Interleukin-6 (IL-6) is a central mediator of chronic low-grade inflammation associated with metabolic disease. Because obesity is characterized by elevated circulating insulin and metabolic endotoxemia, we investigated whether insulin modulates lipopolysaccharide (LPS) induced IL-6 expression in adipocytes and examined the underlying epigenetic mechanisms. Insulin priming markedly enhanced LPS-induced Il6 mRNA expression (25.33 ± 0.833-fold) and protein levels (181.8 ± 2.754 pg/ml) in 3T3-L1 mouse adipocytes. Similar synergistic effects were observed in primary mouse (Il6 mRNA; 1.364 ± 0.287-fold and protein; 298.6 ± 13.79-pg/ml) and human adipocytes (Il6 mRNA; 12.99 ± 0.912-fold and protein; 1441 ± 68.69-pg/ml). In vivo, mice treated with insulin followed by LPS exposure exhibited significantly higher Il6 expression in peripheral blood mononuclear cells and adipose tissue compared to either treatment alone. Pharmacological inhibition of PI3K signaling suppressed this effect and AKT phosphorylation. Mechanistically, epigenetic profiling revealed that insulin increased histone H3 lysine 9 acetylation (H3K9ac), an active chromatin marker, in a PI3K-dependent manner. Chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) analysis demonstrated an enhanced H3K9 acetylation at the NF-κB and CREB loci at the distal region and CREB/NF-IL6 locus at the proximal region of the Il6 promoter following combined insulin and LPS stimulation; this effect was significantly attenuated upon blockade of insulin signaling. This synergistic induction was dependent on H3K9 acetylation, indicating that metabolic and inflammatory signals converge at the Il6 promoter to promote chromatin remodeling and transcriptional co-activator recruitment. Collectively, these findings demonstrate that insulin synergizes with LPS to amplify IL-6 mediated inflammation in adipocytes through epigenetic remodeling of the Il6 locus, linking hyperinsulinemia to chronic inflammation in obesity and insulin resistance.

The SaeRS two-component system is a major virulence regulator in Staphylococcus aureus, and its sensor kinase SaeS represents a potential target for small-molecule intervention.

Recent evidence indicates that Coxsackievirus B3 (CVB3) infection, a common cause of viral myocarditis, triggers the nuclear translocation of transcription factor EB (TFEB) through a mechanism dependent on the serine/threonine phosphatase Protein Phosphatase 3 (PPP3)/calcineurin, independent of its cleavage. Tacrolimus (TAC), a calcineurin inhibitor widely used in immunosuppressive therapy for cardiovascular conditions such as myocarditis and post-transplant vasculopathy, may modulate TFEB activity in this context. This study investigated the effect of TAC on TFEB regulation during CVB3 infection in HeLa cells. Our results demonstrate that TAC significantly suppresses both the nuclear accumulation and transcriptional activity of TFEB. Conversely, knockdown of Protein Phosphatase 3 Catalytic Subunit (PPP3C) enhances TFEB protein expression and its nuclear localization, indicating that TAC calcineurin-dependent mechanism beyond simple enzymatic inhibition. Moreover, TAC similarly inhibits the nuclear expression and transcriptional activity of both Δ60-TFEB (a cleavage fragment lacking the first 60 amino acids) and TFEBQS60LP (cleavage-resistant mutant). Knockdown of PPP3C leads to increased nuclear distribution of these TFEB variants, confirming that TAC targets PPP3/calcineurin to regulate TFEB and its modified forms. These findings suggest that TAC interferes with the CVB3-induced activation of TFEB, thereby influencing cellular autophagy and viral replication. Importantly, TAC treatment attenuates CVB3-induced autophagic response and reduces viral protein expression and RNA levels in infected cells. Collectively, this study reveals a novel role for TAC in modulating TFEB subcellular localization and activity in the context of CVB3 infection, with potential implications for the pharmacological management of viral myocarditis and associated cardiovascular pathologies.

Breast cancer remains a major global health burden, and environmental endocrine-disrupting chemicals may contribute to breast-cancer-related phenotypes. Methyl-4-hydroxybenzoate (MEP; methylparaben) is a widely used preservative with reported weak estrogenic activity, but its molecular association with breast cancer remains incompletely defined. In this study, we used an integrative exploratory framework combining target prediction, breast-cancer expression datasets, protein-protein interaction analysis, functional enrichment, single-cell transcriptomic signature analysis, molecular docking, molecular dynamics simulation, and in vitro assays. Target prediction identified 1067 putative MEP-associated candidates. Integration with breast-cancer-associated gene sets and GEO-derived differentially expressed genes yielded 29 shared genes, from which EGFR, TYMS, EZH2, CDK1, and BIRC5 emerged as highly connected network nodes. Enrichment analyses implicated cell-cycle-related and cancer-associated pathways. Single-cell analyses were revised to describe MEP-target-signature-high and MEP-target-signature-low cell groups rather than direct measurement of MEP as a transcript. Docking and molecular dynamics analyses suggested potential binding and structural stability for selected MEP-protein complexes; however, these computational data were interpreted as evidence of putative association rather than direct kinase activation. In vitro assays and transcriptomic profiling suggested that MEP exposure was associated with altered proliferation-related phenotypes and cell-cycle transcriptional programs. Overall, the findings support a hypothesis-generating model in which MEP is associated with breast-cancer-relevant transcriptional and signaling alterations, while further direct mechanistic validation, including CDK1 activity, loss-of-function, rescue, and in vivo studies, is required.

Drought and salt stresses impose serious effects on plant proliferation and development, with multiple categories of transcription factors (TFs) playing important regulatory effects in modulation stress reaction. In this study, the apple R2R3 MYB TF, MdMYB73L, was cloned and characterized its role in conferring abiotic stress tolerance. Firstly, expression assays demonstrated that the transcript levels of MdMYB TFs changed substantially under salt and drought stresses. Subsequently, MdMYB73L-overexpressing transgenic Arabidopsis, apple calli and tomato plants all showed increased sensitivity to salt and drought treatments, manifesting as short roots and severe growth inhibition compared to controls. These results demonstrate that MdMYB73L functions as a key negative regulator in the response to drought and salt stresses. Overall, these research not only demonstrate the specific function of a MYB TF in stress responses but also provide a crucial framework for elucidating the broader effects of the apple MYB family in abiotic stress tolerance.

Gymnema (G.) inodorum is a medicinal plant with anti-diabetic, anti-obesity, and anti-inflammatory properties traditionally consumed as tea in Southeast Asia. While bioactive stephanosides and gymnemic acids suppress adipocyte differentiation, their effects on skeletal muscle metabolism and circadian regulation remain unclear. This study investigated the effects of gymnemic acid (GiA-7) and stephanosides B and C in differentiated C2C12 myotubes.

Depending on the nitrogen (N) form available to roots, plants activate different transcriptional and metabolic pathways; this can consequently translate into differences in the composition and release of root exudates. To address the existing knowledge gap regarding the relationship between the availability of Iron (Fe) and different N forms applied (nitrate, ammonium, or urea), the molecular mechanisms activated by plants to promote their acquisition have been investigated using omics data integration ("exudomic" × transcriptomic analyses). The transcriptomic and metabolomic analyses reveal a strong crosstalk among nutritional pathways, showing that tomato root responses to Fe resupply depend on the nitrogen form provided. Transcriptomic profiles after 4 h indicate similar responses under urea and ammonium, a trend also observed at the exudomic level after 24 h. Distinct molecular features emerged depending on the specific N form applied. In particular, Fe resupply with urea induced the upregulation of the expression of FER and bHLH66, moderately enhancing the Fe level in roots. Overall, integrated omics data highlight a complex network of transcription factors, metabolites, and transporters that may contribute to improved plant resilience under nutrient stress, such as transcription factors (bHLH, MYB, ZAT12), transporters (UMAMITs, MATEs) and a proteolytic regulator of a phenylpropanoid enzyme (KFB-PAL). Within the framework of sustainable agriculture, this study corroborates the occurrence of a strong interplay between Fe- and N-nutritional pathways and emphasizes how different N forms can modulate root exudation in the rhizosphere, thereby enhancing the uptake of other essential nutrients such as Fe.

Quorum sensing (QS) is widely involved in the regulation of the biological functions and pathogenic processes of bacteria in a cell density-dependent manner. The anthranilic acid signal is directly sensed by the receptor RaaR, a transcription regulator, to control the expression level of downstream target genes in Ralstonia solanacearum, thus affecting the QS signals generation and the bacterial virulence. Here, we reported that 4-Aminobenzoic acid (PABA), a structural analogue of anthranilic acid, not only significantly inhibited the production of extracellular polysaccharides (EPS), biofilm formation, and motility of R. solanacearum, but also reduced the expression level of QS signaling molecules. We also found that PABA can directly bind to RaaR and prevented it from interacting with the promoters of target genes associated with the QS system and virulence of R. solanacearum. Point mutations in RaaR at residues F137 and I270 abolished the binding between RaaR and PABA, indicating that these two amino acid residues are likely critical for the interaction between RaaR and PABA. These findings indicated that PABA could be a candidate inhibitor of anthranilic acid signaling to interfere with the QS systems of R. solanacearum to attenuate the virulence. Together, our work presented a non-antibiotic-based treatment strategy and provided a theoretical basis for the development of novel antibacterial treatment.

The aim of this study was to investigate key target(s), mechanism(s) from hepatoma cells in harsh doxorubicin-resistant conditions (DRCs) from GSE125180 datasets in GEO (Gene Expression Omnibus).

Aluminum toxicity severely limits crop productivity by disrupting nutrient balance, photosynthesis, and cellular redox homeostasis. Gamma aminobutyric acid (GABA) is an important signaling molecule involved in plant stress adaptation, but its role in regulating sulfur metabolism and antioxidant defense under aluminum stress remains poorly understood. This study investigated the impact of foliar application of GABA (100 μmol L-1) on aluminum tolerance in Camelina sativa exposed to Al stress (50 mg kg-1 soil Al) using controlled experiments and naturally aluminum-contaminated mining soil. GABA application significantly improved plant performance by increasing plant height, biomass, root growth, photosynthetic pigments, and gas exchange parameters compared with Al-stressed plants. In addition, GABA enhanced antioxidant protection by increasing the activities of ascorbate peroxidase, catalase, peroxidase, and superoxide dismutase, while reducing reactive oxygen species accumulation and the malondialdehyde content by improving the redox balance. GABA treatment increased glutathione levels and the GSH/GSSG ratio, whereas the accumulation of oxidized glutathione and dehydroascorbic acid induced by aluminum stress decreased, indicating improved antioxidant recycling capacity. Furthermore, GABA restored sulfur metabolism by regulating cysteine, glucosinolate, glutathione S-transferase activity, and the expression of sulfur-related genes, including ST5a b c, CYP83A1, and BCAT4. Functional inhibitor experiments demonstrated that the protective role of GABA depends on calcium signaling and reactive oxygen species signaling pathways. Transcriptome analysis further revealed extensive regulation of genes involved in antioxidant defense and sulfur metabolism. These findings demonstrate that GABA enhances aluminum tolerance through coordinated regulation of sulfur metabolism, redox homeostasis, and stress signaling, providing new insights into sustainable strategies for improving crop resilience in aluminum-affected soils.

Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by tear film instability, inflammation, and epithelial injury, leading to discomfort and visual disturbance. Current treatments remain limited in efficacy and safety. A heparin-like glycosaminoglycan purified from the snail mucus of Achatina fulica (AFG) exhibits potential regenerative and anti-inflammatory properties. This study aimed to evaluate the therapeutic effectiveness and mechanism of AFG in DED.

Accurate prediction of cancer drug responses is essential for advancing cancer treatment strategies and drug development. With the increasing availability of large-scale pharmacogenomic datasets, many deep learning models have been proposed to predict cancer drug responses. However, many existing models lack the capacity to offer critical biomedical insights, such as providing interpretability regarding the potential mechanism of action.

Aging is accompanied by a decline in physiological function and increased vulnerability to disease, with mitochondrial dysfunction and epigenetic alterations recognized as key hallmarks. Nicotinamide riboside (NR), a vitamin B3 precursor to NAD+, and high-intensity interval training (HIIT) have both been proposed to ameliorate aging-related mitochondrial decline, but their effects on skeletal muscle epigenetic aging are not fully elucidated. Here, we assessed the impact of 5-month NR supplementation and 4-6 weeks HIIT on epigenetic age acceleration (EAA, via seven epigenetic clocks) in human skeletal muscle across three independent studies. NR supplementation was associated with reduced muscle EAA, particularly when measured with the PCHannum, MEAT, and DunedinPACE clocks, while HIIT produced opposite effects in some clocks, notably increasing pace of aging by DunedinPACE. Correlation analyses revealed that changes in skeletal muscle mitochondrial content correlated with changes in MEAT-derived EAA after NR and 6 weeks of HIIT. Together, these findings indicate that skeletal muscle epigenetic aging can be modulated by NR and HIIT interventions but in opposing directions, highlighting a potential link between mitochondrial abundance and epigenetic clocks. Further studies are warranted to clarify how NR and exercise regulate epigenetic aging. These results offer new insights into development of strategies for promoting epigenetic outcomes and healthy aging.

Ginsenoside RD2, a bioactive compound derived from ginseng, has been shown to possess various biological activities, including potential anti-cancer effects. However, its therapeutic efficacy and molecular mechanisms, particularly in gastric cancer (GC), remain inadequately understood.

Asynchronous floret opening hinders hybrid rice seed production, particularly between indica and japonica subspecies. Although jasmonate (JA) signaling regulates diurnal floret opening time (DFOT), the mechanism underlying structural changes in the lodicule as a swellable organ driving floret opening remains unclear. Here, we identified OsbHLH091 as a lodicule-specific transcription factor mediating JA-induced floret opening. The null mutants of OsbHLH091 exhibit cleistogamy (closed flowers) without defects in floral organ, while OsbHLH091 overexpression accelerates floral opening. Mechanistically, OsbHLH091 activates cell expansion genes, including EXPANSINs and CELLULOSE SYNTHASEs, and such activity is repressed by JAZ proteins, the JA signaling inhibitors. Increasing JA before anthesis degrades JAZs, which releases OsbHLH091 to trigger lodicule expansion. Natural variation in OsbHLH091 contributes to DFOT differences between subspecies: the japonica haplotype interacts more strongly with JAZs, thus delaying opening. Together, as a lodicule-specific regulator, OsbHLH091 not only reveals a previously unknown mechanism controlling floret opening but also provides a precise tool to synchronize DFOT across subspecies, enabling efficient indica-japonica hybrid breeding.

Prenatal exposure to cigarette smoke has been associated with adverse developmental outcomes and epigenetic alterations; however, the persistence of these effects across generations remains poorly understood. Using zebrafish (Danio rerio), we investigated whether developmental exposure to cigarette smoke total particulate matter (TPM) induces epigenetic changes in exposed larvae (F0) and their unexposed offspring (F1). Embryos were exposed to TPM (0.1, 0.2, or 0.3 μg/mL equi-nicotine units) from 6 to 96 h post fertilization (hpf). Transcript abundance of DNA methyl transferases, global methylation (5-methylcytosine content), and genome-wide methylation profiles were subsequently evaluated in F0 and F1 larvae. TPM exposure did not significantly alter transcript abundance of Dnmt1, Dnmt3a1, Dnmt3a2, Dnmt3b1, Dnmt3b2, or Dnmt3b3 in either generation. In contrast, global DNA methylation was significantly reduced in F0 TPM0.3 larvae, indicating concentration-dependent hypomethylation, whereas no significant differences were observed in F1 larvae. Genome-wide methylation analysis identified 5 and 4157 differentially methylated CpG sites in F0 TPM0.2 and TPM0.3 larvae, respectively, with the majority hypomethylated. In F1 larvae, only 6, 1, and 23 differentially methylated CpG sites were detected in TPM0.1, TPM0.2, and TPM0.3 groups, respectively, and all were hypermethylated relative to controls. Differentially methylated genes in F0 TPM0.3 larvae were associated with developmental, neuronal, metabolic, immune, and stress-response pathways. Fourteen genes exhibited altered methylation in both generations. To our knowledge, this is the first study demonstrating cross-generational DNA methylation changes following developmental exposure to TPM in zebrafish.

Salt stress is a major abiotic factor limiting plant growth and productivity. Herpetospermum pedunculosum, a medicinal plant adapted to high-altitude environments, offers a unique non-model system for investigating salt stress responses. Here, we combined physiological and biochemical assays with time-course root transcriptome profiling to characterize the responses of H. pedunculosum to 200 mM NaCl treatment. Salt stress induced rapid wilting, oxidative stress-related physiological changes, membrane damage, and significant accumulation of ABA, total lignin, and total lignans. RNA-seq across five time points (1, 3, 24, 48, and 96 h) identified nearly 28,000 differentially expressed genes (DEGs), which formed distinct temporal clusters associated with hormone signaling, transcriptional regulation, stress responses, and phenylpropanoid-related metabolism. Antioxidant enzyme-related genes, ABA biosynthesis/homeostasis genes, ABA signaling components, and lignin/lignan pathway biosynthesis genes (LLPBGs) showed stage-specific expression patterns, with several genes responding rapidly during the early phase of salt stress. WGCNA and co-expression analyses further identified trait-associated modules and candidate links among core TFs, ABA-related genes, and LLPBGs. Subcellular localization, yeast transactivation, Y1H and Dual-LUC assays provided preliminary evidence that the AP2/ERF factor HpERF141 can bind to and activate the promoter of the previously characterized lignan-related gene HpDIR17. Overall, this study provides a root-focused transcriptomic resource and identifies candidate regulatory genes potentially linking ABA-related responses with lignin/lignan-associated metabolism in H. pedunculosum under salt stress.

Anthocyanins are important plant pigments responsible for attractive coloration and for enhancing tolerance to various abiotic stresses. Their biosynthesis is known to be regulated by methyl jasmonate (MeJA). Although the promotive effect of MeJA on anthocyanin accumulation has been widely reported, the underlying regulatory mechanisms remain insufficiently understood. In this study, we identified an ethylene-responsive factor (ERF) family transcription factor, PcRAV2, that responds to MeJA signaling and enhances anthocyanin accumulation. PcMYB10, a central gene that positively regulates anthocyanin accumulation, was indirectly activated by PcRAV2. In addition, yeast one-hybrid library screening revealed that PcMYB108 functions upstream of PcMYB10 and acts as a negative regulator of anthocyanin biosynthesis; notably, PcMYB108 expression was suppressed by PcRAV2. Furthermore, PcRAV2 directly activated PcUFGT expression by binding to its promoter. Collectively, PcRAV2 promotes anthocyanin biosynthesis through two pathways: the PcRAV2-PcMYB108-PcMYB10 transcriptional cascade and the PcRAV2-PcUFGT regulatory pathway. These findings reveal a novel MeJA-driven regulatory pathway for anthocyanin biosynthesis in plants and provide a theoretical basis for the genetic improvement of fruit coloration in pear.

Gastric cancer (GC) is one of the most common malignancies, characterized by high mortality and recurrence rates. Quercetin, a natural flavonoid found in various herbs and foods, exhibits potential therapeutic effects against GC. This study aims to explore the potential molecular mechanisms of quercetin in the treatment of GC.

Cancer cells exploit DNA repair to overcome damage and errors induced by rapid proliferation and repressed checkpoints. Thus, the loss of one DNA repair protein can make tumors more susceptible to inhibition of other repair pathways. Here, using in silico methodologies and high-content genetic and cell survival screens, we found that the antimalarial drug quinacrine impaired the DNA damage response (DDR) in multiple cancer cell lines. Quinacrine disrupted the interaction of the stress-response protein NDRG1 with the major segregase VCP, which in turn promoted the degradation of the E3 ubiquitin ligase RNF8 and other proteins that mediate the recruitment of the critical DDR protein 53BP1 to sites of DNA damage. This impaired recruitment of 53BP1 caused increases in the DNA damage marker γH2AX. High NDRG1 expression in tumors correlated with poor survival in patients, and high expression in various cancer cell lines correlated with quinacrine sensitivity. Colorectal carcinoma cells were particularly vulnerable to pharmacological or genetic inhibition of NDRG1, and high NDRG1 expression and mutations in MLH1 and PARP3 resulted in synthetic lethality. Our findings identify combination genetic markers that might be therapeutically exploited in colon cancer, as well as provide a platform for such discovery in distinct cancer types.