated by a uORF that we name 'toiL'. We propose that in the absence of translation stress, a secondary structure in the UR represses translation of the topAI transcript by occluding the ribosome-binding site. Translation repression of topAI leads to premature Rho-dependent transcription termination within the topAI ORF. At least five different classes of ribosome-targeting antibiotics relieve repression of topAI. Our data suggest that these antibiotics function by stalling ribosomes at different positions within toiL, thereby altering the RNA secondary structure around the topAI ribosome-binding site. Thus, toiL is a multipurpose uORF that can respond to a wide variety of translation stresses.

Pancreatic cancer (PC) has a poor prognosis and limited response to therapies. Combinatorial approaches, such as natural product-based therapies, can enhance anticancer efficacy while minimizing side effects. This study evaluated M. sativa's anticancer properties and its potential as adjunctive therapy with Gemcitabine (GEM) to sensitize PANC-1 cells to chemotherapy.

Omaveloxolone is a synthetic oleanane triterpene with considerable antitumor activity. It induces human glioblastoma (GBM) cell death in vitro and in vivo, but the underlying mechanism remains to be determined. In this study, GBM cell lines (GBM8401 and U-87 MG cells) were exposed to different concentrations of omaveloxolone (0, 600, 800 and 1000 nM). A cell viability assay was conducted using the PrestoBlue Cell Viability Reagent. Three-dimensional microscopy revealed changes in cell morphology. Cell cycle, apoptosis and mitochondrial membrane potential were tested using flow cytometry. The expression levels of cell cycle-related proteins and genes were determined through Western blotting and next-generation sequencing, respectively. The results indicated that omaveloxolone had significant selective cytotoxicity against human GBM cells and suppressed the migration and invasion of these cancer cells. It also caused cell cycle arrest through the downregulation of cell cycle-related genes, including cell division cycle 20 homologue (CDC20), as revealed by next-generation sequencing. In a xenograft tumour model, omaveloxolone decreased tumour volume and CDC20 expression. Taken together, these findings suggest that omaveloxolone is a potential drug candidate for GBM treatment by promoting GBM cell death through the downregulation of CDC20 expression.

Common carp is one of the most economically important freshwater fish species globally. Ammonia exposure, a frequent challenge in aquaculture, can lead to significant economic losses. This study investigated the impact of un-ionized ammonia (UIA) exposure on the expression profiles of three key genes in common carp fry: interleukin-1 beta (IL-1β), corticotropin-releasing hormone (CRH), and leptin a1 (Lep-a1). These genes are crucial indicators of immune response, stress regulation, and appetite control, respectively. Fish were exposed to 0.7 mg/L of UIA, and gene expression was analysed in liver and gill tissues at five time points (12 h, 2-, 4-, 7-, and 14-days of exposure) using quantitative real-time PCR (RT-qPCR).

Diffuse large B-cell lymphoma (DLBCL) is an aggressive hematopoietic malignancy, necessitating the exploration of innovative therapeutic approaches. Targeting epigenetic mechanisms has emerged as a promising avenue for cancer treatment. EP300 belongs to the KAT3 family of histone/non-histone lysine acetyltransferases, regulating gene expression by acetylating H3K27. However, the role of EP300 and its potential as a targeted therapy in DLBCL remains unknown.

The prevalence of depression in women is approximately twice that in men. Differences in androgens levels between men and women, due to gonadal differences, may be associated with the development of depression, although the underlying mechanisms are not well understood.

Chromium (Cr) contamination poses food safety and environmental challenges, yet the early-stage physiological and molecular responses to Cr(III) stress remain unclear. Citrus and tomato are economically important crops representing woody and herbaceous species, making them valuable models for studying heavy metal toxicity in plants. This study investigates the impact of Cr (III) exposure on citrus and tomato seedlings, with a focus on physiological phenotypes and transcriptional response. Citrus seed germination declines with increasing Cr(III) concentrations, while low Cr(III) levels promote tomato germination, with inhibition occurring above 1 g/L. Under hydroponic conditions, Cr (III) severely hampers root and leaf growth in both citrus and tomato plants, accompanied by decreased net photosynthetic rate. Using a GFP-based confocal microscopy system, we observed reduced fluorescence intensity within three days of Cr(III) exposure (100 mg/L and 500 mg/L), indicating early cellular damage. Biochemical assays revealed oxidative stress, marked by increased H2O2, malondialdehyde (MDA), and antioxidant enzyme activity. Additionally, low Cr (III) concentrations could result in the death of various microorganisms, including Escherichia coli, Agrobacterium rhizogenes, and Agrobacterium tumefaciens. Transcriptomic analysis identified differentially expressed genes related to "MAPK signaling pathway" and "Plant hormone signal transduction pathway". Transcription of many transcription factors, such as bHLH, WRKY, and MYB, also underwent significant changes.

Long-term exposure to arsenic (As), which is a ubiquitous environmental contaminant, significantly enhances the risk of multiple cancers, including bladder and lung cancers. In recent years, the important roles of circular RNAs (circRNAs) in tumorigenesis and development have attracted widespread attention. However, the specific molecular mechanisms by which circRNAs promote bladder cancer development following exposure to arsenic remain incompletely understood. This study is the first to demonstrate that circPDE3B is significantly upregulated in a cell model of transformation triggered by arsenic and that it promotes this transformation process. Our study elucidated the biological function of circPDE3B in vitro, in SV-HUC-1 cells, showing that it accelerates the malignant transformation from arsenic via increasing cell proliferation and inhibiting apoptosis. Furthermore, we delineated a novel molecular mechanism whereby circPDE3B directly binds to NF-κB and STAT3, inhibiting their ubiquitination and increasing their stability. This, in turn, affects downstream HIF-1α expression, promoting the malignant transformation of SV-HUC-1 cells and eventually resulting in bladder carcinogenesis. Our research reveals the critical regulatory role of circPDE3B in the arsenic-triggered malignant transformation within SV-HUC-1 cells. This study offers broader perspectives on the molecular mechanisms driving bladder cancer progression, while also identifying potential targets for early diagnosis and treatment of bladder tumour.

This study aimed to investigate the target genes of active components in Dingxiang Guanshitong (DGST) and evaluate their significance in the prognosis of esophageal cancer (EC) through integrated approaches, including network pharmacology, molecular docking, prognostic analysis, and in vitro experiments. EC-related data were obtained from TCGA database, while SymMap and TCMSP databases were utilized to identify DGST's bioactive components and their targets. A comprehensive network was constructed to map component-target-pathway interactions. Bioinformatics analysis revealed 113 key signaling pathways and 424 differentially expressed targets associated with DGST and EC. Univariate Cox regression analysis identified 21 target genes significantly correlated with overall survival (OS) in EC patients, among which six exhibited pharmacological activity. Molecular docking confirmed strong binding affinities between DGST's active components and critical targets. In vitro experiments demonstrated that DGST suppressed migration, invasion, and proliferation of TE-1 and EC-109 cell lines while promoting apoptosis. Furthermore, DGST significantly upregulated the protein and mRNA expression of the prognostic factor NFKBIA, while downregulating GPER1, HK2, MAOB, TNFRSF10B, and ECE1. This study is the first to elucidate the molecular mechanisms underlying DGST's anti-EC effects. DGST exerts its anti-cancer activity by targeting prognosis-related genes and modulating the expression of critical molecular markers, thereby inhibiting EC progression and improving therapeutic outcomes. These findings provide a robust scientific foundation for the clinical application of DGST and further exploration of its mechanistic basis.

Prediabetes, also known as impaired glucose tolerance (IGT), is a common metabolic disorder and is often considered a risk factor for the development of diabetes. Metformin (MET) is a widely used medication for the treatment of diabetes and has the potential to improve insulin sensitivity and blood sugar control. This work aimed to investigate the impact of MET treatment on serum miRNA expression in IGT patients and explore the quantitative changes in miRNA after MET treatment.

Nasopharyngeal carcinoma (NPC) is a unique cancer type originating from the nasopharynx. To investigate novel strategies for improving prognosis and reducing the adverse effects of current treatments, this study examined the efficacy of hellebrigenin. Hellebrigenin demonstrated selective cytotoxicity against NPC-BM and NPC-039 cell lines without harming normal nasopharyngeal cells. Treatment with hellebrigenin resulted in G2/M cell cycle arrest in both NPC cell lines. The apoptotic phenomena induced by hellebrigenin included chromatin condensation, increased apoptotic cells and altered mitochondrial membrane potential. Proteomics analysis and the bioinformatic data identified coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) as a candidate oncogene in NPC. Moreover, the combination of CHCHD2 siRNA, CHCHD2 plasmid and hellebrigenin pointed out that CHCHD2 could be a critical mediator of hellebrigenin-induced apoptosis. The combined treatment of hellebrigenin with mitogen-activated protein kinase inhibitors revealed the involvement of the extracellular signal-regulated kinases and c-Jun N-terminal kinases pathways in hellebrigenin-induced apoptosis in NPC cells. In vivo studies demonstrated that hellebrigenin suppressed the tumour volume without affecting body weight, accompanied by the downregulation of Ki67 and CHCHD2 expression. In conclusion, this study provides evidence that hellebrigenin induces NPC apoptosis through regulating CHCHD2 both in vitro and in vivo.