Glycolysis provides growth advantages and leads to drug resistance in colorectal cancer (CRC) cells. SIRT1, an NAD+-dependent deacetylase, regulates various cellular processes, and its upregulation results in antitumor effects. This study investigated the role of SIRT1 in metabolic reprogramming and oxaliplatin resistance in CRC cells.

Gastric cancer (GC) is one of the most aggressive malignancies worldwide and is characterized by its poor prognosis and resistance to conventional therapies. Autophagy and long non-coding RNAs (lncRNAs) play critical yet complex roles in GC, functioning as both tumor suppressors and promoters depending on the disease stage and context. Autophagy influences cellular homeostasis and metabolism, whereas lncRNAs regulate gene expression through epigenetic modifications, RNA sponging, and protein interactions. Notably, the interplay between lncRNAs and autophagy modulates tumor progression, metastasis, chemoresistance, and the tumor microenvironment. This study explored the intricate relationship between lncRNAs and autophagy in GC, highlighting their roles in pathogenesis and treatment resistance. By addressing current knowledge gaps and proposing innovative therapeutic strategies, we have emphasized the potential of targeting this dynamic interplay for improved diagnostic and therapeutic outcomes.

Methyl jasmonate (MeJA) is an effective plant elicitor that enhances secondary metabolism. Chinese chives are prized for their pungent flavor, yet the biosynthetic pathways and regulatory mechanisms of flavor compounds induced by MeJA remain unclear.

The study investigates the relationship between biofilm formation and antibiotic resistance in Escherichia coli (E. coli) isolated from calves. Using biochemical and molecular methods, we identified the isolates and assessed their biofilm-forming ability through an improved crystal violet staining method. The minimum inhibitory concentrations (MICs) of 18 antibiotics against the isolates were determined using the broth microdilution method. The impact of cefoxitin on biofilm formation was analyzed using laser scanning confocal microscopy (LSCM). Additionally, qRT-PCR was employed to evaluate the expression levels of biofilm-related genes (luxS, motA, fliA, pfs, and csgD) in response to varying cefoxitin concentrations. Results indicated a significant correlation between antimicrobial resistance (AMR) and biofilm formation ability. Cefoxitin effectively reduced biofilm formation of multidrug-resistant E. coli isolates at 1/2 and 1 MIC, with enhanced inhibition at higher concentrations. The QS-related genes luxS, pfs, motA, and fliA were downregulated, leading to decreased csgD expression. At 1/2 MIC, csgD expression was significantly reduced. In conclusion, cefoxitin inhibits biofilm formation in multidrug-resistant E. coli by down-regulating key genes, offering a potential strategy to mitigate resistance and control infections in calves caused by biofilm-positive E. coli isolates.

Pteris vittata remediates arsenic (As)-contaminated soils; however, the molecular mechanisms underlying the As management remain largely unknown. Therefore, in this study, we investigated As - related processes by conducting transcriptomic analysis on hydroponically grown P. vittata exposed to 500 ppb arsenate (AsV). Within 24 h, As was translocated to fronds, while As concentration among fronds differed (4.08-1323.35 µg/g-DW). Transcriptomic profiling of roots and fronds with high (PHAs) and low (PLAs) As concentrations revealed distinct As transport mechanisms. In the roots, the induction of PvPht1;3 and one PHO1 genes suggested the facilitation of AsV absorption, while ACR3 and POT genes were induced in both the roots and fronds. Notably, NRT2.5, NIP6;1, BOR2, and ABC transporter genes were specifically activated in PHAs, highlighting their potential roles in As hyperaccumulation. To our knowledge, this is the first report linking PHO1, POT, NRT2.5, NIP6;1, and BOR2 to As accumulation in P. vittata. Gene ontology enrichment analysis further emphasized a tissue-specific As response system. In the roots, differentially expressed genes (DEGs) associated with the activation of glutathione metabolic process, cell wall biogenesis, antioxidant response, and signal transduction pathways enabled a prompt response to As-derived stimuli, facilitating efficient As uptake and transport. In the fronds, DEGs related to cell wall modification, oxidative stress response, signal transduction, and active transport systems may contribute to As detoxification and hyperaccumulation. This study provides novel insights into the molecular basis of As uptake, transport, accumulation, and detoxification in P. vittata, providing valuable strategies for efficient phytoextraction via regulation of As metabolism.

Recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC) is a severe, frequently lethal condition. Oncogene addiction to epidermal growth factor receptor (EGFR) is a hallmark of HNSCC, but the clinical efficacy of EGFR-targeted therapies remains low. Understanding molecular networks governing EGFR-driven progression is paramount to the exploration of (co)-treatment targets and predictive markers.

Patients with breast cancer which lack molecular targets, such as human epidermal growth factor receptor 2 (HER2) or hormone receptors, have limited access to targeted therapies. Somatostatin receptor 2 (SSTR2) is overexpressed in some cancers, and SSTR2-targeted radiopharmaceuticals are FDA-approved for theranostic targeted imaging and therapy in neuroendocrine tumors (NETs). Importantly, histone deacetylase (HDAC) inhibitors can epigenetically modulate SSTR2 expression in NETs with low or variable basal expression. The goal of this study is to characterize SSTR2 basal expression and induction via HDAC inhibition as a potential target for imaging and therapy in preclinical models of triple-negative breast cancer (TNBC). SSTR2 expression in mouse samples was assessed via Western blot and immunohistochemistry. Real-time quantitative PCR (qRT-PCR), flow cytometry, and cell binding assays were utilized to determine if HDAC inhibition can upregulate SSTR2 expression. [68Ga]Ga-DOTATATE positron emission tomography (PET) imaging, which targets SSTR2, was used to non-invasively characterize SSTR2 expression and variability in the EO771 and 4T1 TNBC models before and after HDAC inhibition. These studies demonstrate that HDAC inhibition can upregulate SSTR2 at the transcriptional, translational, and functional levels in breast cancer. Importantly, SSTR2 expression can be characterized non-invasively via PET imaging and modulation with HDAC inhibitors can be monitored longitudinally. Our findings highlight SSTR2 as a promising therapeutic molecular target in TNBC.

The widespread use of water-soluble polymers (WSPs) like polyethylene glycol (PEG) and polyvinyl alcohol (PVA) across multiple industrial and household uses has recently raised concerns about their environmental persistence and potential toxicity to aquatic organisms. Despite being excluded from regulatory oversight, recent studies suggest possible ecological risks associated with sub-lethal exposures to these polymers. In this context, this study investigates the transgenerational effects of PEG and PVA on Daphnia magna, focusing on both life-history parameters and epigenetic modifications at the environmentally relevant concentration of 1 μg/L. Through continuous exposure experiments, spanning three generations (from F0 to F3), and "recovery" groups, where only the parental generation (F0) was exposed, our results reveal significant reductions in the number of newborns and reproductive parameters in the F0 generation exposed to PEG but not in subsequent generations. This suggests a multigenerational plasticity in Daphnia through a compensatory or acclimation reproductive response over time. Global cytosine methylation patterns also showed a significant initial increase in the F0 generation exposed to PEG, which decreased in later generations, indicating a possible epigenetic mechanism underlying observed reproductive effects. In contrast, PVA exhibited no significant changes in both life history parameters and methylation but showed a global methylation trend suggesting its likely epigenetic influence. These findings underscore the need for comprehensive risk assessments of WSPs, particularly their potential for inducing long-term (epigenetic) effects, influencing reproductive functions across generations and how increased plasticity may affect responses against novel other stressors.

The Musashi RNA-binding proteins contribute to proliferation, stemness, and therapy resistance in triple-negative breast cancer (TNBC) and have been associated with reduced overall survival in patients.

Vitamin A (VitA) is an essential nutrient, affecting many cell functions, such as proliferation, apoptosis, and differentiation, all of which are important for the regeneration of various tissues. In this study, we investigated the effects of a VitA-enriched diet on the regeneration of the urothelium of the urinary bladder in mice after cyclophosphamide (CP)-induced injury. Female mice were fed VitA-enriched and normal diet for 1 week before receiving an intraperitoneal injection of CP (150 mg/kg). Urinary bladders were removed 1 and 3 days after CP. On Day 1, RNA sequencing showed that VitA upregulated two Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways: the cell cycle and the PI3K-Akt pathway. This was confirmed by qPCR, which showed significantly increased expression of the Itga3 and Areg genes. In addition, the effect of VitA on the proliferation of urothelial cells was analyzed by immunohistochemistry of Ki-67, which confirmed an increased proliferation rate. No significant effects of the VitA-enriched diet were observed on the expression of apoptosis-related genes and on differentiation-related markers of superficial urothelial cells. Our results suggest that a VitA-enriched diet improves early urothelial regeneration after CP-induced injury by promoting cell proliferation.

Immunotherapy, particularly immune checkpoint inhibitor therapy, has demonstrated clinical benefits in solid tumours. Despite its satisfactory clinical efficacy, it still faces several issues, such as limited eligibility, low response rates and cytotoxicity. Cancer epigenetics implies that tumour cells exhibit unique phenotypes because of their unique characteristics, thus reprogramming of the epigenome holds promise for cancer therapy. Epigenetic regulation plays an important role in regulating gene expression during tumour development and maintenance. Epigenetic regulators induce cancer cell cycle arrest, apoptosis and differentiation of cancer cells, thereby exerting anti-tumour effects. Recent studies have revealed a significant correlation between epigenetic regulatory factors and immune checkpoint therapy. Epigenetics can modulate various aspects of the tumour immune microenvironment and immune response to enhance the sensitivity of immunotherapy, such as lowering the concentration required and mitigating cytotoxicity. This review primarily discusses DNA methyltransferase inhibitors, histone deacetylase inhibitors, enhancer of zeste homolog 2 inhibitors and lysine-specific demethylase 1 inhibitors, which are associated with transcriptional repression. This repression alters the expression of genes involved in the immune checkpoint, thereby enhancing the effectiveness of immunotherapy. We also discuss the potential and challenges of tumour immunotherapy and highlight its advantages, application challenges and clinical research on integrating epigenetic regulatory factors with tumour immunotherapy.

NDRG1, a cell differentiation-associated factor, has recently emerged as a regulator ferroptosis. Nevertheless, its role in modulating ferroptosis within hepatocellular carcinoma (HCC) remains uncharacterized.

Osteoporosis is a chronic metabolic bone disease that is prone to fractures. Isoimperatorin (ISO) has been shown to alleviate the bone loss in ovariectomized (OVX) rats. The aim of this study was to investigate the effect and the mechanism of ISO on osteoporosis using animal study and cell experiments. Osteogenic differentiation was assessed by alkaline phosphatase activity detection, and alizarin red S staining. The expression of osteogenic differentiation-related genes and m5C regulators was measured using quantitative real-time PCR. Hematoxylin eosin (H&E) staining and microCT were performed to evaluate osteoporosis in vivo. The m5C levels in mice were measured by dot blot assay, and the binding between ISO and YBX1 was assessed by biolayer interferometry (BLI) analysis and molecular docking. Methylated RNA immunoprecipitation was performed to identify the target gene of YBX1. The interaction between YBX1 and BGLAP was assessed using RIP and luciferase reporter assay. Results suggested that ISO significantly promoted osteogenic differentiation of MC3T3 cells and alleviated osteoporosis in OVX mice. Moreover, ISO increased m5C level and YBX1 expression in OVX mice, while YBX1 knockdown inhibited osteogenic differentiation in ISO-treated MC3T3 cells, and restored osteoporosis in OVX mice ameliorated by ISO. Additionally, YBX1 knockdown inhibited the m5C level of BGLAP through inhibiting its mRNA stability. In conclusion, we demonstrated that ISO improved osteoporosis through increasing YBX1 expression thereby upregulating the m5C modification of BGLAP. These results may provide a novel theoretical basis for ISO treatment of osteoporosis.

The intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes the interconversion of active glucocorticoid (cortisol) and its intrinsically inert form (cortisone) in metabolic tissues. Although 11βHSD1 is considered a promising therapeutic target in metabolic disorders such as type 2 diabetes, obesity, and nonalcoholic steatohepatitis because of its hepatic functions, its roles in other tissues have received less attention. In this study, we show that the 11βHSD1-specific inhibitor J2H-1702 facilitates the reversion of endothelial-to-mesenchymal transition in multicellular lung spheroid models encapsulating the complex crosstalk among lung cancer cells, vascular endothelial cells, and macrophages. In vascular endothelial cells, J2H-1702 not only suppressed interleukin-1α (IL-1α) expression but also attenuated reactive oxygen species-induced DNA damage by upregulating heme oxygenase-1. Additionally, in macrophages, which are key regulators of fibrogenesis, inhibition of 11βHSD1 markedly reduced IL-1β expression, thereby modulating the pro-inflammatory phenotype of activated macrophages. In mouse models of pulmonary fibrosis, including a bleomycin-induced idiopathic model and a radiation-induced model, J2H-1702 alleviated pulmonary fibrosis and markedly improved the efficacy of nintedanib. Collectively, our data suggest that J2H-1702 holds promise as a clinical candidate for the treatment of pulmonary fibrosis associated with reactive oxygen species-induced DNA damage, endothelial-to-mesenchymal transition, and inflammatory responses.

Chemoresistance remains a major hurdle in ovarian cancer (OC) treatment, as many patients eventually develop resistance to platinum-based chemotherapy and/or PARP inhibitors (PARPi).

The main reason for the failure of chemotherapy therapies based on 5-Fluorouracil (5-Fu) is the development of resistance to 5-Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP-2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5-Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK-8 assay was conducted to evaluate the IC50 of 5-Fu and cell proliferation. ELISA and RT-qPCR were performed to detect TIMP-2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP-2 was significantly increased in CRC drug-resistant cell lines. In addition, the expression of TIMP-2 in the serum of patients with CRC resistance to 5-Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP-2 regulated the resistance of CRC cells to 5-Futhrough the JAK-STAT signalling pathway. Moreover, anti-TIMP-2 antibody or small molecule drug LY2784544 targeting the JAK-STAT signalling pathway can effectively reverse the resistance of CRC cells to 5-Fu. It is exactly TIMP-2 that mediates the resistance of CRC to 5-Fu through the JAK-STAT signalling pathway. Targeting drugs for TIMP-2 or the JAK-STAT signalling pathway are expected to be opportunities to reverse 5-Fu resistance in CRC.

Chlorolipids are produced during the neutrophil respiratory burst as a result of myeloperoxidase (MPO)-generated hypochlorous acid (HOCl) targeting the vinyl ether bond of plasmalogen phospholipids. The initial products of this reaction are 2-chlorofatty aldehydes (2-ClFALDs), which are subsequently oxidized to 2-chlorofatty acids (2-ClFAs). 2-Chlorohexadecanoic acid (2-ClHA) is the 16-carbon 2-ClFA species, and previous studies have shown that increased levels of plasma 2-ClHA associate with acute respiratory distress syndrome (ARDS)-caused mortality in human sepsis. 2-ClHA causes endothelial barrier dysfunction and increases neutrophil and platelet adherence to the endothelium. In this study, click chemistry analogs of 2-ClHA and hexadecanoic acid (HA) were used to identify proteins covalently modified by 2-ClHA and HA in human lung microvascular endothelial cells (HLMVECs). Eleven proteins were specifically modified by 2-ClHA, and an additional one hundred and ninety-four proteins were modified by both 2-ClHA and HA. STRING analysis of 2-ClHA-modified proteins revealed a network of proteins with RhoA as a hub. RhoA is one of the proteins specifically modified by 2-ClHA and not HA. The RhoA inhibitors, Rhosin and C3, inhibited both 2-ClHA-elicited HLMVEC barrier dysfunction and angiopoietin-2 (Ang-2) release from HLMVEC. Further studies showed 2-ClHA activates HLMVEC RhoA activity. The specificity of the 2-ClHA-RhoA pathway for endothelial activation was further confirmed since HA did not cause HLMVEC barrier dysfunction, Ang-2 release and RhoA activation. Collectively, these studies have identified multiple proteins modified exclusively by 2-ClHA in HLMVECs, including RhoA. These proteomics studies led to the key finding that RhoA is an important mediator of 2-ClHA-caused endothelial barrier dysfunction.

Recent studies show that metabolites, beyond their metabolic roles, can induce significant changes in cell behavior. Herein, we investigate the non-canonical role of nicotinamide (vitamin B3) on glioblastoma (GB) cell behavior. Nicotinamide induced senescence in GB cells, characterized by reduced proliferation, chromatin reorganization, increased DNA damage, enhanced beta-galactosidase activity, and decreased Lamin B1 expression. Nicotinamide-induced senescence was accompanied by an unexpected reprogramming of its metabolism, marked by simultaneous downregulated transcription of NNMT (nicotinamide N-methyltransferase) and NAMPT (nicotinamide phosphoribosyl-transferase). Nicotinamide effects on GB cells were mediated by decreased levels of SOX2. Consistently, analyses of patients' single cell transcriptome datasets showed that GB cells with low NNMT and NAMPT expression levels were enriched in gene modules related to senescence. Remarkably, senescent GB cells retained tumor-forming ability in vivo, albeit to a lesser extent compared to control cells. Further experiments at the single-cell level and transcriptomic analyses demonstrated that nicotinamide-induced senescence in GB cells is fully reversible. Overall, our findings identify a novel reversible senescent state in GB tumors and highlight the non-canonical role of nicotinamide as a key driver of cancer cell plasticity.

Androgen deprivation therapy remains a cornerstone in managing prostate cancer. However, its recurrence often leads to the more aggressive castration-resistant prostate cancer (CRPC). Although second-line androgen receptor signaling inhibition treatments such as enzalutamide and abiraterone are available, their effectiveness against CRPC is only transient. High-dose testosterone (Hi-T) has recently emerged as a promising treatment for CRPC, primarily through the suppression of E2F and MYC signaling. However, the roles of Rb family proteins in influencing this therapeutic response remain debated. In this study, we utilized a CRPC patient-derived xenograft model that includes both Rb pathway-proficient and -deficient cell populations based on the positive or negative expression of RB family genes. Single-cell RNA sequencing analysis revealed that Rb-proficient cells displayed a robust response to Hi-T, whereas Rb-deficient cells exhibited significant resistance. Notably, our analysis indicated increased enrichment of the hypoxia signature in the Rb-deficient cell population. Further studies in RB1-silenced CRPC cell lines showed that treatment with a hypoxia-inducible factor-1α inhibitor can restore the sensitivity of Rb-deficient cells to high-dose dihydrotestosterone treatment. In conclusion, our research provides new molecular insights into CRPC tumor cell responses to Hi-T and proposes a new strategy to resensitize Rb-deficient CRPC cells to Hi-T treatment.

The emergence of resistance to antitumor drugs in cancer cells presents a notable obstacle in cancer therapy. Metabolic reprogramming is characterized by enhanced glycolysis, disrupted lipid metabolism, glutamine dependence and mitochondrial dysfunction. In addition to promoting tumor growth and metastasis, metabolic reprogramming mediates drug resistance through diverse molecular mechanisms, offering novel opportunities for therapeutic intervention. Non‑coding RNAs (ncRNAs), a diverse class of RNA molecules that lack protein‑coding function, represent a notable fraction of the human genome. Due to their distinct expression profiles and multifaceted roles in various cancers, ncRNAs have relevance in cancer pathophysiology. ncRNAs orchestrate metabolic abnormalities associated with drug resistance in cancer cells. The present review provides a comprehensive analysis of the mechanisms by which metabolic reprogramming drives drug resistance, with an emphasis on the regulatory roles of ncRNAs in glycolysis, lipid metabolism, mitochondrial dysfunction and glutamine metabolism. Furthermore, the present review aimed to discuss the potential of ncRNAs as biomarkers for predicting chemotherapy responses, as well as emerging strategies to target ncRNAs that modulate metabolism, particularly in the context of combination therapy with anti‑cancer drugs.