Rationale: Ovarian cancer is a highly lethal gynecological malignancy with common platinum resistance. Lactylation is involved in multiple biological processes. Thus, we explored the role of histone and non-histone lactylation in platinum resistance, providing a potential therapeutic target to overcome platinum resistance in ovarian cancer. Methods: We utilized gene set enrichment analysis to investigate lactylation-related pathway alterations between platinum-resistant and platinum-sensitive patients from the TCGA cohort. Differential expression of H3K9la was demonstrated using Western blotting and immunohistochemistry. Progression-free and overall survival were determined using a log-rank test. Drug response to cisplatin was evaluated by CCK8, apoptosis flow cytometry, and clonogenic assays in vitro. ChIP-seq and ChIP-qPCR assays were performed to identify downstream targets of H3K9la, which was further confirmed by qRT-PCR. LC-MS/MS was conducted to identify specific lactylation sites for RAD51. Co-IP was used to reveal the interaction between GCN5 and H3K9la or RAD51la. Cell line-derived and patient-derived xenograft (PDX) models of ovarian cancer were constructed for the in vivo experiments. Results: Our study showed elevated histone lactylation, especially of H3K9la, in platinum-resistant ovarian cancer. Moreover, high H3K9la indicated platinum resistance and poor prognosis of ovarian cancer. Impairing H3K9la enhanced response to cisplatin. Mechanistically, H3K9la directly activated RAD51 and BRCA2 expression to facilitate homologous recombination (HR) repair. Furthermore, RAD51K73la enhanced HR repair and subsequently conferred cisplatin resistance. H3K9la and RAD51K73la shared the same upstream regulator, GCN5. Notably, a GCN5 inhibitor remarkably improved the tumor-killing ability of cisplatin in PDX models of ovarian cancer. Conclusions: Our study demonstrated the essential role of histone and RAD51 lactylation in HR repair and platinum resistance. It also identified a potential therapeutic strategy to overcome platinum resistance and improve prognosis in ovarian cancer.

Mogroside V (MV) is a triterpene glucoside that reportedly exhibits an array of antitumor, anti-inflammatory, hypolipidemic, and hypoglycemic properties. In prior studies, our group determined that MV was able to readily enhance osteogenic bone marrow mesenchymal stem cells (BMSCs) differentiation under high-glucose conditions through mechanisms potentially associated with miR-10b-5p and PI3K/Akt signaling activity. The precise molecular basis for these effects, however, remains to be fully elucidated.

Histone lysine succinylation, an emerging epigenetic marker, has been implicated in diverse cellular functions, yet its role in cancer drug resistance is not well understood. Here we investigated the genome-wide alterations in histone 3 lysine 23 succinylation (H3K23su) and its impact on gene expression in 5-fluorouracil (5-FU)-resistant HCT15 colon cancer cells. We utilized CUT&Tag assays to identify differentially enriched regions (DERs) of H3K23su in 5-FU-resistant HCT15 cells via integration with ATAC-seq and RNA sequencing data. The regulatory network involving transcription factors (TFs), notably FOSL2 and KLF6, and their downstream target genes was dissected using motif enrichment analysis and chromatin immunoprecipitation assays. Our results revealed a strong positive correlation between H3K23su DERs, differentially expressed genes (DEGs) and H3K27ac, indicating that H3K23su enrichment is closely related to gene activation. The DEGs associated with the H3K23su GAIN regions were significantly enriched in pathways related to colorectal cancer, including the Wnt, MAPK and p53 signaling pathways. FOSL2 and KLF6 emerged as pivotal TFs potentially modulating DEGs associated with H3K23su DERs and were found to be essential for sustaining 5-FU resistance. Notably, we discovered that FOSL2 and KLF6 recruit the PCAF-p300/CBP complex to synergistically regulate SEMA3C expression, which subsequently modulates the canonical Wnt-β-catenin signaling pathway, leading to the upregulation of MYC and FOSL2. This study demonstrated that H3K23su is a critical epigenetic determinant of 5-FU resistance in colon cancer cells, exerting its effects through the modulation of critical genes and TFs. These findings indicate that interventions aimed at targeting TFs or enzymes involved in H3K23su modification could represent potential therapeutic strategies for treating colorectal cancers that are resistant to 5-FU treatment.

Our study elucidates the role of FOXP1 in chemoresistance in small cell lung cancer(SCLC). FOXP1 enhances chemoresistance by regulating SP8 expression through its super-enhancer (SP8-SE), with SP8 mediating resistance via the homologous recombination repair (HRR) pathway. We also discovered that FOXP1 forms punctate nuclear structures indicative of liquid-liquid phase separation, crucial for its transcriptional regulation. Targeting the FOXP1-SP8-HR axis with BRD4 and PARP inhibitors showed synergistic effects in reducing tumor growth in vitro and in patient-derived xenograft models. These findings identify FOXP1 as a critical mediator and marker of chemoresistance in SCLC, providing a foundation for developing targeted therapies to overcome this resistance.

Gilteritinib, a multi-target kinase inhibitor, is currently used as standard therapy for acute myeloid leukemia. However, approximately half of the patients encounter liver-related adverse effects during the treatment with gilteritinib, which limiting its clinical applications. The underlying mechanisms of gilteritinib-induced hepatotoxicity and the development of strategies to prevent this toxicity are not well-reported. In our study, we utilized JC-1 dye, and MitoSOX to demonstrate that gilteritinib treatment leads to hepatocytes undergoing p53-mediated mitochondrial apoptosis. Furthermore, qRT-PCR analysis revealed that DNA damage-inducible transcript 4 (DDIT4), a downstream target of p53, was upregulated following gilteritinib administration and was identified as a key factor in gilteritinib-induced hepatotoxicity. After drug screening and western blot analysis, borneol, a bicyclic monoterpenoid, was found to decrease the protein level of DDIT4. This is the first compound found to downregulate DDIT4 levels and ameliorate hepatic injury caused by gilteritinib. Our findings suggest that high levels of DDIT4 are the primary driver behind gilteritinib-induced liver injury, and that borneol could potentially be a clinically safe and feasible therapeutic strategy by inhibiting DDIT4 levels.

Indole acetic acid (IAA) orchestrates a myriad of physiological and biochemical responses in plants under stressful conditions, highlighting its indispensable role in plant resilience. The widespread contamination of chromium (Cr) poses a significant threat to rice cultivation, as its accumulation in plants disrupts various metabolic processes, consequently hindering growth. Of course, the utilization of exogenous growth regulators, including proline (Pro), has notably surged as a strategy to mitigate stress in plants. Pro can trigger the activation of other growth-regulating molecules, including IAA, to coordinate stress responses. To explore the complex interaction between exogenous Pro and the endogenous pool of IAA under Cr(VI) toxicity, a hydroponic system was established. The rice plants treated with exogenous Pro in coupled with Cr(VI) [Cr(VI)+Pro] showed significantly greater content of IAA than the plants not treated with exogenous Pro [Cr(VI)-Pro]. The expression analysis of genes involved in the speciation of IAA reactions reveals that the downregulation of OsNPR1 under "Cr(VI)+Pro" treatments might be the crucial player in increasing the IAA content in rice plants. The increase in IAA by Pro treatment under Cr toxicity might lead to an improvement in root activity and root architecture elements. Importantly, no significant difference was observed in the accumulation of Cr in [Cr(VI)-Pro]- and [Cr(VI)+Pro]-treated rice plants. These results reveal that exogenous Pro can improve plant growth by inducing IAA accumulation in plant tissues exposed to Cr(VI) toxicity, without increasing Cr toxicity in plants.

Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondria-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post-measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force, is significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. Despite these improvements, we did not detect statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age in most ELAM-treated groups. However, pathway analyses revealed that ELAM treatment showed pro-longevity shifts in gene expression, such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation, and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and cardiac dysfunction in an aging mouse model, but that these functional improvements occur independently of detectable changes in epigenetic and transcriptomic age. Thus, some age-related changes in function may be uncoupled from changes in molecular biological age.

Tartrazine (TRZ), a synthetic red azo dye derived from coal tar, is widely used as a food colorant in various food products, pharmaceuticals, and cosmetics. This study aims to investigate the impact of TRZ on the expression levels of DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) and histone deacetylases (HDAC5 and HDAC6). Additionally, we evaluate genomic DNA stability using the alkaline comet assay in three human cell lines: immortalized human keratinocyte (HaCaT), human hepatocellular carcinoma (HepG2), and human lung adenocarcinoma (A549). The research question focuses on whether TRZ exposure alters epigenetic regulation and DNA integrity, potentially implicating its role in carcinogenesis.

Heteroresistance has seriously affected the evaluation of antibiotic efficacy against pathogenic bacteria, causing misjudgment of antibiotics' sensitivity in clinical therapy, leading to treatment failure, and posing a serious threat to current medical health. However, the mechanism of Staphylococcus aureus heteroresistance to ciprofloxacin remains unclear. In this study, heteroresistance to ciprofloxacin in S. aureus strain 529 was confirmed by antimicrobial susceptibility testing and population analysis profiling (PAP), with the resistance of subclonal 529_HR based on MIC being 8-fold that of the original bacteria. A 7-day serial MIC evaluation and growth curves demonstrate that their phenotype was stable, with 529_HR growing more slowly than 529, but reaching a plateau in a similar proportion. WGS analysis showed that there were 11 nonsynonymous mutations and one deletion gene between the two bacteria, but none of these SNPs were directly associated with ciprofloxacin resistance. Transcriptome data analysis showed that the expression of membrane potential related genes (qoxA, qoxB, qoxC, qoxD, mprF) was downregulated, and the expression of multidrug resistance efflux pump gene mepA was upregulated. The combination of ciprofloxacin and limonene restored the 529_HR MIC from 1 mg/L to 0.125 mg/L. Measurement of the membrane potential found that 529_HR had a lower potential, which may enable it to withstand the ciprofloxacin-induced decrease in membrane potential. In summary, we demonstrated that upregulation of mepA gene expression and a reduction in membrane potential are the main heteroresistance mechanisms of S. aureus to ciprofloxacin. Additionally, limonene may be a potentially effective agent to inhibit ciprofloxacin heteroresistance phenotypes.

Abnormal epigenetic reprogramming of nuclear-transferred (NT) embryos leads to the limited efficiency of producing cloned animals. Trichostatin A (TSA), a histone deacetylase inhibitor, improves NT embryo development, but its role in histone acetylation in porcine embryos cloned with mesenchymal stem cells (MSCs) is not fully understood. This study aimed to compare the effects of TSA on embryo development, histone acetylation patterns, and key epigenetic-related genes between in vitro fertilization (IVF), NT-MSC, and 40 nM TSA-treated NT-MSC (T-NT-MSC). The results demonstrated an increase in the blastocyst rate from 13.7% to 32.5% in the T-NT-MSC, and the transcription levels of CDX2, NANOG, and IGF2R were significantly elevated in T-NT-MSC compared to NT-MSC. TSA treatment also led to increased fluorescence intensity of acH3K9 and acH3K18 during early embryo development but did not differ in acH4K12 levels. The expression of epigenetic-related genes (HDAC1, HDAC2, CBP, p300, DNMT3a, and DNMT1) in early pre-implantation embryos followed a pattern similar to IVF embryos. In conclusion, TSA treatment improves the in vitro development of porcine embryos cloned with MSCs by increasing histone acetylation, modifying chromatin structure, and enhancing the expression of key genes, resulting in profiles similar to those of IVF embryos.

Immunosenescence, a process with a dysfunctional immune response that may favor infection is associated with an increase in inflammatory responses mediated by proinflammatory cytokines, characteristic of inflammaging. Aging and immunosenescence have a relationship relating to oxidative stress and inflammaging. Therefore, natural antioxidant compounds could be candidates for the control of the oxidative process. Our purpose was to evaluate the effect of resveratrol (Resv) on the antioxidant, antiviral, and anti-inflammatory responses induced by toll-like receptors (TLRs) 3, 4, and 7/8 agonists stimulation on peripheral blood mononuclear cells (PBMCs) of elderly and healthy female individuals (63-82 years old) and young and healthy female individuals (21-31 years old). Our data show that Resv may upregulate antioxidant factor expression, such as catalase (CAT) and SIRT1, in response to TLR4 and TLR7/8 agonists, similarly in both young and aged groups. Moreover, the Resv anti-inflammatory effect was detected by inhibiting IL-1β, TNF-α, and IL-10 secretion levels, as well as by the chemokines CCL2 and CCL5, induced by TLR4 and TLR7/8 stimulation. Curiously, Resv decreased antiviral genes, such as MxA, STING, and IRF7 expression, possibly by reducing the inflammatory effects of interferon-induced genes. Taken together, our results demonstrate the ability of Resv to stimulate antioxidant factors, leading to a downmodulation of the inflammatory response induced by innate immune stimulation. These findings point out Resv as a strategy to control the upregulation of inflammatory response, even in elderly individuals.

Sainfoin (Onobrychis viciifolia) is a type of leguminous plant with high feeding value. It contains a high concentration of tannins at all growth stages, which can precipitate soluble proteins and form a large number of persistent foams in the rumen, so that ruminant livestock will not develop dilatation disease during green feeding and grazing. The germination rate of O. viciifolia seeds is very low under natural conditions. The preliminary experiment showed that 600 mg/L GA3 treatment significantly improved the germination rate and seed vitality of sainfoin seeds. In comparison to CK, GA3 significantly decreased the relative content of endogenous inhibitors, with the most notable reduction observed in 4-nitroso-N-phenyl-benzenamine. Therefore, we selected the dry seed stage (GZ), imbibition stage (XZ), split stage (LK), and radicle emergence stage (MF) of four different germination stages treated with GA3 for transcriptome analysis. RNA-seq identified 1392, 2534 and 4284 differentially expressed genes (DEGs) in GZ vs. XZ, XZ vs. LK, and LK vs. MF, respectively. During seed germination, DEGs are mainly enriched in hormone signaling and phenylalanine biosynthesis pathways, and up-down-regulation of these DEGs may alter hormone and secondary metabolite levels to promote germination. The results of weighted gene co-expression network construction (WGCNA) also indicate that plant hormone signal transduction and phenylpropanoid biosynthesis play a dominant role in GA3-induced seed germination. In conclusion, the combined analysis of transcriptomic and physiological indicators provided new insights into seed germination and a theoretical basis for further study of candidate genes.

Triple-negative breast cancer (TNBC) presents limited therapeutic options and is characterized by a poor prognosis. Although Kinsenoside (KIN) possesses a wide range of pharmacological activities, its effect and mechanism in TNBC remain unclear. The objective of this research was to explore the therapeutic effectiveness and the molecular mechanisms of KIN on TNBC. Xenograft experiment was carried out to assess the impact of KIN on TNBC in vivo. The effect of KIN on TNBC in vitro was evaluated through the analysis of cell cytotoxicity and colony formation assays. Oil Red O staining and BODIPY 493/503 fluorescence staining were employed to detect the effect of KIN on lipid droplet (LD) formation. Transcriptomics and inhibitor-rescue experiments were conducted to investigate the role of KIN on TNBC. Mechanistic experiments, including quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting, diacylglycerol acyltransferase 1 (DGAT1) overexpression assay, and flow cytometric assay, were employed to uncover the regulatory mechanisms of KIN on TNBC. KIN inhibited tumor growth without causing obvious toxicity to the liver and kidneys. In vitro experiments demonstrated that KIN significantly inhibited the viability and proliferation of TNBC cells, accompanied by decreased LD formation and lipid content. Polyunsaturated fatty acids (PUFAs) levels were significantly increased by KIN. Furthermore, transcriptomics and inhibitor-rescue experiments revealed that KIN induced ferroptosis in TNBC cells. KIN could significantly regulate ferroptosis-related proteins. Lipid peroxidation, iron accumulation, and GSH depletion also confirmed this. The LD inducer mitigated the KIN-induced ferroptosis in TNBC. The overexpression of DGAT1 attenuated the effects of KIN on cell viability and proliferation. Furthermore, the overexpression of DGAT1 inhibited the effect of KIN to trigger ferroptosis in TNBC cells. Our findings confirmed that KIN could trigger ferroptosis by suppressing DGAT1-mediated LD formation, thereby demonstrating a promising therapeutic effect of KIN in TNBC.

Estrogen receptor β (ERβ) is the most highly expressed subtype in the colon epithelium and mediates the protective effect of estrogen against the development of colon cancer. Indeed, the expression of this receptor is inversely related to colorectal cancer progression. Structurally estrogen-like compounds, including vitamin E components, affect cell growth by binding to ERs. In the present study, cell proliferation was measured by cell counting in a Bürker hemocytometer, and ERβ expression was measured by Real-Time qPCR and immunoenzymatic methods. The results obtained show that natural δ-tocopherol (δ-Toc) and two of its semi-synthetic derivatives, bis-δ-tocopheryl sulfide (δ-Toc)2S and bis-δ-tocopheryl disulfide (δ-Toc)2S2, play an antiproliferative role and upregulate ERβ expression, similar to 17-β-estradiol (17β-E2), in human colon adenocarcinoma HCT8 cells engineered to overexpress ERβ protein (HCT8-β8). These events are not present in HCT8-pSV2neo and in HCT8-β8 pretreated with ICI 182,780, suggesting that they are mediated by the binding of compounds to ERβ, as also boosted by an in silico assay. The antiproliferative effect is independent of the intracellular redox state and (δ-Toc)2S and (δ-Toc)2S2 reduce cell proliferation at concentrations lower than that of δ-Toc and all tested compounds are also able to upregulate ERβ expression. Taken together, the data indicate that, through the involvement of ERβ activity and expression, δ-Toc, (δ-Toc)2S, and (δ-Toc)2S2 may provide potential therapeutic support against colorectal cancer.

Feedstock plants for biofuel production can be cultivated on polluted sites that are unsuitable for edible crop production. This approach combines environmental restoration and renewable energy production, therefore enhancing the economic viability of plant-derived biofuels. Previous studies have indicated that exposure to environmental pollutants may elevate lignin levels in exposed plants, potentially impacting the biomass digestibility and the efficiency of bioethanol conversion. In this study, we investigated the impact of the antimicrobial agent chlortetracycline on lignin biosynthesis in the reference organism Arabidopsis thaliana. Toxicity testing showed that exposure to chlortetracycline significantly reduced plant growth at concentrations above 2.5 mg L-1. Using Fourier-transform infrared spectroscopy (FTIR) analysis, we observed a significant increase in the lignin signature, ranging from 16 to 40%, in plants exposed to chlortetracycline as compared to non-exposed control plants. Transcriptomic analysis (RNA sequencing) was conducted to determine the molecular basis of plant response to chlortetracycline, revealing significant enrichment of several genes involved in lignin biosynthesis and the phenylpropanoid pathway, including cinnamyl alcohol dehydrogenase and peroxidases. Exposure to chlortetracycline also resulted in the overexpression of genes involved in the metabolism of xenobiotic compounds, including cytochrome P450 monooxygenases, glutathione S-transferases, and glycosyltransferases. Chlortetracycline also induced several genes involved in plant response to stress and defense mechanisms, including transcription factors (e.g., WRKY, MYB, AP2/ERF families), pathogenesis-related proteins, and genes involved in stress signaling. These results suggest that the antibiotic chlortetracycline triggers multiple stress responses in A. thaliana, which may cause changes in lignin biosynthesis, reductions in plant growth, increases in the lignin content, and induction of defense metabolic pathways.

Tumor-associated macrophages (TAMs) significantly influence tumor progression and patient responses to conventional chemotherapy. However, the interplay between anti-cancer drugs, immune responses in the tumor microenvironment, and their implications for cancer treatment remains poorly understood. This study investigates the effects of vinorelbine on M2 macrophages in lung cancer and its capacity to modulate TAMs toward an M1 phenotype. Peripheral blood mononuclear cells (PBMCs) were polarized into M2 macrophages, and subsequent phenotype alterations upon vinorelbine treatment were assessed. Additionally, we evaluated vinorelbine's impact on gene and protein expression associated with cancer progression and cell invasion in non-small-cell lung cancer (NSCLC) cells indirectly co-cultured with M2 macrophages. Notably, vinorelbine, particularly at low concentrations, reprogrammed M2 macrophages to exhibit M1-like characteristics. While M2 macrophages enhanced cancer cell invasion, vinorelbine significantly mitigated this effect. M2 macrophages led to the overexpression of numerous genes linked to tumor growth, angiogenesis, invasion, and immune suppression in NSCLC cells, increasing the BCL2/BAX ratio and promoting cellular resistance to apoptosis. The anti-tumor efficacy of vinorelbine appears to be partly attributed to the reprogramming of M2 macrophages to the M1 phenotype, suggesting that low-dose vinorelbine may optimize therapeutic outcomes while minimizing toxicity in cancer patients.

Dinaciclib, a potent cyclin-dependent kinase (CDK) inhibitor, has demonstrated considerable antitumor effects in various malignancies. However, its impact on oral squamous cell carcinoma (OSCC), a predominant and highly aggressive form of head and neck squamous cell carcinoma (HNSC) with limited treatment options, remains underexplored. We conducted gene set enrichment analyses in HNSC patients that reinforced the relevance of these cell cycle-related genes to OSCC pathogenesis. Given the known dysregulation of cell cycle-related genes in HNSC patients, we hypothesized that Dinaciclib may inhibit OSCC growth by targeting overexpressed cyclins and CDKs, thereby disrupting cell cycle progression and inducing apoptosis. This study investigated Dinaciclib's effects on cell proliferation, cell cycle progression, and apoptosis in the OSCC cell lines Ca9-22, OECM-1, and HSC-3. Our results demonstrated that Dinaciclib significantly reduces OSCC cell proliferation in a dose-dependent manner. Flow cytometry and Western blot analyses showed that Dinaciclib induces cell cycle arrest at the G1/S and G2/M transitions by downregulating Cyclins A, B, D, and E, along with CDKs 1 and 2-key regulators of these checkpoints. Furthermore, Dinaciclib treatment upregulated apoptotic markers, such as cleaved-caspase-3 and cleaved-PARP, confirming its pro-apoptotic effects. In conclusion, these findings highlight Dinaciclib's therapeutic promise in OSCC by simultaneously disrupting cell cycle progression and inducing apoptosis. These results support further exploration of Dinaciclib as a viable monotherapy or combination treatment in OSCC and other HNSC subtypes to improve patient outcomes.

This study investigates the molecular mechanisms by which Hariman mitigates damage and productivity losses caused by Cucumber Aphid-Borne Mosaic Virus (CABMV) in the passion fruit genotypes 'FB300' and 'H09-110/111' under greenhouse and field conditions in Rio de Janeiro, Brazil. Hariman treatment induced the upregulation of key defense genes and phytohormones in response to CABMV infection, enabling treated plants to counteract virus-induced developmental impairments effectively. The relative accumulation of CABMV and disease severity were significantly reduced, with treated plants showing no decline in growth parameters such as height, leaf count, flower production, or fruit set. Over 18 months, total productivity increased by 65.7% and 114% for 'FB300' and by 44% and 80% for 'H09-110/111' after one and two applications of Hariman, respectively. Notably, infected plants treated with Hariman outperformed healthy plants grown under similar conditions, underscoring the biofertilizer's dual role in promoting plant growth while enhancing resistance to biotic stressors. These findings indicate that Hariman stimulates robust growth and induces the expression of the defense-related genes PR-3, SOD, POD12, PAL, and LOX2 alongside the expression of the phytohormone-associated genes SAUR20 and GA2ox across different passion fruit genotypes. The adoption of these sustainable technologies holds significant potential for enhancing passion fruit productivity in the face of diseases that severely threaten this crop.

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, arises from skeletal muscle cells that fail to differentiate terminally. Two subgroups of RMS, fusion-positive and fusion-negative RMS (FPRMS and FNRMS, respectively), are characterized by the presence or absence of the PAX3/7-FOXO1 fusion gene. RMSs frequently exhibit increased expression of human epidermal growth factor receptor-2 (HER2). Trastuzumab is a humanized monoclonal antibody targeting HER2, and its potential role in RMS treatment remains to be elucidated. Syndecan-4 (SDC4) is a heparan sulfate proteoglycan (HSPG) affecting myogenesis via Rac1-mediated actin remodeling. Previously, we demonstrated that the SDC4 gene is amplified in 28% of human FNRMS samples, associated with high mRNA expression, suggesting a tumor driver role. In this study, after analyzing the copy numbers and mRNA expressions of other HSPGs in human RMS samples, we found that in addition to SDC4, syndecan-1, syndecan-2, and glypican-1 were also amplified and highly expressed in FNRMS. In RD (human FNRMS) cells, elevated SDC4 expression was accompanied by low levels of phospho-Ser179 of SDC4, leading to high Rac1-GTP activity. Notably, this high SDC4 expression in RD cells decreased following trastuzumab treatment. Trastuzumab decreased the levels of G1/S checkpoint regulators cyclin E and cyclin D1 and reduced the cell number; however, it also downregulated the cyclin-dependent kinase inhibitor p21. The level of MyoD, a transcription factor essential for RMS cell survival, also decreased following trastuzumab administration. Our findings contribute to the understanding of the role of SDC4 in FNRMS. Since HER2 is expressed in about half of RMSs, the trastuzumab-mediated changes observed here may have therapeutic implications.

Nanoplastics (NPs) represent a major challenge in environmental contamination resulting from the physical, chemical, and biological degradation of plastics. Their characterization requires advanced and expensive methods, which limit routine analyses. The biological effects of NPs depend on their chemical and physical properties, which influence toxicity and interactions with biological systems. Studies in animal models, such as Daphnia magna and Danio rerio, show that NPs induce oxidative stress, inflammation, DNA damage, and metabolic alterations, often related to charge and particle size. NPs affect endocrine functions by acting as endocrine disruptors, interfering with thyroid and sex hormones and showing potential transgenerational effects through epigenetic modifications, including DNA hyper- and hypomethylation. Behavioral and neurofunctional alterations have been observed in Danio rerio and mouse models, suggesting a link between NP exposure and neurotransmitters such as dopamine and serotonin. Despite limited human studies, the presence of NPs in breast milk and placenta underscores the need for further investigation of health effects. Research focusing on genetic and epigenetic markers is encouraged to elucidate the molecular mechanisms and potential risks associated with chronic exposure.