To explore the underlying mechanism behind the fine particulate matter's (PM2.5)-mediated regulation of reproductive function in male rats, and to determine the role of vitamins in this process.

Seed priming is an effective way to activate defense mechanisms before germination, enhancing seed vigor and stress resistance. Ascorbic acid (AsA) is an important signaling molecule that plays a crucial role in balancing cellular reactive oxygen species. However, whether AsA priming can enhance seed vigor in oat (Avena sativa) and the underlying mechanisms remain unclear. This study primed aged seeds (controlled deterioration at 45°C for 5 days) with 1.5 mM AsA for 24 h. Primed seeds were then sampled after 36 h of imbibition for seed assays. Significant increases in germination percentage, vigor index, shoot and root length, coupled with a significant reduction in mean germination time, demonstrated that AsA priming effectively restored seed vigor. Ultrastructural observations of mitochondria isolated from embryos presented that AsA priming repaired structural damage in aged seeds, with intact double membranes and clear internal cristae observed. Excessive H2O2 accumulation was discovered in mitochondria of aged seeds, while AsA priming reduced H2O2 levels by increasing the activities of CAT, GR, MDHAR and DHAR. AsA priming also increased antioxidant content, particularly DHA, contributing to reduced oxidative stress. Furthermore, transcriptomic analysis highlighted the upregulation of genes associated with antioxidant defense, including APX, CAT, DHAR and MDHAR, indicating enhanced repair and protection pathways in the mitochondrial AsA-GSH cycle. This suggests that AsA priming would increase the activity of antioxidant enzymes, the content of antioxidants, and expression of genes related to AsA-GSH cycle in aged oat seeds, which was conducive to repairing mitochondrial damage and enhancing seed vigor.

Cadmium (Cd) contamination in maize poses a significant threat to global food security due to its persistent accumulation in crops. In this study, the effects of foliar application of glycerol on Cd accumulation in maize seedlings were studied. Our results demonstrated that under Cd treatment, biomass, total chlorophyll content, net photosynthetic rate (Pn), Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) activity, Phosphoenolpyruvate carboxylase (PEPC) activity, sucrose levels, and carbohydrate levels in maize seedlings significantly increased after glycerol application. H2O2 and MDA levels in both the aboveground and belowground portions of the maize plants significantly decreased. Moreover, superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities in the aboveground parts significantly increased. Notably, maize plants used glycerol to chelate Cd, which was fixed within the cell wall and soluble fraction of the roots, reducing Cd transport to the shoots and significantly lowering the Cd transport coefficient (TF). Transcriptomic data suggested that glycerol-mediated alleviation of Cd stress in maize seedlings may be associated with phenylpropanoid biosynthesis, plant-pathogen interactions and photosynthesis pathways. These molecular patterns align with the observed physiological improvements. This study provided a novel approach to effectively alleviate excessive Cd in maize and suggested possible applications of glycerol in cultivating plant resistance to heavy metals.

Esophageal squamous cell carcinoma (ESCC) is a deadly cancer with a poor prognosis and a high recurrence rate after chemotherapy, posing a significant clinical challenge. To elucidate the molecular basis of chemotherapy (chemo)-resistance and to develop methods to effectively eliminate chemo-resistant tumor clones, we established an ESCC organoid (ESCCO) library from 24 ESCC patients of various stages, ages, and treatments. These ESCCOs faithfully recapitulate the oncogenic mutations observed in the original ESCC tissues and manifest tumorigenic properties when xenografted. The ESCCOs respond differently to cisplatin and 5-fluorouracil, chemotherapeutic agents commonly used to treat ESCC patients, with 7 ESCCOs exhibiting potent chemo-resistance. Notably, the chemo-resistant ESCCOs show higher genes involved in antioxidant stress response pathways and more accessible chromatin at their loci than the sensitive ESCCOs. These genes can serve as valuable biomarkers to stratify chemo-resistant ESCCs in histopathological specimens. Through drug screening using the ESCCO library, we reveal that fedratinib effectively induces cell death in chemo-resistant ESCCOs. Collectively, our human ESCCO model offers novel insights into the mechanism of chemo-resistance in ESCCs, which is critical for developing effective therapeutic approaches to eradicate the recurrence of ESCCs.

Protein ubiquitination is a dynamic and reversible process involved in gene transcription, protein metabolism, and cellular apoptosis. Ubiquitin specific proteases (USPs), as the largest family of deubiquitinating enzymes, are able to remove the ubiquitin from target proteins, rescuing them from degradation. Here, we characterized the small molecule antitumor agent YM155 as a broad-spectrum USP inhibitor. By inhibiting the deubiquitinase activity of multiple USPs, YM155 causes the degradation of oncogenic substrate proteins, such as c-Myc and intracellular domain of Notch1. In cancers driven by these proteins, YM155 induces profound cell apoptosis and markedly inhibits tumor growth in xenograft models. Together, these findings demonstrate that YM155 is a broad-spectrum USP inhibitor, and a potential drug candidate for cancers which depend on hyper-active oncogenic proteins that are regulated by the ubiquitin-proteasome pathway.

Salt stress significantly limits wheat production worldwide, jeopardizing food security and sustainable agriculture. Developing strategies to enhance wheat's resilience to salinity is critical for maintaining yield in affected regions. This study investigates the potential of chitosan-proline (Cs-Pro) and chitosan-glycine (Cs-Gly) nanoparticles in mitigating salt stress in salt-tolerant Heydari and salt-sensitive Sepahan wheat cultivars, with a special question on genotype-dependent differences. Plants were treated with nanoparticles at concentrations of 0, 200, and 400 mg L⁻¹ under salt stress levels of 0, 200, and 400 mM NaCl. The salt-tolerant Heydari cultivar exhibited superior adaptability to saline conditions, in addition reacted more positively to nanoparticle treatments. Results demonstrated significant physiological improvements, including increased relative water content (RWC), enhanced chlorophyll content and elevated proline levels, especially after 400 mg L⁻¹ Cs-Pro treatment. Oxidative stress markers, such as malondialdehyde (MDA) and hydrogen peroxide, were substantially reduced, while antioxidant enzyme activity was boosted. Certain stress-responsive genes (e.g., TaADC, TaPxPAO, TaSAMDC, TaSPDS, TaSOS1, TaNHX1) were upregulated, highlighting the importance of ionic balance and polyamine metabolism in improved stress tolerance. The application of Cs-Pro and Cs-Gly nanoparticles presents a promising approach to enhance wheat's salinity tolerance by improving physiological, biochemical, and molecular responses.

In this investigation, the significance of purple potato (Solanum tuberosum L.) extract treatment was assessed against oxidative stress and fat metabolizing transcription factors in the liver of high-fat (HF) diet-fed rats.

A precise balance between ubiquitination and deubiquitination is crucial for cellular regulation. Ubiquitin-specific peptidase 54 (USP54), an active deubiquitinase (DUB), modulates the ubiquitination of the epidermal growth factor receptor (EGFR). While the significance of USP54 in tumorigenesis is known, its specific function in cancer progression remains unclear. This study investigates the role of USP54 in gefitinib sensitivity in gefitinib-resistant non-small cell lung cancer (NSCLC) cells. Using western blotting and next-generation sequencing, we examined gene expression changes in ubiquitination pathways. USP54 deficiency and its impact on cell viability and gefitinib response were evaluated in 2D and 3D spheroid cancer models. Prolonged gefitinib exposure altered the expression of 20 deubiquitinase-regulating genes. Notably, ubiquitin C-terminal hydrolase L3, downregulated by gefitinib, was identified as a key regulator of EGFR ubiquitination in gefitinib-sensitive PC9 cells. Silencing USP54 in resistant NSCLC cells increased gefitinib-induced EGFR ubiquitination and G0/G1 cell cycle arrest, enhancing drug susceptibility in resistant spheroids. USP54 upregulation in gefitinib-treated cells was associated with reduced EGFR ubiquitination, stabilizing EGFR and promoting cell survival. These findings suggest USP54 as a critical modulator of EGFR stability and a potential therapeutic target to overcome gefitinib resistance in NSCLC.

The vitamin D endocrine system, primarily mediated by its main metabolite calcitriol and the vitamin D receptor (VDR), plays a critical role in numerous human physiological processes, ranging from calcium metabolism to the prevention of various tumors, including cervical cancer. In this study, we comprehensively investigated the genomic regulatory effects of calcitriol in a cervical cancer model. We examined the transcriptional changes induced by calcitriol in CaSki cells, a cervical cell line harboring multiple copies of HPV16, the primary causal agent of cervical cancer. Our microarray findings, revealed that calcitriol regulated over 1000 protein-coding genes, exhibiting a predominantly repressive effect on the CaSki cell transcriptome by suppressing twice as many genes as it induced. Calcitriol decreased EPHA2 and RARA expression while inducing KLK6 and CYP4F3 expression in CaSki cells, as validated by qPCR and Western blot. Functional analysis demonstrated that calcitriol effectively inhibited key processes involved in cancer progression, including cell proliferation and migration. This was further supported by the significant downregulation of MMP7 and MMP13 mRNA levels. Our microarray results also showed that, in addition to its effects on protein-coding genes, calcitriol significantly regulates non-coding RNAs, altering the expression of approximately 400 non-coding RNAs, including 111 microRNA precursors and 29 mature microRNAs, of which 17 were upregulated and 12 downregulated. Notably, among these calcitriol-regulated microRNAs are some involved in cervical cancer biology, such as miR-6129, miR-382, miR-655, miR-211, miR-590, miR-130a, miR-301a, and miR-1252. Collectively, these findings suggest that calcitriol exhibits a significant antitumor effect in this advanced cervical cancer model by blocking critical processes for tumor progression, underscoring the importance of maintaining adequate vitamin D nutritional status.

Cancer cells reprogram metabolic pathways to meet energy demands and sustain rapid growth, a hallmark of malignancy. Identifying molecular signatures underlying these changes can aid in early detection and inform targeted therapies. miR-526b has been shown to promote migration, invasion, angiogenesis, and metastasis, yet its role in dysregulated glucose metabolism remains underexplored.

Malignant plasma cell proliferation characterizes multiple myeloma (MM), a hematologic disease. Bortezomib (BTZ) is a protease inhibitor that has been approved for the treatment of MM. Nevertheless, the effectiveness of BTZ is frequently impeded by drug resistance, and the mechanisms responsible for this phenomenon remain incompletely understood. A growing body of evidence indicates that N6-methyladenosine (m6A) plays crucial roles in a wide range of biological functions. However, the impact of m6A on the response of MM cells to BTZ is poorly understood. In our recent research, we discovered that METTL3 facilitated the m6A alteration of lncRNA H19, providing MM cells with resistance to BTZ. Additional examination revealed that H19 functioned as a sponge to negatively regulate the expression of miR-184 in MM cells. Furthermore, we discovered that H19 binds to miR-184, a tumor suppressor, in MM cells. In MM cells, miR184 can suppress the expression of CARM1 by targeting its 3'-UTR. In conclusion, rescue trials have validated the significance of the METTL3/H19/miR-184/CARM1 pathway in determining the susceptibility of cells to BTZ. Consequently, directing efforts toward this pathway could prove to be a powerful approach for enhancing the effectiveness of BTZ for MM therapy.

Fisetin is a natural flavonol with a variety of biological activities, including anti-inflammatory and antitumor activities. However, the effect of fisetin on mammalian oocyte and embryo development is unknown, so in this study, we used porcine oocytes as an experimental model, and added optimal concentrations of fisetin to the in vitro culture medium after parthenogenetic activated to investigate the effect of fisetin on porcine embryo development. It was found that 0.1 µM fisetin significantly increased the cleavage rate and blastocyst formation rate, and the quality of blastocysts was also improved. Staining results showed that the levels of reactive oxygen species (ROS), autophagy, endoplasmic reticulum stress and apoptosis were significantly reduced, while glutathione levels and mitochondrial function were significantly increased in the 0.1 µM fisetin-treated group of early porcine embryos compared with the control group. Meanwhile, fisetin decreased the expression level of the endoplasmic reticulum stress marker protein GRP78 (0.71 ± 0.19). In addition, fisetin decreased the expression of genes related to pro-apoptosis, autophagy and endoplasmic reticulum stress and increased the expression of genes related to antioxidant, pluripotency and mitochondrial. According to our results, fisetin promotes early embryonic development in porcine, and this effect may be realized by down-regulating the expression level of GRP78.

This study used a combination of in vitro and in vivo experiments to investigate the role of amylin in the progression of GC. The expression of amylin in GC and its clinical correlation were evaluated using 38 pairs of GC and healthy human clinical samples. In vitro studies, human GC cell lines were treated with amylin to evaluate the effects of amylin on the proliferation, apoptosis and migration of GC cells. In in vivo studies, xenograft mouse models were established by subcutaneous injection of GC cells into nude mice, followed by treatment with amylin to assess tumor growth. Finally, Next-Generation Sequencing Technology (RNA-seq) was used to explore the potential mechanism of amylin on GC.

Aging is associated with alternative splicing (AS) defects that have broad implications on aging-associated disorders. However, which drug(s) can rescue age-related AS defects and extend lifespan has not been systematically explored. We performed large-scale compound screening in C. elegans using a dual-fluorescent splicing reporter system. Among the top hits, doxifluridine, a fluoropyrimidine derivative, rescues age-associated AS defects and extends lifespan. Combining bacterial DNA sequencing, proteomics, metabolomics and the three-way screen system, we further revealed that bacterial ribonucleotide metabolism plays an essential role in doxifluridine conversion and efficacy. Furthermore, doxifluridine increases production of bacterial metabolites, such as linoleic acid and agmatine, to prolong host lifespan. Together, our results identify doxifluridine as a potent lead compound for rescuing aging-associated AS defects and extending lifespan, and elucidate drug's functions through complex interplay among drug, bacteria and host.

Emerging evidence suggests that folic acid (FA) supports nerve repair, but its beneficial effects in peripheral nerve injury (PNI) remains unclear. This study aims to investigate protective effects of FA against PNI and the underlying molecular mechanisms. High-performance liquid chromatography-tandem mass spectrometry was utilized for precise quantification of metabolites. A sciatic nerve crush injury model was established in rats, followed by assessments of cell proliferation, apoptosis, and motor function using CCK-8 assays, flow cytometry, and the balance beam test, respectively. Neuromorphological observations, electromyography, and ELISA were conducted to evaluate structural, electrophysiological, and biochemical parameters. In vitro, FA restored methionine cycle balance in Schwann cells and neurons disrupted by enzyme inhibition, improving cell viability, reducing apoptosis, and preserving cellular structure. In vivo, FA supplementation restored S-adenosylmethionine and homocysteine levels in a methionine metabolism disorder model and enhanced motor function, neural morphology, neuron survival, and electrophysiological recovery after PNI. Epigenetic analyses revealed that FA modulated DNA methylation and histone modifications of the DNM3 promoter, influencing gene expression. Furthermore, FA facilitated nerve repair via the DNM3-AKT pathway, regulating apoptosis, autophagy, and oxidative stress-related enzymes. These findings highlight FA's potential in promoting nerve repair through metabolic and epigenetic mechanisms.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder driven by autoreactive B cells and characterized by the production of pathogenic autoantibodies. Belimumab, an anti-BAFF monoclonal antibody, has demonstrated efficacy in reducing disease activity and corticosteroid use in SLE patients, although responses remain variable. B-cell activating factor (BAFF) is essential for B cell survival and autoantibody production, positioning it as a key target in SLE pathogenesis. MicroRNAs (miRNAs), critical regulators of gene expression and immune homeostasis, have an emerging role in SLE pathophysiology. However, their regulation in response to anti-BAFF therapies, such as belimumab, remains unexplored. This study investigates miRNA-mRNA interactions in T cells, B cells, and myeloid cells from SLE patients before and after belimumab treatment. A total of 79 miRNAs associated with treatment response and 525 miRNA-gene interactions were identified. Validation in 18 SLE responders revealed significant changes in miRNA expression in T and myeloid cells, but not in B cells. Belimumab was found to modulate B cell development by regulating genes such as BLNK, BANK1, and MEF2C, as well as the CD40/CD40L axis. In T cells, miRNAs influenced interferon signaling and inflammatory cytokines via NF-κB activation. Changes in myeloid cells, characterized by the downregulation of KLF13, CCL5, and IL4, appear to be secondary to T cell modulation. These findings provide novel insights into the miRNA-mediated regulatory networks underlying belimumab's immunomodulatory effects in SLE. Further research is required to validate these findings and through in vitro experiments to better understand the role of miRNAs in guiding treatment responses.

To investigate the antioxidative mechanism of snake venom-derived protein C activator (PCA) in mitigating vascular endothelial cell injury.

Dietary bioactive agents can curb tumour progression through chromatin alterations. Thus, this study attempts to evaluate the influence of kaempferol on epigenome modification in HeLa cells. Biochemical analysis for global DNA methylation-LINE 1, DNMTs (DNA methyltransferases), HAT (histone acetyl transferase), HDACs (histone deacetylases) and HMTs (histone methyltransferases) were examined with their transcript level expression through qPCR. Also, H3 and H4 histone modification marks were quantitated by an ELISA-based assay. Moreover, qPCR and protein profiler were performed to analyse the expression of migratory genes at both mRNA and protein levels, respectively, that was further substantiated through colony formation, invasion, and scratch wound assays. Finally, DNA methyl-sequencing was performed to analyse the promoter methylation of TSGs (tumour suppressor genes) and corroborated by analysing selected TSGs' expression. Kaempferol treatment did not alter the global DNA methylation-LINE 1 compared to untreated control, however, it reduced the expression and biochemical activities of DNMT and HDAC, which can be linked to their hypermethylation by kaempferol exposure. Concordant with the reduced expression of HMTs, HATs and other epi-enzymes, various histone H3 and H4 marks were also observed to be modulated. Kaempferol exposure led to promoter hypomethylation of various TSGs (such as WIF1, RUNX1, RARβ, SOX1), which subsequently led to enhanced expression at the mRNA level, which corresponds to their reactivation. Molecular studies were consistent with cell-based studies, which demonstrated a strong growth inhibitory and anti-migratory effect of kaempferol. This research helps to understand the probable mechanism used by kaempferol as a potential epigenetic modifier.

Ferroptosis, a distinct form of regulated cell death, plays a role in glioma pathogenesis. SRY-box (SOX) transcription factors are key regulators of cancer progression. In this study, we investigated the role of SOX10 in ferroptosis induction in U87 cells following boric acid treatment. First, the cytotoxic effects of boric acid on HMC3 and U87 cells were assessed using CCK8 and BrdU incorporation assays. Subsequently, SOX10, GPX4, ACSL4, GSH, MDA, total ROS, Fe2+, and TFR levels were analysed using ELISA, Western blot, and RT-PCR techniques. Additionally, DAPI staining was performed to evaluate nuclear abnormalities. According to the CCK8 analysis, the IC50 value for boric acid was determined to be 3.12 mM for HMC3 cells and 532 μM for U87 cells, a finding further supported by BrdU incorporation analysis, which indicated that U87 cells were more sensitive to boric acid. Western blot and RT-PCR analyses revealed that SOX10 expression was significantly higher in U87 cells compared to HMC3 cells. Boric acid treatment led to a reduction in GSH, GPX4, and SOX10 levels in U87 cells, while inducing an increase in MDA, total ROS, ACSL4, Fe2+, and TFR levels. Moreover, microscopic analysis demonstrated that boric acid treatment induced both morphological and nuclear abnormalities in U87 cells. In conclusion, our findings demonstrate that SOX10 is involved in the ferroptosis signalling pathway and that boric acid effectively suppresses U87 cell viability by targeting the SOX10/GPX4/ACSL4 axis.

Thalidomide is an infamous drug used initially as a sedative until it was tragically discovered it has highly teratogenic properties. Despite this it is now being used to successfully treat a range of clinical conditions including erythema nodosum leprosum (ENL) and multiple myeloma (MM). Cereblon (CRBN), a ubiquitin ligase, is a binding target of thalidomide for both its therapeutic and teratogenic activities and forms part of an CRL4-E3 ubiquitin ligase complex with the proteins Damaged DNA Binding protein 1 (DDB1) and Cullin-4A (CUL4A). This complex mediates degradation of the zinc-finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), to mediate thalidomide's anti-myeloma response. To better understand the importance of CRBN and its binding partners for thalidomide teratogenesis here we analysed the expression patterns of CRBN and some of its known E3 complex binding partners in wildtype and thalidomide-treated chicken and zebrafish embryos. CRBN and DDB1 are expressed in many tissues throughout development including those that are thalidomide-sensitive while CUL4A and targets of the CRL4-CRBN E3 Ligase Complex IKZF1 and IKZF3 are expressed at different timepoints and in fewer tissues in the body than CRBN. Furthermore, IKZF3 is expressed in tissues of the eye that CRBN is not. However, although we observed rapid changes to the chicken yolk-sac membrane vasculature following thalidomide exposure, we did not detect CRL4-CRBN E3 Ligase Complex expression in the yolk-sac membrane vessels. Furthermore, we did not detect any changes in CRBN, DDB1, CUL4, IKZF1 and IKZF3 expression following thalidomide exposure in chicken and zebrafish embryos. These findings demonstrate that the anti-angiogenic activities of thalidomide may occur independent of CRBN and that thalidomide does not regulate CRL4-CRBN E3 Ligase Complex gene expression at the mRNA level.