DJ-1 is a multifunctional protein involved in diverse cellular processes, including defense against oxidative stress, regulation of gene transcription, and maintenance of mitochondrial function. Mutations in the DJ-1 gene are closely associated with early-onset Parkinson's disease, and loss of DJ-1 function increases the susceptibility of dopaminergic neurons to oxidative damage, potentially driving neurodegeneration. Therefore, DJ-1 represents an attractive therapeutic target for PD. In this study, we screened a library of blood-brain barrier-permeable small molecules to identify compounds that modulate DJ-1 expression in the mouse brain. Through molecular docking, we discovered that URB597, a selective fatty acid amide hydrolase inhibitor, binds to DJ-1 and forms a stable complex. URB597 treatment markedly reduced DJ-1 protein levels in SH-SY5Y cells, leading to decreased cell survival and impaired mitochondrial function under oxidative stress conditions. In addition, URB597-treated mice exhibited motor deficits and dopaminergic neuron loss, indicating that suppressing DJ-1 expression may adversely affect neuronal function. Gene expression and pathway enrichment analyses revealed that URB597 targets DJ-1 in the mouse striatum and regulates the expression of genes involved in protein acetylation. Collectively, these findings underscore the critical role of DJ-1 in protecting dopaminergic neurons from oxidative damage and uncover its potential implications in regulating protein acetylation.

Thallium (Tl) is a hazardous heavy metal widely used in industrial applications, leading to significant environmental contamination. Tl concentrations in surface waters can reach up to 1520 μg/L, exceeding safe limits and posing risks to aquatic ecosystems and human health. Monovalent thallium [Tl(I)] is highly stable and bioaccumulative, readily accumulating in aquatic organisms, plants, and the human food chain. Exposure to Tl has been associated with neurotoxicity, kidney dysfunction, and cardiovascular diseases, particularly affecting children and pregnant women, and may increase the risk of neurodegenerative diseases and cardiac arrhythmias. However, effective strategies to mitigate Tl toxicity remain lacking. This study establishes a zebrafish embryo model to investigate the toxicological mechanisms of Tl and evaluate the protective effects of IXA4, a selective XBP1 activator. Our results show that Tl exposure increases mortality, reduces hatching rates, impairs swim bladder development, and causes pericardial edema and brain abnormalities. Transcriptomic and qPCR analyses confirm that Tl induces endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR), key pathways involved in cellular toxicity. Co-treatment with IXA4 significantly improves survival rates and developmental outcomes by upregulating DNA repair genes, particularly in the nucleotide excision repair (NER) pathway, thereby reducing cardiac and neural damage. This study provides novel insights into the mechanisms of Tl toxicity, underscores the urgent need for stricter regulatory measures, and highlights IXA4 as a potential intervention for mitigating heavy metal toxicity in aquatic ecosystems.

Exposure to pollutants such as non-essential metals and microplastics can have harmful consequences for marine organisms. Detecting the impact of pollutants in wild populations can be especially challenging. Such environmental disturbances might prompt rapid responses in the affected organisms, generating changes in their gene expression mediated by epigenetic regulation. Here we use an epiRADseq approach to determine the effect of four non-essential metals (As, Cd, Hg, Pb) and microplastics (MP) on the methylation pattern of Benguela hake, Merluccius polli, captured in the FAO fishing area 34, along the coasts of Mauritania and Senegal. We analysed 49 hake specimens and generated 44,201 epigenetic loci. Despite moderate levels of pollution identified from tissue analysis, we found significant differentially methylated loci associated with the level of the five pollutants analysed (119 significant loci for As, 134 for Cd, 92 for Hg, 119 for Pb, and 159 for microplastics). Elevated Pb was significantly associated with a reduction in hake condition factor. Differentially methylated loci were associated with diverse pathways associated to responses for all pollutants (e.g. immune response, gene expression regulation), pointing to signs of stress within the population. It is worth noting that all pollutants were differentially methylated for a locus in NLRC3, previously associated with innate immune response in fishes. Overall, we found evidence of the effects of moderate concentration of pollutants in the methylation pattern in wild populations of M. polli.

Phytophthora cinnamomi is a globally destructive pathogen causing disease in over 5000 plant species. As sterol auxotrophs, Phytophthora species rely on host-derived phytosterols for reproduction, yet the effects of pathogen infection on plant sterol biosynthesis remains unclear. We utilised a soil-free plant growth system to analyze the impacts of P. cinnamomi on Nicotiana benthamiana roots, a new model for studying P. cinnamomi -plant root interactions. Our results show that P. cinnamomi successfully infected all ecotypes tested, but infection was inhibited by the systemic chemical, phosphite. While phosphite is traditionally associated with the activation of plant defence mechanisms, we show that phosphite also modulates plant immune receptors and phytosterol biosynthesis. qPCR analyses revealed a two-fold upregulation of the N. benthamiana elicitin receptor, Responsive to Elicitins (REL ), and its co-receptor, suppressor of BIR1-1 (SOBIR ) during P. cinnamomi infection when compared with infected, phosphite-treated plants. Furthermore, key genes related to plant sterol biosynthesis were upregulated in their expression during pathogen infection but were suppressed in phosphite-treated and infected plants. Notably, the cytochrome P450 family 710 (CYP710A ) gene encoding a C22-sterol desaturase, involved in stigmasterol production, a phytosterol known to be linked to plant susceptibility to pathogens, was downregulated in phosphite-treated plants, independent of infection status. These findings reveal novel insights into the role of phosphite in modulating plant immune responses and sterol metabolism, with potential in managing diseases caused by P. cinnamomi .

Glioma is a particularly lethal central nervous system tumor. Identifying the boundary between gliomas and normal tissues is difficult due to their infiltrative and invasive growth characteristics. This can result in the inevitable recurrence of the tumor after surgery. Preventing the residual tumor from growing or spreading is a major obstacle in treating gliomas. An earlier study suggested that hypotaurine could enhance the invasion of glioma cells while inhibiting the activity of demethylases. The hypotaurine synthesis-deficient U251 cell line usage showed a decrease in the cells' invasion capability. Analysis of gene expression profiles showed that reducing the activity of a critical enzyme in hypotaurine production, 2-aminoethanethiol dioxygenase (ADO), had a notable effect on the extracellular matrix-receptor interaction. Decreased intracellular ADO expression led to a significant increase in Wnt5a expression. Cells exposed to hypotaurine exhibited decreased levels of both intracellular Wnt5a protein and its corresponding mRNA. The observed characteristic was linked to increased methylation of the Wnt5a gene promoter, possibly due to hypotaurine's ability to inhibit demethylase enzymes. To sum up, the research showed that U251 cells lacking hypotaurine synthesis were susceptible to epigenetic changes, and Wnt5a seemed to function as a cancer inhibitor in this scenario. It would be beneficial to reevaluate this tumor suppressive effect in real tumor samples, which may contribute to the development of new glioma interference strategies.

Methyl eugenol (ME), a natural compound found in various essential oils, has recently been classified as a Group 2A carcinogen by the International Agency for Research on Cancer.

Anaplastic thyroid cancer (ATC) is a markedly invasive subtype of thyroid cancer with a poor prognosis. The Gynostemma pentaphyllum-derived Gypenoside LI (Gyp LI) can inhibit the growth and metastasis of various tumors. This study was designed to evaluate the pharmacological mechanisms of Gyp LI against ATC via network pharmacology analysis combined with experimental verification.

Platinum-based chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC); however, innate and acquired resistance is clinically seen in many patients. Hence, a combinatorial approach with novel therapeutic agents to overcome chemoresistance is a promising option for improving patient outcomes. We investigated the combinational anticancer efficacy of cisplatin and narciclasine in three-dimensional NSCLC tumor spheroids.

As a major component of air pollution, fine particulate matter (PM2.5) was the second global leading cause of death in 2021. Evidence from humans suggested that PM2.5 was associated with an enhanced coronary calcium score (CAC), and animal studies indicated that PM2.5 induced vascular calcification, while mechanisms remained largely unknown. In this study, PM2.5 enhanced the proliferative potential and migration capacity of human aortic vascular smooth muscle cells (VSMCs), as well as disturbing intracellular Ca2+ homeostasis. Subsequent transcriptomic analysis implicated that PM2.5 could influence genes involved in the IRE1α-mediated unfolded protein responses and reduce the expression of DNAJB9, a co-chaperone that formed a complex with BiP/IRE1α to inhibit the activation of endoplasmic reticulum (ER) stress. Further mechanistic investigations indicated that PM2.5 activated the IRE1α/XBP1 signaling pathway and enhanced the expression of osteogenic phenotype-related hallmarks. In contrast, pretreatment with an ER stress antagonist (4-PBA) could suppress PM2.5-associated calcium dysregulation and osteogenic transformation via alleviation of ER stress. Taken together, this study revealed the role of ER stress in the phenotype switching of VSMCs induced by PM2.5, highlighted the regulation of DNAJB9, provided insights into the mechanisms of air pollution-related vascular calcification, and pointed out molecules for future investigations.

Protein malonylation represents a recently identified posttranslational modification whose role in CD8+ T cell differentiation and functionality remains incompletely understood. In this study, we demonstrate that enhancing protein malonylation through sodium malonate (SM) treatment promotes CD8+ T cell memory formation in response to bacterial infection, subsequently potentiating recall responses. Comparative metabolomic analysis between SM-treated and control CD8+ T cells revealed significant metabolic alterations associated with protein malonylation. We present the first comprehensive proteomic analysis of lysine malonylation in murine CD8+ T cells, identifying 77 malonylation sites across 64 proteins involved in diverse cellular processes, particularly metabolic pathways. Malonylation of STAT6 was confirmed via the use of a specific chemical probe. Notably, we established that malonylation at the lysine 374 site of STAT6 results in increased TCF1 expression, due to alleviated transcriptional repression of TCF1 by STAT6. Collectively, our findings provide compelling evidence that protein malonylation plays a significant role in regulating CD8+ T cell memory formation.

The prevalence of type 2 diabetes mellitus (T2DM) has reached epidemic proportions globally, posing a significant burden on public health. Dysregulation of lipid metabolism and insulin resistance in T2DM often leads to hepatic complications, making the modulation of microRNAs (miRNAs) associated with these pathways a promising therapeutic target. This study aimed to investigate the protective effects of aerobic training (AT) and vitamin D supplementation on the liver of individuals with T2DM by examining the modulation of miRNAs related to lipid metabolism and insulin resistance. Specifically, the miRNAs examined in this study were miR-33, miR-122, miR-29, and miR-9. Thirty-two male Wistar rats with T2DM were randomly assigned to four groups: Control (C), AT, moderate dose of Vitamin D supplementation (MD; 5,000 IU), and high dose of Vitamin D supplementation (HD; 10,000 IU). The AT group underwent an eight-week program consisting of treadmill running sessions, five days per week, with a gradual increase in intensity and duration. The vitamin D supplementation groups received either 5,000 or 10,000 IU of vitamin D, administered via injection once weekly for 8 weeks. The study used the STZ + HFD rat model and collected liver tissue samples for analysis. Total RNA, including miRNA, was extracted from the liver tissue samples, and the miRNA expression levels were quantified using quantitative real-time PCR (qRT-PCR). Statistical analyses were performed using one-way ANOVA followed by Tukey's post hoc test. AT led to significantly lower fasting plasma insulin levels (p < 0.05) and a notable improvement in the homeostatic model assessment of insulin resistance (HOMA-IR) index, indicating enhanced insulin sensitivity compared with the control and other groups. It also resulted in significantly lower triglyceride levels (p < 0.01) and a favorable shift in the HDL/LDL ratio, indicative of improved lipid metabolism. Vitamin D supplementation showed a dose-dependent reduction in insulin resistance, with the 10,000 IU group demonstrating a more pronounced improvement compared with the 5,000 IU group. Rats supplemented with vitamin D exhibited a dose-dependent modulation of lipid profile, with the 10,000 IU group demonstrating a more significant decrease in triglycerides and an increase in HDL/LDL ratio. The expression of miR-33, miR-122, miR-29, and miR-9 differed significantly among the experimental groups. The AT group exhibited a significant downregulation of miR-122 and miR-9 while showing a significant upregulation of miR-33 and miR-29 compared to the C and the MD groups. The HD group showed significant downregulation of miR-122 and miR-9 compared to the C and the MD groups. Both AT and high-dose vitamin D supplementation have beneficial effects on insulin levels, insulin resistance, and lipid metabolism in rats with T2DM by modulating miRNA expression, thereby inhibiting insulin resistance and improving T2DM.

Anesthesia and perioperative management significantly influence long-term outcomes in patients with early and intermediate stage cancer. Midazolam, a commonly used benzodiazepine anesthetic, has shown potential anti-tumor effects. This study aimed to explore the anti-tumor properties of midazolam in non-small cell lung cancer (NSCLC). The anti-tumor effects of midazolam on A549 and H1650 NSCLC cell lines were assessed using CCK-8 assays, colony-forming assays, and the Annexin V-fluorescein isothiocyanate Apoptosis Detection Kit I. Additionally, Transwell assays were conducted in vitro, and subcutaneous tumor models in nude mice were established to assess the anti-tumor effects in vivo. The interaction within the lncRNA XLOC_010706/miR-520d-5p/STAT3 axis was confirmed through dual-luciferase reporter assays, RT-qPCR, and Western blotting. Midazolam significantly inhibited cell proliferation and invasion while inducing apoptosis in A549 and H1650 cells, both in vitro and in vivo, by promoting autophagy (P<0.05). It also down-regulated the expression of lncRNA XLOC_010706 in the tumor microenvironment (P<0.05). Within the signaling pathway, lncRNA XLOC_010706 functioned as a competing endogenous RNA (ceRNA) targeting miR-520d-5p, with STAT3 identified as a functional target gene for miR-520d-5p in NSCLC. Furthermore, lncRNA XLOC_010706 acted as an oncogene, promoting cell proliferation and invasion while inhibiting apoptosis through the miR-520d-5p/STAT3 axis. Midazolam down-regulates the expression of lncRNA XLOC_010706, which acts as an oncogene in NSCLC. The anti-tumor effects of midazolam occur via the lncRNA XLOC_010706/miR-520d-5p/STAT3 pathway, enhancing autophagy in NSCLC. This indicates that lncRNA XLOC_010706 could serve as a novel diagnostic biomarker and therapeutic target for NSCLC patients.

Bisphenol A (BPA) is an estrogen-like endocrine-disrupting chemical commonly found in various daily consumer products. It causes female reproductive disorders by interfering with endocrine signaling. Normal folliculogenesis, oocyte maturation, ovulation, and luteal growth/involution rely on the gap junctional intercellular communication between granulosa cells (GCs) and oocytes. Connexin 43 (Cx43) is a key gap junction protein in GCs. The expression of Cx43 in GCs is regulated by follicle-stimulating hormone (FSH) at every stage of folliculogenesis. Melatonin, which exerts anti-inflammatory and antioxidative effects, is primarily released by the pineal gland and reproductive cells, including GCs. In this study. We investigated the protective role of melatonin against BPA-induced toxicity in GCs.

Exportin-1 (XPO1) is a mediator of nuclear-to-cytoplasmic protein trafficking. The XPO1-targeting selective inhibitor of nuclear export (SINE) Selinexor is FDA-approved for relapsed hematological malignancies. Recently, we reported a unique class of XPO1 modulators that suppressed T cell activation without impairing nuclear export or cell viability (the selective inhibitors of transcriptional activation, or SITAs), suggesting that XPO1 may be a therapeutic target in T cell-driven diseases. Here, we analyzed structure-activity relationships of two structurally distinct subseries of SITAs. A set of pyridine-containing structures attained high cellular potencies (EC50 1 nM), while a complementary set of pyrrolotriazine-containing molecules balanced cellular potency with desirable physicochemical properties. Lead molecules from both subseries demonstrated in vivo XPO1 engagement, were efficacious in a mouse model of graft versus host disease, and showed superior tolerability to Selinexor. This study provides evidence that optimized XPO1-targeting SITAs can extend XPO1 as a therapeutic target to indications beyond oncology.

Alternative splicing of transcriptomes after Al and flg22 treatment for 12 h in response to plant defense of Chinese wild Vitis quinquangularis: genes related to stress resistance and splicing factors were identified in response to Al and flg22 treatment. Alternative splicing (AS) is one of the major post-transcriptional regulation processes that potentially regulates the response to biotic and abiotic stresses in plants. So far, the insight into potential roles of AS in grapevine response to aluminium (Al) and flagellin 22 (flg22) stresses remains poorly understood. We performed transcriptome sequencing of grape leaves before and after Al treatment and flg22 treatment, respectively, to identify AS genes. In this study, a total of 11,805 AS events were identified in Al treatment, of which the skipped exon (SE; 88.72%) type was the most frequent. 9156 AS events were identified under flg22 treatment, of which the SE (88.52%) type was the most frequent. Compared with Al-treated and flg22-treated 0 h, there were 42 and 147 differential alternative splicing (DAS) genes differentially expressed (DASEGs) in Al-treated and flg22-treated 12 h, respectively. Functional analysis showed that DASEGs after Al treatment were mainly enriched in glutathione metabolism pathway; DASEGs after flg22 treatment were enriched in MAPK signaling and plant hormone signal transduction. We further verified seven resistance-related DASEGs with up-regulated expression in Al-treated 12 h, including beta-glucosidase, calcineurin B-like protein, synaptotagmin-3, cysteine synthase and glutathione reductase. Several genes function as leucine-rich repeats receptor-like serine/threonine protein kinase, BRI1 associated receptor kinase 1 and receptor-like protein kinase were also verified by RT-qPCR. We also verified four serine/arginine (SR)-rich proteins SCL30A, SCL28, RS2Z32 and SR45A, which were up-regulated in both Al and flg22 stresses. In conclusion, this study provides an in-depth analysis of the correlation between alternative splicing and grapevine stress tolerance, which helps to identify potential candidate genes for useful traits, provides a theoretical basis for grapevine breeding in plant stress tolerance, and offers new perspectives for understanding grapevine environmental adaptation strategies.

Lung cancer has become a primary illness that severely endangers human life and health due to its extremely high morbidity and mortality rates. Ginkgetin has been proven to have toxic effects on various tumor cells. Nevertheless, the mechanism of Ginkgetin on lung cancer is uncertain. In the present study, the effect and possible mechanism of Ginkgetin on lung cancer were explored.

Fusarium graminearum is a pathogenic fungus that causes devastating plant diseases such as Fusarium head blight, leading to significant food waste and posing a threat to human health due to the accumulation of mycotoxins. As a soil-borne fungus, F. graminearum interacts closely with plants and soil, completing its life cycle in an intricate environment. In this investigation, citric acid (CA), a plant root exudate and heavy metal chelator, was investigated for its effect on F. graminearum at concentrations of 2.5, 5, 10, and 20 mM. The fungus treated with this CA gradient exhibited different growth conditions and mycelial colors. Integrative analysis of transcriptomics and proteomics found that the growth of the fungus was accelerated by the upregulation of carbon source metabolism-related enzymes such as phosphoenolpyruvate carboxykinase (PEPCK), Glpk, and LAI12, and the mycelial pigments were altered by polyketide biosynthetic enzymes like AurF, AurJ, and AurT, which were responsible for the production of aurofusarin and rubrofusarin. Interestingly, many Tri genes and their corresponding proteins along with type B trichothecene biosynthesis were significantly downregulated, though the fungal growth was promoted. In this study, the CK, 2.5, and 5 mM groups had similar expression patterns of RNA and protein, while the 10 and 20 mM groups were alike. With the validation of CK, 5, and 10 mM groups, the discovery of CA as a type B trichothecene biosynthesis inhibitor and growth promoter was expected to facilitate its reasonable application and contribute to further research for the prevention of F. graminearum.

Fibrosis, marked by excessive extracellular matrix (ECM) accumulation, underlies functional decline in numerous diseases and often presents with sex-specific differences in severity. Although biochemical pathways have been widely studied, the contribution of mechanical cues-particularly ECM stiffness-to these disparities remains unclear. Here, we develop an integrative mechanobiological model to investigate how estrogen modulates stiffness-mediated fibrotic progression. The model reveals that ECM stiffness activates fibroblasts through two key pathways: a rapid nuclear translocation of mechanosensitive factors (MRTF and TAZ) and a delayed transforming growth factor β/Smad cascade, both of which enhance α-smooth muscle actin expression and matrix production. Moreover, we uncover a stiffness-induced "mechanical memory" effect, maintained through a miR-21/Smad feedback loop that sustains fibrotic signaling even after stiffness reduction. Estrogen, acting via estrogen receptor α, counteracts this process by promoting Smad degradation and interrupting the feedback loop, thereby dampening fibrosis. This work offers new insight into the mechanochemical regulation of sex-biased fibrosis and points to potential sex-specific therapeutic targets.

Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), poses significant challenges in healthcare settings due to its ability to form biofilms on various surfaces. These biofilms enhance bacterial survival and increase resistance to conventional treatments, complicating infection control efforts. This study evaluated the efficacy of combined povidone-iodine (PVP-I) and hydrogen peroxide (H2O2) to disrupt pre-formed S. aureus biofilms. A series of assays-including crystal violet staining, colony-forming unit (CFU) enumeration, gene expression analysis, and confocal laser scanning microscopy-were performed to assess the effects of each treatment individually and in combination. The combined treatment resulted in significantly greater reductions in biofilm biomass and viable bacteria compared with either agent alone. Gene expression analysis revealed downregulation of key biofilm-associated genes (icaA, icaB, icaD, icaR, and clfA), suggesting interference with biofilm stability and maintenance. While formal synergy quantification was not conducted, the observed effects suggest a potentially synergistic or additive interaction between the two agents. These findings support the use of dual antiseptic strategies as a promising approach to biofilm eradication and highlight the potential clinical utility of dual antiseptic strategies. However, we underscore the need for further optimization and safety evaluation.

Prostate cancer (PCa) is a major global health concern, particularly in advanced stages where chemotherapy resistance and androgen-independent tumor growth reduce survival rates to below 30%. Toll-like receptor 3 (TLR3), regulated by tumor suppressor p53, is a promising therapeutic target due to its role in tumor cell apoptosis. However, chronic exposure to inorganic arsenic (iAs), a known carcinogen, has been linked to PCa progression and reduced TLR3 expression and activation by polyinosinic/polycytidylic acid (Poly(I/C)), a synthetic ligand used in PCa immunotherapy. Here, we demonstrate that chronic sodium arsenite (NaAsO) exposure increases p53 transcript and protein levels in immortalized prostate epithelial cells. Despite this, key p53 target genes, including TLR3, CDKN1A, and BAX, were significantly downregulated, indicating a transcriptionally inactive p53. Chromatin immunoprecipitation (ChIP) confirmed diminished p53 binding to TLR3 and CDKN1A promoters, while sequencing ruled out TP53 mutations. A bioinformatic analysis revealed elevated TP53 but reduced TLR3 and CDKN1A in prostate adenocarcinoma, suggesting that iAs-induced oxidative stress disrupts p53 function. These findings reveal a novel mechanism by which iAs promotes PCa progression through impaired p53 activity, highlighting the need to explore post-translational and epigenetic factors affecting p53. Restoring p53 transcriptional activity may offer a therapeutic strategy for PCa patients exposed to NaAsO.