Rhamnolipids (RLs) are bacterial glycolipids with potential applications in the biocontrol of plant pathogens. Although RLs are known to activate plant immune responses, the underlying signaling mechanisms remain poorly understood. Calcium-dependent protein kinases (CPKs) are a large family of kinases involved in various functions in plants including signaling of the plant immunity. Here, we investigated the contribution of AtCPK5 and AtCPK6 to RL-triggered immunity in Arabidopsis. RL treatment induced the expression of both AtCPK5 and AtCPK6 genes in Arabidopsis leaves. Functional analyses revealed that RL-induced responses, including reactive oxygen species production and the expression of defense-related genes (AtWRKY46, AtFRK1 and AtPR1), were enhanced in cpk5/6 mutants compared to wild-type plants. The cpk5 mutant exhibited intermediate responses, whereas cpk6 alone had little effect, except on AtFRK1 expression, indicating a predominant role for AtCPK5 in regulating RL-triggered signaling. However, cpk5/6 mutations did not affect RL-induced electrolyte leakage or RL-mediated resistance to Pseudomonas syringae pv. tomato DC3000. Together, these results suggest that AtCPK5 and AtCPK6 negatively modulate RL-triggered immune signaling, while additional components contribute to the regulation of downstream defense responses.

Clear cell renal cell carcinoma (ccRCC) is characterized by profound metabolic reprogramming and limited responsiveness to therapeutic stressors, including epigenetic modulation. How glycolytic enzymes contribute to metabolic stress tolerance in ccRCC remains incompletely understood. We investigated the role of the glycolytic enzyme 2,3-bisphosphoglycerate mutase (BPGM) using human tumor specimens, siRNA-mediated gene silencing, functional cell-based assays, and transcriptomic profiling. Epigenetic stress was induced using Vorinostat as a pan-histone deacetylase inhibitor. BPGM expression was consistently elevated in human ccRCC compared with adjacent normal kidney tissue. A498 cells exhibited high basal BPGM levels and limited sensitivity to Vorinostat, whereas BPGM depletion increased cellular stress responses and reduced proliferative capacity. Despite similar phenotypic outcomes, BPGM silencing and Vorinostat treatment triggered distinct transcriptional programs. While HDAC inhibition induced widespread transcriptional changes, BPGM loss elicited a focused stress-associated response, consistent with activation of the unfolded protein response, increased lipid peroxidation, and induction of ER stress-associated genes. Our data identify BPGM as a metabolic player contributing to stress-adaptive transcriptional states in ccRCC and suggest that targeting metabolic stress adaptation may complement epigenetic strategies in renal cancer.

Chemoresistance is a key contributor of ovarian cancer (OC) mortality. Clinical observations of extended survival in OC patients with rheumatic comorbidities following anti-rheumatic treatment suggest hydroxychloroquine (HCQ) and sulfasalazine (SSZ) could act as chemosensitizers. However, how the HCQ/SSZ combination counteracts platinum-taxane resistance remains unclear.

Lespedeza potaninii is a species of flowering plant in the legume family. Due to its strong stress tolerance and nitrogen-fixing capacity, Lespedeza potaninii has become a crucial plant species for reseeding and restoring degraded grasslands in China. However, drought stress during the seedling or germination stage severely impacts the effectiveness of Lespedeza potaninii-based grassland restoration efforts. To screen seed-soaking agents enhancing seed germination under sorbitol-simulated drought stress and explore the underlying mechanisms, seed germination, physiological parameters and transcriptomic regulation of Lespedeza potaninii seeds under different seed-soaking treatments were analyzed. The results revealed that sorbitol-simulated drought stress significantly reduced seed germination of Lespedeza potaninii. However, treatments with 0.04% ZnSO4 or 0.10 mg/L ZnO-NPs could significantly enhance germination percentages. 0.04% ZnSO4 and 0.10 mg/L ZnO-NPs treatments notably decreased hydrogen peroxide (H2O2) levels, with 0.10 mg/L ZnO-NPs also increasing glutathione cycle efficiency. Transcriptomic analysis revealed that a 0.10 mg/L ZnO-NPs treatment improved drought resistance by enhancing energy and nutrient metabolism, particularly nitrogen metabolism, which in turn strengthened antioxidant defenses through the glutathione metabolism. In contrast, the ZnSO4 treatment promoted sulfur metabolism, thereby enhancing glutathione metabolism and increasing the biosynthesis of flavonoids and monoterpenes, further improving drought resistance. Both treatments likely involve zinc ions in promoting antioxidant synthesis and maintaining cell membrane stability by regulating antioxidant defense, particularly glutathione metabolism. These findings offer novel insights and strategies for improving seed emergence and establishment in degraded grasslands.

Na⁺/H⁺ antiporters (NHXs) play essential roles in ion homeostasis and osmotic adjustment under abiotic stress; however, a systematic analysis of the NHX gene family in Medicago sativa remains limited. Here, eight MsNHX genes were identified and mapped to four chromosomes, all encoding multi-pass membrane proteins with conserved Na⁺/H⁺ exchanger domains. Phylogenetic analysis classified MsNHX proteins into vacuolar-type (Vac-type) and plasma membrane-type (PM-type) clades. Gene structure and promoter analyses revealed variation in exon-intron organization and enrichment of cis-acting elements related to hormone signaling, light responsiveness, and stress responses, indicating potential functional diversification. qRT-PCR analysis demonstrated distinct tissue-specific expression patterns, with several MsNHX genes showing relatively higher expression in roots. Under salt stress (200 mM NaCl), MsNHX1, MsNHX3, MsNHX4, MsNHX5, and MsNHX7 were significantly upregulated. Under PEG-induced drought stress (20% PEG6000), MsNHX1, MsNHX2, MsNHX3, MsNHX4, MsNHX5, and MsNHX7 showed increased expression. Under combined salt-drought stress (100 mM NaCl + 10% PEG6000), most MsNHX genes (MsNHX1-MsNHX7) were induced, including MsNHX6. These findings provide a comprehensive overview of the MsNHX gene family and identify candidate genes potentially involved in alfalfa responses to salt, drought, and combined stress conditions.

Strenuous endurance exercise imposes substantial physiological stress on the cardiovascular system and has been associated with transient elevations in cardiac biomarkers. Vitamin D₃ has been suggested to influence oxidative stress and immune responses. In this study, we investigated the effects of vitamin D₃ supplementation on biomarkers of cardiac, muscle, and immune responses following a marathon race.

Human leukocyte antigen E (HLA-E) plays a role in tumor immune escape and is associated with poor prognosis in neuroblastoma (NB). This study aimed to investigate the regulatory effect of suberoylanilide hydroxamic acid (SAHA) on HLA-E expression via the PERK/ATF4/CHOP pathway in NB.

Cancer is the leading cause of death worldwide. This study evaluated the anti-liver cancer influence of the unsaponifiable fraction (UnSap) derived from black Vitis vinifera seed oil (BVVO) using the HepG-2 cell line and a HCC mouse model. Compared with 5-fluorouracil (5-FU), UnSap exhibited a strong antioxidant capacity, excellent safety (in PBMCs), and a higher selectivity index (SI) with a lower IC₅₀ against HepG-2 cells. It effectively induced apoptosis and modulated the expression of key genes involved in cell cycle progression. The docking results predicted that the abundant constituents of UnSap can interfere with the interaction between β-catenin and human T-cell factor-4 (HTCF-4) and may inhibit the activity of key regulatory proteins involved in HCC proliferation and stemness. In HCC-bearing mice, UnSap significantly improved the expression of serum liver function markers (0.4-1.3-fold), restored redox balance (> threefold), and preserved hepatic tissue architecture. It also modulated the expression of critical genes associated with apoptosis (> 20-fold), cell cycle regulation (> fourfold), inflammation (> fivefold), angiogenesis (threefold), and cancer stemness (> 45-fold). These therapeutic effects are likely attributed to its high phenolic and phytosterol content, as confirmed by HPLC analysis. Across all investigated parameters, UnSap demonstrated superior anticancer efficacy compared with 5-FU. These findings highlight the potential of UnSap as a promising natural therapeutic candidate and provide a foundation for future studies on its bioactive constituents for the development of novel anticancer agents.

Z-DNA is a left-handed DNA helix implicated in gene regulation, genome stability, and immune responses, yet effective small-molecule modulators in cells remain scarce. To address this gap, we developed NanoZ, a two-step screening platform designed to identify Z-DNA-inducing molecules. The first step, a DNA condensation assay, detects ligand-induced DNA condensation using gold nanoparticles functionalized with Z-DNA-forming sequences, providing a rapid optical readout through localized surface plasmon resonance. The second step, a biophysical validation pipeline, employs circular dichroism, 2-aminopurine fluorescence, and NMR spectroscopy to confirm Z-DNA formation. Using this workflow, we screened 2000 compounds from the Natural Product and Prestwick Chemical Libraries, identifying 18 positive hits in the condensation assay and selecting Alexidine dihydrochloride as a Z-DNA inducer. Alexidine efficiently promoted the B-to-Z transition and DNA condensation in vitro, and markedly increased Z-DNA formation in cells, as confirmed by immunofluorescence and ChIP-seq. Genome-wide analysis revealed that Alexidine-induced Z-DNA localized to transcriptionally active, purine-pyrimidine repeat-rich loci, leading to gene repression. Molecular dynamics simulations showed that Alexidine bridges adjacent Z-DNA helices, facilitating condensation. Collectively, our findings highlight Alexidine as the first small-molecule Z-DNA inducer that modulates transcription in cells and establish NanoZ as a versatile platform for discovering Z-DNA modulators.

Using transcriptional GFP reporters, we previously found that most antibiotics tested induced acrAB via RamA, whilst other AraC/XylS family transcriptional activators, MarA, SoxS, or Rob, induced fewer signals. Surprisingly, we found that some antibiotics induced ramA with no subsequent acrAB induction. We postulated that expression of RamA, and subsequently AcrAB, must increase above basal levels to induce acrAB transcription. Furthermore, we hypothesized that a certain level of RamA is required to induce a measurable amount of acrAB, and likewise that a certain level of AcrAB is required to give a multidrug resistant (MDR) phenotype. The transcript levels of ramA and acrAB were measured in the presence of a range of concentrations of the ramA inducer, chlorpromazine. In parallel, the levels of RamA, AcrB, and antibiotic susceptibility were determined. Here, we show that a specific level of RamA, and subsequently AcrAB, must be reached before MDR is observed, and up to a maximum amount of RamA, there was enhanced production of AcrAB and MDR; higher RamA concentrations did not increase production of AcrAB or MDR. We postulate that this was due to saturation of the maximum number of RamA binding sites in acrB.

Growth differentiation factor 9 (GDF9) plays a key role in enhancing developmental competence and blastocyst yield during in vitro maturation (IVM). This study investigated whether GDF9 could counteract the harmful effects of lipopolysaccharide (LPS), a gram-negative bacterial component, on bovine in vitro embryo production, while also examining related gene expression in cumulus cells and oocytes. We hypothesized that GDF9 may compensate for LPS through the NF-κB pathway. Ovaries were collected from a slaughterhouse, and oocytes (≥ 50 per group per replicate) were matured under four conditions: control, GDF9, LPS, and GDF9 + LPS. After IVM, fertilization and culture were performed, with blastocyst development evaluated on Day 7. Cumulus cells and oocytes were analyzed for gene expression (RT-qPCR), while IVM media were tested for progesterone and estradiol. Results showed that co-treatment with GDF9 and LPS restored cumulus expansion, cleavage, blastocyst rate, and embryo quality compared with LPS alone (p < 0.05), with no differences from controls. LPS increased mRNA levels of CXCL8, TNFα, and TLR2 in cumulus cells (p < 0.05), but candidate gene expression in oocytes and cumulus cells remained unaffected. Steroid concentrations and estradiol:progesterone ratios were similar across groups. In summary, GDF9 supplementation alleviates LPS-induced impairment in bovine oocytes during IVM, though the underlying mechanisms remain unclear.

Ovarian clear cell carcinoma (OCCC) is an endometriosis-associated ovarian cancer subtype. Somatic mutations in OCCC are reported in ARID1A, PIK3CA, and the TERT promoter (TERTp), as well as less commonly in KRAS and TP53 among other genes. OCCC is typically resistant to standard-of-care chemotherapy, especially after relapse. While recent studies have seen favourable responses to immunotherapy, patients with OCCC face limited therapeutic options.

Androgen deprivation therapy (ADT) remains the standard treatment for advanced prostate cancer (PCa); however, most patients ultimately progress to lethal castration-resistant PCa (CRPC). Emerging evidence implicates RNA N⁶-methyladenosine (m⁶A) modification as a key regulator of cancer biology, yet its role in CRPC remains poorly understood. As a critical adaptor in the m⁶A methyltransferase complex, RNA-binding motif protein 15 (RBM15) directs m⁶A deposition to specific mRNA targets. Here, we identified RBM15 as the key methyltransferase member significantly upregulated in CRPC tissues and strongly correlated with poor patient survival. Functionally, RBM15 overexpression reduces PCa cell sensitivity to enzalutamide, whereas its knockdown suppresses tumor growth and invasion. Mechanistically, RBM15 is an androgen-responsive protein whose expression increases upon chronic androgen deprivation. It catalyzes m⁶A methylation at position A1384 of damaged DNA binding protein 1 (DDB1) mRNA, leading to YTHDF2-dependent transcript decay and reduced DDB1 protein levels. Lower DDB1 impairs K48-linked polyubiquitination of the androgen receptor (AR), thereby stabilizing AR and amplifying AR signaling. Importantly, AR transcriptionally activates RBM15, forming a feed-forward loop that drives CRPC progression. Collectively, our findings establish RBM15 as a central epitranscriptomic driver of CRPC and identify the RBM15-DDB1-AR axis as a promising therapeutic target. Dual inhibition of RBM15 and AR may offer a novel strategy to overcome treatment resistance in advanced PCa.

Ulcerative colitis (UC) remission is marked by gut microbiota restructuring, but how microbial metabolites influence immune-mediated tissue repair is unclear. Here, we demonstrate that oral vancomycin alleviates colitis symptoms in murine models, mirroring its clinical efficacy in inducing remission in patients with UC. Mechanistically, vancomycin's therapeutic effect is achieved by reducing deoxycholic acid (DCA). We reveal that DCA impairs mucosal repair driven by group 2 innate lymphoid cells (ILC2s) by inducing ER stress through direct binding to thioredoxin-related transmembrane protein 2 (TMX2). This interaction disrupts TMX2's role in protein folding, triggering unresolved unfolded protein response via hyperactivation of PERK/eIF2α signaling, which suppresses the production of pro-healing molecules by ILC2s. Pharmacological inhibition of PERK phosphorylation restores ILC2 function and accelerates colitis resolution. Our work uncovers a pathogenic microbiota/DCA/ILC2 axis that obstructs mucosal healing and positions vancomycin as a targeted strategy to eliminate DCA, thereby promoting UC remission.

Pharmacovigilance has revealed an alarming correlation between certain medications and a higher risk of cancer. In this narrative review, included research from 2020 to 2025, along with a few seminal older studies, so that it provides a clear picture of which drugs actually set off cancer and mechanisms involved at the molecular level. An extensive literature review of the subject was designed on PubMed, Embase, Scopus, and Web of Science using systematic search. Search words and phrases included: "Carcinogenic drugs," "drug-induced cancer," "medication-induced carcinogenesis," "immunosuppressant cancer risk," "hormone therapy and cancer," "chemotherapy-induced secondary malignancies," and names of relevant drugs.

Chemotherapy resistance remains a critical bottleneck limiting its clinical efficacy in small cell lung cancer (SCLC), with its core mechanisms and targeted intervention strategies urgently requiring breakthroughs. Our study revealed that the BMX (bone marrow tyrosine kinase on chromosome X)-E2F1 (E2F transcription factor 1) axis is a pivotal regulator of chemoresistance in SCLC. Synchronous upregulation of phosphorylated BMX (Tyr566) and E2F1 was observed in SCLC tissues and cells. Mechanistically, BMX stabilized E2F1 via the ERK1/2 (extracellular signal-regulated kinase 1/2)-Cyclin D1/CDK4/6 (cyclin-dependent kinase 4/6) signaling axis, phosphorylating E2F1 at Ser332/337 and inhibiting its degradation via the ubiquitin-proteasome pathway. Inhibition or knockdown of BMX reduced E2F1 stability, promoting its degradation and reversing chemoresistance. E2F1 knockdown decreased the expression of genes associated with cell cycle regulation, migration, invasion, and DNA repair, further sensitizing chemoresistant SCLC cells to cisplatin. We also discovered IHMT-15137, a potent and selective BMX inhibitor. In vitro studies using SCLC patient-derived cells (PDCs)/patient-derived organoids (PDOs) and chemoresistant cell lines revealed that IHMT-15137, combined with cisplatin, synergistically induced cell cycle arrest, apoptosis, and DNA damage while suppressing cell migration and invasion. In vivo xenograft models demonstrated that the combination significantly inhibited tumor growth without causing significant toxicity. Our findings reveal the molecular mechanisms of SCLC chemoresistance and suggest potential therapeutic strategies targeting the BMX-E2F1 axis to overcome this challenge.

Resistance to lenvatinib remains a major barrier in the treatment of advanced hepatocellular carcinoma (HCC), underscoring the urgent need to elucidate the underlying mechanisms and identify actionable therapeutic targets. In this study, we identified a neurosecretory factor derived from HCC cells, Nerve Growth Factor (NGF), as a critical mediator of lenvatinib resistance. Utilizing an innovative in vivo-in vitro cross-circulated strategy, we established a phenotypically stable lenvatinib-resistant HCC cell line (LenR-cells). Through proteomic screening of conditioned media and subsequent functional validation, we demonstrated that NGF secretion progressively increases with the acquisition of resistance. Mechanistically, we uncovered that the SRPK1-SRSF1 axis drives enhanced NGF production by regulating alternative splicing of its precursor transcript, specifically promoting the expression of a shorter, translationally efficient isoform (proNGF-B). Elevated NGF subsequently activates the non-canonical MAPK pathway (MEK5-ERK5) via its high-affinity receptor TrkA, thereby sustaining tumor cell viability and proliferation under sustained tyrosine kinase inhibitor pressure. Critically, pharmacological co-targeting of TrkA with the clinically approved inhibitor larotrectinib restored lenvatinib sensitivity in both patient-derived organoids and xenograft models, producing marked synergistic anti-tumor effects without evidence of exacerbated toxicity. Clinical analyses of two independent patient cohorts further confirmed that elevated NGF expression is significantly associated with poor response to lenvatinib, shorter recurrence-free survival, and worse overall survival. Our findings unveil a critical and previously underappreciated role for tumor-derived NGF in orchestrating adaptive signaling through a precise post-transcriptional regulatory circuit and propose a readily translatable, biomarker-guided combination strategy to overcome lenvatinib resistance in HCC.

One of the most prevalent oral cancers, oral squamous cell carcinoma (OSCC), is distinguished by its rapid growth, invasiveness, and high metastatic potential. Green AgNPs are important because they can reduce systemic toxicity by inducing oxidative stress, cytotoxicity, and apoptosis in cancer cells. The goal of this study was to use saponins as natural stabilizers to create AgNPs, and the detrimental apoptotic effects on cancer cells were examined using high-content screening (HCS) assays such as TNI, CMP, and VCC.

Cervical cancer is the second leading cause of mortality in women globally, with its incidence increasing due to multidrug resistance (MDR) and adverse side effects associated with chemotherapeutic agents. Hence, this study was carried out to investigate the selective cytotoxicity and apoptotic induction potential of Buddleja polystachya leaf diethyl ether (BPL-DE) extract on cervical cancer HeLa cell lines.

The aim of the study was to determine how the chemotherapeutic alkylating agent dacarbazine, together with the application of the miR-204-5p mimic in vivo, affects the presence of disseminated melanoma cells in distant organs - the lungs and liver.