The degradation of marine plastic debris poses a threat to organisms by fragmenting into micro- and nano-scale pieces and releasing a complex chemical leachate into the water. Numerous studies have investigated harms from plastic pollution such as microplastic ingestion and exposure to single chemicals. However, few studies have examined the holistic threat of plastic exposure and the synergistic impacts of chemical mixtures. The objective of this study was to measure changes in gene expression of gill and gonadal tissue of the eastern oyster (Crassostrea virginica) in response to plastic debris exposure during their first year, using RNA-seq to explore multiple types of physiological responses. Shell and polyethylene terephthalate plastic were used as substrate for the metamorphosis of larval oysters in a settlement tank. Substrate pieces were then transferred to metal cages and outplanted in pairs - shell cage and plastic cage - onto restoration reefs in the St. Mary's River, Maryland, USA. After 10 months of growth, the oysters were collected, gill and gonadal tissue removed, and sex identified. The tissues of six oysters from each sex and substrate type were then analyzed in RNA-seq. Both gill and gonadal tissue samples had altered expression of immune and stress-response genes in response to plastic exposure. Genes upregulated in response to plastic were enriched for gene ontology functions of proteolysis and fibrinolysis. Downregulated genes were involved in shell biomineralization and growth. One male oyster exposed to plastic had "feminized" gene expression patterns despite developing mature sperm, suggesting plastic leachate can alter gene expression and shift protandric individuals to develop as females. Plastic pollution may therefore reduce shell growth, initiate immune and stress responses, alter sex differentiation, and impact reproductive output of eastern oysters through changes in transcription.

A20, a negative regulator of NF-κB signaling, is a potent anti-inflammatory molecule. Its deficiency is associated with a wide variety of inflammatory diseases and tumors and the ability of A20 to restrict TCR-NF-κB signaling pathway and the role of this molecule in the pathogenesis of T-cell leukemia are not completely understood. Here we studied the role of A20 in T cells exposed to staphylococcal enterotoxin A (SEA) and evaluated the results of our in vitro findings of lethal inflammation by long-term administration of SEA at low doses to Jurkat cells, human peripheral blood mononuclear cells, and CD3+ T cells. SEA treatment resulted in chronic inflammation, upregulated the expression of MALT1, IKKβ, and p65, and downregulated the expression of A20, both in dose- and time-dependent manners, in Jurkat cells, regardless of the mRNA or protein level. Thus, SEA-mediated chronic inflammation can activate TCR-NF-κB signals via the downregulation of A20 expression, which increases T-cell immortality and may promote the pathogenesis of T-cell leukemia. Modulation of A20 could be a novel strategy for the treatment of T-cell leukemia.

The phenotypic switch of vascular smooth muscle cells (VSMCs), characterized by the tissue-specific expression of certain microRNAs (miRNAs), is a critical factor in the development of diabetic vascular diseases. Metformin, a widely prescribed anti-diabetic medication for type 2 diabetes treatment, activates the adenosine monophosphate-activated protein kinase (AMPK) pathway and exerts a protective effect on vascular endothelium. Although the regulatory effects of metformin on the switch of the vascular smooth muscle cell phenotype have been identified, the specific role of miRNAs in this process remains unclear. We identified a specific miR-1 in response to metformin treatment and determined its effects on both miR-1 and its targets. Subsequently, we investigated the influence of these factors on the metformin-induced phenotype switch in vascular smooth muscle cells, specifically focusing on proliferation and migration, as well as activation of the AMPK/Transforming Growth Factor (TGF-β) axis. This was achieved using various methodologies, including bioinformatics analysis, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis, wound scratch assays, and Cell Counting Kit-8 assays. Our findings showed that metformin upregulated miR-1, which directly targets cyclin D1 (CCND1) in VSMCs. Metformin was observed to enhance the expression of contractile phenotype proteins, including α-smooth muscle actin (α-SMA) and smooth muscle myosin heavy chain (SMMHC), while simultaneously reducing the expression of proliferative phenotype proteins such as CCND1 and proliferating cell nuclear antigen (PCNA). The inhibition of miR-1 was found to reverse the effects of metformin on the phenotypic switch of VSMCs. This occurs partly through the AMPK/TGF-β signaling pathway and inhibits the migration and proliferation of VSMCs.

Transcriptome proteome association analysis screened candidate DEGs, DEPs, and DEGs/DEPs associated with potato response to drought, alkali, and combined stresses. Overexpression of StCOMT1 enhances potato drought and alkali tolerance. Drought and salinity have severely impeded potato (Solanum tuberosum L.) growth and development, significantly reducing global potato production. However, the molecular mechanisms regulating the combined drought and alkali stress process are not fully understood. This study compared the mRNA and protein expression profiles of potato under drought (PEG-6000), alkali (NaHCO3), and combined (PEG-6000 + NaHCO3) stresses by transcriptome and TMT proteomics sequencing to investigate the common or specific responses of 'Atlantic' potato to single and combined stresses of drought and alkali were preliminarily explored. It was found that 2215 differentially expressed genes (DEGs) and 450 differentially expressed proteins (DEPs) were jointly identified under drought, alkali, and combined stresses. Under drought, alkali, and combined stresses, 234, 185, and 246 DEGs/DEPs were identified, respectively. These DEGs, DEPs, and DEGs/DEPs identified revealed the potential roles of several signaling and metabolic pathways in mediating drought and alkali stress tolerance, including plant hormone signaling, MAPK signaling pathway, phenylpropanoid biosynthesis, and glutathione metabolism. Caffeic acid-O-methyltransferase (COMT) is an essential methylating enzyme in the phenylpropane biosynthetic pathway, which is involved in lignin synthesis and plays an important role in protecting plants from abiotic stresses. In this study, we investigated the changes in physiologic characteristics, such as growth, antioxidant defense, osmotic regulation and lignin accumulation, in overexpressing StCOMT1 (PT0001512/M0ZIL7) transgenic potato after stress. It proved that the gene has the function of adapting to drought and alkali stress, and provided a theoretical basis for further research on the resistance mechanism of the gene in drought and alkali tolerance in potato.

Anthracnose caused by Colletotrichum truncatum severely impacts global fruit/vegetable yields. Unlike other Colletotrichum species, C. truncatum exhibits inherent resistance to some sterol demethylation inhibitors (DMIs), necessitating an understanding of ergosterol synthesis regulation and resistance mechanisms. A transcription factor, CtSR (CTRU02_06681), that regulates the DMI sensitivity in C. truncatum was identified in our study. Deletion of CtSR rendered a naturally resistant isolate highly sensitive to DMIs, significantly reduced total ergosterol levels, decreased CYP51s expression compared to the wild type, and abolished DMI-induced expression of CYP51s. Deletion of CtSR reduced mycelial growth and virulence and made the strain highly sensitive to oxidative stress but did not affect its sensitivity to osmotic stress. Transcriptomic analysis and yeast one-hybrid assays confirmed that CtSR directly binds the conserved promoter motif CGAATACGAA to regulate ergosterol biosynthesis genes. Taken together, our study demonstrates a critical role for CtSR in the regulation of ergosterol biosynthesis and DMI interactions in C. truncatum, which may have significant practical implications.

Adeno-associated virus (AAV) gene therapies typically use constitutive transgene expression vectors that cannot be altered after vector administration. Here, we describe a bioorthogonal platform for tuning AAV expression which enables the controlled activation of viral transgenes after transduction. This platform uses a small, synthetic DNA-binding protein embedded in the AAV genome coupled with a heterobifunctional small molecule that recruits endogenous transcriptional machinery to chemically induce transgene expression in a dose-dependent and reversible manner. In human cells, this strategy successfully activates AAV expression across different viral serotypes, cassette configurations, and transgene payloads. Epigenomic analysis reveals that this technology facilitates direct and specific recruitment of the transcriptional regulator BRD4 to AAV genomes. Our results demonstrate that the expression of native AAV genomes can be tuned through chemically induced proximity, opening the possibility of a new class of AAV vectors that can be dynamically potentiated.

Hepatocellular carcinoma (HCC) continues to pose a substantial worldwide health concern, marked by elevated mortality rates and restricted therapeutic alternatives. Recent studies have highlighted the potential of natural compounds as therapeutic agents in cancer management. This review focuses on the diagnostic and prognostic potential of microRNAs (miRNAs) as biomarkers in HCC, alongside the therapeutic promise of natural products. We explore the intricate role of miRNAs in the pathogenesis of HCC, detailing their regulatory functions in cellular processes such as proliferation, apoptosis, and metastasis. Additionally, we discuss the emerging evidence supporting the use of natural compounds, including phytochemicals, in modulating miRNA expression and their potential synergistic effects with conventional therapies. Key miRNAs discussed include miR-21, an oncogenic factor that promotes tumor growth by targeting the tumor suppressor phosphatase and tensin homolog (PTEN); miR-34a, which enhances apoptosis and may improve treatment efficacy when combined with c-MET inhibitors; miR-203, whose downregulation correlates with poor outcomes and may serve as a prognostic marker; miR-16, which acts as a tumor suppressor and has diagnostic potential when measured alongside traditional markers like alpha-fetoprotein (AFP); and miR-483-3p, associated with resistance to apoptosis and tumor progression. By integrating insights from recent studies, this review aims to highlight the dual role of miRNAs as both biomarkers and therapeutic targets, paving the way for enhanced diagnostic strategies and novel treatment modalities in HCC management.

The breast cancer recurrence and chemoresistance has increased over the years. A novel PKC, PKCε, may promote chemoresistance by causing hypoxia and cancer metabolic rewiring. A natural flavonoid, Zapotin, in colon cancer cells may modulate PKCε expression. Therefore, this study aimed to explore Zapotin impact on PKCε expression and the metabolic profile of breast cancer cells.

TiO2 nanoparticles mitigates the toxicity of Cd to Hemerocallis citrina Baroni (daylily) by modulating the photosynthetic and antioxidative system, as revealed by physiological and transcriptomic analysis. Cadmium (Cd) is a common heavy metal pollutant exerting toxicity to plants. The unique physiochemical properties of titanium dioxide nanoparticles (TiO2 NPs) suggest their potential applications in agriculture. The molecular and physiological responses of Hemerocallis citrina Baroni (daylily) to Cd stress and the ameliorative effect of TiO2 NPs were investigated. KEGG enrichment analysis on differentially expressed genes (DEGs) revealed pronounced enrichment of pathways related to photosynthesis. GO enrichment analysis showed that chlorophyll metabolism and redox process were also notably enriched. Furthermore, weighted gene co-expression network analysis (WGCNA) demonstrated remarkable responses of photosynthetic characteristics and antioxidative system, and identified MYB, NAC, and WRKY transcription factors which played key roles in the Cd-stress response and regulation by TiO2 NPs. Under 5 mmol·L-1 Cd stress, daylily growth was severely inhibited, and cell membrane permeability and osmolytes significantly increased. Additionally, Cd stress pronouncedly impaired photosynthesis, increased the accumulation of reactive oxygen species in leaves, and inhibited the activities of most antioxidants. However, foliar spraying of 200 mg·L-1 TiO2 NPs promoted plant growth and increased osmolytes. The inhibition on leaf photosynthetic antenna proteins, photosystem reaction center activity, electron transfer rate, chlorophyll synthesis, and Calvin cycle process was markedly alleviated by upregulating corresponding gene expression as revealed by photosynthesis-related traits and DEG analysis. The activities of key enzymes in ascorbate-glutathione (AsA-GSH) cycle and thioredoxin-peroxiredoxin (Trx-Prx) pathway were enhanced, and the regeneration of AsA and GSH was promoted. Overall, TiO2 NPs mitigated Cd-induced inhibition of photosynthesis and antioxidative system, and enhanced Cd tolerance of daylily.

Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. MicroRNAs (miRNAs) are key regulators of tumorigenesis. This study investigated the role of the miR-192/215-early growth response protein 1 (EGR1) axis in GC and explored its therapeutic implications.

To elucidate the inhibitory mechanism of antimicrobial peptide WK-13-3D on triple-negative breast cancer (TNBC) by targeting the binding immunoglobulin protein (BiP), a key endoplasmic reticulum (ER) chaperone regulating unfolded protein response and tumor survival.

Xihuang Pill (XHP) is a traditional Chinese medicine formula that was originally used to treat malignant ulcers. Recent studies revealed its therapeutic effects on various malignant tumors. However, its potential efficacy and mechanisms in primary liver cancer (PLC) were not thoroughly investigated.

Breast cancer is one of the leading causes of mortality in women worldwide. Adverse side effects have been reported from chemotherapeutic agents of systematic therapies. Therefore, new agents are still needed for breast cancer treatment. This research aimed to investigate anticancer activity and mechanisms of a piperine derivative, named (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-(2-hydroxyphenyl)penta-2,4-dienamide (1f), against MCF-7 breast cancer cell. The results show that 1f ranging from 7.5 to 60 μg/mL inhibited MCF-7 cells in dose-dependent manner with IC50 values of 17.02 ± 1.74 μg/mL. It inhibited cell migration in dose and time dependent manners. In addition, it induced morphological characteristics of apoptosis and increased the level of intracellular reactive oxygen species (ROS). Phosphatidylserine (PS) exposure staining and DNA fragmentation confirmed the induction of apoptosis. 1f induced the gene expression of TP53, PTEN, and CASP9, while ESR1, BRCA1, BRCA2, PIK3CA, AKT1 CHEK2, BRIP1 and KRAS expression were decreased. STRING protein-protein interaction network and KEGG pathway analysis predicted the induction of apoptosis linked with DNA repair, estrogen receptor-α (ER-α), and PI3K/AKT signaling pathways. Moreover, Fourier transform infrared spectroscopy (FTIR) results shows that 1f reduced the lipid utilization rate and inhibited protein synthesis, resulting in the induction of apoptosis. Overall, 1f is an interesting candidate for development as an anticancer agent for breast cancer.

FAT atypical cadherin 1 (FAT1) is prevalently expressed in non-small cell lung cancer (NSCLC) tissues and is associated with poor prognosis in patients. Using data from the PRISM Repurposing drug sensitivity database, we observed that among compounds related to protein homeostasis, the valosin-containing protein (VCP) inhibitor CB-5083 demonstrated the most significant variation in sensitivity among NSCLC cells, categorized according to FAT1 expression levels. Notably, CB-5083 markedly inhibits cell proliferation and induces apoptosis in NSCLC cells with high expression of FAT1. Targeting VCP may trigger strong endoplasmic reticulum stress (ER stress) in NSCLC cells, leading to inhibition of cell proliferation in tumor cells. Mechanically, knockdown of FAT1 stimulates YAP signaling and target gene transcription, thereby attenuating the UPR pathway signal induced by CB-5083 stimulation in NSCLC cells. Our results suggest that FAT1 regulates the activation of the ER stress pathway through YAP signaling, influencing the susceptibility of NSCLC cells to VCP inhibitors. These insights provide novel perspectives for NSCLC treatment and extend the therapeutic applications of VCP inhibitors in clinical settings.

T4C enhances salt stress tolerance in Arabidopsis by regulating osmotic and oxidative stress responses, activating ABA-related pathways, and inducing stress-responsive genes, including LEA proteins. High soil salinity is a major environmental stress that restricts crop productivity worldwide, necessitating strategies to enhance plant salt tolerance. Thiazolidine-4-carboxylic acid (T4C) has been reported to regulate proline biosynthesis, which is essential for abiotic stress responses, yet its role in stress tolerance remains unclear. This study investigates the physiological and molecular effects of T4C on Arabidopsis thaliana under salt stress conditions. T4C treatment alleviated salt-induced growth inhibition, improving biomass, relative water content, and chlorophyll retention while reducing oxidative stress markers such as malondialdehyde and anthocyanin accumulation. Transcriptomic and quantitative PCR analyses revealed that T4C upregulated proline biosynthesis genes, ABA-dependent signaling (RD29b, ABI3), and Late Embryogenesis Abundant (LEA) genes. Gene Ontology (GO) enrichment analysis identified biological processes related to water deprivation, ABA signaling, and salt stress, while Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated the involvement of phenylpropanoid biosynthesis, plant hormone signal transduction, and MAPK signaling in T4C-mediated responses. Notably, several transcription factors, including NAC, MYB, and WRKY family members, were identified as candidates involved in T4C-mediated stress priming. Collectively, these findings suggest that T4C may enhance salt tolerance by modulating osmotic balance, reducing oxidative stress, and activating stress-responsive genes and transcriptional regulators. Our results provide novel insights into the molecular mechanisms underlying T4C-mediated stress responses, highlighting its potential as a chemical priming agent to improve plant resilience under saline conditions.

Background/Objectives: Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, exhibits anti-inflammatory effects and attenuates the process of colon carcinogenesis. Certain healthy diets increase colonic UDCA concentrations, but its anticancer mechanistic actions remain largely unknown. We hypothesize that UDCA preferentially inhibits cancerous colon cell proliferation with a minimal effect on noncancerous colon cells. Methods: With human noncancerous NCM460 colon cell and cancerous HCT116 colon cell culture models, we performed biochemical, western blotting, PCR array, cell cycle, apoptosis, and immunofluorescent assays to determine the effects of UDCA treatment on colon cell proliferation and the underlying molecular mechanisms. Results: The inhibitory potential of UDCA against cell proliferation (via cell cycle arrest and apoptosis) was 90% greater in cancerous HCT116 cells than noncancerous NCM460 cells when treated with UDCA (0 to 0.4 mM) for 48 h. In UDCA-treated HCT116 cells, we identified 18 genes with ≥80% change (compared to untreated cells) in mRNA levels out of 93 apoptotic genes which were involved in caspase, death receptor, and NFκB pathways. At the molecular level, 0.4 mM UDCA reduced the protein level of the proto-oncogenic c-Myc gene but increased the putative tumor suppressor p21 gene (≥100%) via the ERK1/2/c-Myc/p21 pathway, which regulates cell cycle and apoptosis. These data are consistent with lower c-Myc but higher p21 expression in normal colon tissues compared to cancerous colon tissues. Conclusions: Collectively, UDCA inhibits cancerous HCT116 colon cells to a higher degree than in noncancerous NCM460 colon cells through cell cycle and apoptosis involving ERK1/2/c-Myc/p21 signaling.

This in vitro study aimed to investigate the impact of folic acid on DNA methylation and gene expression in adipocytes from subcutaneous adipose tissue of patients with systemic lupus erythematosus (SLE), with a focus on the influence of obesity on these epigenetic changes.

Efflux pumps in Pseudomonas aeruginosa play an important role in decreasing the bacterium's antibiotic susceptibility. This study aimed to identify P. aeruginosa efflux pumps and examine the effect of Zinc sulfate on these pumps. This study was conducted on 104 P. aeruginosa clinical isolates collected from different types of specimens. The antimicrobial susceptibility pattern of all isolates was examined by disc diffusion and microdilution methods. A Cartwheel test was done for phenotypic detection of P. aeruginosa efflux pumps in the presence and absence of zinc sulfate. The expression of efflux pumps encoding genes and their regulators in the presence and absence of zinc sulfate was measured using real-time reverse transcriptase PCR. A high rate of multidrug-resistant (MDR) pattern was observed among the tested isolates (55.7%). Combining different antibiotics with Zinc sulfate exhibited synergistic effects against most of the studied isolates. The addition of sub-inhibitory concentrations of Zinc sulfate to the cartwheel test was found to inhibit efflux pump activity in all tested isolates. The expression of the positive regulator gene, mexT, was significantly decreased. Additionally, Zinc sulfate significantly upregulated the expression of the mexR gene (P-value < 0.05), a negative regulator of the MexAB-OprM efflux pump. Zinc sulfate demonstrated a strong antimicrobial effect against P. aeruginosa clinical isolates. We recommend the use of Zinc sulfate as an antibiotic adjuvant and efflux pump inhibitor in the treatment of P. aeruginosa infections to enhance the bacterium's susceptibility to antimicrobial agents.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Accumulating evidence suggests that epigenetic dysregulation contributes to the initiation and progression of HCC. We aimed to investigate key epigenetic regulators that contribute to tumorigenesis and progression, providing a theoretical basis for targeted therapy for HCC. We performed a comprehensive epigenetic analysis of differentially expressed genes in LIHC from the TCGA database. We identified fibrillarin (FBL), an rRNA 2'-O-methyltransferase, as an essential contributor to HCC. A series of in vitro and in vivo biological experiments were performed to investigate the potential mechanisms of FBL. FBL knockdown suppressed the proliferation of HCC cells. In vivo studies using cell-derived xenograft (CDX), patient-derived xenograft (PDX), and diethylnitrosamine (DEN)-induced HCC models in Fbl liver-specific knockout mice demonstrated the critical role of FBL in HCC carcinogenesis and progression. Mechanistically, FBL regulates the expression of CAD in HCC cells by recruiting YY1 to the CAD promoter region. We also revealed that fludarabine phosphate is a novel inhibitor of FBL and can inhibit HCC growth in vitro and in vivo. The antitumor activity of lenvatinib has been shown to be synergistically enhanced by fludarabine phosphate. Our study highlights the cancer-promoting role of the FBL-YY1-CAD axis in HCC and identifies fludarabine phosphate as a novel inhibitor of FBL. A schematic diagram depicting the FBL-YY1-CAD signaling pathway and its regulatory role in HCC progression.

Anti-androgen resistance remains a major clinical challenge in the treatment of prostate cancer (PCa), leading to disease progression and treatment failure. Despite extensive research on resistance mechanisms, a reliable prognostic model for predicting patient outcomes and guiding therapeutic strategies is still lacking. This study aimed to develop a novel gene signature related to anti-androgen resistance and evaluate its prognostic and therapeutic implications.