Hypomethylating agents are frontline therapies for myelodysplastic neoplasms (MDS), yet clinical responses remain unpredictable. We conducted a phase 2 trial comparing injectable and oral azacitidine (AZA) administered over one or three weeks per four-week cycle, with the primary objective of investigating whether response is linked to in vivo drug incorporation or DNA hypomethylation. Our findings show that injection results in higher drug incorporation, but lower DNA demethylation per cycle, while global DNA methylation levels in mononuclear cells are comparable between responders and non-responders. However, hematopoietic stem and progenitor cells (HSPCs) from responders exhibit distinct baseline and early treatment-induced CpG methylation changes at regulatory regions linked to tissue patterning, cell migration, and myeloid differentiation. By cycle six-when clinical responses typically emerge-further differential hypomethylation in responder HSPCs suggests marrow adaptation as a driver of improved hematopoiesis. These findings indicate that intrinsic baseline and early drug-induced epigenetic differences in HSPCs may underlie the variable clinical response to AZA in MDS.

Excessive heavy metal pollutants in soil seriously damage ecological systems and the environment. Dianthus spiculifolius shows strong tolerance to Cd/Pb and readily accumulates both metals. Isocitrate dehydrogenase (IDH) is key enzyme in the tricarboxylic acid cycle, which is involved in the plant response to a variety of abiotic stresses. Previous transcriptomic analyses suggested that DsIDH in D. spiculifolius plays a role in Cd/Pb detoxification. In this study, we found that the transcript level of DsIDH was significantly increased under Cd/Pb stress. Transiently expressed DsIDH localized at the chloroplasts in tobacco leaves. Transgenic yeast lines overexpressing DsIDH showed increased tolerance to Cd and Pb and decreased accumulation of Cd and Pb. Compared with their respective wild types, transgenic Arabidopsis and D. spiculifolius overexpressing DsIDH showed increased IDH activity, increased tolerance to Cd/Pb, and decreased heavy metal contents. The increased activity of IDH significantly accelerated the decomposition of isocitrate and increased the production of α-ketoglutaric acid and NADPH, which reduced damage caused by the reactive oxygen species produced in response to Cd and Pb stresses. The DsIDH might be a novel tolerance-related candidate gene useful for decreasing the storage of toxic heavy metals in crops.

Cold atmospheric plasma (CAP), a redox-regulatory tool, has demonstrated its potency in selectively arresting a wide range of cancer cells, yet its molecular mechanism remains elusive that has largely hindered its clinical translation. Accumulating evidence has implicated the role of CAP in attenuating chronic inflammation in multiple diseases. Using triple negative breast cancer, which is short of effective therapies with little adverse effect, as the tumor model, we reported a synergistic approach to enhance the anti-cancer efficacy of CAP both in vitro and in vivo by coupling it with the mimics of miRNA-146b-5p, a known negative regulator of multiple inflammatory genes in diversified types of cells. Moreover, we identified an innovative path leading to CAP-enabled cancer death involving a SCAF11-mediated competition between FOXO1 and METTL14. This mechanistic model caused enhanced FOXO1 protein degradation and increased pri-miRNA-146b-5p m6A methylation for miRNA-146b-5p maturation. Our findings novel in conceptually proposing a competitive ubiquitination mechanism between two proteins under insufficient E3 ligase supply, and a combinatorial onco-therapeutic modality taking advantages of the unique benefits of CAP and miRNA mimics in alleviating chronic inflammation. Our results have also validated our hypothesis on the role of CAP in selectively targeting transformed cells via attenuating chronic inflammation.

Backgrounds Resistance to sorafenib, a frontline therapy for advanced ccRCC, is associated with decreased sensitivity to ferroptosis. Our research focuses on elucidating the mechanisms underlying ccRCC's resistance to sorafenib-induced ferroptosis and identifying potential new agents that could overcome this resistance.

Anionic Polyacrylamide (APAM) is widely used in oil extraction processes, serving as an oil-repellent polymer and constituting a critical component of water-based drilling fluids. The environmental and ecological effects of APAM on fishery resources have attracted significant attention, yet its toxic mechanism in marine fish at early developmental stages remains poorly understood. The potential effects of APAM on marine medaka (Oryzias melastigma) embryos were investigated by exposing them to 0, 120, 240, 480, and 960 mg/L for 18 d. APAM exposure caused developmental toxicity in embryos, leading to reduced heart rates, delayed and decreased hatching, increased mortality and malformations. The activities of superoxide dismutase (SOD) and catalase (CAT) initially increased after 2 d of exposure but decreased after 8 and 18 days of prolonged stress, while malondialdehyde (MDA) concentration increased, causing lipid peroxidation and worsening oxidative damage. After 18 days of APAM exposure, low and medium concentrations increased the expression of cardiovascular genes GATA4 and NKX2.5, while high concentrations decreased NKX2.5, leading to heart defects like elongated hearts and pericardial cysts. Additionally, low concentrations significantly boosted nervous system genes SHHA and SYN2A, enhancing swimming behaviors, whereas high concentrations suppressed these genes, reducing swimming activity. In conclusion, this study demonstrated that APAM exposure causes developmental toxicity, oxidative stress, neurotoxicity, and disrupts early cardiac development in O. melastigma embryos, providing insight into its toxic effects on early marine fish development.

This study investigates the role of DNA Damage Inducible Transcript 3 (DDIT3) in luminal A subtype breast cancer (LABC). DDIT3, a transcription factor linked to various stress responses, has been implicated in tumorigenesis, yet its specific contributions to LABC biology remain poorly understood.

Nitric oxide (•NO) is a free radical that is endogenously produced in plant cells, though its enzymatic synthesis remains a subject of ongoing debate. Plant peroxisomes, subcellular compartments with active nitro-oxidative metabolism, play a role in various metabolic pathways. Sulfite oxidase (SOX), a peroxisomal enzyme requiring the molybdenum cofactor (MoCo), catalyzes the oxidation of sulfite (SO32-) to sulfate (SO42-), along with the concomitant production of H2O2. Using reconstituted recombinant SOX from pepper (Capsicum annuum L.) fruit, it was shown that this enzyme has the capacity to generate •NO using nitrite (NO2-) as a substrate and NADH as an electron donor which was detected by electron paramagnetic resonance (EPR) spectroscopy coupled with the spin-trapping method. Furthermore, this •NO generation was upregulated in the presence of hydrogen sulfide (H2S) but was downregulated by H2O2 which highlights the relationship between H2O2, •NO, and H2S. This data opens new avenues for understanding the enzymatic sources of •NO in higher plants, particularly within peroxisomes.

Cholangiocarcinoma (CCA) is one of the most aggressive cancers with a poor prognosis. Current treatment strategies involve hepatobiliary surgery, chemotherapy, radiotherapy, and supportive care; however, the success of these treatments remains limited. Therefore, this study investigated the potential of Atractylodes lancea (Thunb) D.C. (AL) in limiting the progress of CCA by targeting the expression of cancer-related genes involved in immune responses and circulating tumor cells. The study was part of Phase 2A clinical trial in advanced-stage intrahepatic iCCA (iCCA) patients: Group 1 (n = 16) received low-dose AL (capsule formulation of the standardized extract of AL: CMC-AL) with standard supportive care, Group 2 (n = 16) received high-dose AL with standard supportive care, and Group 3 (n = 16) received standard supportive care alone. Venous whole blood samples (EDTA, 5 ml) were collected from each patient on Day 1 and Day 90 and the non-CCA subjects (n = 16) on Day 1. Fifty-nine samples (48 and 11 samples for Day 1 and Day 90, respectively) were processed for total RNA isolation. Gene expression was evaluated using reverse transcription followed by a PCR array. Regardless of dosage, gene expression patterns in the AL-treated groups closely resembled those of the healthy subjects. Specifically, cancer-associated genes, including VEGF-A, NR4A3, Ki-67, and EpCAM, were significantly down-regulated. Additionally, the expression levels of immune-related genes were modulated in AL-treated patients. The treatment groups exhibited lower levels of the pro-inflammatory cytokine IL-6, increased expression of the anti-inflammatory cytokine IL-10, and cell-mediated immune-related molecules such as CTLA4 and PFR1. These findings suggest the potential of AL for iCCA treatment. However, additional studies are required to confirm the correlation between gene and protein expression profiles, as well as CTCs profile.

GAPDH regulates plant stem cell maintenance. WUSCHEL (WUS) and WUSCHEL-RELATED HOMEOBOX (WOX) family proteins are vital for maintaining the homeostasis of stem cells, which is necessary for the continuous growth and the development of plants. Plants frequently encounter environmental stress that can lead to an increase in reactive oxygen species, such as hydrogen peroxide (H2O2). However, the exact ways in which plant stem cells sense and respond to H2O2 signals remain unclear. This research indicates that cytosolic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) helps regulate stem cell maintenance in Arabidopsis in response to H2O2. Hydrogen peroxide causes the relocation of two cytosolic GAPDH proteins, GAPC1 and GAPC2, from the cytoplasm to the nucleus. These isoforms interact with WUS/WOX proteins and modulate the expression of the WUS/WOX gene by binding to its promoter. When the expression of GAPC1 and GAPC2 is decreased, stem cell homeostasis and overall plant growth become more sensitive to H2O2. Thus, cytosolic GAPDH may serve as a sensor for H2O2, influencing the maintenance of plant stem cells under oxidative stress.

Prolactin (PRL) regulates its own secretion by short-loop feedback to tuberoinfundibular dopaminergic (TIDA) neurons. PRL-induced cellular mechanisms in the regulation of tyrosine hydroxylase (TH) are not completely understood. The objectives were to (1) examine PRL-induced, time-dependent hypothalamic changes in JAK2-STAT5B signaling, TH activity, TH phosphorylation state and Th mRNA levels, and (2) evaluate direct influences of PRLR-STAT5B signaling on Th promoter activity. Ovariectomized rats were administered ovine PRL. JAK2 and STAT5 phosphorylation in the mediobasal hypothalamus peaked at 15 and 30-60 min, respectively. TH Ser40 phosphorylation in the median eminence was increased between 2 and 72 h, correlating with increased dihydroxyphenylalanine (DOPA) accumulation. Th mRNA levels in TIDA neurons were unchanged up to 72 h but elevated by 7 days. PRL did not alter Th promoter activity in CAD cells, and STAT5B did not bind three putative Gamma Interferon Activation Sites (GAS) elements. We conclude that PRL initiates an integrated cascade of cellular mechanisms in TIDA neurons, including JAK2-STAT5B activation, TH Ser40 phosphorylation coupled to increased TH activity, followed by a delayed rise in Th gene expression. PRL-induced changes in Th gene expression are not the result of STAT5-mediated transactivation but likely result from enduring changes in TIDA neuronal activity.

5-Fluorouracil (5-FU) and the Folate Leucovorin (LV) form the chemotherapy backbone for metastatic colorectal cancer (mCRC). Tumoral expression of specific folate-associated genes is associated with the risk of recurrence in stage III CRC following adjuvant 5-FU/LV (FLV)-based combination chemotherapy according to the Nordic bolus regimen. The aim was to evaluate whether expression of folate-associated genes in Pre-therapeutic tumor samples is associated with outcomes of patients with mCRC undergoing palliative FLV-based combination chemotherapy.

This study identifies single-nucleotide polymorphisms (SNPs) associated with cellular response to cyclophosphamide (CTX) using phosphoramide mustard (PM), its primary cytotoxic metabolite, and explores the downstream consequences for breast cancer (BC) patients.

Antibiotics are widely used in animal husbandry to ensure the health of livestock, leading to the exposure of microorganisms to accumulated sub-lethal concentrations (sub-MICs) of antibiotics in meats. This study aimed to investigate the effects and mechanisms of sub-MICs of commonly used antibiotics on the biofilm formation of a S. aureus strain Guangzhou-SAU071 which displays weak biofilm formation despite harboring biofilm-associated genes. CV and MTS assays were used to determine biofilm biomass and cell viability, respectively. Dual-omics sequencing combining genomics and transcriptomics was used to study the global expression changes. Expression of biofilm and two-component system associated genes was further verified by RT-qPCR. Biofilm formation of Guangzhou-SAU071 was enhanced under sub-MIC of ciprofloxacin (2 μg/mL) and streptomycin (128 μg/mL). Nearly half of the genes associated with biofilm formation, cell wall anchoring, and two-component systems exhibited significant differential expression under sub-MIC of ciprofloxacin and streptomycin. As concluded, sub-MIC of ciprofloxacin and streptomycin enhanced biofilm formation of S. aureus, possibly due to its regulation on biofilm and two-component system associated genes.

Considering the different behaviour of cells in response to diseases in different conditions and sex hormone-dependent cancers, we addressed the possible effect of the sex of the source of these cells from adipose tissue on prostate cancer cells. In this in vitro study, we evaluated the effects of male and female MSC Conditioned Media (MCM, FCM) on prostate cancer cells. The assessment included Hoechst dye staining, a scratch-wound assay, a colony formation assay, and a flow cytometric analysis of apoptosis and the cell cycle. We also performed real-time PCR to examine various genes, including apoptosis-related genes, epithelial-mesenchymal transition (EMT) genes, angiogenesis-related genes, and cell growth and survival biomarkers. Our results indicated that the IC50 values were 50% and 75% media in MCM and FCM in each of the three prostate cancer cell lines, respectively. An evaluation of gene expression revealed that in all three prostate cancer cell lines, treatment with MCM was more effective than FCM in reducing the expression of N-Cadherin and Vimentin, EGFR and BCL2 genes (p < 0.001). Furthermore, the MCM significantly increased the expression of BAX and E-Cadherin genes (p < 0.001) in the PC3 cell line. MCM proved to be more effective than FCM in reducing the expression of the epithelial-mesenchymal transition pathway, EGFR gene, and Apoptosis Regulator (BCL2) in the PC3 cell line. Due to its potential in regenerative medicine and cell therapy, this approach may serve as an effective treatment option for advanced prostate cancer.

The effects of hyaluronan (HA) in cancer are widely studied; however, the role of different molecular weight HA is poorly understood. Identifying novel proteins regulated by different molecular weight HA may highlight novel therapeutic targets. Proteomics analysis was performed to identify novel proteins regulated by different molecular weight HA (27, 183 and 1000 kDa) in ES-2 ovarian cancer cells over-expressing Notch3 intra-cellular domain. Our analyses identified sphingosine kinase 1 (SPHK1), a novel protein regulated by 183- and 1000-kDa HA. Utilising online databases and high-grade serous ovarian cancer (HGSOC) patient tissue microarray cohorts, we assessed the relationship between SPHK1 expression and ovarian cancer metastasis, recurrence and patient outcome. We assessed the effects of the HA synthesis inhibitor 4-methylumbelliferone (4-MU) on SPHK1 expression in ovarian cancer cells and HGSOC patient tissues using ex vivo tissue explant assays. SPHK1 was significantly increased in ovarian cancer compared to normal tissues, elevated in metastatic and recurrent HGSOC tissues and associated with poor patient outcome. 4-MU significantly inhibited SPHK1 expression in ovarian cancer cells (ES-2, CaOV3 and A2780) and HGSOC patient tissues. This study highlights a link between HA and SPHK1 expression in ovarian cancer. Our findings confirm an adverse effect on ovarian cancer prognosis. SPHK1 constitutes a novel promising target against ovarian cancer that warrants further investigation.

An elevated extracellular matrix (ECM) and interstitial fluid pressure (IFP) in gastric cancer limits the targeting of HER2-expressing cells when radioimmunotherapy (RIT) with 64Cu-trastuzumab (64Cu-TRZ) is utilized. Here, we used Losartan (LOS) to downregulate ECM and IFP in gastric cancer mice model. In our study we treated the gastric cancer mice model with a dose of 40 mg/kg of LOS. We found that the LOS treatment increases a twofold higher Alexa-647-TRZ accumulation which significantly enhanced 64Cu-TRZ. We determined that the LOS-treated samples exhibited reduced mRNA and protein expression of SERPINE1, a gene associated with the ECM degradation. Additionally, LOS treatment resulted in the downregulated mRNA expression of the TGF-β1 and COL13A1, the genes involved in ECM deposition and an upregulated RNA expression of MMP2, a gene associated with the ECM degradation. There were no significant changes in metastatic markers of N-Cadherin and E-Cadherin. Moreover, our study demonstrates that silencing SERPINE1 increases the activity of the MMP2 and decreases COL13A1 with no effect on the N-cadherin and E-cadherin were observed. Our novel combinational therapy of using 64Cu-TRZ with LOS is attributed to the downregulation of SERPINE1 targeting ECM and IFP is highly effective for treatment of gastric cancer.

Novel of hematopoietic system and hepatic system under the usage of antioxidant plants such as chia seeds and matcha green tea were critical sites in this study which promoted by crucial health of New-Zealand white (NZW) rabbits as a model for mammalia and eukaryotic cell. Our study investigated the effect of chia seeds and matcha green tea on the liver. Eighteen NZW rabbits average weighed of 547.08gm with an average age of 30 days were divided into three groups, control, chia seeds powder group 0.150gm/L, and matcha green tea group 0.075 gm/L. The weekly treatments were weighted from weaning age to marketing age about nine weeks were the experimental period. At the end of this experiment, we studied growth performance, metabolism, carcass characteristics, and some gene expression related to the growth factor family, hepatic metabolism, lipid profile, iron storage, and one of the endoplasmic reticulum stress receptors of NZW rabbits. The data in this study reported that final body weight increased significantly (P < 0.05) in the matcha group compared to the control, carcass trait and dressing parts were increased significantly in comparison to control. However, Red blood cell count, hemoglobin concentration, and ferritin increased in matcha groups in comparison to control while there is no difference significant between chia and control. Cortisol and insulin in plasma were decreased significantly in chia and matcha compared to control. IRP1, APOA2, IGF1, A1BG, and SLC27A5 were up-regulated in matcha tea groups compared to control while, SLC27A5 was down-regulated in chia groups and Leptin and GRP78 were showed down-regulated in chia and matcha groups. This study offers new insights into the role of chia seeds and matcha tea in physiological and biological processes in the liver and achieved a vital and healthy biological body and reduces the incidence of cancer.

High-grade serous ovarian cancer (HGSOC) is the most common and aggressive subtype of epithelial ovarian cancer, often diagnosed at advanced stages with a poor prognosis. Paclitaxel (PTX), a standard chemotherapeutic agent for HGSOC, exerts cytotoxic effects on cancer cells and modulates the tumor microenvironment. This study aimed to elucidate the molecular mechanisms of PTX in HGSOC using bioinformatics, machine learning, network pharmacology, and molecular docking, to identify potential diagnostic biomarkers and therapeutic targets. We identified differentially expressed genes (DEGs) between HGSOC and normal ovarian tissues using the GSE54388 dataset from the Gene Expression Omnibus database. The intersection of these DEGs with PTX targets, identified from the Swiss Target Prediction database, yielded 15 overlapping genes. These genes were analyzed via protein-protein interaction (PPI) network analysis to identify significant interaction relationships. Kaplan-Meier survival analysis was then performed to assess the prognostic significance of these genes. Their protein expression patterns in HGSOC tissues were validated using the Human Protein Atlas (HPA) database. Functional enrichment analysis was conducted using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. A combined diagnostic model was developed using LASSO regression and validated in two independent external datasets (GSE26712 and GSE12470). Molecular docking experiments were conducted to confirm the binding affinity of PTX to key proteins. Immune infiltration analysis was performed to assess the tumor microenvironment, revealing significant differences in immune cell composition between normal and tumor tissues. A total of 2267 DEGs were identified, with 15 overlapping genes related to PTX targets. After PPI network analysis, Kaplan-Meier survival analysis, and HPA validation, five key genes (AURKA, CBX7, CCNA2, HSP90AA1, and TUBB3) were identified as associated with HGSOC progression. The combined diagnostic model demonstrated high accuracy in distinguishing HGSOC from normal tissues, with AUC values of 0.9892 and 0.9465 in the GSE26712 and GSE12470 validation datasets, respectively. Molecular docking confirmed stable binding of PTX to these key proteins, suggesting their role in PTX's therapeutic effects. Immune infiltration analysis revealed significant differences in immune cell composition between normal and tumor tissues, highlighting the potential impact of these genes on the tumor microenvironment. In summary, our findings provide a theoretical basis for improving clinical diagnosis and elucidating the underlying mechanisms of HGSOC.

Per-and polyfluoroalkyl substances (PFAS) are a pervasive family of synthetic compounds with a wide range of reported health effects. Epigenetic clocks, DNA methylation-based predictors of chronological and biological age, are promising biomarkers for characterizing biological aging in humans. The potential impact of PFAS exposure on epigenetic aging in the general US population remains unclear. In the 1999-2000 National Health and Nutrition Examination Survey (NHANES) cycle (N = 262), eleven PFASs were measured in serum and DNA methylation was measured in blood with the EPICv1 array. Seven epigenetic clocks and their respective epigenetic age acceleration (EAA) measures were calculated. Survey-design weighted generalized linear regression models were used to test adjusted associations between individual log2-transformed PFAS concentrations and EAA stratified by sex. Among male participants, doubling of PFNA concentrations was associated with greater EAA across several clocks including the Horvath clock (beta = 1.48, 95 % CI: 0.35, 2.61), Skin&Blood clock (beta = 1.27, 95 % CI: 0.21, 2.32), and PhenoAge (beta = 1.43, 95 % CI: 0.41, 2.44), and doubling of PFOS exposure was associated with greater Skin&Blood EAA (beta = 1.14, 95 % CI: 0.04, 2.24). When considering cell-adjusted EAA measures, each of these associations among male participants remained significant, and PFOSA was associated with decreased PhenoAge EAA (beta = -0.84, 95 % CI: -1.49, -0.18) and GrimAge2 EAA (beta = -0.81, 95 % CI: -1.51, -0.11) among female participants. In summary, we found evidence of sex-specific associations between PFAS exposure and epigenetic aging in a sample of older adults representative of the general US population.

Staphylococcus aureus (S. aureus) is a highly prevalent pathogen capable of strongly adhering to food processing equipment and the contact surfaces, where it forms resilient biofilms that are difficult to eliminate. Prunella vulgaris (P. vulgaris), a traditional Chinese herbal medicine, has demonstrated strong potential in inhibiting S. aureus biofilm formation. This study investigated the inhibitory mechanisms of P. vulgaris extracts against S. aureus growth and biofilm formation, evaluating the biofilm inhibitory concentration, bactericidal concentration and their effects on ica operon gene expression. The P. vulgaris extracts exhibited a minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 1.25 mg/mL. At the MIC level, the extracts not only suppressed S. aureus growth and metabolic viability but also inhibited polysaccharide intercellular adhesion (PIA), prevented biofilm formation and disrupted mature biofilms. Furthermore, P. vulgaris extracts demonstrated concentration-dependent effects on extracellular polymeric substances (EPS) production: while 1/2 MIC concentrations stimulated EPS synthesis, double-MIC concentrations markedly suppressed it. Notably, the extracts consistently downregulated icaA and icaD expression at both MIC and 2 × MIC concentrations. Therefore, P. vulgaris exhibits significant potential against S. aureus-induced foodborne diseases, demonstrating promise as a novel antibacterial agent for future applications in both pharmaceutical development and food safety enhancement.