This study explores the bioactivity and intestinal absorption of peptides from Acheta domesticus (house cricket), emphasizing their potential health benefits and relevance to sustainable protein sources. Six peptides (DVW, AVQPCF, QIVW, CAIAW, PIVCF, and IIIGW) obtained from the simulated gastrointestinal digestion of the A. domesticus proteins acyl-CoA Delta12-desaturase, acyl-CoA Delta-9 desaturase and diuretic hormone receptor were assessed for their effects on gene expression markers related to diabetes (DPP-4, SGLT1) and hypertension (sACE, ACE2). Using Caco-2 cells to model intestinal absorption, the peptides were evaluated for transport, cytotoxicity, and impact on barrier integrity. All peptides were non-cytotoxic up to 2 mM; however, DVW and PIVCF disrupted epithelial integrity. Only DVW crossed the epithelium intact. While none of the peptides significantly affected sACE or ACE2 expression, DVW and PIVCF notably downregulated SGLT1 expression (to 0.42- and 0.52-fold, respectively), suggesting potential antidiabetic effects through reduced glucose absorption.

Bevacizumab (Bev) resistance limits therapeutic efficacy in ovarian cancer (OC) patients. We identified ESM1 as a key gene in Bev-resistant OC. ESM1 secreted by OC-resistant cell lines activates the ITGB1/FAK axis to induce neovascularization and Bev resistance. Additionally, ESM1 overexpression promoted the growth and Bev resistance of OC, lung, intestinal, and hepatocellular carcinoma tumors. Then, we identified TRIM28 as an upstream regulator that stabilizes ESM1 by promoting SUMOylation, inhibiting its proteasomal degradation. In OC mice, TRIM28 overexpression promotes angiogenesis and Bev resistance via ESM1-mediated ITGB1/FAK activation. This work unveils a new molecular pathway underlying Bev resistance in OC and proposes TRIM28 and ESM1 as potential therapeutic targets.

Breast cancer is a global health challenge for women and chemoresistance is a major contributor to its high mortality rates. Quercetin (Que), a flavonoid with antioxidant, antiviral, anti‑tumor and anti‑inflammatory properties, sensitizes cancer cells to chemotherapy. The present study investigated the mechanism by which Que regulates ATP‑binding cassette (ABC) transporter expression in MCF‑7 cells using a PTEN overexpression plasmid and the PI3K inhibitor LY294002. The present study assessed cell viability via Cell Counting Kit‑8 and Hoechst 33342 staining and analyzed mRNA and protein expression levels by reverse transcription‑quantitative PCR and western blotting. Apoptosis was evaluated by flow cytometry and ABCG2 expression was detected by immunofluorescence. Furthermore, the present study determined the effect of Que on drug uptake using a Rhodamine 123 accumulation assay. The results of the present study demonstrated that Que suppresses cell viability and induces apoptosis in MCF‑7 cells. Moreover, it enhances intracellular drug accumulation and downregulates ABC transporter expression by modulating the PTEN/PI3K/AKT signaling pathway.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that the statistical analysis in this study may not have employed the most appropriate statistical tests; namely, the paired Student's t‑test was used for comparisons between independent groups, which the reader considered may have inflated the statistical significance. Neither may the paired Student's t‑test have been the most appropriate test to have been selected for various of the migration and invasion assay experiments, wherein at least three groups were being compared. Owing to the fact that the Editorial Office has been made aware of the possibility of inappropriate statistics handling in this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Molecular Medicine Reports 1: 641‑646, 2008; DOI: 10.3892/mmr_00000005].

Multidrug-resistant Klebsiella pneumoniae poses a growing clinical challenge due to its ability to evade antibiotic treatment, particularly through the overexpression of efflux systems. Among these, the AcrAB-TolC pump is central to resistance against fluoroquinolones. While the global regulator's MarA, SoxS, and Rob are known modulators of efflux in Enterobacteriaceae, their functional relevance in clinical K. pneumoniae remains insufficiently defined and largely correlation-based.

Heat stress is a major abiotic constraint that severely limits maize (Zea mays L.) productivity under changing climate conditions. This study explored a novel integrative strategy to enhance thermotolerance in maize through the combined application of methyl jasmonate-loaded chitosan nanoparticles (MJNPs) and eucalyptus-derived biochar (EBB). Methyl jasmonate was nano-encapsulated using the ionic gelation method and characterized by SEM, TEM, and FTIR analyses, which confirmed uniform spherical nanoparticles and effective surface functionalization. A greenhouse experiment was conducted under controlled heat stress (40 °C) to evaluate physiological, biochemical, nutrient uptake, yield, and gene expression responses across eight treatments. Relative to non-stressed control plants, heat stress alone reduced plant height by 37%, photosynthetic rate (PN) by 46%, relative water content (RWC) by 25%, and grain number and grain weight by 25% and 6%, respectively. However, the combined MJNPs + biochar treatment under heat stress (HEMN) markedly alleviated these adverse effects. Compared with heat-stressed plants without amendments, HEMN increased plant height by 39%, RWC by 8%, membrane stability index (MSI) by 14%, and PN by 21%. In addition, grain number and seed weight increased by 10% and 6%, respectively, relative to heat-stressed plants, while water-use efficiency (WUE) improved by 13% under the same comparison. Nutrient uptake of phosphorus, magnesium, and iron increased by 15-22% in HEMN-treated plants compared with heat-stressed controls. Gene expression analysis revealed pronounced upregulation of stress-responsive genes, including HSP70, DHN3, and LEA-1, as well as auxin biosynthesis-related genes (TAA1, ZmYUC1, CYP79B2) and aquaporins in HEMN-treated plants relative to heat stress alone, indicating activation of coordinated molecular defense mechanisms. Furthermore, principal component analysis (PCA) and hierarchical clustering of gene-expression heatmaps confirmed strong multivariate associations between enhanced physiological performance and transcriptional activation, supporting the integrated nature of thermotolerance regulation. These findings demonstrate that the synergistic application of MJNPs and biochar significantly enhances maize thermotolerance relative to heat stress alone by improving water relations, nutrient homeostasis, photosynthetic performance, and molecular stress responses. This integrated nano-biochar strategy represents a scalable and environmentally sustainable approach for mitigating climate-induced heat stress and improving crop resilience in future agricultural systems.

Osteoclasts and foreign body giant cells (FBGCs) are multinucleated cells derived from monocytes, but they have distinct functions. Osteoclasts resorb bone while FBGCs form in response to foreign material. Regarding bone implants, osteoclasts are responsible for implant integration, but also for bone resorption associated to implant loosening, while FBGCs play a role in the immune response to the foreign material. Little is known about which proteins in the local environment fine-tune the multinucleation of osteoclasts or FBGCs. One candidate is Activin A (ActA). It has been shown to induce larger, more active osteoclasts, but its effect on FBGC differentiation is unknown. We investigated the effect of ActA on the differentiation of osteoclasts and FBGCs from human CD14-positive monocytes. The number of multinucleated cells and the cell area was measured. qPCR was performed to assess the effect of ActA on gene expression. ActA's influence on osteoclast and FBGC formation was studied on plastic, bone and hydroxyapatite coated Titanium discs (ALD-HA). ActA induced fewer, but bigger and more active osteoclasts on plastic and bone. In contrast, ActA did not have an effect on FBGC number. On ALD-HA, ActA reduced the number of FBGCs, but did not influence osteoclast numbers. qPCR showed that ActA upregulated the expression of several genes such as TRAcP, CIITA, OLR1, RHOBTB1 and ALK4, but mainly in osteoclasts. These results show that ActA has a different effect on osteoclasts compared to FBGCs. This difference could be caused by a difference in the expression in the canonical ActA receptor ALK4.

The transcriptional alterations underlying epithelial-to-mesenchymal transition (EMT) in chemoresistant ovarian cancer remain a matter of debate, with emerging evidence pointing to tumour cell plasticity and subclone reprogramming. In this study, we developed a cisplatin-tolerant ovarian cancer model by treating the cisplatin-sensitive OVCAR-3 cell line with a single dose of cisplatin, generating the OVCAR-3 CP variant. These cisplatin-tolerant cells exhibited distinct EMT-related changes at both transcriptomic and protein levels, potentially regulated by epigenetic mechanisms. EMT profiling revealed that OVCAR-3 CP cells did not display a pronounced mesenchymal phenotype but rather retained epithelial characteristics and showed elevated expression of ALDH3A1. In contrast, the parental chemosensitive OVCAR-3 cells expressed canonical mesenchymal markers (CDH2, VIM, ZEB1/2, SNAIL, SLUG) and lacked stemness marker expression. Upon xenografting, both OVCAR-3 and OVCAR-3 CP cells demonstrated phenotypic plasticity, with parental OVCAR-3 xenografts acquiring EMT-like features resembling to those observed in cisplatin-tolerant tumours. These findings suggest a decoupling of EMT from cisplatin-tolerance and instead underscore a stronger association between stemness traits and cisplatin tolerance. Our data further indicate that xenografting can induce significant cellular reprogramming. Comprehensive characterization of ovarian cancer cell-derived xenograft is therefore essential, as they represent a valuable translational platform for investigating therapy adapted ovarian cancer cells.

Oxaliplatin resistance significantly impairs therapeutic outcomes in colorectal cancer. However, reliable diagnostic markers for early detection of resistance remain limited. This study aimed to identify novel diagnostic signatures through integrative bioinformatics and machine learning approaches.

To investigate the effects of fungal volatile organic compounds (FVOCs) on the mycelial growth of Ganoderma lucidum, and to elucidate the molecular mechanisms underlying the growth-promoting effect of 3-octanone. G. lucidum was cultivated with 1-octen-3-ol, 3-octanol and 3-octanone for 7 days, after which colony diameter and mycelial dry weight were measured to assess their effects on mycelial growth. RNA-seq was used to investigate gene expression changes following 3-octanone exposure. While 1-octen-3-ol or 3-octanol inhibited mycelial growth in G. lucidum, 3-octanone promoted it. In total, 590 differentially expressed genes (DEGs), including 162 upregulated and 428 downregulated genes, were identified following 3-octanone exposure. Functional annotation revealed that among the DEGs, 23 genes were related to fungal cell wall biosynthesis and remodeling, whereas 21 genes were involved in plant-derived polysaccharide degradation. Furthermore, significant expression changes were observed in genes related to secondary metabolism. Our results indicate that G. lucidum can use 3-octanone as a signal to recognize other fungi, potentially facilitating the expansion of its own territory within wood in nature.

Acute pancreatitis (AP) remains a challenging clinical condition with limited therapeutic options and high mortality rates in severe cases. Traditional anti-inflammatory approaches have shown disappointing results in clinical trials, highlighting the urgent need for novel therapeutic strategies targeting the underlying pathophysiological mechanisms. The study by Jia et al presents compelling evidence for a previously unrecognized mechanism through which rutaecarpine, a bioactive alkaloid from traditional Chinese medicine, exerts protective effects against AP. This research demonstrates that rutaecarpine alleviates AP by targeting the epigenetic machinery, specifically through enhancer of EZH2-mediated suppression of FBXW11. The authors employed both in vitro cerulein-induced AR42J cell models and in vivo sodium taurocholate-induced rat models to establish the therapeutic efficacy of rutaecarpine and elucidate its molecular mechanisms. Their findings reveal that rutaecarpine upregulates EZH2 expression, leading to increased histone H3 methylation at the FBXW11 promoter region, thereby suppressing FBXW11 expression and consequently reducing inflammatory infiltration and oxidative stress. The significance of this work extends beyond demonstrating rutaecarpine's protective effects. It identifies FBXW11 as a novel therapeutic target in AP and provides the first evidence that traditional Chinese medicine compounds can modulate epigenetic reprogramming in pancreatic inflammation. Recent studies have confirmed FBXW11's role as an inflammatory biomarker in pancreatitis, supporting the clinical relevance of this pathway. The study's comprehensive approach, combining molecular docking, cellular thermal shift assays, and co-immunoprecipitation studies, strengthens the mechanistic insights. These findings open new avenues for AP treatment by targeting epigenetic regulators rather than relying solely on conventional anti-inflammatory strategies, potentially leading to more effective therapeutic interventions for this devastating condition.

Polygonum cognatum (Madımak) is a plant traditionally consumed for medicinal purposes in Turkey. Unlike previous studies examining samples from different regions and seasons, this research presents the first comprehensive characterization of P. cognatum collected from the Central Black Sea Region (Tokat, 40°01'02″N, 36°28'15″E; 1210 m altitude) during the vegetative growth phase (June 2024), where geographical origin and collection time significantly influence secondary metabolite profiles. This study evaluates the phytochemical profile and multitarget biological activities of P. cognatum extracts obtained using solvents of different polarities (hexane, ethanol, and water). Advanced analytical techniques (liquid chromatography-tandem mass spectrometry, high-performance liquid chromatography-diode array detector, and gas chromatography-mass spectrometry) identified 28 phenolic compounds, with the ethanol extract showing the highest diversity (24 compounds) and total phenolic content (78.6 ± 2.3 mg GAE/g). Compounds identified for the first time in P. cognatum include isoquercetin-3-O-rhamnoside, apigenin-7-O-glucoside, and luteolin-4'-O-glucoside. The ethanol extract demonstrated superior multitarget bioactivity: potent antioxidant activity ( 2,2-diphenyl-1-picrylhydrazyl (DPPH) IC50: 76.4 ± 2.1 μg/mL), moderate but selective anti-inflammatory effects (COX-2 IC50: 145.3 ± 5.2 μg/mL; selectivity index: 2.06, indicating preferential COX-2 inhibition over COX-1) and significant antidiabetic potential (α-amylase IC50: 89.3 ± 3.1 μg/mL; α-glucosidase IC50: 76.8 ± 2.9 μg/mL), and antimicrobial activity (MIC: 62.5 μg/mL against S. aureus). Notably, this study demonstrates for the first time the histone deacetylase (HDAC) inhibitory activity of P. cognatum (IC50: 92.4 ± 3.8 μg/mL), revealing novel epigenetic modulation properties. Molecular docking studies showed strong correlations between binding affinities and experimental IC50 values (r = -0.87 to -0.91; p < 0.01). Cytotoxicity evaluation showed favorable safety profiles (CC50 > 500 μg/mL). Docking, IC50, and compositional data consistently indicate that quercetin, rutin, chlorogenic acid, and kaempferol are key contributors to the observed antioxidant, antidiabetic, anti-inflammatory, and HDAC inhibitory effects. These findings establish P. cognatum as a promising multitarget therapeutic agent with novel epigenetic regulatory mechanisms, supporting its potential development for inflammatory, metabolic, and epigenetic-related disorders.

Epigenetic memory enables the propagation of gene expression patterns following transient stimuli. Although three-dimensional chromatin organization is emerging as a key regulator of genome function, it is unknown whether it contributes to cellular memory. Here we establish that acute perturbation of the epigenome can induce cellular memory of gene expression in mouse embryonic stem cells. We uncover how a pulse of histone deacetylase inhibition translates to changes in transcription, histone modifications and genome folding. While most epigenomic and transcriptional changes are initially reversed once the perturbation is removed, some loci remain transcriptionally deregulated and genome architecture partially maintains its perturbed conformation. Consequently, a second pulse of transient hyperacetylation induces stronger memory of transcriptional deregulation. Using ultradeep Micro-C, we associate memory of gene expression with repressive Polycomb-mediated chromatin topology. These results demonstrate how cells can record transient stresses in their genome architecture, thereby enabling an enhanced response to subsequent perturbations.

This study investigates the role of arachidonate 5-lipoxygenase (ALOX5) in upregulating programmed death-ligand 1 (PD-L1) expression via its metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) in ovarian cancer cells, and explores the effects on lipid metabolism and ferroptosis. Additionally, the study examines the role of Tectorigenin (TEC) in this process. Using network pharmacology, bioinformatics analysis, molecular docking, and drug affinity reaction target stability (DARTS) experiments, we identified ALOX5 as a potential therapeutic target for TEC in ovarian cancer treatment, possibly through lipid metabolism and ferroptosis pathways. In vitro experiments showed that TEC inhibits proliferation and invasion and promotes apoptosis in ovarian cancer cells without significant cytotoxicity in normal ovarian epithelial cells. TEC also inhibits lipid metabolism and promotes ferroptosis, reducing ovarian cancer cell viability. Inhibition of ALOX5 similarly suppresses lipid metabolism and enhances ferroptosis, effects that can be reversed by exogenous 5-HETE. In vivo studies using a nude mouse model demonstrated that TEC inhibits tumor growth and downregulates ALOX5, 5-HETE, and PD-L1 expression in tumor tissues. The findings suggest that the ALOX5/5-HETE signaling pathway is crucial for regulating lipid metabolism and ferroptosis in ovarian cancer, and TEC may exert its anti-tumor effects, at least in part, by modulating this pathway (The graphical abstract was shown in Fig. 1).

Cancer signaling encompasses a wide array of entangled molecular cascades that promote oncogenic progression and counteract the effect of tumor suppressors. Transforming growth factor β (TGFβ) induces complex and stage-dependent effects throughout tumor progression. During pre-malignant hyperplastic growth, TGFβ restricts cell proliferation and inflammation, while on the other hand, TGFβ promotes migration and distal metastasis of cancer cells. To dissect the temporal chromatin-based transcriptional response to TGFβ, we employed 3D culture models of isogenic human breast epithelial cells, exemplified by non-oncogenic MCF-10A (MI) and their HRAS-transformed counterpart (MII). Genome-wide chromatin accessibility profiling revealed an extensive chromatin opening induced by TGFβ at transcription start sites and enhancer elements in both models, with a marked enrichment of SOX4 binding motifs in oncogenic cells. Transcriptomic analyses unexpectedly revealed the upregulation of DNA replication and DNA damage response pathways, following TGFβ stimulation of oncogenic MII 3D cultures. Canonical TGFβ-driven programs, including epithelial-mesenchymal transition and metabolic reprogramming, were activated in both models. Notably, single-cell RNA-seq of primary breast tumors confirmed co-expression of SOX4 and cell cycle regulators. Mechanistically, we show that TGFβ induces the interaction between the MH2 domain of SMAD3 and the intrinsically disordered regions of SOX4, co-activating downstream gene targets. Validating the genome-wide analyses, we found that resistance of breast cancer cells to the CDK4/6 inhibitor palbociclib conferred by TGFβ stimulation was functionally dependent on SOX4. Collectively, our findings reveal an apparent oncogenic function of TGFβ in promoting cell cycle progression and drug resistance through SOX4, highlighting the pro-tumorigenic role of TGFβ signaling in breast cancer progression.

Exogenous Glutathione S-transferase Mu 2 (GSTM2) supplementation has emerged as a promising strategy to counteract aging. However, approaches to enhance endogenous GSTM2 expression remain underexplored. Here, we identify HCY-NBD, an SO2-targeting small molecular that binds GSTM2 and stabilizes GSTM2 protein levels under high-glucose (HG)-induced vascular endothelial senescence. Mechanistically, HCY-NBD promotes sulfenylation at Cys174 of GSTM2 and inhibits its K48-linked ubiquitination at this residue, thereby stabilizing GSTM2 protein. In cellular studies, we observe that HCY-NBD upregulates GSTM2 and inhibits HG-induced senescence and calcification in vascular endothelial cells. Consistent with this, in vivo administration of HCY-NBD in db/db mice increases GSTM2 levels and mitigates senescence and calcification in the thoracic aorta. Collectively, our findings demonstrate that HCY-NBD inhibits HG-induced vascular senescence and calcification by stabilizing GSTM2 protein levels via enhancing Cys174 sulfenylation and suppression of site-specific ubiquitination-mediated degradation. Here, we first develop a new strategy to enhance endogenous GSTM2 and provide a novel therapeutic strategy for the prevention and treatment of vascular aging.

Pancreatic neuroendocrine neoplasms (pNEN) are rarely encountered, accounting for about 2% of all pancreatic neoplasms. Disease progression is frequently observed as recurrence or distal metastasis. Mechanisms underlying pNEN progression are still poorly investigated, and treatments against pNEN are challenging due to the pronounced neoplastic heterogeneity. Here, by performing clinicomolecular analysis, we report a novel mechanism of positive regulatory circuit between Cav1.2-mediated calcium signaling and epigenetic control by H3K27 acetylation (H3K27ac). Tumor-cell-specific expression of Cav1.2 strongly contributes to disease progression and correlates with malignant biological behaviors of pNEN. Moreover, we find calcium channel blockers (CCBs), especially amlodipine, remarkably inhibit pNEN progression in vitro and in vivo. Clinically, administration of CCBs correlates with better progression-free survival (PFS) and a lower rate of distal metastasis. Our work uncovers the novel mechanism of the Cav1.2-epigenetic circuit and expands the scope of therapeutic strategy for further investigation in pNEN.

Despite decades of investigation into bacterial pathogens, the conditions met by intracellular bacteria are still unclear. These conditions can include access to nutrients, such as amino acids, and exposure to toxic compounds, like copper. To investigate the ability of Brucella abortus, a facultative intracellular pathogen responsible for a major zoonosis, to cope with copper, we performed a Tn-seq analysis to identify copper-sensitive mutants. Unexpectedly, we realized that classical copper resistance systems (involving CopA and CueO homologs) do not appear to be robustly needed, while histidine and purine biosynthesis pathways are crucial to cope with copper. We show that hisA, hisB, hisC, and hisD mutants are auxotrophic for histidine and sensitive to copper. This suggests that the reported attenuation of his mutants in macrophages could be based on auxotrophy and/or copper sensitivity. Therefore, we generated suppressor strains with a restored resistance to copper for hisC, but still auxotrophs for histidine. Our data suggest that this suppression is due to the overproduction of a homolog of OppA, a periplasmic oligopeptide-binding protein. Analysis of these suppressors shows that the absence of histidine biosynthesis capacity, and not copper sensitivity, is required for optimal growth of B. abortus in macrophages.IMPORTANCEInvestigating conditions in which intracellular bacteria grow inside host cells is challenging and often involves the characterization of attenuated bacterial mutants obtained by screening. But a single mutant can display two different phenotypes related to intracellular conditions. It was the case for histidine auxotrophs of Brucella abortus, an important zoonotic pathogen. These histidine auxotrophs are attenuated in a macrophage cell line, and they are also sensitive to copper stress. Using a suppressor strain still auxotroph for histidine but with an improved resistance to copper, we show that histidine auxotrophy, and not sensitivity to copper excess, is the main cause of attenuation in the conditions tested here.

To identify the transcriptomic changes induced by dexamethasone (DEX) in trabecular meshwork (TM) and Schlemm's canal endothelial (SCE) cells with RNA sequencing (RNA-seq).

Tea plant (Camellia sinensis (L.) O. Kuntze) is particularly vulnerable to abiotic stresses, with impacts on its growth and the production of bioactive compounds. SMALL AUXIN UP RNA (SAUR) genes, the largest family of early auxin-responsive genes, regulate plant growth and abiotic stress responses. However, their roles in tea plant remain unknown. In this study, we conducted a comprehensive genome-wide analysis of CsSAURs, including phylogenetic relationships, gene structure, chromosomal distribution, duplication events, motif composition, cis-elements, and gene ontology (GO) annotations. Expression profiles were examined using transcriptome data and validated by qRT-PCR. A total of 97 CsSAURs were identified and classified into eight phylogenetic groups, with 90 mapped to 15 chromosomes and seven to contigs. Genes within the same group exhibit conserved gene structures and motif compositions. Segmental duplication predominantly contributes to family expansion. The predominant CsSAUR expression was found in flowers, with their promoters containing auxin-responsive, phytohormone, and stress-related cis-elements. A limited number of CsSAURs exhibit responsiveness to cold, drought, salinity, and methyl jasmonate (MeJA). Notably, CsSAUR10, 16, and 73 exhibited significant upregulation under abiotic stress and auxin treatment. Overall, this study characterizes the SAUR family in tea plant and highlights its potential roles in the regulation of growth and stress responses. The identified auxin and stress-responsive CsSAURs represent potential targets for genetic improvement of tea plants.