The epidermal growth factor receptor (EGFR) is a key driver in bladder cancer progression. This study investigated the tumor-suppressive role of miR-124-3p and its regulatory effect on EGFR.

Pancreatic cancer is known to be one of the most challenging and complex types of cancer owing to its late diagnosis, rapid growth, and resistance to treatment. The use of iron-nickel (Fe-Ni) nanoparticles in cancer treatment is an innovative method that can reduce side effects. This study investigates the anticancer effects of Fe-Ni nanoparticles on the activity of the PANC-1 cell line.

Astrocytes actively phagocytose amyloid beta (Aβ), enhancing cerebral clearance and positioning themselves as viable therapeutic targets for Alz-heimer's disease (AD). Atractylenolide III (ATL-III), the primary bioactive compound in the traditional Chinese herb Baizhu, demonstrates established neuroprotective properties. However, the research on its effects on astrocytes has not yet been elaborated. To induce an astrocyte-based AD model, Aβ1-42 was utilized. Cell viability assays were conducted to screen for the optimal concentration of ATL-III treatment. Molecular docking was performed to investigate the binding between ATL-III and aquaporin 4 (AQP4). Additionally, an Aβ1-42-induced AD mouse model was adopted. In this study, ATL-III effectively reduced the accumulation level of Aβ1-42 in the cell supernatant, and at the same time, significantly enhanced the internalization of Aβ by astrocytes. Of interest, the study reveals that ATL-III not only has the property of binding to AQP4 but also up-regulates the expression level of this protein. Mechanistic probes suggest that the role of ATL-III in promoting Aβ clearance by astrocytes may be partially dependent on its regulation of AQP4 expression. Animal behavioural experiments confirmed that the compound ameliorated Aβ1-42-induced cognitive dysfunction, and pathological analyses revealed significantly elevated AQP4 expression in the hippocampus. The combined findings suggest that ATL-III may play a role in ameliorating the pathological process of AD by enhancing the efficiency of astrocyte-mediated Aβ clearance through the up-regulation of AQP4 expression.

Ovarian cancer remains one of the most lethal gynaecological malignancies, with paclitaxel resistance being a major therapeutic challenge that limits treatment efficacy and patient survival. We found that although the BARD1 level was not signi-ficantly altered in patients with ovarian cancer (OC), patients with higher BARD1 levels had increased survival time, suggesting that the down-regulation of BARD1 may be related to the paclitaxel sensitivity. Through examining the expression of BARD1 in tumour samples from paclitaxel responders and non-responders, we observed that the BARD1 level was significantly reduced in non-responders. CYP2C8 was up-regulated in non-responders. Also, the BARD1 level was negatively correlated with the level of CYP2C8. BARD1 over-expression in OC cells could repress the CYP2C8 expression, while knockdown of BARD1 could up-regulate CYP2C8 expression, which could be rescued by H2A-Ub. Results from gain and loss of functional experiments indicated that BARD1 functions as a tumour suppressor during paclitaxel treatment, and BARD1 down-regulation increased the IC50 of paclitaxel from 2.46 nM to 5.33 nM in SK-OV-3 cells and from 3.11 nM to 7.51 nM in CaoV-3 cells. We are the first to demonstrate that the down-regulation of BARD1 contributes to paclitaxel resistance via up-regulating CYP2C8 in patients with OC, which provides a potent target for clinical OC treatment.

The dopamine transporter (DAT) exerts temporal and spatial control over dopaminergic neurotransmission through reuptake of extracellular dopamine (DA). The functional capacity of DAT is under the control of signaling inputs and post-translational modifications that confer acute presynaptic regulation of reuptake in response to physiological needs, and dysregulation of these processes may contribute to DA imbalances in mood disorders and drug addiction. A key modification of DAT is palmitoylation, a lipid adduction that enhances transport velocity, is suppressed by protein kinase C, and opposes protein kinase C-mediated down-regulation. Here we now show in rat striatum and heterologous cells that transporter palmitoylation is also linked to methamphetamine (METH), undergoing rapid and transient reductions in response to the drug. The time course and other characteristics of palmitoylation reduction parallel those of METH-induced transport down-regulation, and a palmitoylation-deficient DAT mutant shows enhanced down-regulation to METH, supporting a mechanistic link between reduction of the modification and reduced reuptake activity. Recovery rates differed, however, with palmitoylation returning to starting levels more rapidly than reuptake, indicating that down-regulation mechanisms remain engaged with transporters that have undergone repalmitoylation. These results support palmitoylation as a rapid response mechanism that modulates the entry of DAT into METH-induced down-regulation states and suggest a broader role for the modification in control of reuptake in additional physiological and pathophysiological conditions.

Clinical evidence demonstrates that induction differentiation therapy is a useful treatment strategy for melanoma. Circular RNAs (circRNAs) plays a crucial role in melanoma cell proliferation, resistance and metastasis. However, the roles of circRNAs during melanoma cell differentiation have not been fully investigated. This study aimed to investigate the role and mechanism of circSipa1l1 in melanoma cell differentiation.

Iron homeostasis is essential for fundamental biological processes, yet its impact on epigenetic aging and mortality remains poorly understood. This study aimed to investigate associations between dietary iron intake and DNA methylation (DNAm) aging markers and to determine whether these epigenetic signatures mediate iron's effects on mortality outcomes.

NaCl up-regulates ion transporters to accelerate Na and Cd to the shoots and Cd into vacuoles, shifts intracellular homeostasis to lower Cd toxicity, and promotes YCF1/2-driven photosynthesis for faster organic-mass accumulation to relieve Cd stress. Due to the rapid development of industry and agriculture, heavy metals (HMs) pollution in saline soil has become increasingly severe. Suaeda salsa is a promising candidate for the phytoremediation of HMs in saline soils. In this study, we identified a pathway by which high salt concentrations enhance cadmium (Cd) tolerance in S. salsa. The results indicated that NaCl improved resistance to Cd by modulating the levels of proline and carbohydrates, particularly in the range of 100 to 200 mM NaCl. Roots, the main sink for Cd2+, immobilize the ion in the cell wall through cytoplasmic pathways and block its transmembrane transport. Moreover, NaCl significantly increased the Cd content in the cell wall while decreasing Cd accumulation in organelles and the soluble fraction. Notably, 100 and 150 mM NaCl were more effective in promoting the transport of Cd from roots to leaves, helping to alleviate Cd toxicity in Suaeda salsa. Furthermore, NaCl induced the transformation of Cd into a less toxic form, which was associated with higher water transport capacity and increased ion transportation-related proteins. Proteomic analysis indicated that under Cd stress, NaCl may maintain cellular osmotic homeostasis by up-regulating SOS1, NHX1 and HKT1, and may enhance the adaptability of plants to abiotic stress by up-regulating YCF1 and YCF2. Additionally, NaCl may maintain the reduction state of glutathione (GSH) by up-regulating CSD2 and PRXQ, which indirectly affects the chelation of HMs. This study may provide a sustainable approach for phytoremediation of HMs contaminated saline soil.

CD8+ T cells exert a significant effect in immune infiltration, drug resistance and cell survival in cancers, but the roles and mechanisms in skin cutaneous melanoma (SKCM) remain unclear. In the present study, prognostic biomarkers associated with CD8+ T cell subsets were screened, and the significance of CD8+ T cells in SKCM immunotherapy was explored by integrated single-cell RNA sequencing (scRNA-seq) and Bulk RNA sequencing (Bulk RNA-seq) analyses. Based on scRNA-seq analysis, CD8 + T cells were divided into two subgroups: CD8 + LAG3 + T cells and CD8 + LAG3-T cells. Cell-cell communication analysis revealed that both subsets closely interact with melanoma cells. Differential gene expression analysis showed that LAG3 was up-regulated in SKCM, and immune infiltration analysis showed that the survival prognosis was significantly better in the Score-High group than in the Score-Low group. Assay results demonstrated that both the LAG3 inhibitor ZYF0033 and the monoclonal antibody Miptenalimab significantly suppressed tumor proliferation and metastasis, while enhancing immune cell infiltration in murine models. This study revealed the functional heterogeneity of CD8 + T cells in SKCM and demonstrated that LAG3 inhibition suppresses tumor proliferation and metastasis. Moreover, reduced LAG3 expression significantly enhanced CD8 + T cell immune infiltration, highlighting the regulatory role of LAG3 in CD8 + T cell function within the tumor microenvironment. These findings provided further evidence that SKCM may be effectively treated by targeting LAG3.

The study presents the development of a small-molecule epigenetic regenerative therapy that combines a demethylating agent, zebularine, with retinoic acid, acting as a transcriptional activator, and an alginate carrier. Subcutaneously injected formulations based on 2% sodium alginate containing high loads of zebularine (240 mg/ml) and retinoic acid (0.8 mg/ml) promoted regenerative responses in a mouse model of ear pinna punch wound involving the restoration of tissue architecture, the growth of nerve and vessel networks, and extensive alterations in gene methylation and expression profiles with no adverse effects in the animals. Among the remarkable changes in global gene methylation are those in neurodevelopmental genes. In vitro studies showed rapid discharge of zebularine but not retinoic acid from the alginate formulations. Live ultrasound imaging demonstrated gradual absorption of the subcutaneously injected alginate formulations, which may explain the in vivo activity of retinoic acid following subcutaneous administration. Cell culture tests exhibited no significant cytotoxicity of the alginate formulations. The simplicity of composition, preparation, and administration of alginate-based drug formulations is a distinctive advantage. The effective induction of regenerative response, together with a high safety profile of subcutaneously administered pro-regenerative alginate formulations, opens the way to testing further regenerative therapies for hard-to-reach lesions.

Bipolar disorder (BD) is a complex psychiatric condition usually requiring long-term treatment. Lithium (Li) remains the most effective mood stabilizer for BD, yet it benefits only a subset of patients, and its precise mechanism of action remains elusive. Exome sequencing has identified AKAP11 (A-kinase anchoring protein 11) as a shared risk gene for BD and schizophrenia (SCZ). Given that both the AKAP11-Protein Kinase A (PKA) complex and Li target and inhibit Glycogen Synthase Kinase-3 beta (GSK3β), we hypothesize that Li may partially normalize the transcriptomic and/or epigenomic alterations observed in heterozygous AKAP11-knockout (Het-AKAP11-KO) iPSC-derived neurons. In this study, we employed genome-wide approaches to assess the effects of Li on the transcriptome and epigenome of human iPSC-derived Het-AKAP11-KO neuronal culture. We show that chronic Li treatment in this cellular model upregulates key pathways that were initially downregulated by Het-AKAP11-KO, several of which have also been reported as downregulated in synapses of BD and SCZ post-mortem brain tissues. Moreover, we demonstrated that Li treatment partially rescues certain transcriptomic alterations resulting from Het-AKAP11-KO, bringing them closer to the WT state. We suggest two possible mechanisms underlying these transcriptomic effects: (1) Li modulates histone H3K27ac levels at intergenic and intronic enhancers, influencing enhancer activity and transcription factor binding, and (2) Li enhances GSK3β serine 9 phosphorylation, impacting WNT/β-catenin signaling and downstream transcription. These findings underscore Li's potential as a therapeutic agent for BD and SCZ patients carrying AKAP11 loss-of-function variants or exhibiting similar pathway alterations to those observed in Het-AKAP11-KO models.

Acute mesenteric ischemia-reperfusion is a life-threatening condition that causes severe intestinal injury through oxidative stress, inflammation, and apoptosis. Despite its high mortality rate, no pharmacological treatment is currently available to reduce tissue damage. This study aimed to evaluate the therapeutic potential of phosphatidylserine in a rat model of mesenteric ischemia-reperfusion and to explore its underlying mechanisms, with particular focus on the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. Thirty-six male Wistar rats were randomly assigned into six groups: sham, ischemia-reperfusion, and phosphatidylserine-treated groups at doses of 10, 20, and 40 mg/kg. Ischemia was induced by clamping the superior mesenteric artery for 60 min, followed by 60 min of reperfusion. Phosphatidylserine or vehicle was administered intraperitoneally 15 min before reperfusion. Ileal tissues were collected for histopathological evaluation, measurement of malondialdehyde, interleukin-6, glutathione peroxidase and superoxide dismutase activity, analysis of tumor necrosis factor-alpha, BAX, B-cell lymphoma 2, and assessment of Akt and mTOR phosphorylation by western blot. Reverse and molecular docking studies were conducted to identify potential targets of phosphatidylserine. Phosphatidylserine at 40 mg/kg significantly improved intestinal injury and modulated oxidative, inflammatory, and apoptotic markers. The findings support involvement of Akt/mTOR pathway and suggest phosphatidylserine as a potential therapeutic candidate.

Multiple myeloma (MM) is an incurable plasma cell malignancy in which drug resistance remains a significant limitation to treatment. SKP2, the substrate-recognition component of the SCF-SKP2 ubiquitin-protein ligase complex, plays a critical role in the progression of various cancers, including MM. Targeting SKP2 as a therapeutic strategy offers a promising avenue for combating drug resistance in myeloma. Here, we show that SKP2 expression increases as the disease progresses from pre-myeloma to newly diagnosed and relapsed stages. Gene set enrichment analysis (GSEA) and immunoblotting further revealed that SKP2 inhibition by the preclinical chemical inhibitor SkpinC1 leads to decreased STAT3 inflammatory signalling and c-MYC expression in myeloma cells. When tested in SKP2-overexpressing cells, SkpinC1 retained the ability to reduce activated STAT3, c-MYC, and c-MAF protein levels to impair cell growth and induce apoptosis. Furthermore, SkpinC1 synergistically enhanced the sensitivity of patient myeloma samples to bortezomib. Taken together, these findings underline the potential of SKP2 inhibition to overcome drug resistance in MM.

Oleamide (cis-9-octadecenamide), a primary fatty acid amide derived from oleic acid, is well known in mammalian systems for its roles in neural and immune regulation. However, its function in plant immunity has remained unexplored. In this study, oleamide was identified as the major bioactive metabolite of Streptomyces lydicus JCK-6019 and was characterized as a novel plant resistance inducer (PRI) in cucumber. Although oleamide exhibited no direct antifungal activity against Fusarium oxysporum f. sp. cucumerinum and Rhizoctonia solani AG-4 in vitro, in vivo assays demonstrated strong disease suppression. Preventive application of oleamide achieved 66.28 % control of Fusarium wilt at 0.1 ng/mL, comparable to the commercial PRI Bion (69.77 %), and 80 % control of damping-off at 0.01 ng/mL, whereas Bion was ineffective. Physiological assays revealed that oleamide reduced malondialdehyde accumulation while enhancing peroxidase and polyphenol oxidase activities, indicating activation of antioxidant defense. Gene expression analysis further revealed upregulation of key defense-related genes (PR1, PR2, PR4, WRKY30, WRKY67, ERF003, peroxidase, and cellulose synthase), which are involved in salicylic acid and jasmonic acid/ethylene signaling, transcriptional regulation, reactive oxygen species metabolism, and cell wall strengthening. Collectively, these results indicate that oleamide primes cucumber defense responses rather than acting as a fungitoxic compound. To our knowledge, this is the first report identifying oleamide as a PRI effective against two major soil-borne cucumber diseases. Its nanogram-level efficacy, non-toxic nature, and capacity to activate plant immunity highlight its potential as an eco-friendly alternative to synthetic fungicides for sustainable crop protection.

Rhizoctonia solani anastomosis group (AG)-5 is the predominant pathogen inciting maize banded leaf and sheath blight in Shanxi province, China, for which the sensitivity baseline to thifluzamide has been established. However, no risk assessment of thifluzamide resistance in R. solani AG-5 has been conducted. Consequently, thifluzamide-resistant mutants of R. solani AG-5 were generated by combined UV irradiation and fungicide selection in the laboratory. Fitness, genetic stability, intracellular structures, and fitness-related differentially expressed genes were subsequently analyzed. Ten resistant mutants were obtained, all of which exhibited moderate-to-high resistance that remained stable for 20 generations. These mutants showed a subtle expansion in their optimal growth temperature and pH ranges as their resistance to thifluzamide increased. Despite this, they exhibited reduced mycelial growth, sclerotia production, melanin formation, and virulence, whereas sclerotia germination rates were higher than in the parental sensitive strain. The mutant Y94.4R maintained vacuole numbers and size post-thifluzamide treatment, whereas the sensitive strain Y94 exhibited vacuole disappearance. Compared to Y94 strain, the expression levels of Atg22, Vps45, Ktr1_3, Aha1, DnaJ, Hikeshi, and Stip1 gene were less upregulated (1.81-3.65 folds) in Y94.4R strain under thifluzamide stress. No amino-acid substitutions were detected in SdhA, SdhB, and SdhD subunits; however, alanine (A) at position 46 of SdhC subunit was replaced by threonine (T) in thifuzamide-resistant mutants. This study showed that the resistant mutants exhibited reduced ecological fitness and competitiveness, suggested that the observed fitness costs might partially support the durability of thifluzamide under field conditions, and provided candidate genes for future disease-management strategies.

Digitaria sanguinalis (L.) Scop is recognized as one of the most problematic agricultural weeds, with chemical control remaining a crucial management strategy. However, increased selection pressures have led to the emergence of resistant populations that reproduce and establish themselves as dominant communities, thereby severely jeopardizing crop yields. It is especially crucial to reveal the resistance mechanism of D.Sanguinalis, and the lack of weed histology resources has always been an obstacle to the study of resistance mechanism, nowadays, with the development of histology technology, the combination of multi-omics applied to the identification of weed resistance genes is becoming more and more perfect. In our previous study, we have preliminarily demonstrated that the resistance of D.Sanguinalis to ALS inhibitors is related to the increase of P450 enzyme activity. Here, we employed single-molecule real-time (SMRT) sequencing technology to obtain full-length transcripts of D. sanguinalis. Using DIA proteomics, we identified upregulated herbicide-metabolizing proteins, which were validated via PRM analysis. By integrating the transcriptomic and proteomic results, we identified CYP709B2 and CYP74B2 as key effector genes that mediate resistance in D. sanguinalis. We elucidated the resistance patterns and specific genes associated with D. sanguinalis, thereby enriching the bioinformatics resources available for this species and providing a foundation for herbicide-resistant weed management.

Pyroxasulfone has been widely used to control malignant weeds in wheat fields. However, differences in pyroxasulfone tolerance across wheat varieties warrant attention owing to their potential impact on food production security. In this study, 54 wheat varieties were collected for screening, and Yunong 922 with 6.01-fold higher tolerance than Zhengmai 1354 was identified. Ultra-performance liquid chromatography-mass spectrometry analysis revealed that Yunong 922 exhibited a significantly shorter degradation half-life of pyroxasulfone (5.03 days) than Zhengmai 1354 (7.02 days). The P450 inhibitor malathion and the glutathione S-transferase (GST) inhibitor NBD-Cl reduced the tolerance factor of Yunong 922 to pyroxasulfone from 6.01 to 1.44 and 1.16, respectively, with no significant difference in tolerance to pyroxasulfone compared with Zhengmai 1354. RNA-Seq transcriptome analysis was used to identify candidate genes that may confer metabolic tolerance to pyroxasulfone in wheat. Eight candidate genes (five P450 enzymes and three GSTs) exhibited significantly different expression levels between Yunong 922 and Zhengmai 1354, as validated by qRT-PCR. Pyroxasulfone tolerance in Yunong 922 is associated with the coordinated upregulation of CYP72A397, CYP72A14, and GSTDHAR1, each contributing approximately 33.7 %, 32.6 %, and 33.7 % to the dominant principal component 1 that accounts for 88.7 % of the explained variance. These results revealed that the faster degradation of pyroxasulfone observed in Yunong 922 could be linked to the higher expression of P450s and GSTs, though this relationship remains to be confirmed. This study also offers valuable insights into mechanisms underlying crop tolerance and informs the development of herbicide management strategies.

Tobacco mosaic virus (TMV) is a major pathogen of Solanaceae, threatening tobacco yield and quality. In this study, 12 compounds from Mikania micrantha were evaluated for their inhibitory effects on TMV using the half-leaf method and ID-ELISA assay. Compound 1 (Mikanolide) showed superior protective (63.43 %) and therapeutic (69.09 %) activities compared to other compounds and Ningnanmycin. It also exhibited inactivation (50.98 %) and proliferation inhibition (60.64 %) against TMV. Molecular docking revealed its binding to TMV-CP through hydrogen and hydrophobic bonds. Mechanistic analyses indicated that Mikanolide elevated chlorophyll contents, flavonoid and total phenol biosynthesis, and salicylic acid accumulation, thereby enhancing defense-related enzymatic activity. Transcriptome analyses showed increased expression of cell wall-related EXP and PG genes, as well as LYKs defense response genes, while suppressing LRR protein 66, Hsc70, BTB/POZ-TAZ, polygalacturonase, and expansins, indicating maintenance of cell wall integrity during TMV infection. RT-qPCR confirmed these results. In conclusion, Mikanolide enhances tobacco's resistance to TMV by inhibiting viral replication and proliferation and activating the plant's disease resistance signaling.

Sugarcane leaf scald, caused by Xanthomonas albilineans, is a significant bacterial disease that poses a substantial threat to global sugar production. The quorum-sensing (QS) system in X. albilineans presents a promising target for anti-virulence strategies. Here, we demonstrate that penicillic acid exhibits potent antibacterial activity against X. albilineans, with a minimum inhibitory concentration (MIC) of 6 μg/mL and an effective concentration for 50 % inhibition (EC₅₀) of 3.703 μg/mL. Transcriptome analysis, molecular docking, and surface plasmon resonance (SPR) confirmed that penicillic acid competitively binds the sensory histidine kinase RpfC, disrupting DSF-mediated QS signaling. At sub-inhibitory concentrations (½ MIC), penicillic acid significantly suppressed twitching, swimming, and swarming motility by downregulating genes associated with type IV pili, flagellar assembly, and chemotaxis. At full MIC, direct binding of penicillic acid to the FlgE and CheW proteins further impaired motility. These findings elucidate the molecular mechanism of penicillic acid and support its potential as a quorum-sensing inhibitor for biocontrol of sugarcane leaf scald.

The pepper plant, a member of the Solanaceae family, is widely cultivated and valued as an important spice in many dishes worldwide. Viruses cause significant damage to both the quality and quantity of pepper production, with cucumber mosaic virus (CMV) being particularly detrimental. Chitosan oligosaccharide (COS), a natural oligosaccharide derived from chitosan degradation, act as a plant immunity inducer. The present study aimed to verify the role of COS in inducing CMV resistance in capsicum and to explore its potential defense-related signaling pathways. The optimal condition for inducing resistance to CMV is 100 mg/L of COS pretreatment on day 5 of CMV inoculation. COS enhances the removal of harmful free radicals by increasing the activity of antioxidant enzymes including peroxidase (POD), catalase (CAT), superoxide dismutase (SOD), and phenylalanine ammonia-lyase (PAL). Concurrently, COS treatment can increase the increases chlorophyll content. Additionally, COS upregulates the expression of defense-related genes (such as NPR1, PR1, PR5, PR10, CAT, POD, SOD, PAL, and LOX), which contribute to pepper resistance against CMV. Proteomic analysis revealed that COS induces resistance in capsicum by activating the calcium signaling pathway. Taken together, these data indicate that COS enhances capsicum's innate immunity against CMV through the salicylic acid pathway in combination with calcium signaling. This study sheds light on the effects of COS and its signaling mechanisms in plant viral immunity and offers a foundation for the discovery of novel antiviral agents and further mechanistic studies.