Graves' ophthalmopathy (GO) is characterized by orbital fibroblast (OF) proliferation, hyaluronic acid (HA) secretion, and inflammation. Modulating these pathological mechanisms may offer a therapeutic strategy for GO. This exploratory study aimed to investigate the effects of enalapril and losartan on gene expression related to inflammation, fibrogenesis, and apoptosis in OFs derived from a GO patient.

Ferroptosis is defined as iron dependent non-apoptotic cell death. It is based on peroxidation of polyunsaturated phospholipids and subsequent membrane rupture. Lipid peroxidation is induced mainly by the hydroxyl radical, the product of the Fenton reaction between iron and hydrogen peroxide. Ferroptosis is connected to many organs and diseases including neuroinflammation. The most common inflammatory disease of the central nervous system in Western countries is multiple sclerosis leading to inflammatory demyelination and neurodegeneration. Fumarates, dimethyl fumarate (DMF) and its successor diroximel fumarate (DRF), are approved disease modifying therapies for multiple sclerosis and activate the Nrf2 pathway regulating the expression of many antioxidative enzymes. Since some of these enzymes are anti-ferroptotic, we here investigated whether the therapeutic effect of fumarates is connected to modulated sensitivity towards ferroptosis. Indeed, myelin damage induced by ferroptosis is diminished in presence of DRF or its active metabolite monomethyl fumarate. Moreover, anti-ferroptotic enzymes are upregulated in oligodendrocytes upon DRF treatment as well as in cerebellum of DMF-treated mice and in peripheral blood mononuclear cells of patients receiving DMF. This effect is absent in primary fibroblasts derived from osteo- or rheumatoid arthritis patients. In summary, our data offer a new organ- and disease-specific molecular anti-inflammatory mechanism of DRF.

Seed immune responses are an underexplored area in host-pathogen interactions, leaving seed-pathogen interactions poorly understood despite their considerable economic impact. This study examined tomato seed defences by assessing the antimicrobial activity (AA) of seed exudates during germination. Results showed genotype-dependent and constitutive defence responses from seeds showing AA in exudates. Seed priming with a panel of elicitors such as methyl jasmonate (MeJA) enhanced AA in certain genotypes, highlighting an inducible defence response. Both constitutive and inducible (elicitor-dependent) seed defences were genotype-dependent and more effective against the non-host pathogen Alternaria brassicicola (Abra43), while host pathogens seemed resistant to exudates' AA, suggesting that they developed strategies to neutralise exudates' AA. Multi-omic analyses revealed distinct hormonal and molecular pathways involved in constitutive and inducible defences. By characterising exudates and correlating genotype- and elicitor-specific AA, candidate antimicrobial compounds were identified. As proof of concept, we functionally validated the AA of a putative defensin (Solyc07g007755) whose expression was highly correlated with the observed AA of the seed exudate against Abra43, demonstrating the potential of our dataset for the development of phytosanitary strategies to protect seeds during germination.

Lithium chloride (LiCl) has emerged as a promising alternative to synthetic acaricides for controlling Varroa destructor, a major threat to honey bee health. However, its potential side effects on bees and their products require further investigation. This study aimed to assess the effects of LiCl on honey bee health, focusing on survival, behavior, and molecular responses. We investigated the effects of varying doses and feeding durations of LiCl on honey bee survival, aggression, stress- and immune-related gene expression, and recovery potential after treatment cessation. Our results show that LiCl feeding reduced honey bee survival in a dose-dependent manner, with higher concentrations leading to greater accumulation of lithium in bee tissues. Furthermore, LiCl suppressed aggression behavior and altered the gene expression related to honey bee health, such as vitellogenin, antimicrobial peptides, antioxidant enzymes, and heat shock proteins. The duration of LiCl feeding was a critical factor, as shorter feeding periods followed by recovery with control diets restored gene expression and survival rates to the levels of control groups. These findings highlight the importance of optimizing LiCl dosage and feeding duration to balance its Varroa controlling efficacy with honey bee safety, and further research is needed to ensure its long-term safety for colonies and ecosystems.

Oocyte quality, governed by metabolic and epigenetic regulation, is essential for fertilization and embryogenesis. This study aimed to elucidate the dose-dependent and multifaceted roles of α-ketoglutarate (α-KG) in modulating the molecular and metabolic dynamics of cumulus-oocyte complexes (COCs) during in vitro maturation (IVM). Notably, supplementation with 100 μM α-KG resulted in the most pronounced improvement in maturation and developmental outcomes. α-KG remolds energy metabolism in both oocytes and their cumulus cells (CCs) during maturation via suppression of the citric cycle (TCA cycle) and pentose phosphate pathway (PPP), while enhancing glycolysis and β-oxidation in oocytes, alongside enhanced amino acids related to the methionine salvage pathway and folate cycle. Conversely, CCs exhibited a low metabolic status during maturation, characterized by suppressed glycolysis, the TCA cycle, β-oxidation, and fatty acid levels, suggesting a metabolic shift to prioritize oocyte support. These findings underscore a synergistic yet divergent metabolic adaptation: oocytes amplify energy and biosynthesis pathways, while CCs adopt a catabolic conservation strategy. Critically, α-KG's modulation of cyclic nucleotides (cAMP/cGMP) highlights its role in relieving meiotic arrest, linking metabolic shifts to cell cycle regulation. This study fills a crucial gap in our understanding, elucidating how α-KG regulates the environment around follicles and laying the groundwork for utilizing α-KG in reproductive technology to enhance embryo survival rates.

Colorectal cancer (CRC) is a leading cause of global cancer-related mortality, necessitating the identification of novel therapeutic targets. Integrating genetic and transcriptomic data may reveal key molecular drivers of CRC progression and treatment opportunities.

WRKY transcription factors are key regulators of plant signaling pathways associated with both biotic and abiotic stress responses. Here, we identified and characterized TaWRKY76. Expression of TaWRKY76 was detected across all tissues analyzed and was upregulated under cadmium (Cd) and abscisic acid (ABA) treatments. Transgenic Arabidopsis thaliana plants containing the TaWRKY76 promoter exhibited higher GUS activity following Cd stress, and the C-terminal region of TaWRKY76 was shown to play a role as a transcription activator with a particular binding affinity for the W-box region. To examine the TaWRKY76 function, Arabidopsis and wheat overexpression lines were generated and were shown to exhibit improved tolerance to Cd. The transgenic plants exhibited a superior germination rate, increased root development, and higher chlorophyll and proline contents compared to the wild-type (WT), while displaying mitigated electrolyte leakage and lower levels of malondialdehyde. Additionally, Cd stress triggered increased activity of ROS-scavenging enzymes and diminished ROS buildup in both transgenic Arabidopsis and wheat plants. Moreover, TaWRKY76 overexpression in wheat also led to upregulation of ABA-related genes compared with the WT under Cd stress. These results indicate that TaWRKY76 is essential to the Cd stress response and may be a useful target for increasing tolerance to this toxic metal in wheat.

Endothelin-1 (ET-1) plays a critical role in diabetic vasculopathy. Although clinical trials have shown promise for ET-1 receptor antagonists in treating diabetic nephropathy, their clinical use remains limited by adverse effects. MiR-454-3p targets ET-1. This study aimed to investigate the role of miR-454-3p in modulating ET-1 expression and related molecular changes in endothelial cells (ECs) under high glucose conditions using both bioinformatics and experimental approaches. Bioinformatics analysis identified 10 miR-454-3p target genes expressed in ECs previously implicated in diabetic vascular complications: ET-1, GJA1, IRF1, PIK3CB, TRPC3, SLMAP, ESR1, ITGB8, MAPK1, and PPARG. With the exception of PPARG, which protects ECs from hyperglycemia-induced damage, all have been reported to exacerbate endothelial dysfunction. Western blotting showed that high glucose increased ET-1 expression in human umbilical vein ECs (HUVECs) and human dermal microvascular endothelial cells (HDMECs), while miR-454-3p overexpression significantly suppressed this effect in both cell types. Conditioned medium (CM) from HUVECs transfected with miR-454-3p mimics enhanced eNOS expression in recipient cells, compared to control CM. Pre-treatment of HUVEC control CM with an anti-ET-1 antibody also increased eNOS expression, supporting that miR-454-3p promotes NOS production partly via ET-1 suppression. MiR-454-3p overexpression in HUVECs did not affect PPARG expression or cell proliferation. In conclusion, miR-454-3p overexpression inhibits high glucose-induced ET-1 expression in HUVECs and HDMECs, and promotes eNOS production without affecting PPARG expression in HUVECs. Our findings suggest that miR-454-3p modulates ET-1 expression under hyperglycemic conditions in vitro, which may provide a foundation for future studies exploring its potential application in managing diabetic vasculopathy.

Bortezomib (BTZ) containing regimens induces significant antitumor response in multiple myeloma (MM) and are considered as the first-line treatment. However, resistance is still one of the unsolved problems. This study aims to explore the mechanism underlying BTZ resistance in MM.

Diabetic retinopathy (DR) is a microvascular complication of diabetes characterized by damage to the retina's neurons and blood vessels. Ginkgo biloba extract (GBE) has demonstrated neuroprotective properties, however, its specific mechanisms in DR remain incompletely understood. This research aims to elucidate the underlying mechanisms of GBE in DR.

Sex expression in plants is a complex process influenced by genetic, environmental, and hormonal factors. In cucumbers, a high male-to-female flower ratio significantly contributes to low yields. The application of exogenous plant growth regulators can modify the sex ratio and flowering sequence, potentially improving productivity. In this experiment, effects of plant growth regulators, Spermidine (Spd) at concentrations of 0.25, 0.5, and 0.75 mmol/L and methyl jasmonate (Mj) at concentrations of 0.1, 0.25, and 0.5 mmol L- 1 on sex expression, chlorophyll content, antioxidant capacity, and fruit quality and yield of cucumber plants evaluated.

Terpenoids constitute a diverse group of primary and secondary metabolites that are extensively distributed in living organisms and play key roles in growth, development, and environmental adaptation. Terpenoids are derived from two isomeric precursors that are interconverted by isopentenyl-diphosphate delta-isomerase (IDI), in both the plastids and cytoplasm of plants. The plastidial pathway supplies precursors for diterpenoids and carotenoids, whereas the cytoplasmic pathway provides precursors for sesquiterpenoids and triterpenoids. A family of terpene synthases (TPSs) produce most terpenoids such as sesquiterpenes, hemiterpenes, monoterpenes, diterpenes and sesterterpenes, which in allotetraploid peanut (Arachis hypogaea L.) have been relatively underexplored.

SA-triggered H2S signaling improves maize seed germination under drought stress by bolstering osmoregulatory system. Salicylic acid (SA) is a plant hormone, whereas hydrogen sulfide (H2S) is a novel signaling molecule, they modulate plant abiotic tolerance including drought tolerance. Their interactions, however, in maize seed germination under drought stress (DS) remains unclear. In this study, maize seeds were primed with SA, H2S, and their inhibitors alone or together, and then germinated under DS. The results showed that SA and H2S priming significantly increased germination rate of maize seeds under DS. The SA-increased germination rate was enhanced by H2S, but abolished by H2S scavenger hypotaurine (HT) and inhibitor DL-propargylglycine (PAG), indicating the cooperative effect of SA and H2S in improving seed germination under DS. Also, SA priming increased L-cysteine desulfhydrase, D-cysteine desulfhydrase, and O-acetyl-serine (thiol) lyase activities and H2S level, up-regulated ZmLCD and ZmOAS-TL expression. These effects were enhanced by H2S, but weakened by HT and PAG. However, H2S was not significant effect on SA and its metabolic enzymes in germinating seeds under DS. These data indicated that H2S functioned as a downstream signaling molecule in SA-improved maize seed germination under DS. Furthermore, SA and H2S alone or together increased ornithine aminotransferase, Δ1-pyrroline-5-carboxylate synthase, and betaine aldehyde dehydrogenase activities and proline, glycine betaine, trehalose, sucrose, and fructose levels, up-regulated ZmOAT expression. These effects were enhanced by H2S, but weakened by HT and PAG. These results implied that SA-triggered H2S signaling improved maize seed germination under DS by bolstering osmoregulatory system.

Cold atmospheric plasma (CAP) has demonstrated anti-proliferative activity in various cancer cells, yet its efficacy against drug-resistant cancer cells remains largely unexplored. This study investigates CAP's potential to restore drug sensitivity in fulvestrant-resistant breast cancer cells. Fulvestrant-resistant T47D/fulR and MCF-7/fulR cell lines were developed through 32-week drug exposure. CAP treatment effectively inhibited growth of both resistant cell lines and restored sensitivity to fulvestrant when used as pretreatment. Genome-wide expression analysis revealed that CAP significantly impacts ribosomal and mitochondrial components during resistance acquisition and treatment. The oncogene CCND3 emerged as a key contributor to drug resistance, being highly upregulated in resistant cells but downregulated following CAP treatment. Functional validation through CCND3 knockdown in both resistant cell lines induced increased apoptosis and extended G1 phase, confirming its critical role in resistance mechanisms. These findings demonstrate that CAP can revert fulvestrant-resistant breast cancer cells to a sensitive state by targeting CCND3 and modulating critical cellular pathways, suggesting promising therapeutic potential for overcoming drug resistance in breast cancer treatment.

2,3,7,8-Tetrachlorodibenzio-p-dioxin (TCDD) is a persistent environmental contaminant known for aryl hydrocarbon receptor (AHR)-mediated liver effects, including metabolic dysfunction-associated steatotic liver disease (MASLD)-like pathologies such as steatosis, inflammation, and fibrosis. Although previous studies have focused on AHR-mediated regulation of protein-coding genes, recent attention has turned to long non-coding RNAs (lncRNAs) because of their potential roles in the progression of steatotic liver disease (SLD). Using bulk and single-nuclei (sn)RNAseq datasets, we compared the dose-dependent AHR-mediated induction of lncRNA and mRNA expression by TCDD in the mouse and rat liver. This study also investigated cell-specific lncRNA-gene regulation within the murine liver to identify divergent lncRNA expression patterns across different hepatic cell types. Lastly, differentially expressed (DE) lncRNAs associated with human liver diseases were examined to investigate potential mechanistic roles. Comparative analysis of gene expression identified 2,386 mouse and 916 rat DE lncRNAs, with 203 common to both species. In contrast, mice had 6,071 compared to 3,056 rat DE mRNAs, with 1,492 in common. Integration of AHR genomic enrichment and putative dioxin response elements (pDRE) data with DE lncRNAs revealed regulation patterns similar to mRNA-coding genes, with both exhibiting greater frequency proximal to the transcription start site in both mice and rats. snRNAseq analysis also revealed 5,495 DE lncRNAs across all liver cell subtypes. Pericentral and periportal hepatocytes exhibited the most significant changes, with 3,339 and 3,550 DE lncRNAs respectively, followed by macrophages with 2,116. Among all DE genes, 52 previously annotated lncRNAs in hepatocytes were differentially expressed by TCDD, many of which are associated with steatosis, fibrosis, and hepatocellular carcinoma. Collectively, these results suggest AHR-mediated differential expression of lncRNAs may play a significant role in the progression of steatosis to steatohepatitis with fibrosis elicited by TCDD.

Allergic rhinitis (AR) is a common immune-mediated chronic inflammatory disease with a complex pathogenesis involving multiple responses of the immune system and epigenetic changes. In recent years, DNA methylation, a key epigenetic mechanism, has been shown to play an important role in the onset and development of AR. GuoMinKang (GMK) have been used in the treatment of AR through their multi-component properties. However, its specific epigenetic regulatory mechanisms have not been fully investigated. The aim of this study was to explore the epigenetic regulatory mechanisms of the traditional Chinese medicine compound GMK in the treatment of AR. By analysing DNA methylation and transcriptome data from AR patients, we identified differentially methylated regions (DMRs) and differentially expressed genes (DEGs) associated with AR. Through network pharmacology analysis, we screened the active components of GMK and their potential target genes, particularly those related to DNA methyltransferases (DNMTs). An AR mouse model was established to observe the behavioural and pathological changes of the nasal mucosa of mice after drug administration; the expression of IgE cytokines was detected by ELISA, and the expression of nasal mucosa genes was verified by qPCR. Total IgE (tIgE) levels were significantly reduced in AR patients after GMK treatment, suggesting a possible role in immunomodulation. Our analysis revealed that GMK was able to restore aberrant methylation patterns in AR patients by modulating specific DNA methylation regions. Through differential methylation analysis, we identified 10 genes whose methylation levels were significantly restored to normal after GMK treatment and which already showed significant differential expression in AR patients, particularly in immune regulation and epithelial cell function. These genes include LERP, NFIA, etc., suggesting that they may play a key role in the onset and development of AR. Further through target prediction and network pharmacological analyses, we confirmed that the active ingredients of GMK (e.g., quercetin, coumarin, and geranylgeranyl) may exert their epigenetic regulatory functions by targeting the protein activity of DNMTs. In vivo experiments showed that GMK reduced the number of nose scratching and sneezing in mice, glandular hyperplasia in the nasal mucosa was alleviated, with a reduction in the number and volume of glands, and serum tIgE levels were reduced. The increase in LERP expression in the AR model was reduced after treatment with GMK, and the change in NFIA expression was not significant. It suggests that GMK may regulate LERP activity through DNMTs to alleviate allergic symptoms. This study reveals the potential therapeutic mechanism of the traditional Chinese medicine compound GMK in regulating AR through epigenetic mechanisms. These findings provide a theoretical basis and molecular foundation for the clinical application of GMK in AR and open up new research directions.

Oxaliplatin resistance remains a major challenge in colorectal cancer (CRC) treatment. We investigated the FBXL5/IREB2/TFRC axis in ferroptosis-mediated resistance reversal. Bioinformatics analysis identified IREB2 as co-expressed in oxaliplatin resistance and ferroptosis pathways. Clinical samples revealed elevated iron metabolism in resistant CRC tissues. In vitro, FBXL5 knockdown in oxaliplatin-resistant cells (HCT-116/OXA) upregulated IREB2/TFRC, increased Fe²⁺/MDA, and reduced viability/proliferation. Combining oxaliplatin with ferroptosis inducer Erastin enhanced cell death, reversed by ferroptosis inhibitor Ferrostatin-1. Our findings demonstrate that targeting FBXL5 disrupts iron homeostasis, triggers ferroptosis, and overcomes oxaliplatin resistance in CRC.

Castration-resistant prostate cancer (CRPC) is the advanced stage of prostate cancer (PCa) progression, characterized by limited therapeutic options and significant challenges from drug resistance development. We show that PFKFB3, an essential regulator of glycolytic metabolism, is significantly upregulated in PCa tissues and CRPC cell lines, where it plays a pivotal role in driving CRPC progression. Knockdown of PFKFB3 or inhibition by a small molecule inhibitor significantly inhibits the growth and invasion of CRPC cells, whereas overexpression promotes malignant behaviors. Mechanistically, PFKFB3 modulates the PI3K/Akt-Wnt/β-catenin pathway, resulting in enhanced tumor cell proliferation. Additionally, combining a PFKFB3 inhibitor with docetaxel produces synergistic anti-CRPC effects and reduces toxicity. Therefore, PFKFB3-mediated metabolic reprogramming underlies CRPC progression, highlighting its potential as a therapeutic target and emphasizing the need for further exploration in the development of safe and effective PFKFB3 inhibitors for precise targeted therapy in CRPC.

In this study, the inhibitory effects of gentisic acid on biofilm formation and virulence gene expression in Listeria monocytogenes were systematically evaluated. Based on growth curve analysis, sub-inhibitory concentrations (SICs) chosen for gentisic acid were 0.0625, 0.125 and 0.25 mg/mL. Gentisic acid at SICs significantly inhibited biofilm formation by L. monocytogenes in a dose-dependent manner, as confirmed by scanning electron microscopy (SEM). Additionally, gentisic acid significantly reduced bacterial adhesion to and invasion of Caco-2 cells, with adhesion rate decreased by 31.43 %-70.87 %, and invasion rate decreased by 18.58 %-50.72 %. Moreover, gentisic acid impaired bacterial motility and aggregation, reduced the swimming diameter by 52.41 %-92.89 % and the swarming diameter by 34.69 %-87.76 %. It also suppressed the secretion of extracellular polymeric substances. Furthermore, RT-qPCR analysis showed that all six genes related to biofilm formation and virulence were regulated following treatment with gentisic acid. Meanwhile, gentisic acid also inhibited the formation of biofilm by 25.89 %-45.93 %. Moreover, gentisic acid significantly inhibited biofilm formation by L. monocytogenes on food and its contact surfaces. Collectively, these findings suggest that gentisic acid is a promising anti-biofilm agent that offers new strategies for the prevention and control of L. monocytogenes biofilm formation in food systems.

Copper treatment can lead to the accumulation of reactive oxygen species, alter the cellular redox state in plants, and trigger plant adaptive mechanisms such as changes in gene expression and shifts in secondary metabolism. We investigated the effects of copper treatment on the redox state of Scutellaria baicalensis Georgi, characterized by glutathione (GSH) and oxidized glutathione (GSSG) levels. We also determined the concentrations of baicalin and baicalein, and analyzed the correlation between the redox state and these metabolites. Moreover, we analyzed the activity of glutathione reductase (GR, EC 1.6.4.2) and the expression levels of GR, phenylalanine ammonia lyase (PAL, EC 4.3.1.5) and isochorismate synthase (ICS, EC 5.4.4.2) genes. Results indicated that copper treatment increased GSH concentration at 24 and 48 h, and the ratio of GSH:GSSG, and upregulated GR expression. While the baicalin concentration showed a non-significant increase at 24 h and 72 h, baicalein exhibited a significant decrease at 48 h and 72 h. The two key genes in the salicylic acid pathway, PAL and ICS, exhibited opposite trends at 24 and 48 h after copper treatment, followed by significant decreases in both PAL and ICS at 72 h. Our results suggest that plants can mitigate the toxic effects of copper through increasing GSH biosynthesis. Baicalin and baicalein showed varying accumulation patterns in S. baicalensis subjected to different copper treatments.