Alternative splicing is a central procedure that increases the variety of the transcriptome and helps regulate several neuronal processes. Various pharmacological factors have the capacity to alter splicing patterns, which could potentially affect cellular function. Sertraline, a selective serotonin reuptake inhibitor widely used in the treatment of neuropsychiatric disorders, also regulates intracellular pathways linked with calcium signaling and other cellular processes. However, information about its potential impact on the post-transcriptional regulation of the transcriptome is still insufficient.

Red light promotes PsbS transcription through the PHYs-COP1 module, blue light through the CRY1/CRY2-COP1 pathway, and UV-B via the UVR8-COP1-HY5 cascade. ABA negatively regulates PsbS through the PYLs-SnRK2s-ABI5 signaling pathway. Non-photochemical quenching (NPQ) is a central photoprotective mechanism that enables plants to dissipate excess excitation energy under high light conditions, with PsbS functioning as a key regulatory protein. However, the environmental cues controlling PsbS transcription and the underlying regulatory mechanisms remain largely unclear. Analysis of the core promoter region of PsbS identified light-responsive element G-box and abscisic acid-responsive element (ABRE) cis-elements; dual-luciferase reporter assays confirmed that the core PsbS promoter can respond to light and abscisic acid (ABA) signals. Expression analyses showed that red, blue, and ultraviolet-B (UV-B) light significantly induced PsbS transcription, whereas ABA treatment repressed it. Genetic and signaling analyses revealed that red light promotes PsbS transcription through the PHYs-COP1 module, blue light through the CRY1/CRY2-COP1 pathway, and UV-B via the UVR8-COP1-HY5 cascade. In contrast, ABA negatively regulates PsbS through the PYLs-SnRK2s-ABI5 signaling pathway. Yeast one-hybrid (Y1H) screening identified 36 candidate transcription factors targeting PsbS. Dual-luciferase assays and electrophoretic mobility shift assays (EMSA) further confirmed that bZIP2, bZIP16, bZIP43, CCA1, and IDD1 act as candidate transcriptional repressors of PsbS. This study systematically integrates known light and ABA signaling pathways that regulate PsbS expression, providing potential molecular targets for improving crop photosynthetic efficiency.

Breast cancer (BC) is the most commonly diagnosed malignant disease in women worldwide. Resistance to neoadjuvant chemotherapy (NAC) still limits treatment efficacy despite the enormous progress in systemic therapy. Because pathological complete response (pCR) is strongly associated with favorable clinical outcomes, especially in triple-negative and HER2-positive breast cancer, the discovery of reliable predictive biomarkers before treatment has become a key clinical goal. This narrative review summarizes the available evidence of genetic and transcriptomic biomarkers associated to responses to conventional anthracycline, taxane and platinum-based NAC. Current evidence suggests biomarkers can be broken down into three interconnected biological pathways. Dysregulation of immune and interferon signaling, including interferon-stimulated genes (ISG15, IFIH1, MX1, OAS family, IFI27, and IFITM1), affects chemotherapy response by modulating immune activation, apoptosis, and DNA damage tolerance. Second, alterations in DNA damage response (DDR) pathways for BRCA1, TP53, PARP1, ATM, and CHK1 affect the cells' vulnerability to genotoxic stress and contribute to the subtype-specific differences in treatment efficacies. Third, dysregulated cell cycle components (CCND1, CDK4/6, RB1, and E2F1) affect proliferation, checkpoint control, and susceptibility to chemotherapy-induced apoptosis. These pathways act in concert, rather than as independent mechanisms, to influence NAC sensitivity. Available data suggest that no single biomarker has sufficient predictive accuracy for all breast cancer subtypes. Subtype-specific multi-gene models integrating immune, DDR and cell-cycle biomarkers represent a more powerful tool to predict pCR and improve patient stratification before NAC. Further prospective clinical validation is needed before these biomarkers can be implemented in routine clinical practice.

Pulmonary fibrosis (PF) is a chronic and progressive respiratory disorder marked by aberrant activation of pulmonary fibroblasts and the occurrence of epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AECs). This disease process is primarily driven by inflammation and oxidative stress (OS), leading to excessive deposition of the extracellular matrix (ECM). Current treatments provide limited efficacy and are associated with significant side effects. Leonurine and its sulfate derivative SCM198, derived from Herba Leonuri, exhibit anti-inflammatory and antioxidant properties. However, their therapeutic effects and mechanisms of action in PF remain poorly understood.

To investigate the mechanisms underlying benzo[a]pyrene-induced esophageal cancer (EC), and to screen and identify the key targets and biomarkers associated with benzo[a]pyrene-related EC.

The tumour microenvironment (TME) of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) patients is associated with resistance of DLBCL cells to CD19 CAR-T cells. How to improve TME in DLBCL and improve the efficacy of CAR-T cell therapy remains to be further explored. We observed the sensitivity of HBL-1/U2932 cells pretreated with BTK inhibitors (BTKi) to CAR-T cells with flow cytometry (FCM). The effect of pretreatment of BTKi on the polarisation state of alternative activated M2 macrophages was observed with FCM, real-time PCR and Western blot method. The effect of Notch1 agonist on expressions of Arg-1 protein, iNOS protein, Notch1 protein and RBP-J protein in alternative activated M2 macrophages was observed by Western blot method. Then the expression consistency of Notch-1 and RBP-J in activated M2 macrophages was observed by siRNA transfection of Notch-1. The cytotoxicity of CD19 CAR-T cells on HBL-1/U2932 cells pretreated with ibrutinib/orelabrutinib was higher than that of HBL-1/U2932 cells unpretreated with ibrutinib/orelabrutinib. Cytotoxicity of CAR-T cells to HBL-1 cells in coculture system with alternative activated M2 macrophages was very low. This drug resistance could be reversed by replacing the M2 macrophages (M2 macrophages after 48 h pretreatment with BTKi) in coculture system. Pretreatment with BTKi could down-regulate the expression of CD206 and IL-10 in activated M2 macrophages. And pretreatment with BTKi down-regulated the expression of Arg-1 and upregulated the expression of iNOS in activated M2 macrophages. The upregulation polarisation of M2 macrophages by Notch1 agonist could be reversed by BTKi. Expression of RBP-J protein decreased in alternative activated M2 macrophages by siRNA silencing Notch 1. Pretreatment with BTKi could down-regulate the polarisation of M2 macrophages and reverse the resistance of DLBCL cells which were cocultured with alternative activated M2 macrophages to CAR-T cells. This effect might be achieved by downregulating the Notch-RBP-J pathway.

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) represents a major clinical challenge in the management of non-small cell lung cancer (NSCLC). Chromosome 4q12 locus is an important gene locus associated with progression-free survival (PFS) in NSCLC patients receiving EGFR-TKIs therapy. However, it remains poorly characterized how genes at this locus function in NSCLC development and resistance to EGFR-TKIs. Here, we found that CLOCK at this locus is highly expressed in NSCLC tissues and correlates with unfavorable PFS of patients. CLOCK promotes malignant proliferation and metastasis of NSCLC in vitro and in vivo. CLOCK could attenuate treatment efficacies of gefitinib (one of the first-generation EGFR-TKIs) or osimertinib (one of the third-generation EGFR-TKIs). Mechanistically, CLOCK functions as a transcriptional factor to upregulate LAMC2 transcription and expression in NSCLC cells. There was significantly elevated LAMC2 expressed in NSCLC tissues and its high levels were associated with shortened survival of patients. Indeed, CLOCK could activate multiple kinase signaling pathways, such as the PI3K-Akt signaling and the MAPK signaling, by facilitating either the LAMC2-ITGB1 interaction and the LAMC2-EGFR interaction and thereby accelerating NSCLC proliferation and conferring EGFR-TKI resistance. Collectively, these findings for the first time identify CLOCK as a critical mediator of EGFR-TKIs resistance and a promising target to overcome EGFR-TKIs resistance in NSCLC.

Di (2-ethylhexyl) phthalate (DEHP) is an endocrine disruptor commonly present in environment, with metabolic disturbances and reproductive toxicity. DEHP remains one of the most widely utilized plasticizers, is still consumed in large quantities with limited prospects for complete replacement in short term. Consequently, human population is inevitably at risk of DEHP exposure. Previous studies have revealed the adverse effects of maternal perinatal DEHP exposure on offspring glucose homeostasis, however, whether paternal pre-pregnancy DEHP exposure disrupts offspring glucose metabolism through epigenetic inheritance remains unclear. In this study, we aimed to investigate the transgenerational epigenetic mechanism of abnormal glycometabolism in paternal DEHP exposed offspring, and to identify potential intervention targets. Here, male rats are administrated DEHP (0.1, 0.5 and 1.0 mg/kg body weight/d) by gavage for 15 weeks and then mated with females to produce offspring. This study finds that paternal DEHP exposure impaired glycometabolism in adult male offspring across generations. Mechanistically, paternal DEHP exposure down-regulated miR-10a-5p expression in the F0 generation sperm and offspring pancreatic islets, then led to Klf11-dependent β cell dysfunction and insulin synthesis reduction. Further evidence confirmed that miR-10a-5p bound Klf11 mRNA 3'-untranslated region (3'- UTR) and repressed its expression. Therefore, DEHP induced miR-10a-5p reduction resulted in Klf11 disinhibition, which functions as a transcriptional suppressor of Kit and Ins2 genes expression, eventually exacerbating glycometabolism disorders. Ultimately, our findings reveal that long-term DEHP exposure induced glycometabolism disorders exhibits transgenerational genetic characteristics and identify miR-10a-5p/Klf11 axis as a potential molecular target to mitigate offspring metabolic risk associated with paternal environment exposures.

This study investigated the effects of selenium supplementation in the form of selenium nanoparticles (SeNPs) and sodium selenite (SSe) on the transcriptional regulation of heat shock proteins (HSP60, HSP70, and HSP90) in periparturient cloned and non-cloned Saanen goats and their offspring.

Vitamin D is a crucial regulator of immune responses and has recognized anti-proliferative effects in cancer. However, its clinical use is limited by poor solubility and bioavailability. Nanocarrier systems, such as carbon quantum dots (CQDs), may improve vitamin D delivery and activity.

Oral squamous cell carcinoma (OSCC) is associated with aggressive clinical behavior and poor outcomes. In this study, we investigated the anticancer efficacy and underlying mechanisms of Stellettin B, an isomalabaricane triterpene isolated from the marine sponge Jaspis stellifera, in OSCC cells. Our results demonstrate that Stellettin B significantly inhibited the proliferation of HSC-3 and OC-2 cells while sparing normal oral keratinocytes. Mechanistically, Stellettin B triggers a predominantly caspase-independent apoptotic program, evidenced by the pronounced mitochondrial-to-nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) following DNA damage, whereas classical caspase activation functions as a dispensable, secondary event. Furthermore, Stellettin B suppressed migration and invasion by reversing epithelial-mesenchymal transition (EMT), characterized by E-cadherin upregulation and downregulation of Vimentin, Snail, Slug, and β-catenin. Transcriptomic profiling further revealed significant suppression of mTORC1 signaling and EDIL3 expression. In conclusion, these findings demonstrate that Stellettin B exerts multimodal antitumor activity in OSCC and highlight its therapeutic potential as a marine-derived anticancer agent.

Protein S-palmitoylation, the reversible thioesterification of cysteine side chains, is emerging as a druggable post-translational modification that couples membrane topology to oncogenic, metabolic, immune, and epigenetic networks in cancer. ZDHHC palmitoyltransferases and depalmitoylating enzymes, including acyl-protein thioesterases and palmitoyl-protein thioesterase 1, constitute a dynamic circuitry that governs the localization, stability, and signaling competence of key regulators of tumor growth, metabolic adaptation, and immune phenotype. Here, we synthesize recent structural and chemical biology advances that clarify how human ZDHHC enzymes achieve acyl-chain recognition and substrate engagement. Structural studies show that these enzymes adopt a four-transmembrane, "tent-like" fold, in which the helices create a membrane-embedded cavity for acyl-chain accommodation. We also discuss how ankyrin-repeat domains and accessory partners shape substrate recruitment and subcellular localization, and we highlight emerging high-throughput platforms that enable quantitative profiling of isoform- and site-selective modulators. We then discuss how ZDHHC-substrate circuits rewire canonical growth-factor signaling and epithelial-mesenchymal transition programs, metabolic and ferroptotic control nodes, innate immune sensing, and chromatin-linked regulation. These convergent mechanisms position ZDHHC-mediated S-palmitoylation as a context-dependent regulator of tumor progression, therapy response, ferroptosis sensitivity, and immune phenotype. Finally, we outline a translational framework encompassing clinical-stage PPT1 inhibitors, selective ABHD17 blockade, emerging ZDHHC modulators, substrate-competitive strategies targeting checkpoint palmitoylation, and selected comparator approaches affecting Wnt and Hedgehog ligand lipidation. Current evidence positions ZDHHC-mediated S-palmitoylation as a regulatory layer with potential biomarker and therapeutic relevance; however, not all reported ZDHHC-substrate associations carry equivalent evidentiary weight. Mechanisms supported by convergent site-directed, genetic, biochemical, functional, and in vivo evidence should be distinguished from associations inferred mainly from expression profiling, overexpression systems, single-model observations, or broad pharmacological perturbation. Clinical translation remains preliminary and is constrained by isoform selectivity, substrate redundancy, incomplete pharmacodynamic read-outs, and the absence of validated biomarker-guided patient stratification.

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) selectively induces apoptosis in cancer cells. However, many cancer cells are resistant to TRAIL because of downregulation of death receptors (DRs) and overexpression of anti-apoptotic proteins. Ubiquitin-conjugating enzyme E2N (UBE2N), also known as Ubc13, plays a central role in ubiquitin-mediated cellular activities. In this study, we aimed to explore the sensitization effect of UBE2N inhibition in TRAIL-mediated apoptosis in cancer cells. NSC697923 (a potent inhibitor of UBE2N) alone and TRAIL alone did not induce apoptosis in renal carcinoma Caki cells. However, combined treatment with NSC697923 and TRAIL significantly enhanced apoptotic cell death in cancer cells, but not in normal cells. Mechanistically, NSC697923 induced upregulation of DR5 mRNA and protein levels through CHOP-mediated DR5 transcriptional activation and ubiquitin-mediated DR5 stabilization. NSC697923-mediated DR5 mRNA upregulation was regulated by upregulation of CHOP expression, a key transcriptional factor of DR5. CHOP siRNA treatment inhibited NSC697923-mediated DR5 protein expression. Moreover, NSC697923 generated ROS, and pretreatment with ROS scavengers inhibited DR5 upregulation and NSC697923 plus TRAIL-mediated cell death. These findings suggest that UBE2N inhibitor enhances TRAIL-induced apoptosis by DR5 upregulation and UBE2N inhibition may serve as a potential strategy to overcome TRAIL resistance in cancer therapy.

Ethylene glycol monomethyl ether (EGME) is a testicular germ cell toxicant that selectively targets spermatocytes. In rats, male-only EGME exposure reduces mating success and can lead to an increase in resorbed fetuses. In a previous study, 5-d exposure to 50, 60, or 75 mg/kg/d EGME in male rats led to a decrease in sperm motility and increase in retained spermatid heads with a lowest observed adverse effect level (LOAEL) of 75 mg/kg/d. At 60 mg/kg/d, EGME exposure altered the proportion of sperm small RNA reads mapped to different small RNA categories and the distribution of read lengths. To understand the possible role of sperm sncRNAs in EGME-mediated reduction in spermatogenesis, fertility, and embryonic development, we analyzed sperm sncRNA data from EGME-treated male rats to identify differential expression at the individual RNA level. EGME treatment resulted in dose-dependent increases in the expression levels of microRNAs (miRNAs), piRNAs, and tRNA-derived small RNAs (tsRNAs), and mixture of dose-dependent increases and decreases in abundance of rsRNA reads. We identified 12 miRNAs that were differentially expressed at all EGME doses, with a monotonic, dose-dependent increase. High-confidence targets of these 12 miRNAs are known to be expressed in preimplantation embryos and statistically enriched for Gene Ontology (GO) biological processes related to early development, such as cell fate commitment and regulation of developmental growth. These results demonstrated that the EGME-induced changes in sperm sncRNA levels were reproducible, dose-dependent, and provided a putative mechanism of paternal EGME effects on embryonic development, which will be investigated in future studies.

ObjectiveTo investigate whether naringin enhances the chemosensitivity of nasopharyngeal carcinoma-derived CNE2 cells to paclitaxel and identify potential molecular mediators.MethodsCNE2 cells were treated with naringin alone or in combination with paclitaxel, cisplatin, or 5-fluorouracil. Cell viability, proliferation, and migration were assessed using cell counting kit-8 and Transwell assays. Transcriptomic profiling followed by bioinformatic analysis of Gene Expression Omnibus datasets (GSE53819, GSE12452, and GSE102349) was performed to identify nasopharyngeal carcinoma prognosis-related genes. AKR1C3 overexpression was established via lentiviral transduction, and pharmacological inhibition was performed using ASP9521. mRNA and protein expression were validated using reverse transcription quantitative polymerase chain reaction and Western blot analysis.ResultsNaringin (160 μM) demonstrated a trend toward reducing the half-maximal inhibitory concentration of paclitaxel from 10.52 to 8.04 nM; however, it did not significantly alter sensitivity to cisplatin or 5-fluorouracil. Combined treatment with 2 nM paclitaxel and 160 μM naringin synergistically suppressed CNE2 proliferation and migration compared with that using either agent alone (p < 0.05). Bioinformatic analysis revealed that high AKR1C3 expression was correlated with improved survival in patients with nasopharyngeal carcinoma (p < 0.05), whereas high PAIP1, PRKDC, PTPRR, and COL12A1 expressions were correlated with poorer outcomes. Reverse transcription quantitative polymerase chain reaction confirmed that both naringin and paclitaxel upregulated AKR1C3 mRNA, with the combination producing the strongest effect. Gain-of-function studies demonstrated that AKR1C3 overexpression significantly enhanced paclitaxel sensitivity, with half-maximal inhibitory concentration values decreasing from 13.63 to 6.994 nM in CNE2 cells and from 8.534 to 4.668 nM in CNE1 cells. Furthermore, the specific AKR1C3 inhibitor, ASP9521, significantly attenuated the synergistic anti-proliferative and anti-migratory effects of paclitaxel + naringin in CNE2 cells, confirming that naringin enhances chemosensitivity to paclitaxel by upregulating AKR1C3 expression.ConclusionsNaringin sensitizes CNE2 cells to paclitaxel, potentially via AKR1C3 upregulation. This flavonoid may represent a low-toxicity adjunct to enhance the efficacy of paclitaxel in nasopharyngeal carcinoma.

Colorectal cancer (CRC) continues to be a significant global health issue. Thymoquinone (TQ), a bioactive component of Nigella sativa, has shown anticancer capabilities by inducing apoptosis. This systematic review and meta-analysis aim to assess the impact of TQ on the levels of pro-apoptotic (BAX, CASP3) and anti-apoptotic (BCL2) markers in colorectal cancer cells.

Stemona tuberosa Lour. is a traditional Chinese medicinal plant whose tuberous roots contain alkaloids with antitussive and antimicrobial activities. This study investigated the effects of selenium nanoparticles (SeNPs) on alkaloid accumulation in S. tuberosa. Plants were treated with different SeNP concentrations (0, 10, 20, 40, and 80 mg L-1) for 10, 20, 30, and 40 days. Alkaloid and total selenium contents in tuberous roots were determined, and integrated metabolomic and transcriptomic analyses were performed. SeNPs induced concentration- and time-dependent changes in alkaloid accumulation, with the highest level observed at 20 mg L-1 after 30 days. Total selenium content generally increased with treatment duration. Based on these results, the Se20 treatment at 30 days was selected for omics analyses. Metabolomic profiling revealed significant alterations in amino acids, organic acids, and alkaloids. Differential metabolites were mainly enriched in isoquinoline alkaloid biosynthesis, purine metabolism, and cofactor biosynthesis pathways. A total of 55 differential alkaloids were identified, of which 39 differed significantly between Se0 and Se20, including 29 upregulated and 10 downregulated compounds. Transcriptomic analysis showed upregulation of PPO and TAT and downregulation of NCS. In addition, transcription factors from the AP2/ERF, bHLH, and MYB families were differentially expressed. These results suggest that SeNPs promote alkaloid accumulation by modulating precursor metabolism and key biosynthetic pathways. Overall, this study provides insights into the molecular basis of SeNP-mediated alkaloid accumulation and supports the cultivation of selenium-enriched medicinal plants.

Glioblastoma (GBM) is a highly aggressive and therapy-resistant brain tumor. In our earlier study, we demonstrated that the antihyperlipidemic drug Gemfibrozil, when repurposed, exerts strong cytotoxic effects on GBM cells by modulating autophagy. In the present study, we further investigated the complex interplay among key homeostatic pathways, specifically autophagy, endoplasmic reticulum (ER) stress, and calcium signalling, following Gemfibrozil exposure in the context of GBM progression and treatment resistance. Our findings reveal that Gemfibrozil-induced inhibition of autophagy triggers the unfolded protein response (UPR), leading to activation of ER stress pathways, as evidenced by altered expression of canonical markers, including IRE1α, PERK, and CHOP. Notably, CHOP silencing reduced levels of cleaved Caspase-3 and Caspase-9, confirming the involvement of ER stress-mediated apoptosis following disruption of autophagy. Moreover, the induction of ER stress and inhibition of autophagy were accompanied by disturbances in calcium homeostasis, demonstrated by reduced expression of the calcium-binding proteins Calmodulin and Calreticulin. This imbalance resulted in mitochondrial calcium overload, loss of mitochondrial membrane potential, and elevated reactive oxygen species (ROS) production, ultimately culminating in caspase activation and cell death. Mechanistically, PGC-1α emerged as a key regulator of Gemfibrozil-mediated anti-tumor activity. Collectively, our findings uncover a critical molecular cascade involving suppression of autophagy, induction of ER stress, calcium dysregulation, mitochondrial dysfunction, and oxidative stress that drives GBM cell death. These insights not only highlight Gemfibrozil as a potential therapeutic agent but also emphasize the importance of targeting homeostatic vulnerabilities in GBM.

This study aims to examine whether oral glutamate administration is associated with accelerated atherosclerosis progression in high-fat diet-fed ApoE ⁻ / ⁻ mice and to identify candidate protein associated with this process.

Infants exposed to opioids in utero are at risk of developing Neonatal Opioid Withdrawal Syndrome (NOWS). Rodent models of perinatal opioid exposure can reliably recapitulate the acute withdrawal and developmental deficits exhibited in clinical NOWS, but few persisting phenotypes are consistently observed between studies, limiting mechanistic insight into the long-lasting effects of early-life opioid exposure.