Temozolomide (TMZ) based chemotherapy remains the standard frontline treatment for advanced pancreatic neuroendocrine tumors (PNETs). However, the therapeutic efficacy is frequently compromised by primary or acquired resistance, and the underlying mechanisms beyond MGMT expression remain poorly understood. In this study, we identify acetyl coenzyme A synthetase 2 (ACSS2) as a critical driver of TMZ resistance in PNETs through a metabolic epigenetic signaling axis. Integrated single-cell RNA sequencing and clinical cohort analyses reveal that ACSS2 is significantly upregulated in PNETs and positively correlates with a chemoresistant transcriptomic profile. Mechanistically, ACSS2 mediated acetate metabolism facilitates histone hyperacetylation, which directly promotes the transcription of BCL6, a potent transcriptional repressor. BCL6 in turn binds to the promoter of the master tumor suppressor TP53 and silences its expression, thereby bypassing TMZ induced G2/M arrest and suppressing apoptosis. Pharmacological inhibition or genetic ablation of the ACSS2/BCL6 axis restores P53 mediated DNA damage response and re-sensitizes PNET cells to TMZ. Notably, combined treatment with an ACSS2 inhibitor and anti-PD1/L1 immunotherapy demonstrates superior synergistic efficacy in patient derived organoids and immunocompetent Rip1-Tag2 mice. This study delineates a non-redundant metabolic epigenetic barrier to chemotherapy and suggests that targeting the ACSS2/BCL6/P53 axis represents a promising strategy to overcome chemoresistance in PNET patients.

The increasing problem of antibiotic resistance over recent decades calls for alternative methods to reduce bacterial pathogenicity. Targeting quorum sensing (QS) is gaining attention as a promising alternative treatment. This study investigates the potential of plumbagin, a natural naphthoquinone derived from Plumbago species, to inhibit quorum sensing and biofilm formation in Chromobacterium violaceum using both in vitro and in silico methods. In vitro assays revealed that sub-minimum inhibitory concentrations of plumbagin significantly suppressed QS-regulated traits compared to controls. These included a reduction in violacein production by up to 40%, exopolysaccharide levels by up to 30%, and swarming motility and biofilm formation, which were reduced by up to 40%. Quantitative real-time PCR analysis demonstrated that plumbagin (at 2.42 μg/ml, corresponding to 1/4th MIC) decreases the expression of key QS genes (with relative fold changes of 0.36 ± 0.06, 0.35 ± 0.06, and 0.18 ± 0.01 for cviI, cviR, and vioA, respectively), indicating interference with bacterial communication pathways. Furthermore, the hemocompatibility assay demonstrated that the plumbagin concentrations used in this study are safe. Complementary in-silico molecular docking and dynamic simulations confirmed stable interactions between plumbagin and the QS regulatory protein CviR, suggesting its plausible mechanism of action. These results highlight plumbagin as a promising anti-QS agent that could be developed into alternative antibacterial therapies.

Acetylation, a key post-translational modification, is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among HDACs, HDAC6-a class II deacetylase with predominant cytoplasmic localization-plays a unique role in cellular processes that extend beyond histone modification. It is ubiquitously expressed throughout the central and peripheral nervous systems and is integral to key physiological functions including protein quality control, autophagy, mitochondrial transport, and oxidative stress responses. Notably, under pathological conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and peripheral nerve injury, HDAC6 undergoes nuclear translocation and contributes to epigenetic dysregulation by modulating the transcription of genes such as brain-derived neurotrophic factor, thereby impairing synaptic integrity and function. This dual role-cytoplasmic in protein homeostasis and nuclear in transcriptional regulation-highlights the HDAC6 paradox in neurological disorders. This review summarizes recent understanding of HDAC6's structure, expression, and functions within the nervous system, and discuss how targeting HDAC6 with selective inhibitors offers a promising therapeutic strategy for mitigating neurological disease pathogenesis. The goal is to provide insights that bridge HDAC6's roles in protein quality control and epigenetic regulation, fostering further exploration of HDAC6 inhibition in neurologic therapeutics.

Classic heat stroke (CHS) results from prolonged exposure to high environmental temperatures without physical exertion. However, the involvement of α7 nicotinic acetylcholine receptors (α7nAChR) in CHS-associated neurobehavioral abnormalities remains unclear.

Methyl jasmonate (MeJA) regulates climacteric fruit ripening, but its non-climacteric grape mechanisms are unclear. We treated 'Zhuosexiang' (V. vinifera L. × V. labruscana Bailey) grapes with MeJA at pre-veraison, tracking physiology, hormones, metabolites and transcripts. The results show that treated berries ripened faster, as shown by earlier color break and higher sugar content. MeJA triggered a transient spike in jasmonic acid-isoleucine (JA-Ile) at veraison, followed by a decline, while abscisic acid (ABA) increased gradually and remained at high levels. Weighted gene co-expression network analysis (WGCNA) identified a hub gene, VlWRKY71, which binds W-box motifs in the promoter of VlDXS1. VlWRKY71 expression correlated with JA-biosynthetic VlLOX1/VlOPR3, suggesting a JA feedback loop. Overall, VlWRKY71 links MeJA perception to terpene production and ripening.

Endometritis in dairy cows is a common reproductive disease that severely affects reproductive performance and milk production, resulting in significant economic losses. Lipopolysaccharide (LPS) as a PAMP capable of inducing inflammatory responses in the endometrium through the NF-κB pathway. Interferon-tau (IFN-τ) is a type I interferon with significant anti-inflammatory properties. Currently, transcriptomics sequencing technology has gradually become an attractive tool for studying such diseases. This study established an inflammatory model of bovine endometrial cells (BENDs) using LPS induction and employed RNA-seq technology to investigate the expression profiles of mRNAs in BENDs from the Control group (C), the LPS-treated group (L), and the IFN-τ + LPS-treated group (F). The results showed that there were 109, 1109, and 962 Differentially Expressed mRNAs (DEmRNAs) in the C vs L, C vs F, and L vs F. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that these DEmRNAs were mainly involved in the regulation of host immune responses (e.g., NOD-like receptor signaling pathway, IL-17 signaling pathway and RIG-I-like receptor signaling pathway, NF-kappa B signaling pathway), signal transduction molecules and interactions (e.g., Cytokine-cytokine receptor interaction; Cell adhesion molecules), metabolic process (e.g., Glycosphingolipid biosynthesis-lacto and neolacto series) and Antigen processing and presentation, Complement and coagulation cascades, Th17 cell differentiation, etc. biological process. This study not only elucidates the molecular mechanisms by which BENDs respond to microbial invasion but also reveals the specific regulatory network through which IFN-τ exerts its anti-inflammatory effects via multiple synergistic pathways. It provides crucial theoretical support for the clinical application of interferon therapy in treating endometritis, demonstrating significant research value and promising applications.

The B. juncea cv. BJ was more tolerant of Cd than the cv. JTN, and exhibited a strong tolerance to Cd via regulating antioxidant systems, sulfur metabolism, and the glutathione biosynthesis pathway. The findings offer a strategy for cultivar selection in Cd-contaminated soil phytoremediation. Cadmium (Cd) is considered one of the most poisonous metallic elements in the environment, posing a considerable threat to plant growth and productivity. Brassica juncea is anticipated to be a candidate plant for the phytoremediation of Cd contamination. In this study, different cultivars of B. juncea were used to elucidate the molecular mechanisms underlying the greater Cd tolerance of BJ (Cd tolerant) compared to JTN (Cd sensitive) by examining growth, antioxidant enzyme activity, non-enzymatic antioxidant content, and Cd transport. The results showed that BJ effectively mitigated the reduction in biomass, cell viability, and photosynthetic pigment levels, as well as the increase in malondialdehyde content and relative conductivity, in comparison with JTN. Furthermore, BJ exhibited enhanced antioxidant enzyme activities and augmented levels of non-enzymatic antioxidants. A total of 11,774 differentially expressed genes were discovered between BJ and JTN. Notably, there was a rise in the expression levels of adenosine 5'-phosphosulfate kinases (APK) genes (APK1 and APK4) and glutathione (GSH) synthetase genes (GSH1 and GSH2) linked to ATP production in the sulfur metabolic pathway and GSH synthesis pathway. Conversely, there was a decrease in the relative expression levels of ATP sulfurylase (ATPS) genes (APS1, APS2, and APS4), which regulate sulfate-activating functions and enzymatic activities associated with the GSH pathway intended to alleviate Cd stress.

Ziziphora clinopodioides Lam., a valuable medicinal plant, exhibits significant potential for flavonoid production, which significantly contributes to its therapeutic properties. In the initial phase of this ongoing study, phenolic derivatives were analyzed in 13 populations during two vegetative growth stages under greenhouse conditions. In the next phase, the effects of precursors [phenylalanine (Phe) and naringenin (Nar)], biotic elicitor [yeast extract (YE)], and abiotic elicitors [salicylic acid (SA) and methyl jasmonate (MeJA)] were evaluated on the accumulation of specific flavonoids and phenolic acids in a selected population. Younger plants (2-MO growth stage) exhibited higher phenolic content than older ones (5-MO growth stage). Selected populations (P1, P4, P5, and P10 for shoots; P4, P8, P11, and P13 for roots) were subjected to further LC-MS/MS analysis, revealing that P5 shoots had the highest potential for producing quercetin (QUE), rutin (RUT), and apigenin (API). Treatment with 5 mM Phe resulted in its highest level in 96 h post-treatment, reaching 3.49- and 6.66-fold higher levels than the control, respectively. Nar at concentrations of 0.4- and 0.8-mM enhanced API and QUE production by 1.91- and 3.28-fold, respectively. YE notably increased API and ACA (acacetin) levels, while SA resulted in the highest accumulation of QUE and RUT, highlighting its crucial role in flavonol biosynthesis. YE and Nar significantly enhanced FNSII gene expression, with Nar being the most effective. This makes Nar an effective candidate for increasing flavonoid production in Z. clinopodioides. This finding may have important implications for industries seeking to elevate flavonoid content, particularly the medicinal compound ACA, in plant-based products.

Paclitaxel (PTX) resistance limits cervical cancer therapy. Ferroptosis suppression via GPX4 and redox remodeling has emerged as a resistance mechanism, but upstream regulators remain unclear. To determine whether ANO6 drives PTX resistance by inhibiting ferroptosis and to define the ANO6-GPX4 axis mechanistically and therapeutically. Transcriptomic analyses, immunohistochemistry on clinical specimens, and cervical cancer cell models with gain/loss of ANO6 were combined with ferroptosis assays, mitochondrial imaging, apoptosis/viability assays, and Co-IP/CHX chase to assess ANO6-GPX4 interaction and stability. GPX4 transcriptional control was probed by ChIP-qPCR and dual-luciferase. PTX sensitivity was tested in vitro and in xenografts, with or without the ferroptosis inducer RSL3. ANO6 was overexpressed in cervical cancer and associated with worse prognosis. ANO6 knockdown reduced GPX4, SLC7A11, and NRF2, increased ACSL4, elevated lipid peroxidation and iron load, disrupted mitochondrial integrity, and heightened PTX cytotoxicity; ANO6 overexpression had opposite effects. ANO6 physically associated with GPX4 and preserved its protein stability; NRF2 enhanced GPX4 promoter activity, supporting a dual (post-translational/transcriptional) maintenance of GPX4 under ANO6 control. In PTX-resistant cells, ANO6 was upregulated; its depletion restored ferroptosis and PTX sensitivity, whereas GPX4 overexpression rescued resistance. In vivo, ANO6 overexpression promoted tumor growth and PTX resistance, while PTX + RSL3 synergistically suppressed tumors and reversed GPX4-axis signaling. ANO6 confers PTX resistance by sustaining GPX4-dependent ferroptosis evasion and mitochondrial homeostasis. Targeting the ANO-GPX4 axis, alone or combined with ferroptosis induction, may improve chemotherapy sensitivity in cervical cancer.

Foliar application of silicon nanoparticles (SiNPs) is a promising strategy for mitigating cadmium (Cd) contamination in rice; however, the systemic mechanisms remain poorly understood. Here, we reveal that foliar SiNPs activate a coordinated defense orchestrated by jasmonate (JA) signaling. 100 mg/L SiNPs reduced grain Cd by 66.58% and increased yield by 38.14%. Driven by this systemic regulation, the defense manifests in two dimensions: (1) internally, SiNP-activated JA signaling promoted Cd sequestration in leaf hemicellulose 2 fraction by 8.94% and regulated key transporter genes (upregulation of OsHMA3; downregulation of OsNramp1, OsZIP1, and OsZIP7); and (2) externally, this shoot-to-root signaling induced rhizosphere metabolic reprogramming (accumulation of secondary metabolites, lipids, and fatty acids) and recruited functional microbes (Desulfovibrio, Gallionellaceae, and Bacillus), resulting in a 17.02% reduction in bioavailable Cd via enriched oxygen-containing functional groups in soil. This work elucidates a novel biogeochemical framework for developing nanotechnology-based strategies for safe rice production in Cd-contaminated fields.

Imeglimin (IME) is a novel oral anti-diabetic agent with a similar chemical structure to metformin, which has shown broad-spectrum anti-tumor activity. However, the activity of imeglimin on tumor cells remains unclear. This study investigated the effects of IME on multiple myeloma (MM) cells and explored the underlying mechanisms.

The widespread occurrence of ibuprofen in aquatic environments poses potential risks to aquatic organisms. This investigation employed a multigenerational exposure approach to address the transgenerational toxicity of ibuprofen in Daphnia magna across an environmentally observed to upper end concentration range (0.5-500 μg/L). The experimental design encompassed direct F0 exposure, continuous exposure until F3 (F3C), and cessation-of-exposure in F3 (F3R). Ibuprofen exposure significantly compromised growth and reproductive capacity of Daphnia magna, induced morphological deformities including tail spine curvature and eyes abnormalities, impaired swimming behavior like the decreased speed and distance. In particularly, these adverse effects persisted across generations, manifesting in both F3C and F3R lineages. The investigations revealed that ibuprofen disrupted endocrine signaling pathways critical for molting and reproduction (EcR, CYP314, VTG) through COX inhibition, alongside mitochondrial dynamic imbalance and oxidative stress. Whole-genome bisulfite sequencing demonstrated generation-specific DNA methylation patterns: widespread epigenetic disruption in F0, "adaptive reprogramming" in F3C, and "transgenerational imprinting" in F3R. Differential methylation in key pathways (FOXO signaling, autophagy, actin organization) provided compelling epigenetic evidence for the observed transgenerational toxicity. Overall, the results indicated that measurable adverse effects can occur at environmentally realistic concentrations (0.5-5 μg/L), whereas mechanistic and epigenetic signatures were most evident under upper-end/hotspot scenario exposure (50-500 μg/L), highlighting the value of incorporating multigenerational assessments into ecological risk evaluation frameworks.

Histamine H2 receptor (HRH2) is a key mediator of histamine signaling, regulating gastric acid secretion and contributing to immune modulation. Naringenin chalcone is a natural chalcone compound and an important synthetic intermediate. Previous work showed that naringenin chalcone binds HRH2 and suppresses HRH2-induced cAMP production. Here, we used RNA sequencing to characterize transcriptomic and alternative splicing changes triggered by HRH2 activation and to assess how these responses are modulated by naringenin chalcone. HRH2 activation by histamine induced 11,507 differentially expressed genes (DEGs), primarily enriched in cytoplasmic translation and oxidative phosphorylation. Low-dose naringenin chalcone shifted enrichment toward centriole assembly and synaptic signaling, whereas high-dose treatment produced patterns similar to histamine alone, suggesting concentration-dependent effects. Compared with histamine alone, high-dose naringenin chalcone altered the expressions of 2794 genes, strongly enriched in RNA-splicing-related processes. We further analyzed genes with differential transcript usage (gDTUs). Under histamine treatment, gDTUs were enriched in nuclear matrix and histone methyltransferase activity, while naringenin chalcone redirected enrichment toward RNA splicing and its regulation, a pattern consistent with the DEG-based results. When compared with baseline 293T cells, over 60% of gDTUs overlapped with DEGs; however, when examining the specific influence of naringenin chalcone, the overlap dropped below 20%. These findings suggest that naringenin chalcone differentially affects gene expression and alternative splicing, although these regulatory layers may converge on related biological outcomes. Overall, our study provides new insights into the molecular interplay between naringenin chalcone and HRH2 and offers a reference for further mechanistic investigation.

Heavy metal-induced stress is an abiotic form of stress that significantly restricts crop yield and quality. This stress affects plants at all stages, but they are particularly vulnerable as seedlings, when it can directly influence later growth and development. Cd2+ is an important heavy metal stressor and negatively influences plant growth. However, the regulation mechanism underlying Cd2+ stress resistance has not been adequately elucidated, especially in major cultivars, which restricts the application of Cd2+ resistance. Here, exogenously applied melatonin (N-acetyl-5-methoxytryptamine) was tested on rice seedlings as a practical solution to enhance the plants' stress tolerance. The modern variety Longjing 203 was used for the experiments due to its extensive cultivation in Heilongjiang Province, China. Seedlings were treated with 50μMol/L CdCl2 and 100μMol/L exogenous melatonin to investigate the molecular mechanism underlying exogenous melatonin's ability to enhance Cd2+ tolerance. The results revealed that Cd2+-induced stress limited growth, while melatonin alleviated the stress-induced damage on seedlings. Specifically, differentially expressed gene (DEGs) analysis showed that the phenylpropanoid biosynthesis pathway was enriched in plants treated with melatonin, which was also verified by qRT-PCR, enriched enzyme activity assays, and molecular docking. Also, the results of lignin content and Cd2+ distribution in subcellular compartments indicated that melatonin promoted lignin accumulation and intercepted Cd2+ into the cell wall, limiting influx into organelles and the cytoplasm. Then, the group of applied melatonin had shown to enhance stress tolerance by reducing DNA damage, as evidenced by the DNA cross-linking, 8-hydroxy-20-deoxyguanine levels, relative density of apurinic sites, and random amplified polymorphic DNA (RAPD) analysis. These findings also revealed that exogenous melatonin relieved cellular damage caused by Cd2+ by reinforcing the cell wall lignin barrier to regulate cellular homeostasis.

Dravet syndrome is a severe developmental and epileptic encephalopathy caused primarily by SCN1A haploinsufficiency. Risks of sudden unexpected death in epilepsy and cognitive deficits are higher among patients with this syndrome than in the general population with epilepsy. The effects of zorevunersen, an antisense oligonucleotide designed to up-regulate NaV1.1 sodium channels, in patients with Dravet syndrome are not known.

Ventral hippocampus (vHPC) CA1 pyramidal neurons send glutamatergic projections to nucleus accumbens (NAc), and this vHPC-NAc circuit mediates cocaine seeking and reward, but it is unclear whether vHPC-NAc neuron properties are modulated by cocaine exposure to drive subsequent behavior. The immediate early gene transcription factor FosB/ΔFosB is induced throughout the brain by cocaine and is critical for cocaine seeking, but its function in vHPC-NAc neurons is not understood. We now show that circuit-specific knockout of FosB/ΔFosB in vHPC-NAc neurons impaired cocaine reward expression and forced abstinence-induced seeking. We also found that vHPC-NAc excitability was decreased by experimenter-administered repeated cocaine and cocaine self-administration, and this cocaine-induced excitability decrease was mediated by ΔFosB expression. To uncover the mechanism of this change in circuit function, we used circuit-specific translating ribosome affinity purification to assess cocaine-induced, FosB/ΔFosB-dependent changes in gene expression in vHPC-NAc. We found that cocaine causes a FosB/ΔFosB-dependent increase in the expression of calreticulin, an endoplasmic reticulum-resident calcium-buffering protein. Calreticulin expression mediated vHPC-NAc excitability and was necessary for cocaine reward. These findings uncover a noncanonical mechanism by which cocaine increases calreticulin in vHPC leading to decreased vHPC-NAc excitability and drives cocaine seeking and reward.

Binding of GLP-1 to its receptor in pancreatic beta cells triggers activation of the cAMP pathway and phosphorylation of CREB, leading to induction of cellular target genes containing CREB binding sites. By contrast with their acute effects on beta cell gene expression, chronic exposure of beta cells to stable GLP-1 analogs like Exendin-4 stimulates sustained expression of beta cell-specific genes, leading to increases in beta cell viability and insulin secretion. In a proteomic screen for transcriptional coregulators that contribute to the transcriptional effects of GLP-1, we identified Med14, the scaffolding subunit of the conserved 30 subunit Mediator complex. Exposure to Exendin-4 and other GLP-1 receptor agonists stimulates sustained phosphorylation of Med14 at Ser983, which corresponds to a conserved PKA recognition site. Mutation of Med14 at Ser983 blocked Exendin-4 effects on cellular gene expression by interfering with CREB-mediated activation of beta cell-specific enhancers. Med14 mutation results in higher alpha-to-beta cell ratios and blunted gene regulation in response to Exendin-4 in Ser983-mutant primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.

Fomesafen, a diphenyl ether herbicide, imposes severe phytotoxicity on a certain plant through soil residues. To clarify the phytotoxicity mechanism of fomesafen residues on subsequent sugar beet and the mitigation the basis of biochar, this study was conducted on sugar beet (Beta vulgaris L.), a sensitive subsequent crop. At 0.025 mg kg-1, it reduced biomass by 61.79%, specific leaf weight by 33.34%, chlorophyll a and b by 14.88% and 45.23%, and photosynthetic performance (PIABS) by 22.28%, while increasing DIo/RC by 5.80%. Net photosynthetic rate declined by 28.73%, with leaf deformities, yellowing, and oxidative stress indicated by superoxide, hydrogen peroxide, antioxidant enzyme activation, and 95.14% higher malondialdehyde. Biochar (1%) alleviated toxicity by upregulating psbA genes, enhancing glutathione and proline metabolism (BVRB_9g206010, BVRB_2g025900), and improving stress resistance. This study reveals the mechanisms of fomesafen-induced photosynthetic inhibition and oxidative damage, and biochar's mitigation potential, providing guidance for residue management in rotation systems; future research will integrate field pesticide metabolism analysis and conduct field trials to verify the effect.

Merremia tridentata of the Convolvulaceae family exhibits multiple therapeutic properties and is commonly utilized in ethnomedicine. The anti-cancerous property of M. tridentata ethyl acetate extract (MtEAE) was evaluated in HepG2 hepatocellular carcinoma cells. Cytotoxicity was assessed using the MTT assay in a dose-dependent manner with an IC50 value of 57.55 µg/mL. The PI and AO/EB staining revealed membrane damage and stimulation of cell death in treated cells. DNA damage was visualized by DAPI staining in treated cells. The Rhodamine 123 detects the mitochondrial membrane damage of the cells treated with MtEAE. The intracellular ROS distribution was assessed with DCFH-DA staining. The cell migration assay indicated suppression of cell migratory ability. Gene expression analysis showed augmented expression of p53 and BAX, a pro-apoptotic gene, along with downregulation of BCL-2, an anti-apoptotic gene indicating the induction of apoptosis. The hepatocellular carcinoma biomarker PCNA was downregulated causing inhibition of cell proliferation. Cell cycle analysis showed 71.82% of cells in the G0/G1 phase and it decreases further, confirming cell cycle arrest. These findings demonstrate that M. tridentata extract exerts potent anticancer activity by inducing apoptosis and inhibiting proliferation in HepG2 cells.

Cervical cancer remains one of the most prevalent gynecological malignancies worldwide, and therapeutic resistance continues to limit the effectiveness of current treatment strategies. Aldehyde dehydrogenase 1 (ALDH1) has been associated with chemoresistance and cellular stress responses in cervical cancer, while bromodomain and extraterminal (BET) proteins have emerged as regulators of transcriptional and epigenetic programs involved in tumor progression. In this study, we investigated whether BET inhibition by JQ1 modulates cellular responses to temozolomide (TMZ) in cervical cancer cells.