Cyclooxygenase-2 (COX-2), a key enzyme to catalyzes the formation of prostanoids from arachidonic acid, is involved in inflammatory events. Furthermore, the calpain/PARP/NF-κB inflammatory pathway has been implicated in the damage to the neurovascular unit (NVU) following ischemic stroke. This study investigated the effects of parecoxib, a specific COX-2 inhibitor, on calpain, PARP, NF-κB inflammatory signaling, and NVU damage in the rat model of ischemic stroke. Male Sprague-Dawley rats (n = 107) were subjected to 90 min of ischemia, followed by reperfusion. Parecoxib was administered intraperitoneally 5 min post-ischemia, and the activation of calpain, PARP, and NF-κB-inflammatory signaling, and the NVU damage were evaluated 24 h post-ischemia. It was found that parecoxib alleviated neurological deficits, brain swelling and apoptotic cell death, and decreased infarct volumes 24 h post-ischemia. It decreased the levels of calpain 1 and 2, enhanced the levels of calpastatin, and repressed the activities of calpain in penumbra and core. Meanwhile, it reduced the levels of cytosolic PARP and HMGB1, elevated the level of cytosolic IκBα, lowered the levels of nuclear PARP, poly(ADP-ribose) and NF-κB p65, lessened the levels of cytosolic ICAM-1, IL-1β, MMP-2, and MMP-9, and suppressed the MPO activities in penumbra and core. Additionally, it attenuated the NVU and blood-brain barrier damage in penumbra and core. These data demonstrated that parecoxib exerts its protective effects on the NVU by blocking the over-activation of calpain and PARP, as well as by suppressing NF-κB-mediated inflammatory response during ischemic stroke. Moreover, the findings suggest that COX-2 contributes to NVU damage by up-regulating the calpain/PARP/NF-κB inflammatory pathway during brain ischemia.

Transforming growth factor‑β1 (TGF‑β1) plays a dual role in cancer progression, acting as both a tumour suppressor and a tumour promoter, with complex and stage‑dependent mechanisms of action. This article systematically reviews the molecular switching mechanism of TGF‑β1 from a tumour suppressor to a tumour promoter and its systemic regulatory network in the tumour microenvironment. In the process through which TGF‑β1 regulates cancer progression, its signalling pathways promote tumour invasion, metastasis and chemotherapy resistance through SMAD mutation, receptor expression downregulation, epithelial‑mesenchymal transition activation, immune escape, non‑SMAD pathway activation and remodelling of the tumour microenvironment. Although TGF‑β1‑targeting therapies such as antibodies, kinase inhibitors and antisense oligonucleotides face limitations in terms of efficacy and toxicity, combination immunotherapy (such as anti‑PD‑1 therapy) has the potential to enhance antitumour responses. Future precision intervention needs to integrate the dimension of time to distinguish between early tumour suppression and late tumour promotion windows, the dimension of spatiality and cell type to analyse the signal heterogeneity between primary and metastatic lesions, the dimension of signalling networks to selectively inhibit SMAD and non‑SMAD pathways, and the dimension of technology, such as using single‑cell sequencing and organoid models to guide personalised treatment, thereby achieving effective regulation of the complex role of TGF‑β1 in cancer progression.

Kv10.1, also known as Eag1 or KCNH1, is a voltage‑gated potassium ion channel, which exists in cell membrane and is closely associated with cancer and multiple precancerous lesions. Emerging experimental evidence shows that Kv10.1 is essential for the occurrence, growth, metastasis, proliferation and death of various malignant tumors. The pathogenesis of Kv10.1 and the signal pathways involved in its regulation are different in different cancers. The present review explored the origin, structure, distribution in normal and tumor cells, physiological and pathological characteristics, roles in cancer and tumor regulation mechanisms of Kv10.1. Finally, Kv10.1 related signaling pathways and its current use as a pharmacological modulator are summarized, aiming to provide new insights into the pharmacological research of Kv10.1 in cancer.

Colorectal cancer is recognized as one of the leading causes of cancer death amongst both sexes in the U.S. Despite rigorous screening, those diagnosed with colon cancer often face poor prognosis, and approximately 70% of affected patients will develop metastatic relapse. The investigation of colon carcinoma cell lines' genetic variability and response to chemotherapy panels may aid in targeting therapies to improve outcomes. This study aims to find correlations between metastasis status, gene variability, and drug response. We used two cell lines that were isolated from the same 51-year-old male with colorectal adenocarcinoma: a primary tumor-derived line (SW480) and a secondary metastasis-derived line (SW620). Live cell imaging using time-lapse microscopy over 3 days exhibited differential cell death responses following treatment with multiple chemotherapeutic agents, particularly cediranib and Nu-7441, with SW620 demonstrating greater sensitivity. Western blots revealed changes in DNA repair machinery expression (particularly NHEJ proteins) between SW480 and SW620. RNA sequencing and Gene Ontology analysis corroborated our findings, demonstrating upregulated DNA repair and metabolic survival genes including TGM2 in SW620 and PROM1 in SW480. An SW620 line grown in non-attachment plates and then reattached (SW620F) exhibited high DNA-PKcs activation and drug sensitivity. Correlation between drug response and gene expression crucial to cell growth and successful metastasis may reveal new biomarkers to target potential treatments.

Bromodomain and extraterminal proteins have emerged as key epigenetic regulators that coordinate transcriptional programs fundamental to cardiovascular physiology and disease. Although bromodomain and extraterminal protein inhibitors exert multiple cardiovascular effects, they cannot fully explain clinical heterogeneity in outcomes and responses, highlighting the need to clarify the context- and disease-specific roles of individual bromodomain and extraterminal protein family members. This narrative review delineates the distinct molecular roles of bromodomain-containing protein 2, bromodomain-containing protein 3, bromodomain-containing protein 4, and bromodomain testis, summarizing their domain architecture and epigenetic regulatory functions. We then synthesize current evidence linking bromodomain and extraterminal protein activity to cardiovascular disease pathogenesis, emphasizing their contributions to major pathological processes, including inflammatory amplification, fibrotic remodeling, dysregulated energy metabolism, aberrant cell proliferation, endothelial-mesenchymal transition, and ferroptotic cell death. Furthermore, we evaluate advances in bromodomain and extraterminal protein inhibitors across preclinical and clinical research, highlighting agents that demonstrate anti-inflammatory, antifibrotic, and cardioprotective efficacy in animal models of cardiovascular disease. By integrating mechanistic and translational evidence, this review provides a framework for understanding bromodomain and extraterminal proteins in cardiovascular diseases and guides the rational design of targeted therapies.

The pseudoknot secondary structure in SARS-CoV-2 RNA is essential for regulating protein synthesis through -$$ - $$ 1 programmed ribosomal frameshifting ( -1$$ -1 $$ PRF), a mechanism that allows the virus to generate both structural and non-structural proteins from overlapping reading frames. This pseudoknot exhibits both threaded and unthreaded long-lived topologies. The influence of ligand binding on its folding is a process critical for the development of -$$ - $$ 1 PRF small-molecule inhibitors. Understanding this process through unbiased molecular dynamics (MD) simulations can be facilitated by introducing collective variables (CVs) that capture the corresponding slowest dynamical modes. Here, we use spectral map (SM), a thermodynamics-driven machine learning technique, to learn such CVs directly from all-atom MD trajectories of the SARS-CoV-2 RNA pseudoknot in complex with the -$$ - $$ 1 PRF inhibitor merafloxacin and its two structural analogs in neutral and ionized forms. Free-energy landscapes (FELs) derived from the learned CVs indicate that ligand-induced destabilization is topology-selective. In the threaded pseudoknot, the inhibitors destabilize the S2 stem, while in the unthreaded pseudoknot, destabilization occurs in the S1 and S3 stems. Furthermore, the extent to which each ligand reshapes the FEL matches experimentally reported antiviral potency, whereas the protonation state qualitatively alters dynamics within the same RNA topology. Overall, our results show how pseudoknot topology, ligand type, and protonation state collectively influence the slow conformational dynamics of viral RNA and establish physiological protonation as a critical factor for modeling RNA-targeted drug action.

Proteins belonging to the Schlafen family are interferon-inducible and participate in the regulation of antiviral responses, immune signaling, and proteotoxic stress. Schlafen 11 (SLFN11) also kills cells with replicative damage, serving as a predictive biomarker for chemotherapeutic response. In this study, we examined SLFN11 expression and significance in multiple myeloma. The Cancer Genome Atlas and MMRF CoMMpass datasets were analyzed for SLFN11 expression. Bone marrow and cell lines samples were analyzed for SLFN11 protein. SLFN11-knockout multiple myeloma cell lines were used to explore how SLFN11 affects bortezomib (BTZ) response. Retrospective analysis of the HOVON-65/GMMG-HD4 phase III trial (n = 327) assessed clinical relevance. SLFN11 is consistently highly expressed across multiple myeloma subtypes (except CD1 and MAF/MAFB) and in normal plasma cells, and its expression strongly correlates with super-enhancer-driven plasma cell transcriptional programs. CD138-positive normal and myeloma plasma cells retain SLFN11 expression even when proliferative activity (MKI67/Ki-67) increases with disease progression. BTZ, a first-line multiple myeloma treatment, induces SLFN11 nucleolar translocation with suppression of ribosomal RNA (rRNA) synthesis. Knocking out SLFN11 in multiple myeloma cells enhances BTZ sensitivity and exatecan resistance, supporting SLFN11's protective role in proteotoxic stress and sensitizing role in replication stress. In the HOVON-65/GMMG-HD4 trial, SLFN11-low patients seemed to preferentially benefit from BTZ-based therapy, suggesting that SLFN11 expression may guide therapeutic stratification in multiple myeloma.

Glutamate (Glu), a key amino acid in nitrogen (N) metabolism, also functions as a signaling molecule in plants. When supplied as the sole N source, Glu acts both as an N nutrient and as a signaling molecule in Arabidopsis, depending on the physiological context. Compared with NH4NO3, Glu inhibited primary root growth, which was associated with reduced auxin responses and diminished stem cell niche activity in the root apex, likely reflecting Glu's signaling role. In contrast, Arabidopsis seedlings grown on Glu accumulated more anthocyanins than those grown on NH4NO3, possibly reflecting its metabolic function. Glu differentially regulates Gln synthetase (GS) genes, inducing cytosolic GS1 while repressing chloroplastic GS2, suggesting transcriptional regulation independent of substrate availability. Glu also altered amino acid profiles, increasing Glu and Glu-dependent amino acids while decreasing Gln and Gln-derived amino acids, consistent with limited NH4+ availability in Arabidopsis seedlings grown on Glu as the sole N source. Transcriptome analysis revealed that Glu preferentially induced defense-related genes and repressed photosynthesis-associated genes relative to NH4NO3. Notably, Glu rapidly induced defense-related transcripts within 30 min in N-starved seedlings, supporting Glu's signaling role associated with induced defense responses. In addition, Glu promoted root hair elongation by repressing GLABRA2 and activating the ROOT HAIR DEFECTIVE6 signaling pathway. This effect involved ethylene and salicylic acid signaling and persisted in the presence of NH4NO3. Together, our findings demonstrate that extracellular Glu functions both as an N nutrient and as a signaling molecule that coordinates growth, defense, and root hair development in Arabidopsis.

Chemotherapy remains the most preferred therapeutic option for Triple-Negative breast cancer (TNBC), but patients frequently develop resistance over time, which remains a major clinical challenge, leading to poor patient treatment outcomes.

Colorectal cancer (CRC) progression is driven by metastatic potential, metabolic reprogramming, and immune evasion. In this study, we investigated the effects of a di-rhamnolipid, Rha2-C10-C10 (1), on CRC cell motility, energy metabolism, and immune-related signaling. Compound 1 exhibited minimal cytotoxicity in AGS, A549, and MDA-MB-231 cells, while modestly reducing viability in Caco2 cells at higher concentrations. Notably, it significantly suppressed invasion and migration, with the most pronounced effects observed in Caco2 cells. These effects were associated with downregulation of mesenchymal markers, including N-cadherin and transcription factors Snail and Slug, as well as matrix metalloproteinases (MMP2, MMP3, and MMP9), accompanied by increased TIMP2 expression. In addition, compound 1 attenuated metabolic activity by reducing the expression of key glycolytic regulators, including GLUT1, LDHA, and HK2. It also suppressed immune evasion-related factors such as PD-L1, IDO1, IDO2, and Galectin. Mechanistic investigations using BaP and the AKT inhibitor MK2206 suggest that the effects of compound 1 involve modulation of AKT-associated signaling while also engaging additional regulatory pathways. Collectively, these findings demonstrate that compound 1 suppresses colorectal cancer cell motility, metabolic activity, and immune evasion, highlighting its potential as a natural compound targeting multiple tumor-promoting processes.

Elevated glucocorticoid levels during the sensitive period of early ontogenesis cause long-term changes in the functioning of neurotransmitter systems and the functions they regulate. One such system is the noradrenergic system, whose activity depends on the effects of stress or hormonal therapy during perinatal ontogenesis, altering stress response and psycho-emotional reactions in adult animals. Tyrosine hydroxylase (TH), a key enzyme in norepinephrine synthesis, is induced by glucocorticoids in the brain of fetal rats but remains unaffected by hormone administration on the 8th day of life. To evaluate the involvement of AP-1 transcriptional complex proteins in the age-dependent regulation of TH, we examined the relationship between the expression levels of the genes and proteins of the Jun and Fos families during and outside of hormonal induction of the enzyme gene. Hormonal induction of the TH gene and protein expression was found to occur during the periods of elevated Jun family gene expression (JunB, c-Jun, JunD) relative to Fos family genes (c-Fos, FosB) in the brainstem of 20-day-old fetuses and 3-day-old rat pups, and was absent when this ratio decreased on the day 8 of life. Chromatin immunoprecipitation followed by qPCR (ChIP-qPCR) demonstrated that, following dexamethasone administration on postnatal day 3, the number of the JunB protein-bound AP-1 sites on the Th gene promoter was significantly higher compared to the day 8. Consequently, the period of hormonal induction is accompanied by the relative predominance of the Jun/Jun homodimeric complexes on the Th gene promoter, which activate transcription of the regulated genes. This is in contrast to the day 8 of life, when the balance of Jun/Fos complexes shifts toward formation of heterodimers that do not alter transcription. The established dynamics of the ratio of AP-1 complex proteins may underlie the age-dependent manifestation of glucocorticoid induction of TH expression in vivo in the perinatal brain.

This study aims to elucidate the potential pharmacological mechanisms by which colchicine confers clinical benefits in patients with atherosclerotic cardiovascular disease, focusing on its effects on cholesterol efflux.

Sulfur Mustard (SM) is a potent vesicant chemical agent with profound and complex toxic effects. Traditionally, its toxic mechanism has been attributed to DNA alkylation-induced cytotoxicity and genomic instability. However, growing evidence indicates that dysregulation of epigenetic regulatory mechanisms constitutes a central link in SM toxicity, particularly in its long-term and delayed effects. Our study establishes an in vitro SM exposure model and employs integrated multi-omics profiling-including six histone modifications, DNA methylation, transcriptomic, and non-coding RNA analyses-to systematically investigate SM-induced epigenetic reprogramming. Our results demonstrate that SM drives extensive chromatin state remodeling, accompanied by altered expression of genes involved in DNA damage repair, cell cycle regulation, and immune response. We further constructed a predicted ceRNA network, identifying key lncRNAs, potentially associated with promoter hypomethylation, that may participate in ceRNA interactions involving cancer- and apoptosis-related genes. Additionally, we developed and validated a mass spectrometry-based method for precise quantification of 37 histone H3 modifications, providing a robust tool for profiling epigenetic biomarkers of exposure. These findings provide systems-level evidence for acute epigenetic reprogramming induced by SM exposure and reveal relevant associations between epigenomic dysregulation and genomic instability-related pathways in keratinocytes, suggesting candidate targets for future functional validation and early intervention studies.

Drug resistance remains a critical clinical bottleneck restricting long-term curative efficacy of chemo-, targeted, and other therapies against human malignancies. Drug-tolerant persister (DTP) cancer cells and intratumoral heterogeneity substantially compromise therapeutic responses and worsen patient clinical prognosis. This review summarizes core epigenetic regulatory mechanisms of drug resistance, including DNA methylation, histone modifications, non-coding RNAs (ncRNAs), N⁶-methyladenosine (m⁶A) RNA methylation, and metabolism-epigenetic crosstalk axis, elaborating the mechanistic links between epigenetic programming and the acquisition of tumor drug resistance. The dynamic epigenetic alterations remodel aberrant transcriptional landscapes to empower cancer cells to circumvent cytotoxic drug elimination. Distinct from irreversible genomic mutations, epigenetic modifications are pharmacologically reversible; such biological plasticity enables combinatorial regimens pairing epigenetic modulators with conventional cytotoxic agents as a viable strategy to reverse therapeutic resistance. In-depth dissection of the epigenetic regulatory networks facilitates identification of novel epigenetic biomarkers and druggable targets, providing rationale for developing personalized combination therapies and ultimately improving clinical outcomes of drug-resistant cancer patients.

Stem growth and development greatly influence plant architecture and yield, which are intimately associated with cell wall remodeling. However, the regulatory mechanisms governing cell wall remodeling in crops remain poorly understood. Xyloglucan endotransglucosylase/hydrolase (XTH) plays a pivotal role in xyloglucan metabolism. Here, we demonstrated that SlXTH19 controls cell wall remodeling and stem growth. Knockout or knockdown of SlXTH19 decreased cell wall thickness and cellulose and hemicellulose content in tomato stems. We demonstrated that ETHYLENE RESPONSE FACTOR (ERF) transcription factor SlERF1B binds directly to the SlXTH19 promoter, repressing its expression. Knockdown of SlERF1B showed greater stem growth and cell wall composition, whereas SlERF1B-overexpressing plants had shorter plant heights and thinner stems than the wild type. Further investigation revealed that SlERF1B directly binds to the SlGA3ox1 promoter and represses production of gibberellins (GA). In addition, SlGAI, the core negative regulator of GA signaling, interacts with SlERF1B, and these interactions enhanced the inhibitory effect of SlERF1B on its downstream targets SlXTH19 and SlGA3ox1. Collectively, these results reveal a signaling module in which GA signaling modulates the degradation of SlGAI, attenuates ethylene (ETH) signaling to inhibit SlXTH19 expression, and regulates stem growth in tomato plants.

Glioblastoma (GBM) is a devastating cancer with a dismal prognosis. Current treatment includes temozolomide (TMZ), which is more effective in about 50% of GBMs that have O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. MGMT is a DNA repair protein that reverses TMZ-induced DNA damage. EGFR is a prime oncogene in GBM. Here, we report that EGFR inhibition induced the down-regulation of MGMT in GBM cells, revealing a previously unidentified link between EGFR signaling and response to TMZ. EGFR inhibition led to activation of two transcription factors, activator protein-1 (AP-1), which repressed MGMT transcription, and nuclear factor κB (NF-κB), which up-regulated MGMT transcription. EGFR inhibition also induced AP-1-mediated transcription of miR-616. miR-616 inhibited both MGMT translation and NF-κB activation. Thus, the overall effect of EGFR inhibition was down-regulation of MGMT expression. In addition, we provided an explanation for the prior failure of clinical trials that used concomitant EGFR tyrosine kinase inhibitors (TKIs) and TMZ. TMZ up-regulated MGMT, and concomitant treatment with EGFR TKIs and TMZ failed to down-regulate MGMT. However, pretreatment with EGFR TKIs followed by TMZ efficiently down-regulated MGMT and enhanced TMZ sensitivity in experimental models. Posttreatment tumor tissues from two clinical trials were used to validate these findings. We demonstrated that EGFR inhibitors induced down-regulation of MGMT in posttreatment resected tumor tissues from patients with GBM and the failure of EGFR inhibition to down-regulate MGMT if TMZ was used concomitantly. These data support using EGFR TKIs before TMZ treatment as a therapeutic approach in MGMT unmethylated GBM.

The evolution of drug-tolerant persister (DTP) cells into resistant clones remains a major clinical obstacle to targeted therapies. Transcriptomic profiling across melanoma (A375, SK-MEL-28), non-small cell lung cancer (NSCLC; HCC827, PC-9), and colorectal cancer (CRC; SW480) models revealed a conserved biphasic telomerase regulation during DTP evolution. Combining targeted therapies with the telomere dysfunction-inducing agent 6-thio-dG effectively suppressed DTP outgrowth and resistance in vitro and in vivo. Mechanistically, 6-thio-dG induces telomere dysfunction-driven chromatin remodeling, which reduces the accessibility of the SUCLG2 locus to transcription factors. The subsequent downregulation of this mitochondrial enzyme severely disrupts the metabolic stability required for DTP survival. Consistently, SUCLG2 knockdown recapitulated these therapeutic effects. Furthermore, bulk RNA sequencing (RNA-seq) of HCC827 xenograft-derived samples confirmed that this combination therapy coordinately suppresses mitochondrial metabolism, telomere maintenance, and persister transcriptional programs. Collectively, preemptively combining 6-thio-dG with targeted therapies offers a potent strategy to disrupt DTP evolution and overcome adaptive resistance across diverse malignancies.

Hepatocellular carcinoma (HCC), the most frequent type of liver cancer, is a major source of cancer-related morbidity and mortality worldwide. B7-H6 is overexpressed in a variety of cancers including HCC and plays a key role in tumor biology and augments hepatoma cell proliferation, invasion, migration and cell-cycle progression. So, in this investigation we examined the role of B7-H6 silencing by specific siRNA in HepG2 cell line together with Paclitaxel treatment to reveal the potency of combining efficient targeted therapy with chemotherapy against tumor.

Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide, underscoring the need for novel therapeutic strategies. In this preliminary study, the cytotoxic and metabolic effects of Ornithogalum sigmoideum bulb extracts were explored in HT29 colorectal adenocarcinoma cells.

This study aimed to investigate the effect of welan gum on camptothecin (CPT) accumulation in Camptotheca acuminata leaves. We evaluated the impact of welan gum treatment on CPT biosynthesis by measuring CPT accumulation and the expression of key CPT biosynthetic genes in C. acuminata leaves. Transcriptome analysis was performed to elucidate the underlying molecular mechanisms driving welan gum-induced CPT biosynthesis. Welan gum application significantly enhanced CPT accumulation by upregulating the expression of CPT biosynthesis genes. Transcriptome data revealed strong activation of the salicylic acid (SA) signaling pathway through increased SA production, which appears to play a central role in mediating CPT biosynthesis in response to welan gum. In addition to SA signaling, jasmonic acid (JA), abscisic acid (ABA), and gibberellin (GA) signaling pathways also responded to welan gum, highlighting a complex regulatory network underlying the plant's adaptation to microbial polysaccharide signals. Welan gum treatment robustly activates multiple signaling pathways, particularly SA signaling, thereby promoting CPT accumulation in C. acuminata leaves. The coordinated modulation of these pathways reflects the intricate transcriptional reprogramming that balances growth and defense responses, enabling the plant to dynamically adjust to environmental cues triggered by microbial polysaccharides.