Nonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional protein. The absence of protein expression and the consequent loss of essential cellular functions are responsible for the severe phenotypes in the so-called genetic nonsense-related diseases (NRDs), such as cystic fibrosis, hemophilia, Duchenne muscular dystrophy, Fabry disease, Choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and even certain types of cancer. Nonsense mutations pose a significant challenge in the treatment of NRDs, as a specific approach directly addressing this genetic defect is currently unavailable. Developing new therapeutic strategies for nonsense suppression is a crucial goal of precision medicine. This review describes some of the most promising therapeutic approaches and emerging strategies for treating NRDs. It considered both the use of small molecules to interfere with molecular mechanisms related to nonsense mutations, such as translational readthrough-inducing drugs (TRIDs) or inhibitors of the nonsense-mediated decay (NMD) pathway, and also innovative approaches involving nucleic acids, such as gene editing, anticodon engineered-tRNA (ACE-tRNA), or mRNA-based therapy. Future research should focus on refining these approaches and exploring integrated and personalized treatments to enhance therapeutic outcomes and ensure continuous improvement in the quality of care.

Endocrine disrupting chemicals (EDCs) are ubiquitous in the environment and have been shown to interfere with the endocrine system, leading to adverse effects on reproductive health. In females, EDC exposure has been linked to menstrual irregularities, infertility, and pregnancy complications. Epigenetic regulation, which involves modifications to DNA and histones that do not alter the underlying genetic code, plays a crucial role in female reproduction. EDCs have been shown to disrupt epigenetic mechanisms, leading to changes in gene expression that can have long-term effects on reproductive outcomes. Several EDCs, including bisphenol A (BPA) and phthalates, dioxins, and polychlorinated biphenyls (PCBs), have been shown to alter DNA methylation patterns and histone modifications in female reproductive tissues. These changes can lead to altered expression of genes involved in ovarian function, implantation, and placental development. Here, we integrate epidemiological and experimental evidence from the last 20 years to profile the types of diseases that EDCs trigger in the female reproductive system in relation to the uterus, and the corresponding molecular mechanisms that have been studied. In addition, this review will outline the state of knowledge of EDC epigenetic regulation in the uterus and how it impacts reproductive health, as well as identify areas for future research.

Triple negative breast cancer, an inherently aggressive disease, is further impaired by the limited therapeutic options and chemotherapy-resistance; hence, elucidating the signaling nodes underlying chemotherapy resistance is of major interest. Focusing on the differentially expressed genes in recurrent TNBC, we identified TRIM29, a ubiquitin ligase belonging to TRIM family, as a uniquely enriched protein in chemoresistant TNBC. Here, we demonstrate that chemoresistant TNBC cells are inherently aggressive, exhibiting elevated growth and migration potential compared to chemosensitive cells, and in particular, they possess higher TRIM29 expression whose expression level modulation results in altered chemosensitivity. TRIM29 overexpression reduces chemotherapy response whereas TRIM29 knockout not only increases chemosensitivity but also reduces TNBC tumor growth. Tumor-dissociated cells maintain TRIM29 knockout status as well as exhibit similar functional alterations as chemoresistant TNBC cells. Mechanistically, RNA-sequencing of parental-chemosensitive, chemoresistant-inherently overexpressing TRIM29 and chemoresistant-TRIM29 knockout TNBC cells reveals a unique set of genes (S100P, SERPINB3, SERPINB4, CEACAM5, CEACAM6 and CDH6) showing significant upregulation with the acquisition of chemoresistance and downregulation with the TRIM29 knockout. Furthermore, an enrichment of β-catenin pathway in chemoresistant TNBC cells is observed. We uncovered a functional network where S100P, a metastasis inducing secretory factor, bidirectionally interacts with TRIM29, and modulates the expression of SERPINB3, SERPINB4, CEACAM5, CEACAM6 as well as β-catenin pathway genes. Showing the functional importance, S100P inhibitor reduces the growth and mammosphere formation in chemoresistant TNBC. Moreover, combining β-catenin inhibitor with chemotherapy shows synergistic inhibition of chemoresistant TNBC cells. Indeed, higher expression of TRIM29, S100P and β-catenin associates with reduced recurrence free survival. This work proposes TRIM29 as an important node that modulates a unique gene network in chemoresistant TNBC and whose biological impact is mediated by modulation of S100P and β-catenin.

Brassinosteroids (BRs) are known to regulate fruit development, ripening, and metabolic processes in plants. In this study, the impact of exogenous 24-epibrassinolide (EBR) on tomato fruit quality was examined using 'Micro-Tom' tomatoes.

Temozolomide (TMZ) resistance is one of the critical factors contributing to the poor prognosis of glioblastoma (GBM). As a first-line chemotherapeutic agent for GBM, TMZ exerts its cytotoxic effects through DNA alkylation. However, its therapeutic efficacy is significantly compromised by enhanced DNA damage repair (DDR) mechanisms in GBM cells. Although several DDR-targeting drugs have been developed, their clinical outcomes remain suboptimal. Post-translational modifications (PTMs) in GBM cells play a pivotal role in maintaining the genomic stability of DDR mechanisms, including methylguanine-DNA methyltransferase-mediated repair, DNA mismatch repair dysfunction, base excision repair, and double-strand break repair. This review focuses on elucidating the regulatory roles of PTMs in the intrinsic mechanisms underlying TMZ resistance in GBM. Furthermore, we explore the feasibility of enhancing TMZ-induced cytotoxicity by targeting PTM-related enzymatic to disrupt key steps in PTM-mediated DDR pathways. By integrating current preclinical insights and clinical challenges, this work highlights the potential of modulating PTM-driven networks as a novel therapeutic strategy to overcome TMZ resistance and improve treatment outcomes for GBM patients.

Chronic kidney disease (CKD) is a global health challenge marked by progressive renal decline and increased mortality. The interplay between CKD and hypothyroidism, particularly nonthyroidal low-triiodothyronine (T3) syndrome, exacerbates disease progression, driven by HPT axis dysfunction and reduced Klotho levels due to the Wnt/β-catenin pathway activation. This study explored Klotho as a link between CKD and hypothyroidism using an adenine-induced CKD aged mouse model. Exogenous T3 and baicalein (BAI), targeting the Wnt pathway, were used to upregulate Klotho expression. Combined T3 and BAI treatment significantly increased Klotho levels, surpassing individual effects, and suppressed key signaling molecules (TGF, NFκB, GSK3), mitigating renal fibrosis and CKD complications, including cardiovascular disorders and dyslipidemia. This bidirectional approach, enhancing Klotho via T3 and sustained Wnt pathway inhibition, offers a novel and effective strategy for CKD management, particularly in elderly patients with hypothyroidism.

Obesity, nowadays a common disease, due to its complexity can cause many other disorders. In this study, a model of preadipocytes isolated from human adipose tissue was used. Cells after differentiation were additionally fattened with fatty acids such as palmitic, oleic and linoleic. Compared to control cells, obtained cells constitute a strongly reliable research model that mimics obesity occurring in humans. Achieved results have shown that adipocytes treated with fatty acids exhibited a greater number of both 'large' and 'small' lipid droplets, and an increase in lipid droplet formation and maintenance-related proteins, elevated expression of genes encoding proteins involved in the transport of fatty acids and raised secretion of cholesterol and glutamate. Fattening has also resulted in changes in the phenotype of vimentin filaments and actin cytoskeleton reorganisation. Finally, it has also been observed that hypertrophy of adipocytes was accompanied by modifications in cell metabolism, phenotypic and quantitative changes in mitochondria with a simultaneous downregulation of genes involved in mitochondrial fusion. In summary, the human research model that we propose allowed us to demonstrate several adjustments in cells mimicking the obesity state, which may contribute to expanding knowledge about obesity and improving treatment strategies for this disease.

DNA methylation is an epigenetic modification involved in cancer. The clinically approved nucleoside DNA methyltransferase (DNMT) inhibitors 5-azacytidine and 5-aza-2'-deoxycytidine lack selectivity and stability, resulting in high toxicity. Previously, we discovered 3-halo-3-nitroflavanones as non-nucleoside DNMT inhibitors. Here, we designed and synthesized a new series of 2-substituted haloflavanones to increase compound chemical stability. Moreover, replacement of the nitro by an additional halogen enhanced compound potency. Indeed, compound 34b (anti-3-bromo-3-chloro-2-methoxyflavanone) exhibited submicromolar DNMT3A inhibitory activity, upregulated the expression of DNMT-targeted genes, and impaired cell proliferation. Importantly, 34b triggered a critical cell cycle arrest in the G1/S transition, notably in p53-depleted HCT-116 colorectal cancer cells, which paves the way for novel therapeutic opportunities. 34b competes for the same DNMT catalytic pocket as confirmed by saturation transfer difference-nuclear magnetic resonance, but assuming different docking poses as shown by computational studies. Overall, the high stability and activity of 34b make it a promising DNMT inhibitor for anticancer research and therapy.

Tumors are characterized by global changes in epigenetic modifications such as DNA methylation and histone modifications that are functionally linked to tumor progression. Accordingly, several drugs targeting the epigenome have been proposed for cancer therapy, notably, histone deacetylase inhibitors (HDACi) such as vorinostat and DNA methyltransferase inhibitors (DNMTi) such as zebularine. However, a fundamental challenge with such approaches is the lack of genomic specificity, i.e., the transcriptional changes at different genomic loci can be highly variable, thus making it difficult to predict the consequences on the global transcriptome and drug response. For instance, treatment with DNMTi may upregulate the expression of not only a tumor suppressor but also an oncogene, leading to unintended adverse effect.

5-Fluorouracil (5-FU) is a mainstream drug used in chemotherapy and chemoradiotherapy regimens for the clinical treatment of malignancies, such as gastric cancer (GC), colorectal cancer, and breast cancer. However, the molecular mechanism of action of 5-FU in GC has not yet been studied using a network pharmacology approach.

Objective To investigate the gene expression and regulatory mechanisms of mouse embryonic fibroblasts (MEFs) under inflammatory conditions, aiming to elucidate the role of MEFs in inflammatory responses and provide a foundation for discovering anti-inflammatory drugs that act by modulating MEF function. Methods MEFs cultured in vitro were divided into the following groups: lipopolysaccharides (LPS)-treated group, inflammatory conditioned medium (CM)-treated group, and control group, which were treated with LPS, CM, and equal volume solvent, respectively. Transcriptome sequencing was used to analyze the effects of two stimuli on gene expression profile of MEFs. Real time fluorescence quantitative PCR (RT-qPCR) was employed to verify the transcription levels of highly expressed genes of MEFs induced by CM. ELISA was performed to determine the concentrations of cytokines in cell supernatants. Finally, the regulatory effects of CM on the activation of signaling pathways in MEFs were analyzed by immunoblotting. Results Transcriptome analysis showed that both LPS and CM induced the transcription of a large number of genes in MEFs. Compared with LPS, CM potentiated the mRNA transcription of some acute phase proteins, inflammatory cytokines, chemokines, matrix metalloproteinases (MMP), prostaglandin synthetases, and colony-stimulating factors. The transcriptome analysis was verified by RT-qPCR. The results of ELISA showed that CM treatment significantly increased the secretion of interleukin 6 (IL-6), C-C motif chemokine ligand (CCL2), and C-X-C motif chemokine ligand (CXCL1) by MEFs compared with LPS. Mechanism study showed that both LPS and CM induced the phosphorylation of nuclear factor-κB p65 (NF-κB p65), p38 mitogen-activated protein kinase (p38 MAPK), extracellular regulated protein kinases 1/2 (ERK1/2), and TANK-binding kinase (TBK) in MEFs, and CM strongly stimulated the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in MEFs. Conclusion Both LPS and CM can induce transcription and protein secretion of various inflammation-related genes in MEFs. CM can partly enhance LPS-induced activation of MEFs, and the mechanism may be related to the enhancement effect of CM on the activation STAT3 signaling pathway.

Puerarin is the major bioactive ingredient extracted from Pueraria lobata. Puerarin has an antitumor effect on many kinds of cancer. Accordingly, the aim of this study was to investigate the effect and mechanism of puerarin on thyroid cancer (TC) proliferation and apoptosis.

Arctigenin, a natural lignan from Arctium lappa L., exhibits potent antifibrotic activity, yet its molecular mechanisms remain unclear. Endoplasmic reticulum (ER) stress is known to promote hepatic stellate cell (HSC) activation and liver fibrosis. This study investigates the therapeutic potential of arctigenin in HSC activation through ER stress modulation. Primary rat HSCs were activated (3-7 days) and treated with tunicamycin (ER stress inducer) or 4-PBA (ER stress inhibitor). Arctigenin attenuated ER stress markers (e.g., GRP78) and suppressed the expression of fibrotic marker α-SMA in ER stress-challenged activating (day 3) and activated (day 7) HSCs. Arctigenin restored lipid homeostasis by modulation of both lipogenesis (via Dgat2 and Ppar-γ upregulation) and lipolysis (suppression via ATGL inhibition). ER stress activated ER-associated degradation (ERAD), triggering the formation of small lipid droplets (LD). Arctigenin normalized the ERAD activity, thereby rescuing LD integrity and suppressing HSC activation. Our findings demonstrate that arctigenin mitigates HSC activation by suppressing ER stress and restoring lipid homeostasis via modulating ERAD-mediated lipid dysregulation. As a dietary and medicinal compound, arctigenin emerges as a promising therapeutic candidate for liver fibrosis.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, necessitating the development of novel therapeutic strategies. We explore the expression characteristics of SLC39A6 in CRC by combining multiple cohorts and multi-omics. The therapeutic effect and potential mechanism of BRY812 on CRC were explored through in vitro experiments. Our research results show that the expression of SLC39A6 in CRC tissues is higher than that in normal tissues, and it is closely related to tumor pathways, making it a good therapeutic target. BRY812 has an inhibitory effect on the growth, migration and stemness of CRC cells, and may exert its killing effect by downregulating the AKT pathway. This study has identified SLC39A6 as a potential therapeutic target in CRC. BRY812 is expected to become a highly promising therapeutic drug, bringing new hope to patients with CRC.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), has dramatically transformed the treatment landscape for patients with EGFR-mutant NSCLC. However, the long-term success of this therapy is often compromised by the onset of acquired resistance, with non-genetic mechanisms increasingly recognized as pivotal contributors. Here, we exploit a multi-omics approach to profile genome-wide chromatin accessibility and transcriptional landscapes between drug sensitive and resistant EGFR-mutant cells. Our findings reveal a robust concordance between epigenetic regulome and transcriptomic changes that characterize the osimertinib resistant state. Through CRISPR-based functional genomics screen targeting epigenetic regulators and transcription factors, we uncover a critical regulatory network featuring key members of the NuRD and PRC2 complexes that mediate resistance. Most critically, our screen identifies FOSL1 and JUN, two subunits of the AP-1 transcription factor within this network, as the most significant hits. Mechanistically, we demonstrate that cis-regulatory elements exhibiting altered chromatin accessibility in the resistant state are enriched for cognate AP-1 binding motifs, enabling AP-1 to orchestrate a gene expression program that underpins the druggable MEK/ERK signaling axis, potentially enhancing cell viability and fitness of resistant cells. Importantly, genetic depletion or pharmacological inhibition of AP-1 reinstates cellular and molecular sensitivity, and reverts resistance-associated phenotypes, such as epithelial-to-mesenchymal transition, upon anti-EGFR rechallenge by repressing AKT and ERK signaling. These findings provide novel insights into the epigenetic and transcriptional control of osimertinib resistance in EGFR-mutant NSCLC, highlighting AP-1 as a targetable vulnerability of resistance-related hallmarks and offering a promising avenue for developing resistance reversal strategies.

Soybean (Glycine max L. Merrill), a vital source of edible oil and protein, ranks seventh in global agricultural production, yet its productivity is significantly hindered by potential toxic metal/liods (PTM) stress. Arsenic (As), a highly toxic soil contaminant, poses substantial risks to both plants and humans, even at trace concentrations, particularly in China.

Cetuximab resistance severely restricts its effectiveness in the treatment of patients with metastatic colorectal cancer (CRC). Previous studies have predominantly focused on the genetic level, with scant attention to the nongenetic aspects. This study aimed to identify the crucial microRNA (miRNA) that is responsible for cetuximab resistance.

Fusobacterium nucleatum (Fn) has been implicated in various diseases, including colorectal cancer (CRC). This study elucidates Fn's contribution to cholesterol synthesis and the underlying link with CRC, as well as butyrate's counteracting effects in this process. Cells and mouse models were treated with Fn followed/accompanied by butyrate treatments to investigate the interplay between butyrate and Fn's oncogenic properties. Transcriptomics analysis pinpointed Fn's profound impact on cholesterol biosynthesis genes and pathways. Fn treatment upregulated the expression of genes involved in cholesterol synthesis (FDPS, FDFT1, and SQLE) and increased SREBF2 activity in cells and mouse intestines, elevating cholesterol levels in cells, intestines, and sera. Fn upregulated miR-130a-3p, identified through transcriptomics and target prediction, through nuclear factor-κB activation. miR-130a-3p subsequently downregulated AMPKα/β1 expression to activate SREBF2 and upregulate cholesterol biosynthesis genes. These effects were predominantly mitigated by butyrate. Notably, analysis of TCGA data revealed that fusobacterial abundance correlated significantly with the expression of FDPS, FDFT1, SQLE, and AMPKα/β1 in CRC. Fn abundance and miRNA expression in human stools were quantified using qPCR and RT-qPCR. Fecal miR-130a-3p levels increased progressively from normal subjects through adenoma patients to CRC patients, correlating significantly with fecal Fn abundance. Additionally, heightened fecal Fn abundance was associated with an increased incidence of hypercholesterolemia in CRC patients. Fn promotes cholesterol biosynthesis by upregulating miR-130a-3p, which downregulates AMPK proteins and activates SREBF2. This study highlights the influence of gut bacteria on host cholesterol synthesis. Targeted modulation of gut microbiota to reduce cholesterol may represent a promising preventive strategy for CRC.

The Wnt/β-catenin signaling pathway regulates key cellular processes, including proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Dysregulation of this pathway has been implicated in various human cancers, including colorectal cancer (CRC), where it plays a critical role in promoting EMT and metastatic progression. In a recent study, triazole derivatives were shown to possess anti-EMT activity in cancer cells. Building on this finding, we synthesized a triazolyl-quinoxaline-based small molecule, SRN-18, and evaluated its impact on EMT in CRC cells. Specifically, we investigated the effect of SRN-18 on the mRNA and protein expression levels of CXCR4 and CXCR7, as well as its influence on the expression of MMP-2, MMP-9, and key EMT-associated proteins. As CXCL12 is a known ligand for both CXCR4 and CXCR7, we also examined the effects of CXCL12 stimulation on cell migration and invasion. Western blot analyses were conducted to determine whether SRN-18 modulates the expression of CXCR4/7, MMP-2/9, and EMT markers in the presence or absence of CXCL12 stimulation. Additionally, our findings revealed that the Wnt/β-catenin signaling pathway is involved in SRN-18-mediated EMT suppression. Since inhibition of the Wnt/β-catenin pathway has been shown to reduce the expression of CXCR4 and CXCR7, SRN-18-mediated suppression of this pathway led to the downregulation of CXCR4- and CXCR7-associated signaling proteins, including NF-κB and JNK. In summary, SRN-18 exerted its anti-EMT effects in colorectal cancer cells by targeting the Wnt/β-catenin signaling axis and its downstream signaling cascades.

The aim of this study was to determine the freezability of ram semen with extenders containing mitoquinone or caffeic acid. Collected ram semen samples were pooled and divided into seven equal aliquots. Each aliquot was diluted with Tris-based extender according to control and antioxidant groups (Control, Mitoquinone (MitoQ) 100 nM, 150 nM, 200 nM; Caffeic Acid (CA) 50 µM, 100 µM, 150 µM). The post-thaw spermatological, antioxidant parameters and OGG1/ROMO1 gene expression and methylation were evaluated. It was determined that the CASA post-thaw motility of MitoQ200, CA100 and CA150 antioxidant groups were statistically higher than the control group (P < 0.05). The post-thaw plasma membrane integrity of MitoQ groups was compared with CA groups, CA100 group, which had the lowest plasma membrane integrity among the antioxidant groups. The post-thaw acrosome membrane damage of all the antioxidant groups were statistically lower than control group, except CA50 and CA100 groups (P < 0.05). For the post-thaw mitochondrial membrane potential, all groups except the CA50 group were determined to be superior to the control group (P < 0.05). No statistical difference was observed among all groups including control group in terms of post-thaw DNA fragmentation, MDA and TAC values. MitoQ significantly altered the expression of the OGG1 genes, an effect mediated through DNA methylation (P < 0.05). Furthermore, caffeic acid altered the ROMO1 gene expression (P < 0.05). Based on the spermatological parameters and gene expression and methylation levels obtained in the current study, it was determined that mitoquinone 200 nM and caffeic acid 150 µM doses had a positive effect on the freezability of ram semen.